M Dawei Zhang

Directeur De

M Alexandre

Martinez Co

M Guohua Gao

Jeanne Mme

Crassous

M Rinaldo Poli

M Mingyuan

Estelle Mme

Metay

Professeur M Julien Leclaire

Dr Jean-Pierre Dutasta

Membre Invité

Mme Laure

Professeur M Alexandre Martinez

M Guohua

Dawei Zhang

Alexandre Martinez

Benjamin Bousquet

Jean-Christophe Mulatier

Marion Jean

Nicolas Vanthuyne

Laure Guy

James Robert Cochrane

Guohua Gao

Hemicryptophanes and Beyond : Synthesis, Recognition, Molecular Machines and Supramolecular Catalysis Les hémicryptophanes : Synthèse, Reconnaissance, Machines Moléculaires et Catalyse Supramoléculaire

Martinez, who introduced me to the field of supramolecular chemistry and gave me constant

discussions on cryptophanes and fluorescence, Christian for solving computer problems; Damien, Edwige and Marie-Francoise for the administrative affairs of the lab. I would also like to thank Dr. Christian Díaz-Urrutia and Dr. Kaitie Giffin at the University of Ottawa for their help in both research and life in Canada, and Dr. Tanya Ronson and Dr. Jesús Mosquera at the University of Cambridge for their great help, advice and direction in research while I was in the UK.

I would like to express my sincere gratitude to my PhD committee members Prof.

Mingyuan He, Prof. Julien Leclaire, Prof. Rinaldo Poli, Prof. Jeanne Crassous, and Prof. Estelle Metay for their contributions and witness of my professional development during my graduate education.

I gratefully acknowledge the collaboration program between ENS-Lyon and ECNU, so that I could have this chance to study here four years ago. This is a very successful program, which has cultivated hundreds of PhD students who currently work across academia and industries spread all over the world. I would like to specially show my thanks to Mme Yunhua Qian, a respected woman who established this program and was in charge of it for more than ten years. She has greatly promoted the development of the collaboration between ENS and ECNU and cultural communication between France and China, which has benefited hundreds of students including myself. Without her, I couρdn t have come to ENS-Lyon successfully, especially one year ahead, due to several serious barriers I met including the problem of funding.

Definitely, I would also like to acknowledge grants from the China Scholarship Council (four years), Accueil Doc Bursary from France Rhône-Alpes Region (six months) and Enveloppe Attractivité Fellowship from ENS-Lyon (four years) for my PhD study. With their financial support, I could not only complete my PhD research, but also enjoy my life. Besides China and France, I have travelled to many cities and countries, such as Switzerland, Italy, Spain, Germany, Belgium, Luxembourg, Netherlands, UK, Canada and Korea, which has greatly broadened my horizon and become the wealth of my life.

My time in Lyon was enjoyable in large part due to the many friends and group members that became a part of my life. I am grateful for time spent with all of them, they are from all over the world, Zheng, Jinping, Nanan, Jingyun, Chongzhi, Qingyi, Shuai, Kaiheng, Xiaopeng, Lianke, Ling, Wenyue, Xin, Xinnan, Laure-Lise, Maelle, Sara, Estelle, Orsola, Aline, Bastien, Nicolas, and all the members in the Laboratory of Chemistry. I cherish all the wonderful moments that we spent together.

Lastly, I would like to thank my family for all their love and encouragement. I have obtained constant unconditional support from my parents and my older sister both emotionally and financially. Thank you!

In Part V, my attention has opened to a more prospective view focusing on cages constructed by self-assembly. In Chapter 11, we have demonstrated the feasibility of introducing azaphosphatranes, the units mentioned in Chapter 10, into tetrahedron capsules using subcomponent self-assembly, and also proved for the first time the utility of azaphosphatranes as anion binding moieties.

Except Chapter 2, which outlines the objectives of this thesis, all the other chapters have been prepared as manuscripts for journals, in which Chapters 1, 3, 4, 5, 6, 7, 8, 10 and 11 have been published, and Chapter 9 is being prepared. Therefore, each chapter is based partially on the corresponding publication.

Résumé

XI

Résumé

Les hémicryptophanes, moρécuρes constituées d une unité cycρotriveratryρène CTV reρiée à une autre groupement de symétrie C3 sont des molécules cages qui trouvent de nombreuses applications dans le domaine de la chimie hôte-invité.

La première partie de ce manuscrit (Part I) présente une revue des dévelopements récents de la chimie des hémicryptophanes (Chapter 1). Plus précisément, sont abordés un bref historique, les voies de synthèse connues ainsi que les applications dans les domaines de la reconnaissance moléculaire, des machines moléculaires et de la catalyse supramoléculaire. Le deuxième chapitre (Chapter 2) définit les objectifs de ce travail de thèse dans le développement et la synthèse de nouveaux hémicryptophanes pour améliorer les propriétés de reconnaissance et de catalyse de type supramoléculaire. La cinquième partie (Part V) de ce manuscript est consacrée à des développements nouveaux dans le domaine de la formation de cages par auto-assemblage. Elle est composée du chapitre 11 (Chapter 11) qui montre que nous avons réussi à former par coordination, des tétraèdres dont les quatre faces comportent une sous-unité azaphosphatrane. Et pour la première fois, dans ce type de cage, l unité azaphosphatrane joue un rôle prépondérant dans la complexation d anions.

" ρ exception du chapitre

Chapter 2) qui aborde les objectifs de ce travail de thèse, tous les chapitres ont été rédigés comme des articles scientifiques dont les chapitres 1, 3, 4, 5, 6, 7, 8, 10 et 11 ( Chapters 1, 3, 4, 5, 6, 7, 8, 10 and11

Preface

As this thesis is focused on my efforts to develop hemicryptophane cages, Chapter 1

chronicles the previous development of hemicryptophane chemistry and highlights their syntheses and applications in recognition, molecular machines and supramolecular catalysis.

In Chapter 2, the objectives of this thesis are postulated. The aim I try to achieve is to forward hemicryptophanes moving toward targeted functions by the rational design.

It should be noted that Chapter 1 is based particially on our review article published on Chemical Reviews (2017, 117, 4900 4942). The numbers of compounds, figures, schemes and tables have been renumbered in each chapter from the beginning, and the numbers of compounds between chapters have no relationship. The Table of Contents in Chapter 1 has been presented in the chapter cover. The cited references are listed at the end of the corresponding chapter.

Abstract

In the wide area of host-guest chemistry, hemicryptophanes, combining a cyclotribenzylene (or cyclotriveratrylene CTV) unit with another different C3 symmetrical moiety, appears as a recent family of molecular cages. The synthesis and recognition properties of the first hemicryptophane was reported in 1982 by Collet and Lehn; but the very little attention received by this class of host compounds in the twenty years following this first promising result can account for their apparently novelty. Indeed, in the last ten years hemicryptophanes have aroused a growing interest and new aspects have been developed.

Thanks to the rigid shaping unit of the north part (CTV), and also the variable and easily functionalized south moiety, hemicryptophanes reveal to be inherently chiral ditopic host compounds, able to encapsulate various guests, including charged and neutral species. They also enter the field of stimuli-responsive supramolecular systems exhibiting controlled functions. Moreover, endohedral functionalization of their inner cavity leads to supramolecular catalysts. The confinement of the catalytic center affords nanoreactors with improved catalytic activities or selectivities when compared to model systems without cavity.

The current trend shows that reactions in the confined space of synthetic hosts, mimicking enzyme behavior, will expand rapidly in the near future. Molecular cages, defined as hollow structures delineating a three-dimensional cavity, are attracting considerable attention in modern supramolecular chemistry due to their possible applications in molecular recognition, catalysis, drug delivery, biosensing, separation and storage. [1][2][3][4][5][6][7][8] Among the classes of molecular containers, such as crown-ethers, 9,10 cryptands, 10 calixarenes, [11][12][13] resorcinarenes, 14,15 curcurbiturils, [16][17][18] cyclodextrines, 19,20 or pillararenes, [21][22][START_REF] Ogoshi | Monographs in Supramolecular Chemistry[END_REF] cryptophanes and hemicryptophanes based on a cyclotribenzylene core, most of the time identified to a derivative of the cyclotriveratrylene (CTV) unit (Figure 1.1), recently received a growing interest. Cryptophanes, are homotopic host compounds built from two CTV units, which can efficiently encapsulate small molecules such as methane or epoxides, cations, anions, and xenon or radon noble gases. [START_REF] Brotin | [END_REF]25 A previous comprehensive review on cryptophanes by Brotin and Dutasta has highlighted the synthesis methods, their binding and chiroptical properties, and their potential applications as biosensors and chiral agents. [START_REF] Brotin | [END_REF] In contrast, the related hemicryptophanes combining a CTV unit with another C3 symmetrical moiety via covalent bonds or non-covalent interactions are heteroditopic hosts able to recognize various charged or neutral guests, such as ion pairs, zwitterions, ammoniums, carbohydrates, and fullerenes. Currently, hemicryptophanes are mainly used as molecular receptors, supramolecular catalysts and as functional molecules anticipating molecular machines. The chemistry of hemicryptophane was developed quite slowly before 2005. [START_REF] Collet | Comprehensive Supramolecular Chemistry[END_REF] In 1982, Lehn and Collet described the first two members of a new type of molecular cages called speleands

Introduction

(1 and 2 in Figure 1.2a), which associated a CTV and a crown ether unit, showing potential recognition properties toward methylammonium cations. [START_REF] Canceill | [END_REF] Then in 1989, Nolte et al. reported the synthesis of a molecular host derived from CTV and diphenylglycoluril units presenting potential catalytic properties related to its easily functionalized arm (5 in Figure 1.2a). 28 Ten years later, Diederich and Echegoyen described the synthesis of the two covalent CTV-C60 adducts 3 and 4 (Figure 1.2a) prepared by the tether-directed Bingel reaction. 29 The C3-symmetry of the two cage adducts was evidenced by NMR spectroscopy. Nevertheless, it is obvious that the free space in the cavity of the two compounds is quite restricted due to the interactions between the electron rich aromatic rings of the CTV and the electron poor C60, limiting their applications as receptors. The same year, Dutasta and co-workers reported the synthesis and crystal structure of the thiophosphorylated molecular cage 6 (Figure 1.2a) based on the CTV unit, and proposed the term hemicryptophane for this type of molecular cages, which has been widely used thereafter. 30 At last, based on suitably functionalized CTVs, metal complexes were obtained that possess the hemicryptophane structure. In some specific cases, the CTV cap was used as ligand platform for iron(II) and iron(III) coordination. 31 Hence, it can be seen that this class of host compounds has received little attention before 2005 since only few relevant papers were reported during this period, and even less have really focused on their applications. Unexpectedly, after 2005, this chemistry received a growing interest leading to a blossoming field of research, particularly for molecular recognition. For instance, a series of sophisticated enantiopure hemicryptophanes has been synthesized beneficiating from the inherent chirality of the CTV unit and used for the stereoselective recognition of chiral guest molecules. They have also entered the field of controlled molecular motions, exhibiting solvent-responsive properties. Moreover, confinement of catalytic sites in the inner space of the cavity of hemicryptophanes resulted in supramolecular organic and organometallic catalysts, with remarkable properties. We should mention herein the important contribution of Kuck et al. who synthesized cryptophane and hemicryptophane-like molecular cages based on the tribenzotriquinacene (TBTQ) scaffold.

Recently, they reported the synthesis of hemicryptophanes where the CTV part is replaced by the TBTQ unit. This type of molecular receptors does not strictly belong to the CTV-based derivatives, but their closely related structures deserve to be pointed out in this review (Figure 1.2b). 32 In this review article, we will first introduce the general synthetic methods (Section 1.3), to obtain racemic, enantiopure, water-soluble and metallated hemicryptophane hosts. Next, the applications of hemicryptophanes in molecular recognition (Section 1.4), as molecules with controllable motions (Section 1.5), and as supramolecular catalysts (Section 1.6), will be presented. Finally we will conclude and present the perspectives on the future development of hemicryptophanes, and highlight the key challenges in this emerging area of research (Section 1.7).

Synthesis of hemicryptophanes

Hemicryptophane hosts can be classified into two main families according to the method of preparation used: covalent hemicryptophanes and self-assembled hemicryptophane capsules.

Covalent hemicryptophanes refer to compounds, where the two main C3 symmetrical units defining the ditopic character of these hosts are connected by covalent bonds. The access to covalent cages most of time needs multi-step syntheses and often the main drawback of these syntheses is a low overall yield. Although some cage compounds are only accessible on a milligram scale, a range of laboratory-scale synthesis schemes has been developed to afford hemicryptophanes with various functionalities that can be obtained easily on gram scale, allowing wider applications. The different approaches to the syntheses of covalent hemicryptophane hosts will be presented in Section 1.3.1. The formation of self-assembled hemicryptophane capsules is currently attracting great attention due to the developments in self-assembling strategies and will be described in Section 1.3.2. For instance, hemicryptophanes formed of two interacting molecular subunits have been reported using reversible dynamic covalent interactions such as the reversible formation of boronate esters, or supramolecular ionic interactions between charged moieties. Finally, Section 1.3.3 of this review is devoted to the functionalization of hemicryptophanes to develop specific properties and to investigate their applications in catalysis and sensing in organic or aqueous media.

An important aspect of hemicryptophanes is their inherent chirality arising from the CTV unit. A greatly growing demand for chiral hosts exists and consequently, the production of enantiopure hemicryptophanes should be considered as a significant breakthrough for applications in chiral recognition or catalysis. Particular attention will be paid to this aspect throughout this chapter. The C3 symmetry of the CTV moiety confers to the hemicryptophanes an inherent chirality with P or M configuration. 33 When associated to other stereogenic centers the hemicryptophane molecules exist as diastereomers. Thus, the synthesis of enantiopure compounds either leads to enantiomers or diastereomers and it is essential to determine their absolute configuration. A convenient method relies on the determination of the X-ray crystal structure of the enantiopure compounds. However, obtaining crystals suitable for X-ray analysis is not always easy and successful. 34 The use of electronic circular dichroism (ECD) spectroscopy has been widely described in the literature, and is particularly suitable to determine the absolute configuration of compounds bearing the CTV unit. 35 Indeed, the spectra can be interpreted as the result of the excitonic coupling of the three aromatic rings of the CTV unit, which gives a specific ECD signature. [35][36][37][38] This method is relatively easy and reliable, but may also fail in some specific cases, when the ECD signals of the CTV overlap with those of other aromatic groups. In such cases, chemical correlation methods were developed and successfully applied to hemicryptophane molecules.

When compared to racemic hemicryptophanes, enantiopure cages are more useful since chirality plays a crucial role in most of the biological events, and chiral synthetic bio-inspired supramolecular systems can be designed to mimic and understand these processes. [39][40][41] However, the easy synthesis of this type of enantiopure molecular cages is a difficult challenge because of the high complexity of such molecules. Two main strategies can be followed to prepare enantiopure hemicryptophanes. (i) The resolution of racemic mixtures using chiral semi-preparative high-performance liquid chromatography (HPLC). The major drawbacks of this method are the necessity of a chiral HPLC and the difficulty in providing sizable amounts of compounds. (ii) The introduction of additional stereocenters to form diastereomers. This second strategy needs more complex synthesis pathways, and in most cases the separation of two diastereomers reveals tedious, but affords more sizeable amounts of enantiopure cages. Both methods appeared in the literature and will be precised in the following sections. Throughout this review article, without specific indications, the chiral compounds described are racemates.

Synthesis of covalent hemicryptophanes

Covalent hemicryptophanes can be obtained by three main pathways. The first one is a cage-closing reaction to form the CTV unit (arbitrary named north part) and is related to the "template method" used for the synthesis of cryptophanes (Figure 1.3a). [START_REF] Brotin | [END_REF] The Friedel-Crafts condensation of the veratryl precursors is a convenient and common approach for the synthesis of cryptophanes and hemicryptophanes. The acid catalyzed cyclization reaction, using mainly HCOOH or Sc(OTf)3, gives rise to the CTV moiety leading to the desired hemicryptophanes. The performances of this intramolecular cyclodehydration to generate the CTV in the last step, in terms of yield and difficulties in their purification, usually depend on the structures of the hemicryptophane precursors. The second way is the [1+1] coupling between the north part and the other C3 unit (arbitrary named south part), which is very effective in many cases and is particularly well suited for the preparation of enantiopure hemicryptophanes (Figure 1.3b). Moreover, this strategy allows the preparation of a wide range of ditopic molecules thanks to the numerous and versatile available southern moieties, and involve different approaches like the reactions of acyl chloride with primary or secondary amine, carboxyl with primary amine, Ugi reaction-type, and disulfide-bond formation, for the most common. For instance, sophisticated structures such as crown-ethers, calixarenes and cyclodextrines were combined with the CTV cap to afford ditopic hosts with fairly good yields. This method usually requires high dilution conditions to avoid the formation of polymeric compounds.

The third way is to introduce the southern C3 unit from the suitably functionalized CTV scaffold (Figure 1.3c). By this way, hemicryptophanes are formed by appending on the CTV three linkages bearing suitable functions for an intramolecular reaction that leads to the cage structure. This approach has been seldom used compared to the strategies based on the cage closure reaction at the north part or the [1+1] coupling presented above.

For a given compound, the authors often used either of the methods described above to increase the yields and/or to produce sizable amounts of enantiopure compounds. For instance, the [1+1] coupling between two modules has been often advantageously applied to the synthesis of hemicryptophanes already obtained by the formation of the CTV cap according to the first synthetic pathway. In the following subsections we will thus emphasize the various approaches reported in the literature for the synthesis of racemic and enantiomerically pure hemicryptophanes according to the nature of the southern units.

Triamide-and tren-hemicryptophanes

Scheme 1.1 Synthesis of Hemicryptophanes 14 and 15a.

The triamide and the tris(2-aminoethyl)amine (tren) structures have been used to build receptors for the complexation of anionic 42,43 and cationic species. 44 In particular, transition metal ions such as cobalt, zinc 45 and copper, 46 form complexes with these ligands, presenting interesting catalytic or recognition properties. Different hetero-elements have been also trapped into a tren moiety, leading, in the case of phosphorus, to pro-azaphosphatrane compounds, which constitute a remarkable class of basic and nucleophilic organo-catalysts. 47 The racemic triamide-and tren-hemicryptophanes 14 and 15a were first synthesized following the first method (Figure 1.3a) as depicted in Scheme 1.1. 48 The reaction of vanillyl alcohol 7 with dibromoethane in EtOH at 80 °C affords compound 8, which is protected with THP to give 9 with an overall yield of 27%. 49 The C3 symmetry precursor of the south part of the host is obtained from the nitrilotriacetic acid 10 that reacts with 3 equiv. of p-methoxy benzylamine in the presence of P(OPh)3 to give the tripodal triamidoamine derivative 11. The methoxy groups in 11 are then removed using BBr3 to give the triphenol derivative 12.

Reacting 9 and 12 in DMF in the presence of Cs2CO3 affords the hemicryptophane precursor 13. The cyclization is then performed in HCOOH to give the desired hemicryptophane 14 in 30% yield. Finally, the reduction of the amide functions is achieved with BH3 in THF to give the tren-hemicryptophanes 15a in 30% yield. The racemic triamide-hemicryptophane rac-14

was resolved by chiral semi-preparative HPLC, leading to the enantiopure compounds M-14

and P-14. 50 Applied to rac-15a the resolution reveals unsuccessful, underlining the limitation of the method.

Scheme 1.2 Synthesis of Hemicryptophanes 15a-i.

The convenient and efficient modular approach of the [1+1] coupling reaction (Figure 1.3b) was developed for the synthesis of the tren-based hemicryptophanes 15a-i (Scheme 1.2). 51 The alkyl-brominated CTV 18a is first synthesized in two steps from vanillyl alcohol and dibromoethane according to the procedure described by Dmochowski et al. 52 The preparation of the hemicryptophane precursor 20a is then conducted under standard conditions by reacting 18a with 4-hydroxybenzaldehyde (19a) in DMF in the presence of Cs2CO3 with excellent yields and without purification by column chromatography. The condensation of 20a with tris(2-aminoethyl)-amine in CHCl3/CH3OH mixture, followed by a reduction step with NaBH4, affords 15a in 77% yield. Hemicryptophane 15a is thus obtained in 8% overall yield via a four-step synthetic route, which improves the previous seven-step procedure (3% overall yield; Scheme 1.1) and allows the synthesis of 15a on the gram scale. Moreover, the size, shape, and functionalities of the molecular cavity are easily modified by changing the nature of the aromatic linkages (Scheme 1.2). For instance, the cavity size was modified by changing the relative position of the aldehyde and the hydroxy groups on the aromatic rings (hemicryptophanes 15b and 15c). An electron-donating group was also incorporated in the aromatic part of the linkages at different positions, leading to hemicryptophanes 15d and 15e, and the chlorine electron-withdrawing group was successfully integrated in the aromatic wall of the hemicryptophane 15f. Hemicryptophanes 15g-i with larger aromatic walls (naphthyl moieties) were obtained and showed fluorescent properties. Thus, this synthetic pathway constituted an important step in the chemistry of hemicryptophanes as it allowed production of larger amounts of compounds, which helped further applications as receptors or supramolecular catalysts.

Dutasta, Martinez et al. followed the pathway shown in Scheme 1.2 to develop the gram-scale preparation of enantiopure hemicryptophanes M-15a and P-15a. 53 The synthesis starts from the enantiopure CTV-18a obtained by the resolution of its racemates by chiral HPLC. To prevent the racemization of the enantiopure 18a and 20a, the two subsequent steps were performed at 25°C, affording the expected product with good yields and excellent enantiomeric excess for the final cages (ee % . Moreover, the enantiopure hemicryptophanes 15d, 15f and 15i were also prepared from the corresponding phenols 19d, 19f and 19i, respectively, highlighting the modularity of this strategy.

Makita and co-workers followed a similar strategy to synthesize the tren-hemicryptophane rac-22 and triamide-hemicryptophane rac-24 having smaller cavities (Scheme 1.3). 54,55 It is noteworthy that hemicryptophane 22 was obtained in 97% yield from the precursor 21, 54 demonstrating the high efficiency of this synthetic method. The triamide derivative 24 was obtained in a two-step synthesis. Removal the tri-tert-butoxycarbonyl (Boc) protecting groups from precursor 23, and subsequent coupling with nitrilotriacetic acid tris (p-nitrophenyl ester) afforded hemicryptophane 24 in 31% overall yield. Hemicryptophane 24 was able to bind tetraalkylammonium salts and exhibited a strong affinity for acetylcholine neurotransmitter. Compared to respectively 14 and 15a, hemicryptophane stereoisomers M-(S,S,S)-29/30, P-(S,S,S)-29/30, M-(R,R,R)-29/30 and P-(R,R,R)-29/30, possess three additional stereogenic centers (Scheme 1.4). 56,57 Interestingly, by introducing these new chiral centers in 29 avoids chiral HPLC to separate the enantiomers, and also makes this class of hosts more promising for stereoselective recognition experiments. A synthetic pathway similar to that used for 14 afforded hemicryptophanes 29 starting from the chiral (S/R)-4-methoxy--benzylamine. The two diastereomers M-(S,S,S)-29 and P-(S,S,S)-29 were separated by preparative achiral TLC.

Direct reduction of the amides of the mixture of the two diastereomers 29 gives the two stereoisomers of 30, which are readily separated by column chromatography on silica gel. 57

Scheme 1.4 Synthesis of Hemicryptophanes M-(S,S,S)-29/30 and P-(S,S,S)-29/30.

An easy synthesis of enantiopure hemicryptophanes 31a-c via the thermodynamic resolution of the racemic CTV 20a (Scheme 1.2), leading to enantiomerically pure compounds, was reported (Scheme 1.5). 58 It was found that when using enantiopure tren derivative as the other modular compound, only one diasteromeric cage was formed whatever the nature of the substituents located on the tren s stereoμenic centers. This route provides an oriμinaρ access to enantiopure hemicryptophanes avoiding the separation of two diastereomers. Ugi-peptoid backbones. 59 In this approach, four components, i.e. CTV-tricarboxylic acid 32, a primary amine, an oxo compound, and an isocyanide are required for the three-fold Ugi-reaction (Scheme 1.6). A methanol solution of tetra-n-butyl ammonium salt of CTV-tricarboxylic acid 32 is gradually added to a solution of paraformaldehyde and amine, followed by the slow addition of tris (2-isocyanoethyl)amine. The hemicryptophane 33 is thus obtained with acceptable yields after purification by flash column chromatography. Apart from the simplicity for constructing complex molecules, another key feature is the variability of the tris-functionalized scaffolds with defined geometries to build various molecular cages.

Scheme 1.6 Synthesis of Hemicryptophane 33.

Trialkanolamine hemicryptophanes

Scheme 1.7 Synthesis of Hemicryptophanes M-(R,R,R)-41 and P-(R,R,R)-41.

Hemicryptophanes combining CTV and triethanolamine groups such as compound 41

(Scheme 1.7), are particularly interesting for their potential as ligands for endohedral metal coordination. The synthesis of the enantiopure hemicryptophanes 41 was reported in 2005 and was facilitated by the introduction of additional stereocenters to form diastereomers. 60 As shown in Scheme 1.7, allyloxyphenol 34 reacts with compound 9 in the presence of Cs2CO3 in DMF to give 35, which is subsequently deprotected to generate the phenol derivative 36. The

Hemicryptophanes based on a tripodal benzenic-platform

The benzenic ring is a simple and attractive unit to close a covalent cage because of its high modularity. Indeed, depending on the nature of the substituents attached to this moiety Another example of tris amido-aromatic hemicryptophane was also synthesized from CTV derivative 53 and benzene-1,3,5-tricarbonyl trichloride, still using the [1+1] coupling reaction, to give compound 54 (Scheme 1.9). 63

Hemicryptophanes based on a macrocyclic platform

Macrocyclic units like calixarenes or cyclodextrines have been linked to CTV units, in order to combine in a single hemicryptophane molecule the recognition properties of both compounds. The syntheses of the resulting heteroditopic hosts are presented below.

Hemicryptophanes based on an aza-crown ether: speleands. The synthesis of the first two hemicryptophane derivatives (speleands 1 and 2) developed by Collet and Lehn were achieved using the [1+1] coupling method. [START_REF] Canceill | [END_REF] As shown in Scheme 1.12, condensation of the trichloride 58 with the azacrown ether [18]-N3O3 under high dilution conditions afforded the tricarboxamide hemicryptophane 59 in 35% yield. Then, reduction of 59 with diborane gave the hemicryptophane 1 in 85% yield. Starting from the trichloride 60 and following the same reaction sequence, the hemicryptophane 2 with a larger cavity was synthesized with an overall yield of 26%. Scheme 1.12 Synthesis of Speleands 1 and 2.

Hemicryptophanes based on a cyclopeptide platform. Hutton et al. synthesized a new class of enantiopure cyclic peptide-containing hemicryptophanes PL-67 and ML-67 (Scheme 1.13) able to recognize the biologically relevant carnitine zwitterion. 65 Three tyrosine residues provide hydrophobic waρρ to the cavity, and μρycine was chosen λor the aρternate residues to facilitate the synthesis of the cyclic peptide and to minimize steric bulk within the cage. Firstly, cleavage of the hexapeptide from the resin with 5% TFA gives the unprotected linear peptide 63. The cyclization of compound 63 generates the cyclic peptide 65 in quantitative yield after 1 h. Compound 65 can also be prepared starting from the cleavage of the hexapeptide from the resin with 1% TFA, however, an additional deprotection step is required (see Scheme 1.13).

The cyclic hexapeptide 65 is then triply alkylated with bromoethyl vanillyl alcohol 9 to give hemicryptophane precursor 66 in 55% yield. Finally the CTV unit was generated by treatment of 66 with HCOOH, providing 67 in good yields (64%) as a mixture of two diastereomers. The P-and M-isomers were formed in a 2:1 ratio and were separated by column chromatography. hemicryptophane precursor has been tested with HCOOH or Sc(OTf)3 as catalysts, however, both of them gave very low yields for the mixture of the two diastereomers of 71, 8% and 5%, respectively. The separation by column chromatography of the two diastereomers obtained in a 6:1 ratio allowed the authors to isolate the main diastereomer in pure form. Interestingly, hemicryptophane 71 acts as a solvent sensitive NMR and ECD probe. Inclusion of a solvent molecule in the -CD component of the hemicryptophane induces conformational changes that resuρt in the shieρdinμ oλ the primary methoxy -OMe protons oλ the -CD unit, which increases with the size of the chloroalkane solvent. 67 The formation of disulfide bonds was also used for constructing hemicryptophanes based on a -cyclodextrine scaffold following the [1+1] coupling strategy (Scheme 1.15). 68 The trimesyρate -cyclodextrine 72 reacts with potassium thioacetate in DMF to give compound 73 in quantitative yield after column chromatography. Subsequently, methanolysis of 73 in the presence of K2CO3 in MeOH followed by acidification of the mixture with HCl, affords the tris-methyρthioρ -cyclodextrine 74. The addition of a solution of I2 in MeOH to a methanol solution of 74 and racemic cyclotrithiophenolene 75 in the presence of KI and triethylamine, generates the final hemicryptophane 76 in 11% yield as a 5:3 mixture of two diastereomers that could not be separated. 1.16). 69 This synthesis follows the seldom-used strategy consisting in preparing a cyclotribenzylene bearing suitably functionalized pendant arms that react together to form the hemicryptophane derivative (Figure 1.3c). The authors first treated 18a or 18b with an excess of NaN3 in DMF to form the triazide derivatives 77a and 77b, respectively. Then, the alkynyl-methylbenzoate derivative 80 was prepared from 78 and 79 in DMF in the presence of K2CO3 at 80 o C and was further hydrolyzed with LiOH to give 81 quantitatively. The acid 81 was then coupled with 82 in CHCl3 to generate the compound 83, which then reacts with 77a or 77b in the presence of CuI to give the hemicryptophane precursors 84a or 84b. Finally, the hemicryptophanes 85a and 85b are assembled quantitatively by forming three imine bonds from arylamide-derived foldamer segments after adding TFA to the CHCl3 solution of 84a and 84b. In principle, each of the two hemicrytophanes should have four stereoisomers, two pair of enantiomers, because of the relative orientation of the CTV and triimine macrocyclic units. However, only one set of signal is observed in the 1 H NMR spectra, suggesting that only one isomer (or a pair of enantiomers) was formed in the final step. Molecular dynamic simulations demonstrated that isomers, where the methoxy of the CTV moiety and the imine groups are arranged in anti with respect to one another located on either side of the related linkages, are more energetically favorable and are probably the observed products in solution.

Hemicryptophanes 85a and 85b turned out to be good receptors for C60 and C70 fullerenes (see Section 1.4.2.5).

Scheme 1.16 Synthesis of Hemicryptophanes 85a and 85b.

Hemicryptophanes based on calixarene. Based on the reaction between tris-acyl chloride and tris-amino compounds, Jabin and coworkers synthesized hemicryptophane 90 with a calix [6]arene platform (Scheme 1.17). 70 The [1+1] macrocyclization reaction between calix [6]arene 86 and CTV 87 was first performed under high dilution conditions giving the hemicryptophane 90 in 15% yield after flash chromatography purification. With the aim of improving the yield, they also tested and optimized the reaction between calix [6]trisamine 86 and CTV tris-acid 88 in the presence of peptide-coupling reagents such as PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), to produce 90 with a much better yield (46%). Under the same reaction conditions, they also obtained the hemicryptophane 91 containing a wider cavity and a larger number of hydrogen bond donors, in 33% yield (Scheme 1.17). Scheme 1.17 Synthesis of Hemicryptophanes 90 and 91.

Hemicryptophanes based on heteroatomic pivot

Hemicryptophanes with a phosphotrihydrazone core. Following the [1+1] strategy, the racemic hemicryptophane 6 was successfully obtained (Scheme 1.18a). 30 The trisallyl CTV 93 was first prepared from the allyl-protected vanillyl alcohol 92 in perchloric acid and methanol.

The Pd-catalyzed deprotection of 93 in the presence of Et2NH in THF/H2O led to the cyclotriguaiacylene 94, which reacted with the brominated derivative 95 in the presence of aqueous NaOH in DMF-HMPA to give the precursor 96 bearing three benzaldehyde moieties.

Finally, 96 reacted with phosphotrihydrazide 97 in THF under high dilution conditions affording the hemicryptophane 6 in 23% yield. It was proposed that the success of the last reaction is partly attributed to the rather rigid conformation of the phosphorus derivative.

A similar synthetic scheme led to hemicryptophane 101, which was specifically designed to complex iron and gallium ions (Section 1. 3.3.2). The reaction of the cyclotriguaiacylene platform 94 with allyl-protected benzaldehyde 98 afforded the precursor 99. Subsequent deprotection step led to compound 100 that was allowed to react with phosphotrihydrazide Scheme 1.18 Synthesis of Hemicryptophanes 6 (a) and 101 (b).

Hemicryptophanes with an amine core. The synthesis of hemicryptophane 105 was reported by Dmochowsky et al., 52 where vanillyl alcohol 7 reacted with dibromo-p-xylene 102 in the presence of K2CO3 to form compound 103, which was treated with a catalytic amount of Sc(OTf)3 in CH3CN to afford the hemicryptophane precursor 104 (Scheme 1.19). In the last step, compound 104 reacted with 7N NH3 in MeOH at high temperature to give the hemicryptophane 105 in 67% yield. It can be noted that this short streamlined synthetic scheme utilizes mild conditions and results in a fairly good overall yield (13%).

Hemicryptophanes formed from a covalent CTV-C60 adduct

The concave electron-donor aromatic surface of the CTV scaffold is known to interact favorably with electron-acceptor fullerenes C60 or C70. [72][73][74] Diederich et coll. used this property to build a covalent CTV-C60 assembly that led to a hemicryptophane-like architecture. The tether-directed Bingel reaction of C60 with the tris-malonate CTV derivative 106 led in one step to C3-symmetrical CTV-C60 tris-adducts 3 and 4 (Scheme 1.20). 29,75 Although no available cavity is observed in 3 and 4, these adducts can be considered as hemicryptophane structures. Many regioisomers are expected that complicate the determination of the stereochemistry of the isolated compounds. 76 In their former work, Diederich and colleagues isolated the trans -3,trans-3,trans-3 and e,e,e regioisomers, which Although they are not strictly covalent hemicryptophane hosts, several CTV metal complexes gave rise to original hemicryptophane structures. Functionalized CTVs with three pendant arms have been prepared as new C3 symmetrical ligands for metal coordination. For example, by incorporating thiol groups on the arms, the cyclotriveratrylene derivatives thus obtained were able to complex iron-sulfur clusters. Collet et al. reported in 1994 the formation of complexes 109 and 110 (Figure 1.5). 78 The same year, the group of Nolte synthesized very similar ligands, which reacted with various [4Fe-4S] clusters affording complexes such as 111 and 112 presented in Figure 1.5. It was shown that for hemicryptophane 111 with Fe-Cl bond, the chloro ligand was pointing toward the cavity, whereas the Fe-SR group in 112 is oriented outside the cavity. 79 Several C3 cyclotriveratrylene ligands featuring three arms ending with catecholate, hydroxamate, bipyridine or iminopyridine moieties were synthesized for the octahedral coordination of iron(II) and iron(III) (Figure 1.6). Ligands bearing various pendant arms (a-h in Figure 1.6) were generally obtained by reaction of CTV precursors such as 52, 53 or 88 with the corresponding suitable reagents. 31 Magnetic and electrochemical properties of iron(II) complexes 113e-h were investigated. As an example, compound 113g was characterized by X-ray diffraction and Mössbauer spectroscopy, and it has been shown that both low-spin and high-spin states coexist in the solid. These iron complexes contains two stereogenic elements possibly leading to the two diastereomeric racemates (MΔ/PΛ) and (MΛ/PΔ . Interestinμρy, in the X-ray molecular structure of 113g only the (MΔ/PΛ) pair of enantiomers was found. 80 In 1995 Nolte and co-workers published also a rhodium complex of a CTV ligand bearing three arms terminated by triphenyl phosphite functions. The hemicryptophane complex thus obtained is quite flexible and the cavity occupied by the spacer arms. 81

Hemicryptophanes obtained by metal coordination

Formation of hemicryptophane capsules by reversible bonds/interactions

Association of two or more CTV units has led to interesting self-assembled supramolecular systems, which present a molecular cavity. We will not report on these cage structures, which are out of the scope of this review article. They are more like reversible capsules with C3 symmetry when two cyclotribenzylene caps self arranged to form a cryptophane like structure. [82][83][84][85] Some can also form MOF-type structures, 86 when several cyclotribenzylene units are held together through metal coordination. [87][88][89][90][91][92] However, besides the covalent synthesis of hemicryptophane cages, reversible covalent bonds, such as dynamic boronate esterification, 93,94 and reversible supramolecular interactions, such as ionic interaction, 95 have also been developed for the construction of hemicryptophane capsules. Compared to the covalent synthesis, the self-assembling is straightforward and can avoid tedious purification procedures. However, the lower stability of the resulting cages can be a main drawback, as mentioned for self-assembled architectures using reversible bonds/interactions. [96][97][98][99] Furthermore, the assemblies are usually driven by external template molecules, which may go inside the cavity of the hemicryptophane capsules, preventing the access to their inner cavities to other guest molecules. 100

Formation by boronate esterification

Boronic acids can rapidly and reversibly form cyclic boronate esters with diols showing great promise for developing self-assembled hemicryptophane capsules.

Formation by ionic interactions

Ionic interactions between anion and cation have also been utilized for constructing self-assembled hemicryptophane cages. 95 In a first experiment the addition of 1 equiv. of calix [6]trisamine 86 to a suspension of CTV-triscarboxylic acid 88 in CDCl3 did not generate [1+1] hemicryptophane capsule, and instead, various aggregated species were formed probably because of the flexibility of the calix [6]arene structure. However, subsequent addition of 3 equiv. of neutral polar molecules, such as imidazolidin-2-one (IMI) to this 1:1 mixture led to a discrete [1+1+1] self-assembled ternary hemicryptophane capsule IMI@119 composed of 86, 88 and encapsulated IMI.

Futhermore, other polar molecules, such as imides, alcohols, amides, sulfoxides, carbamates, or ureas could also induce the formation of the hemicryptophane capsules through an induced-fit process. These polar molecules can go inside the cavity of the calix [6]tris-ammonium via hydrogen bonding, CH-interactions with the aromatic waρρs, and charge-dipole interactions, leading both to the expulsion of the methoxy groups from the calix cavity, the rigidification of the calixarene core, and the preorganization of the ammonium arms, which are necessary for the assembly of the [1+1] ion-paired complex.

Interestingly, when using the CTV building block 89, a new self-assembled ditopic hemicryptophane capsule 2IMI@120 including simultaneously two IMI molecules, one in the calixarene cavity and one in the CTV cavity, was formed thanks to the larger size of the building block 89 and the flexibility of 86.

Scheme 1.24 Formation of Hemicryptophane Capsules IMI@119 and 2IMI@120. Effective molecular recognition or catalysis in water is especially meaningful and attractive since it can mimic more accurately biological systems. 103,104 Accordingly, supramolecular events should take place in water at physiological pH without the addition of organic solvent, requiring water-soluble molecular hosts. The design of water-soluble hemicryptophanes is a real challenging task that mainly relies on the introduction of hydrosoluble functions on the CTV unit. Two strategies that address this issue have been reported, where hydrosoluble groups allow the solubilization of the host in strong basic aqueous solution, 105 or in water at physiological pH. 106 The two strategies that either introduce phenol functions or incorporate carboxylate groups on the CTV units originate from the synthesis of water-soluble cryptophanes. [107][108][109] The tren-hemicryptophane 123 bearing three phenol functions on the CTV cap was synthesized from hemicryptophane 15a (Scheme 1.25). 105 The tren unit in 15a was first

Functionalization of hemicryptophanes

Endohedral functionalization of hemicryptophanes

Endohedral functionalization of a molecular cavity is a highly challenging topic, arousing a growing interest from the international community. [110][111][112][113][114][115] Endohedral non-metal or metal functional groups inside the molecular cavity can participate as binding sites to enhance the host-guest interactions or can act as reactive centers to promote catalytic reactions in the confined space of the inner cavity, mimicking biological entities such as enzymes. [113][114][115][116][117] The endohedral functionalization of the hemicryptophane cages reported so far are mainly concerned with (pro)azaphosphatrane derivatives, and the vanadium (V(V)), zinc (Zn(II)), copper (Cu(II)) and ruthenium (Ru(II)) hemicryptophane complexes, the crucial role of which as supramolecular catalysts has been investigated.

Encaged (pro)azaphosphatranes: synthesis and cage effect. Proazaphosphatranes, also πnown as Verπade s superbases, and their azaphosphatrane protonated counterparts, exhibit catalytic properties in a wide range of reactions. 47,118-122 In 2011, Dutasta, Martinez et al. synthesized the first hemicryptophane-Verπade s superbase P@15a and its conjugated acid PH + @15a from their precursor 15a using the experimental conditions reported for other azaphosphatranes (Scheme 1.27). The addition of hemicryptophane 15a to a solution of [(CH3)2N]2PCl in CH3CN afforded PH + @15a in 35% yield, which was then deprotonated using potassium t-butoxide (t-BuOK) in THF to give the encaged superbase P@15a in 80% yield. 123,124 The azaphosphatrane-hemicryptophanes PH + @15a was optically resolved by chiral semi-preparative HPLC, leading to the enantiopure compounds PH + @M-15a and PH + @P-15a. 125 Likewise, hemicryptophane-superbases P@15b, P@15g, P@15i and their corresponding protonated forms were also obtained using the same synthetic pathway.

Makita et al. also prepared the encaged azaphosphatrane PH + @22, 126 but the depronation of the PH + failed even with an excess of t-BuOK or sodium hexamethyldisilazide (Scheme 1.27).

This was attributed to the smaller size of the molecular cavity that protects the endohedral proton. Most of the encaged azaphosphatranes display a characteristic single 31 P NMR signal, which is about 20 ppm downfield shifted compared to non-encaged azaphosphatranes. 125 Scheme 1.27 Synthesis of (pro)Azaphosphatrane Encaged Hemicryptophane Complexes.

Then, Martinez et al. investigated the cage effect on the basicity and reactivity of the superbases. 123 Indeed the kinetics and thermodynamics of proton transfer in biological systems can be strongly modified by the surrounding medium. 127 Changes in the reactivity in such confined biological entities have led to the design of bio-inspired supramolecular structures. 128,129 These investigations are likely to provide valuable information for a better understanding of enzymes or other complex biological systems. For that purpose, the model compounds P@126 and P@126a were prepared (Figure 1.7), and competition experiments were run for the determination of pKa of P@15a and P@126a relative to P@126 in CD3CN using 31 P and 1 H NMR spectroscopy. This afforded a value of Ka = 1.03×10 -33 for P@15a, 7 times smaller than that of its model superbase P@126a (Ka = 7.25×10 -33 ), making the encaged superbase P@15a 7 times more basic than the model molecule P@126a. In addition, the deprotonation rate constant is more than 500-fold lower with the encaged PH + @15a than with the model PH + @126a. In spite of the higher basicity of the superbase P@15a, the rate constant for its protonation is nearly 2 orders of magnitude lower than that for the model superbase P@126a, meaning that the rate constant is unrelated to the thermodynamics of proton transfer.

These observations indicate that the encapsulation of phosphorus moiety inside the cage affects the basicity of the superbase, and strongly decreases the rate of proton transfer. Figure 1.8 X-ray crystal structures of the encaged Verkade's superbase P@15b and the azaphosphatrane cations PH + @15a, PH + @15i and PH + @126a: (a) space filling top views of the phosphorus centers (for P@15b, PH + @15a and PH + @15i, the CTV units have been removed for clarity); (b) stick views.

In order to further investigate how the size and the shape of the nanospace around this highly reactive center can control the basicity and the rate of the proton transfer, the authors prepared a series of encaged proazaphosphatrane superbases having a molecular cavity with different volumes and shapes, and also their corresponding model compounds without cavity (Figure 1.7). 124 The X-ray crystal structures reveal that from P@15b to PH + @15a and PH + @15i, the molecular cavity grows along the pseudo C3 axis of the molecule but also becomes narrower (Figure 1.8). It has been shown that the encapsulation greatly affects the basicity of the superbase. For example, according to the pKa values, the encaged superbase P@15a is 7 times more basic than its model P@126a, whereas P@15b is more than 30 times less basic than its model P@126b, and P@15i was found to be over 100 times more basic than its model P@126i. These results were closely related to the geometry of the environment around the P-H site, and the congestion of the inner space around the phosphorus center corresponds to an increase of the basicity of the superbases P@15a and P@15i compared to their respective models P@126a and P@126i. In addition, the kinetic data show that the rates of the proton transfer for these superbases are in the order of PH + @126a > PH + @15b > PH + @15a > PH + @15i, which is consistent with the accessibility of the reactive phosphorus center also observed from the crystal structures.

Synthesis of endohedral metal@hemicryptophane complexes. Metal complexes possess a variety of coordination topologies, thermodynamic stabilities and kinetics, and have found wide applications in molecular recognition and catalysis. They can serve both as binding and catalytic sites in the development of sensors and catalysts, similar to the function of metalloenzymes in bioinorganic chemistry. [130][131][132][133][134][135] The hemicryptophane cages including tren and trialkanolamine units, such as 15a and 41, can easily coordinate a metal ion such as Zn(II), Cu(II), Ru(II), Al(III) or V(V), to form atrane structures, which are an interesting class of compounds well represented across the periodic table and widely studied. 44,[136][137][138] The oxidovanadium hemicryptophane complexes, such as the two diastereomers V(V)@M-(S,S,S)-41 and V(V)@P-(S,S,S)-41, were synthesized in one step from their precursors bearing trialkanolamine moieties (Scheme 1.28). 60,139 Hemicryptophane M-(S,S,S)-41 reacted with 1 equiv. of vanadium oxytriisopropoxide to give the corresponding complex quantitatively. Noteworthy that these vanadium complexes present potential catalytic sites in chiral environments, which may find applications in asymmetric catalysis. 140 Another point is that besides vanadium(V), titanium(IV) and zirconium(IV) are also known to form stable complexes with trialkanolamine ligands. [141][142][143] Scheme 1.28 Synthesis of the Oxidovanadium Hemicryptophane Complex.

Scheme 1.29 Synthesis of Zn(II) Hemicryptophane Complexes.

Tren-hemicryptophane 22 reacted with Zn(ClO4)2(H2O)6 to yield the Zn(II)@22 complex (Scheme 1.29). Following this method, Makita et al. also synthesized Zn(II)@22 with CH3COO as counterion, 54,144 and the RuCl2@22 hemicryptophane complexes. 145 The tren unit easily binds Cu(II) ions, and a series of Cu(II)@hemicryptophane complexes have been described. Different tren-hemicryptophane ligands reacted with stoichiometric amounts of Cu(ClO4)2 in a CH2Cl2/MeOH mixture to produce Cu(II)@15a, Cu(II)@15b, Cu(II)@15i and Cu(II)@125 complexes with high yields (Scheme 1.30). 146 It is important to point out that Cu(II)@125 constitutes the first water-soluble Cu(II)@hemicryptophane complex. 106 Scheme 1.30 Synthesis of Cu(II) Hemicryptophane Complexes.

Recently, Dutasta et al. reported the preparation of Ga(III)@101 and Fe(III)@101 hemicryptophane complexes presenting an octahedral coordination site inside the molecular cavity of the host molecule. 71 The complexes were obtained by addition of Ga(acac)3 or Fe(acac)3 to a solution of 101 in 1,1,2,2-tetrachloroethane and were characterized by 1 H, 13 C and 31 P NMR spectroscopy. The EPR spectrum of the iron complex Fe(III)@101 indicated a high-spin Fe(III) ion in an octahedral environment. The isostructural X-ray molecular structures of both complexes showed the metal ions nested in the phosphorylated part of the ligand (Figure 1.9). It is interesting to note that the chiral CTV cap induces a helical arrangement of the three linkers of the host molecule, whose configuration is related to that of the CTV unit. Moreover, the complexes present two stereogenic centers, the CTV unit with P or M conλiμuration, and the octahedraρ coordination site with Δ or Λ conλiμuration, that should lead to two diasteromeric racemates (PΔ/MΛ and MΔ/PΛ . In the present case the authors only observed the (PΔ/MΛ racemate. This seems to be a general feature observed with other hemicryptophane structures where the CTV imposes the right or left-handed conformation of the linkers and also the stereochemistry of other stereogenic elements present in the host molecule.

Host-guest chemistry of hemicryptophanes

The use of molecular containers for the complexation and recognition of neutral or charged guests is of increasing interest as they can lead to a better understanding of recognition phenomena in biological systems. 12,[START_REF] Brotin | [END_REF][147][148][149][150] In particular, hemicryptophane molecular receptors present several advantages. (i) The rigid CTV scaffold results in a preorganized cavity, in terms of shape and size, enhancing guest binding. Futhermore, the size of the cavity can be controlled and adjusted by changing the linkages between CTV and south units. (ii) The versatile south unit is easily modified to specifically recognize cations, anions or neutral molecules depending on its interacting sites, thus, various homoditopic and heteroditopic hosts can be designed when combined with the electron-rich CTV moiety. (iii) Signaling groups, for instance fluorophore, can be incorporated into the cages to provide fast responses with low detection limit for the host-guest complexation. The position of the signaling groups is relatively flexible as they can be tethered to the north or south units, or included in the three linkages. (iv) Taking advantage of the chirality of the CTV unit, enantio-and dia-stereoselective recognition properties are expected.

The first complexation experiment was described in 1982 with hemicryptophane 1, [START_REF] Canceill | [END_REF] followed 26 years later by a second example reported by Le Gac and Jabin. 70 Only recently, hemicryptophanes have been investigated as complexing agents for various chiral or achiral guests such as ammoniums, 94,105,151,152 ion pairs, 49,70,153 zwitterions, 63,65,143,154 carbohydrates, 56,57,61,155 and C60 or C70 fullerenes. 69 This section aims at reporting the complexation properties in the solid state and in solution of hemicryptophane hosts, emphasizing the enantioselective recognition with enantiopure receptors.

Guest inclusion in the solid state: X-ray structures

Dutasta et al. reported in 1999 the first structure of a guest imprisoned in the lipophilic cavity of a hemicryptophane host. 30 The crystal structure of hemicryptophane 6, recrystallized from toluene, shows a well-preorganized cavity defined by the CTV and phosphotrihydrazone moieties, with the S=P bond oriented outward of the cavity (Figure 1.10). One toluene guest is totally encapsulated in the cavity of the host to form a host-guest complex stabilized by van der Waals and C-H••• interactions. In the soρid, host 101 encapsulates a toluene molecule and displays the two P and M configurations of the CTV unit. 71 Interestingly, the linkers adopt an or helical conformation and only the P--helix or M--helix enantiomers coexist in the crystal (Figure 1.10). Single crystals of hemicryptophane 14 were also obtained by slow evaporation from a CH2Cl2 solution (Figure 1.10). 48 Hemicryptophane 14 exhibits an asymmetric structure with respect to the C3 axis of the CTV cap, introduced by the inward orientation of one C=O amide bond stabilized by H-bonds with the adjacent NH groups. The two other C=O groups are oriented outward and participate in the crystalline cohesion through intermolecular hydrogen bonding. One CH2Cl2 guest molecule is fully encapsulated in the host cavity and localized close to the CTV unit in the more lipophilic environment of the cavity. This important feature indicates the possible ditopic character of the hemicryptophane host towards guest compounds. Slow diffusion of pentane in a solution of 15a in CH2Cl2 gave crystals suitable for X-ray analysis (Figure 1.10). 48 The structure presents a C3 symmetrical axis with a well-preorganized cavity encapsulating a molecule of n-pentane. In the complex, C-H••• interactions between CH3 groups of the guest and aromatic groups of the linkers are observed. Interestingly, water molecules can also be included into the cavity of hemicryptophanes. In the X-ray structure of 54, crystallized from CH3CN/H2O, three water molecules are encaged inside the hemicryptophane cavity. 63 Two of them interact with an amide group of the host through hydrogen bonding and one is in the proximity of the electron-deficient aromatic ring. This anticipates the recognition properties of this host towards hydrophilic species.

Figure 1.10 Crystal structures of toluene@6, toluene @101, 3H2O@54, n-pentane@15a and CH2Cl2@14.

Makita et al. also described a series of crystal structures of inclusion complexes with hemicryptophane hosts. For example, the X-ray crystal structure of hemicryptophane 22 Interestingly, the Zn(II) coordinated complex of 22 (ClO4 -as counterion) also bound a CH3CN molecule as observed from its crystal structure prepared by slow diffusion of THF into a CH3CN solution. 144 In this case, the cage maintains the C3 symmetry and includes a CH3CN moρecuρe throuμh CH••• interactions. In addition, the CH3CN N atom also loosely coordinates to the Zn(II) ion, which indicates the binding ability of this metal center. However, when AcO -was used as the counterion, the Zn(II)@22 complex does not include a CH3CN molecule despite the crystals were obtained by slow diffusion of Et2O into a CH3CN solution. 54 Instead, an AcO -counterion was embedded inside the molecular cavity according to the coordination bond between the O atom in AcO -and Zn(II). This inclusion behavior of Zn(II)@22 towards AcO -was also observed in solution. These results underline the strong binding ability and heteroditopic character of the Zn(II)@22 host.

(Figure 1.
Figure 1.11 Crystal structures of CH3CN@22, CH3CN@Zn(II)@22, AcO -@Zn(II)@22 and acetylcholine@22.

Most of the X-ray structures of guest inclusion in hemicryptophane hosts reported so far are restricted to solvent@hemicryptophane complexes. However, in 2016 Makita et al.

reported the solid-state structure of an acetylcholine molecule encaged in the cavity of hemicryptophane 24. 55 A partial encapsulation of the neurotransmitter was observed: indeed the ammonium head of acethylcoline is trapped inside the cavity whereas the acetyl group is located outside, leading to an original pseudo-rotaxane structure (Figure 1.11). This important result highlight the ability of hemicryptophane to tolerate partial encapsulation and thus to complex only a part of large guest molecules.

X-ray molecular structures of free hosts, without guest molecules in the molecular cavity have also been reported, and result from two main factors. (i) The cavity is too small to accommodate any guest molecules as for instance in the crystal structure of hemicryptophane 105 described by Dmochowski et al. 52 or in hemicryptophane 15b where hydrogen bonds involving the three linkages induce a twisted structure, giving rise to very small available space inside the cavity (Figure 1.12). 51 (ii) The hemicryptophane structure collapses and the molecule adopts a compact structure with the molecular cavity occupied by one of the linkages or the south moieties such as the crystal structures of V(V)@P-(S,S,S)-41. 156 Therefore, when designing a hemicryptophane host with the purpose of complexing molecules, these factors, that may induce no guest encapsulation, should be taken into account. Interestingly, the X-ray molecular structures can be used to assign the absolute configuration of the chiral CTV unit. For instance, in the solid-state structure of hemicryptophane 31a, recrystallized from a dichloromethane solution, a well-defined molecular cavity was observed (Figure 1.12). Because the S configuration of the three stereogenic carbons of the tren moiety was controlled during the synthetic pathway, it has been possible to assign the M configuration of the CTV unit (Flack parameter = 0.00(1)). 58

Complexation in solution

Most of host-guest systems with hemicryptophane hosts have been investigated in solution.

The binding affinities rely on the lipophilic and electron-donor properties of the CTV moiety, which can be associated to various southern units leading to a wide range of suitable guests.

Thus, the peculiar properties of the hemicryptophanes are strongly related to their hetero-ditopic character with modulable cavity size and shape, polarity, hydrophilicity and hydrophobicity. Among the various noncovalent interactions that can take place with hemicryptophane hosts, hydrogen-bonding and cation-or anion-interactions prevaiρ due to the aromatic environment of the receptors built from the CTV platform. This review will cover the most encountered hemicryptophane-guest complexes reported in the literature including charged species (ammonium, ion pairs, zwitterions) and neutral guests such as fullerenes and carbohydrates.

Because of the chirality of the CTV unit, the recognition of achiral molecules by hemicryptophane hosts usually involves racemic mixtures. Conversely, the complexation of chiral guests uses enantiopure hemicryptophane hosts. The enantioselective recognition of chiral molecules with C3 symmetrical hosts is highly challenging. Indeed, the first enantioselective recognition of chiral primary ammonium ions with C3 symmetric tripodal receptors was reported by Ahn et al. only in 2002, 157 followed by few other examples. 158,159 Then, Moberg et al. were able to rationalize the enantioselectivity observed with C3 symmetric hosts, putting an end to an old scientific controversy. 160,161 This highlights that enantioselective recognition of chiral molecules with C3 symmetrical hosts remains a difficult task. The access to enantiomerically pure hemicryptophanes as described in the preceding sections, allowed important investigations in the field of chiral recognition in solution that will be underlined in the following sub-sections.

Recognition of ammonium guests

The first hemicryptophane, speleand 1, developed by Collet and Lehn, was shown to be an efficient binding receptor for primary ammonium. [START_REF] Canceill | [END_REF] A schematic representation of the inclusion complex is shown in Figure 1.13: the NH3 + group interacts with the azacrown ether by hydrogen bonding, and the CH3 head is located inside the molecular cavity. A host-guest complex with the CH3 group located outside of the cavity below the azacrown ether is also detected, and a 2:1 ratio between the exo-and endo-complexes is observed. The second example of encapsulation of ammoniums was reported in 2009 using the n-Bu3N-triggered hemicryptophane capsule 118 in CD3OD/CD3CN. 94 The n-Bu3NH + cannot go inside the cavity because of its too large size. However, the addition of ammoniums Et4N + and Me4N + , or phosphonium Me4P + , to a solution of the empty capsule 116 gave rise to new signals in the range of 0.3-0.7 ppm on the 1 H NMR spectra, indicating the formation of encapsulated species. The authors then used competition experiments to investigate the relative binding affinities of the hemicryptophane capsule towards these three guests. For instance, when a 1:1 mixture of Et4NI and Me4NI was added to 116, two kinds of guest-filled capsules Et4N + @116 and Me4N + @116 appeared in a 2.3:1 ratio. In this way, the relative binding abilities were determined in the following order: Et4N + > Me4N + > Me4P + . Interestingly, the authors also characterized the encapsulation of the Cs + cation by host 116. However, for the two above cases no binding constants are reported.

Tren-hemicryptophanes were also used for the recognition of primary ammonium. For example, host 15a was demonstrated to be an efficient primary alkylammonium receptor in CDCl3/MeOD solution. 152 Upon addition of the host 15a to the solution of picrate salts of ammoniums, such as BnNH3 + , MeNH3 + , t-BuNH3 + and n-PrNH3 + , the μuest s protons The efficient complexation of choline neurotransmitter in water using the water-soluble hemicryptophane 123, was reported, constituting a real advance in host-guest recognition, rarely described in aqueous medium. 105 Estimated error: 10%. c No 1:1 complex observed after fitting the titration curves.

The large scale and easy synthesis of enantiopure hemicryptophanes M-15a and P-15a, allowed the authors to investigate their stereoselective recognition properties towards norephedrine in CDCl3/CD3OD solution. 53 1 H NMR titration experiments and binding stoichiometry similar to those for enantiopure 30 were observed for hosts M-15a and P-15a.

Interestingly, compared with 30, the two simplest hosts exhibited higher enantioselectivity towards norephedrine (91:9), indicating the important role of the inherently chiral CTV and highlighting the high potentiality of such simple and easy accessible enantiopure hemicryptophane hosts.

Makita et al. reported the formation of the 1:1 complex between acetylcholine and hemicryptophane 24 in a 20/1 CDCl3/CD3OD solution. 55 A binding constant of 1.3 x 10 4 M -1 was obtained by fitting the curve obtained from the NMR titration experiment. Interestingly, the 1 H NMR signals of the NCH2CH2 and N(CH3)3 protons of acetylcholine are broadened in the presence of host 24, whereas those of the acetyl CH3 remain sharp, suggesting that the formers are encapsulated inside the cavity of the hemicryptophane and the latter are outside the cavity, as observed in the solid state (Figure 1.11). Recognition of ammonium-chloride salts was also achieved using hemicryptophane 24. In the 1 H NMR spectra, the protons of the guests display downfield shifts upon progressive addition of the ammonium salts to the host solutions. The binding constants were measured for Me4NCl (6.5 x 10 4 M -1 ), Et2Me2NCl (9.8 x 10 3 M -1 ) and Et3MeNCl (5.5 x 10 2 M -1 ) and showed that the decrease of the affinity of 24 for the guests is related to the size of the cation, the highest the size the lowest the affinity. 55 Concerning the ammonium cation, in addition to the electrostatic interaction with its counterion, it is aρso probabρy stabiρized throuμh a combination oλ CH••• interactions and hydrogen bonding to the ethereal oxygen atoms of the amide arms. Furthermore, by using nBu4NCl and RNH3Pic salts, the authors demonstrated that the complexation of the Cl anion might only occur when an ammonium cation is present in the calixarene cavity, and corollary efficient binding of ammonium needs the presence of the Cl anion. This remarkable positive cooperativity benefits from a combination of polarization and induced-fit effects. Hemicryptophane 14, which bears a tripodal anion binding site (triamide moiety) and a cation recognition site (CTV unit) is an efficient ion-pair receptor in CDCl3. 153 Firstly, anion binding properties of 14 were evaluated by 1 H NMR titration and showed binding constants in with the order of Ka(F ) > Ka(Cl )> Ka(Br ) > Ka(AcO ), which is related with the hydrogen-bond-accepting ability and symmetry factors. Then the complexation of ammonium cations was investigated and showed that the affinity of hemicryptophane 14 decreases from Me4N + (K = 380 M -1 ) to Et4N + (K = 97 M -1 ) in accord with an increase of the steric hindrance. Finally, the ability of 14 to accommodate associated organic ion pairs was achieved by measuring the apparent anion binding constants Ka' of 14 in the presence of 1 equiv. of Me4N + . As shown in Figure 1.16a, host 14 binds anions more strongly in the presence of 1 equiv. of Me4N + emphasizing the heteroditopic character of receptor 14. Especially, a cooperativity factor, defined by the ratio K a/Ka = 15, was observed for the complexation of Cl , which also exhibits the largest binding constant. DFT calculations demonstrated that efficient hydrogen bonding between Cl and triamide, and CH-interactions between Me4N + and CTV, together with maximized electrostatic interactions between the bound Me4N + and Cl account for this high positive cooperativity (Figure 1.16b).

Recognition of zwitterions

Zwitterions, such as those shown in Figure 1.17, play an important role in the transfer of neuronal information, which is the subject of studies involving chemical, biochemical and clinical approaches. 165,166 As these guests are strongly solvated species in aqueous media, their biomimetic encapsulation through endohedral weak interactions in a hydrophobic neutral molecular pocket is still a challenge. The principle of complexation of zwitterions using heteroditopic hemicryptophane hosts is almost similar to that of ion pairs, i.e. stabilizing the cation part oλ zwitterions with the CTV unit via CH••• /cation-interactions and bindinμ the anion part with the south moiety using other supramolecular interactions.

Figure 1.17 Structures of zwitterionic guests.

Hemicryptophane 14, used for the recognition of ion pairs, is also an efficient heteroditopic hosts for the recognition of zwitterions since, as mentioned above, the CTV unit can stabilize the ammonium part and the triamide subunit can form hydrogen bonds with the anionic part. 154 The binding constants determined by NMR experiments in CD3CN/D2O are shown in Table 1.2. These results indicate that the encapsulation of guests by hemicryptophane 14 relies on three main criteria: (i) the zwitterionic character of the guest, (ii) its van der Waals volume since the pacπinμ coeλλicient has to be cρose to %, in aμreement with the Rebeπ s criteria, 167,168 and (iii) its shape. Indeed, two CH2 groups, between the anionic and cationic parts, are necessary to have an optimal recognition process. Only the simultaneous existence of these three factors allows optimum complexation with this receptor. As a consequence, host 14 is highly selective towards taurine. DFT calculations emphasize that only weak intermolecular interactions stabilize the host-guest association (Figure 1.18a). The authors noted that the structure of 14 revealed one major drawback as the three linkages are formed of electron-rich aromatic rings, which can induce electrostatic repulsions with the guest anion located inside the cavity. To tackle this problem, aromatic rings were replaced by an electron-deficient system in hemicryptophane 54, which improved the stability of the host-guest complex by favorable anion-interactions. 63 Adding three amide functions also increased the number of hydrogen bond donors, and the binding abilities of host 54 towards zwitterions have been significantly improved compared to host 14 (Table 1.3).

For some guests, binding constants are up to three orders of magnitude larger than those previously reported for host 14, whereas the solvent is even more competitive (20% of water in CD3CN vs. 10% initially). In particular, the binding constant for taurine reaches 5×10 5 M -1 , which was attributed to the good complementarity in size and shape between the host and guest, as demonstrated by DFT calculations (Figure 1.18b). In order to investigate whether this recognition process was driven by both hydrogen bonding and ion-interactions (cation-in the north part and anion-in the south part) or the contribution of these latter could be neglected in the formation of the complex, multireference wavefunction-based calculations 164 were carried out to have a deeper insight on ion-interactions. The results

showed that the two ion-interactions cation-and anion-interaction pρay a cruciaρ roρe in the recognition process and could be combined in a synergistic manner. Benefiting from the heteroditopicity of the hemicryptophane hosts, stereoselective recognition of chiral zwitterions was also achieved. For instance, Hutton et al. synthesized the enantiopure hemicryptophanes ML-67 and PL-67 (Section 1.3.1.4), which associate a CTV and a cyclic peptide (Scheme 1.15), for the enantioselective binding of (R/S)-carnitine in CD3CN. 65 During 1 H NMR titration experiments, significant downfield shifts were observed for the glycyl and tyrosyl NH protons of the cyclic peptide, indicating the encapsulation of the guest within the cavity to form 1:1 host-μuest compρex in accord with Job s pρot and ESI-MS.

Binding of carnitine with PL-67 was found to be enantioselective with (R)-carnitine with a 1.5-fold greater Ka than with (S)-carnitine (Table 1. 4). With ML-67, a 1.3-fold larger Ka was observed for (R)-carnitine compared to the (S)-enantiomer. In addition, considering that the association constant for the d-tyrosine-glycine hemicryptophane complex of (R)-carnitine (PDR-complex) is identical to the known enantiomeric l-tyrosine-glycine hemicryptophane complex of (S)-carnitine (MLS-complex), the authors determined a 5.9-fold difference in association constants of (R)-carnitine with the PL-

Recognition of carbohydrates

The recognition of carbohydrates, such as those in Figure 1.20, is involved in numerous biological processes such as protein folding, cell-cell recognition, infection by pathogens or tumour metastasis. 171 Thus, there is a great interest in mimicking biological receptors of carbohydrates. [172][173][174][175][176][177] However, these guests are challenging for supramolecular chemists as they possess complex three-dimensional structures, which often present subtle changes, so that a large selectivity is difficult to achieve. In this regard, hemicryptophane hosts appears as potential carbohydrate recognition receptors, since they can provide appropriate matches for both polar functionalities (through hydrogen bonding in the south part with the OH group of In 2011, the first octyl--D-μρucopyranoside Oct Gρc and octyρ--D-glucopyranoside Oct Gρc recoμnition usinμ enantiopure hemicryptophanes M-14 and P-14 (Scheme 1.1) was reported. 155 The binding constants, measured in CDCl3 solution reveal two main features (Table 1.5). Firstly, a good diastereo-discrimination is observed for host M-14, with a factor of ca.

between the bindinμ constants with Oct Gρc and Oct Gρc, and excρusive diastereoseρective recoμnition oλ Oct Gρc is achieved with P-14. Secondly, The four stereoisomers of hemicryptophane 29, which bear four stereogenic centers, (three asymmetric carbons and the CTV unit, Scheme 1.4), were also tested for the stereoselective recognition of glucopyranoside in CDCl3. 56 As shown in Table 1.5, the binding abilities of 29

have been improved compared to the previous hosts, with Ka values up to one order of magnitude larger. For example, host M-(S,S,S)-29 shows the largest binding constant for Oct Gρc M -1 and Oct Gρc M -1 ). The trend in diastereoselectivity is opposite to that of host 14, since for all the isomers of 29 Oct Gρc shows ρarμer bindinμ constants than its -anomer with a diastereoselective ratio of 2. Remarπabρe diastereoseρective recoμnition oλ -mannoside in CDCl3 was achieved using the four stereoisomers of hemicryptophane 30 (Scheme 1.4). 57 An overall trend of the selectivity, defined from the binding constants towards the different guests with the four hosts, was observed with the following order (Table 1. Oct Man > Oct Man > Oct Gρc > Oct Gρc > Oct Gaρ > Oct Gaρ, which is in μood aμreement with the diλλerent abiρities oλ the guest to be involved in intermolecular hydrogen bonds. 178,179 The more the saccharide can make hydrogen bonds with other molecules, the higher is the binding constant. This also highlights that hydrogen-bonding interactions are crucial for the recognition process. For instance, receptor M-(R,R,R)-30 can compρex aρmost excρusiveρy Oct Man λacinμ to Oct Gaρ with the higher binding constant Ka = 2511 M -1 . However, the authors report an excellent diastereoselectivity for the four stereoisomers of 30 with the carbohydrate guests, but a moderate enantioselectivity. Oct Man > Oct Glc > Oct Man ≈ Oct Glc. Nevertheless, a better stereoselectivity was achieved with the cage compounds, probably due to a better preorganization. For instance, excellent enantioselectivities were observed with P-(R,R,R)-56 and M-(R,R,R)-56 with binding constants of 182 M -1 and 287 M -1 toward Oct Man and Oct Glc, respectively, whereas no complexation occurred with the enantiomer hosts (Table 1.5). Furthermore, the role played by the inherent chirality of the CTV unit of the hemicryptophanes in the recognition process is highlighted by the fact that the affinity for Oct Man guest is ten times higher with the host

P-14 31 -c 155 M-(R,R,R)-41 123 226 -c -c 155 P-(R,R,R)-41 -c 115 -c -c 155 M-(S,S,S)-41 155 184 -c -c 155 P-(S,S,S)-41 -c -c -c -c 155 M-(S,
P-(R,R,R)-2 than with its diastereomer M-(R,R,R)-2.
A good 1:16 diastereoselectivity ratio was also reached in the recognition of Oct Glc over Oct Man using hemicryptophane P-(R,R,R)-1 as receptor.

Recognition of fullerenes

Hemicryptophanes 85a and 85b (Scheme 1.16) are good receptors for C60 and C70

fullerenes. 69 The were also performed and the number-average molecular weights of 85b, C60@85b and C70@85b were determined to be 2500, 3200 and 3500 u, respectively, in agreement with the corresponding calculated values. Finally, UV-vis titrations were used for determining the binding constants of 85a and 85b towards C60 and C70, giving values up to 10 5 M -1 .

Hemicryptophanes in motion: towards molecular machines

There is an increased interest in the synthesis and development of complex systems capable of performing a well-defined function at the molecular level like brakes, gears, propellers, ratchets, turnstiles, rotors, scissors, gyroscopes, and molecular springs. [180][181][182][183][184][185][186][187][188][189] Most supramolecular assemblies are particularly concerned with those novel approaches of functional intelligent molecules and materials. We may assume that changes in the molecular cage conformational space can affect not only thermodynamic properties, such as binding affinity, but also dynamic properties, such as molecular motions, on different time scales and rates, due to conformational changes. In this section we would like to report recent works involving hemicryptophane structures, which have been investigated for their reversible and controllable conformational changes, foreseeing molecular machines and switches.

Molecular gyroscope

Molecular gyroscopes are chemical compounds or supramolecular complexes containing a rotor that moves freely relative to a stator. 190

Molecular propeller

Atrane structures are an interesting class of compounds, which adopt a right-or left-handed propeller-ρiπe μeometry deλininμ a heρicaρ chiraρity with Δ or Λ conλiμuration, respectively. 138,191,192 For instance, the vanatrane derivatives obtained from the triethanolamine core and oxidovanadium compounds provide Δ/Λ enantiomers Fiμure 1.22). If an additional chiral element, for example with S-configuration, is introduced to the framework, the two S- and S- diastereomers combining the new stereocenter with the helical chirality of the atrane structure are formed. If the two diastereomers are rigid so that the stereoconversion of the clockwise and anticlockwise orientations of the properller-like arrangement is slow on the NMR time scaρe, the Δ or Λ λorms correspondinμ to the two species couρd be observed on the 1 H NMR spectra. More importantρy, iλ the Δ and Λ conλiμuration oλ the atrane structure can be controlled by external stimuli, such as chemical, electrochemical, photochemical or thermal input, a real molecular propeller system with molecular switch function could be developed. Similarly, the V(V)@P-(S,S,S-Λ -41 and V(V)@P-(S,S,S-Δ -41 diastereomers were obtained in the 1:0.17 ratio. The molecular structures obtained from DFT calculations and from X-ray diffraction demonstrate that the major species in each complex adopts the Λ conλiμuration, more stabρe than the Δ one. Interestinμρy, it was λound that the nature oλ the soρvent stronμρy aλλects the Δ/Λ ratio soρvent driven process . For instance, when the soρid oλ V(V)@M-(S,S,S)-41, obtained by evaporation from a CHCl3 solution, is dissolved in C6D6, the Δ/Λ ratio μraduaρρy decreased λrom / . to / as a resuρt oλ interconversion between the two diastereomers. Afterwards, evaporation and re-dissolution of the solid in CDCl3 resulted in the sρow increase oλ the Δ/Λ ratio λrom 1/1 to 1/0.35. Therefore, alternating change of the solvent could give rise to a diastereoselective interconversion between the two stable states havinμ Λ-41/Δ-41 ratios of 74/26 and 50/50 respectively (Figure 1.23a). At least, six switching cycles in the reversible bistable system were performed. Alternating change of the solvent for V(V)@P-(S,S,S)-41 also led to a diastereoselective interconversion (Figure 1.23b). These results

show that not only the motion of the hemicryptophane molecular propellers can be controlled, but they could also be developed as molecular chiral switches by means of the solvent as an externaρ stimuρus. The enerμy barriers λor the ΔΛ equiρibrium were determined by NMR experiments, and gave high values (around 100 kJ.mol -1 for both complexes). This class of atrane propellers can be considered as a novel mode of chiral switching that is worth of being explored for potential applications. [193][194][195][196]

Hemicryptophanes: supramolecular catalysts

Because of their high activity and selectivity, enzymes have been a source of inspiration for supramolecular catalysis. 111,116,117 The peculiar confined environment induced by the cavity around the substrate should provide a structural preorganization that can stabilize a transition state and ensure the desolvation of the guest molecules. Thus, catalysts, involving host-guest complexes, have been synthesized to mimic such properties of enzymes. To avoid any misunderstandinμ, by supramoρecuρar cataρysis we mean here a cataρysis λor reactions that involve supramolecular interactions that do not form part of the basic catalytic reaction . 110 Therefore, hemicryptophanes, presenting a well-defined cavity just above a reactive center, constitute a class of supramolecular catalysts. From the above sections, it has been shown that hemicryptophane cages can encapsulate various guests, including both charged and neutral species. It is thus expected that endohedral location of highly reactive species in such artificially protected and confined space of hemicryptophanes will lead to new catalytic activities and selectivities because of the specific size, shape and chemical environment that may impose specific orientation and conformation of the guest substrates.

Moreover, the rigid framework of the host molecule may also protect the catalytic site inside the cavity from degradation during the reaction, improving the stability of the catalyst. In this section, we will report on the use of hemicryptophane complexes that possess endohedral functions acting as supramolecular catalysts. A peculiar attention is paid to the comparison with the corresponding model catalyst, which lacks cavity, in order to highlight the key role of the confinement on the catalytic activity. Two main topics have been investigated: organocatalysis with (pro)azaphosphatrane derivatives (Section 1.6.1) and catalysis using metal-hemicryptophane complexes (Section 1.6.2).

Hemicryptophanes as organocatalysts

Pro-azaphosphatranes, oλten named Verπade s superbases pKa ≈ , dispρay remarπabρe properties as basic or nucleophilic catalysts in numerous reactions, such as transesterification, allylation, silylation and elimination. 118,122,197 In contrast, their conjugated acid azaphosphatranes, resulting from the protonation of the phosphorous atom of the proazaphosphatrane, have received less attention. In this section, the use of encaged azaphosphatrane and Verπade s superbase hemicryptophane compρexes as orμanocataρysts is described. Yields were determined from NMR spectra using 2,4-dibromomesitylene as internal reference. b Diastereomeric excesses were determined by NMR. c The major product is 127-endo.

Encaged Verkade's superbases for Diels-Alder reactions

A first example concerns the use of pro-azaphosphatranes in Diels-Alder reactions. Despite Verπade s superbases dispρay remarπabρe properties as basic or nucρeophiρic cataρysts in numerous reactions, their use in Diels-Alder reaction was only reported in 2014. The encaged Verπade s superbase P@15a and the model one P@126a, which lacks a cavity (Figure 1.7), were used as organocatalyst for the base-catalyzed Diels-Alder reactions (Table 1.6). 198 The model catalyst P@126a is able to perform this reaction efficiently for both substrates with high yields, while the supramolecular catalyst P@15a displays a catalytic activity that is substrate-dependent. For instance, a quantitative yield is achieved with N-methylmaleimide as dienophile, whereas no reaction occurs with dimethylfumarate (Table 1.6). According to the authors, the confinement of the organocatalyst in a deep and narrow cavity combined with steric hindrance of the trans-dimethylfumarate can account for this result. In addition, it could be noticed that both catalysts exhibit quantitative yields for the reaction between 3-hydroxy-2-pyrone and N-methylmaleimide, but the caged catalyst P@15a displays much higher diastereomeric excess than the model P@126a (77% and 43%, respectively, both in favor of the 127-endo product). It is suggested that large active sites allow various transition-state geometries, whereas a catalyst encaged in a tight space can limit them, thus favoring the most compact ones and leading to an overall improvement of the selectivity. These results indicate that not only the yields and catalytic activities are altered by the confinement of the active site, but the encapsulation of the organocatalyst also improves the stereoselectivity of the Diels-Alder reaction. This case constitutes an important step in the development of stereoselective catalysis based on active sites confined in a hemicryptophane cavity.

Encaged azaphosphatrane catalysts for CO2 conversion

The use of azaphosphatranes as organocatalysts for CO2 conversion was developed recently.

The conversion of carbon dioxide (CO2) into cyclic carbonate has emerged as a powerful tool to produce renewable chemical feedstocks for organic synthesis from this greenhouse effect gas, since this carbon source is abundant, cheap and non-toxic. [199][200][201] In 2013, Dufaud, Martinez et al. found that azaphosphatranes, such as those in Scheme 1.31, can be used as efficient catalysts for the synthesis of cyclic carbonates from CO2 and epoxides. 202 They demonstrated that the catalytic reaction was first-order rate dependent on epoxide, catalyst and CO2, and proposed a mechanism where both the epoxide and the CO2 were simultaneously activated at a single molecule of catalyst. They also found that the substitution pattern on the catalyst greatly affects activity and stability; for instance, catalysts PH + @126a and PH + @129 are much more efficient and stable than PH + @126, because of the steric protection of the + P-H site in the former catalysts.

Scheme 1.31 Synthesis of Cyclic Carbonates from Epoxide and Carbon Dioxide Catalyzed by

Azaphosphatranes PH + @126, PH + @126a and PH + @129.

In order to further improve the efficiency and stability of the catalyst, azaphosphatrane@hemicryptophane catalysts, such as PH + @15a, PH + @15b and PH + @15i (Scheme 1.27), were engaged in CO2 conversion into cyclic carbonates. 203 The caged catalyst PH + @15a was found to be much more efficient than the corresponding model catalyst PH + @126a, as shown in Figure 1.24. Firstly, regarding the turnover number (TON) after 24 h, the caged PH + @15a was twice as active as its model PH + @126a when a ratio of 1000:1 was inputted between the epoxide (styrene oxide) and catalyst (1 bar, 373 K). In addition, no noticeable alteration of activity for PH + @15a was observed, whereas a steady decline in activity occurred for model catalyst PH + @126a. Hence, these results indicate that the P-H active site of PH + @15a is protected from degradation. The preorganization of the molecular cage likely reinforces the ability of the catalytic core to maintain its atrane structure during the catalytic cycle, thus improving the stability. Interestingly, it was also found that the reactivity of the caged catalyst PH + @15i, which has a narrower cavity, was much lower than PH + @15a. These observations suggest that the size and shape of the nanospace for the caged catalysts significantly affect their reactivity in the conversion of CO2 to cyclic carbonates.

Metal-hemicryptophane complexes as catalysts

It is widely recognized that metal ion embedded in the proteic cavity has key roles not only in the recognition events but also in catalysis for generating transient species and directing their reactivity. 111,112,116 Thus the design of biomimetic cage complexes for the modelling of these metallo-enzyme active sites is very meaningful. Although most of the supramolecular systems designed for catalysis are not so active either because they are too rigid, or they should be used in stoichiometric amounts since the reaction product remains in the cavity preventing the next catalytic cycle, the metal-hemicryptophane complexes have proved to be very efficient in catalysis achieving usually very high turnover number (TON). In this section, the organometallic hemicryptophane complexes bearing metal active sites, such as vanadium(V), zinc(II), copper(II) and ruthenium(II) for supramolecular catalysis will be presented.

Encaged Vanadium(V) catalysts for sulfoxidation

In 2009, the first metal-hemicryptophane complex used for catalysis was reported. 204 The diastereomeric hemicryptophane-oxidovanadium(V) complexes, V(V)@M-(S,S,S)-41 and V(V)@P-(S,S,S)-41 succeeded in efficient oxidation of sulfide to sulfoxide. With a 10 mol% catalyst and cumene hydroperoxyde (CHP) as oxygen source, the oxidation of thioanisole is much faster with the encaged catalyst V(V)@M-(S,S,S)-41 than with the model catalyst V(V)@(S,S,S)-126a, which lacks a cavity (Figure 1.25). Within 90 min, the yield reaches 95%

with high selectivity (98%). In addition, when decreasing the amount of catalyst to 0.5 mol% and performing the catalysis at r.t., TON up to 180 was obtained, indicating the high efficiency of these supramolecular catalysts. The catalysis is also very efficient when t-butyl hydroperoxide (TBHP) is used as oxidant.

Almost the same catalytic performance is achieved using catalyst V(V)@P-(S,S,S)-41. The kinetic constants for the reaction are estimated up to 6-fold higher with the hemicryptophane complex 41 than with the model complex V(V)@126. The improvement in the reaction rate by the cage was attributed to the guest activation via molecular encapsulation, and also by the relative flexibility of this cage that can allow fast responsiveness.

Encaged Zinc (II) catalysts for carbonate hydrolysis

The Zn(II)-coordinated hemicryptophane complex Zn(II)@22 and the Zn(II)@132 model catalyst were used for the hydrolysis of alkyl carbonates. 54,205 The Zn-catalysts were generated in situ by adding Zn(OAc)2 to a solution of the corresponding ligand. The reaction conditions and kinetic data for the hydrolysis of alkyl carbonate 133a-f are shown in Table 1.7. DMSO-d6

was used as the solvent because it was found that the reaction rates are much faster in DMSO-d6 than in other solvent, such as CDCl3 or CD3CN. From Table 1.7 it can be seen that for all the substrates, except 133f, the reaction rates with hemicryptophane catalyst Zn(II)@22 are much higher than with the model catalyst Zn(II)@132 with a ratio ranging from 1.8 to 3.5.

In addition, different reactivities are also observed for different substrates with the hemicryptophane catalyst.

For example, the hydrolysis of substrate 133a bearing a methyl group gives the highest rate constant and a 2.2 ratio for kZn(II)@22/kZn(II)@132. Despite the large size of benzyl and p-nitrophenoxy groups in 133c, the rate constant is still acceptable, suggesting that part of the substrate goes inside the cavity. The hydrolysis of 133d and 133e gives rise to the largest value of kZn(II)@22/kZn(II)@132 between hemicryptophane and model catalysts. Surprisingly, the hydrolysis of 133f with the hemicryptophane catalyst is slower than the model compound,

indicating that the t-Bu group has fully hindered the access to the inner zinc site. Hence, all these results demonstrate that the higher catalytic reactivity of the hemicryptophane catalyst is due not only to the proximity thanks to the substrate encapsulation within the cavity, but also to the control of the solvent access, inhibiting DMSO coordination with the zinc site into the cavity.

Encaged Ru (II) catalysts for the oxidation of alcohols

RuCl2@22 was tested as catalyst in the oxidation of alcohols into aldehyde and carboxylic acid, using cerium(IV) ammonium nitrate (Ce(NH4)2(NO3)6) as stoichiometric oxidant (Table 1.8). 145 The cage catalyst was found to be much more selective than the model compound based on the tris(2-benzylaminoethyl)amine ligand 132 (RuCl2@132). Indeed, a complex mixture of aldehyde and carboxylic acid was obtained when catalyst RuCl2@132 was used for the oxidation of primary alcohols, whereas the hemicryptophane complex RuCl2@22 strongly favored the formation of the aldehyde and suppressed the over-oxidation to the carboxylic acid. Moreover, using the electro-deficient 4-nitrobenzyl alcohol substrate, the cage complex was found to be both more efficient and selective than the model one. However, with the 2-dodecanol secondary alcohol, the model catalyst RuCl2@132 displayed a better activity: the higher steric hindrance of the secondary alcohol could prevent its access to the encaged catalytic site, accounting for this experimental result.

Encaged Copper (II) catalysts for cycloalkane oxidation

The direct conversion of largely available alkanes into more valuable products is a subject of great interest. [206][207][208][209] An example with industrial significance concerns the oxidation products of cyclohexane, cyclohexanol and cyclohexanone, since they are used for the production of adipic acid and caprolactame involved in the manufacture of nylon-, and nyρon-6

respectively. [210][211][212][213] The industrial process uses homogeneous cobalt(III)-naphtalenate as catalyst and dioxygen as oxidant at high temperature (150°C) forming cyclohexanone in low yield (4%) to achieve good selectivity (85%). Hence, alternative approaches to transform alkane efficiently and selectively under relatively mild conditions are necessary.

Efficient alkane C-H bond oxidation with H2O2 as a clean oxidant under mild conditions was achieved using the Cu(II)-hemicryptophane complex Cu(II)@15a. 214 As shown in Figure 1.26, when using 1 mol% catalyst for the oxidation of cyclohexane (CyH) by H2O2 in MeCN at r.t., a much higher yield is obtained after two hours with the hemicryptophane catalyst Cu(II)@15a than with the model catalysts Cu(II)@126 or Cu(ClO4(H2O)6, indicating the important role of the cage structure. The time course also shows similar initial reaction rates for Cu(II)@15a and Cu(II)@126, however, the reaction stopped after 1 hour with Cu(II)@126 (14% yield), whereas it still proceeded using Cu(II)@15a until 2-fold higher yield was displayed. These observations suggest that the improved catalytic performance of the hemicryptophane catalyst is attributed to the prevention of active site degradation protected by the cage, rather than the direct increase of reactivity of the catalytic center. Self-oxidation reactions between two molecules of the hemicryptophane catalysts should be avoided because of the location of the active site in the inner cavity. When decreasing the catalyst amount to 0.1 mol%, a TON of about 110-130 was achieved, indicating the high efficiency of the Cu(II)@15a for CyH oxidation. Furthermore, competition experiments between the closely related CyH and cyclooctane or adamantane were performed and show that Cu(II)@15a is able to discriminate more efficiently CyH from cyclooctane or adamantane than its model, emphasizing that the oxidation occurs inside the catalyst cavity similar to enzyme catalysis.

Conclusions and perspectives

In this article, advances in hemicryptophane chemistry have been thoroughly reviewed. A brief history about its development is first given in the introduction part. Then synthetic methods and applications in recognition, molecular machines and supramolecular catalysis are respectively described. When compared to other molecular containers such as cryptophanes, hemicryptophanes appear as a young family of molecular cages, which were only gradually recognized within the last decade. It cannot be neglected that they bear plenty of inborn advantages that have greatly promoted their development.

(1) With respect to the synthesis, their synthetic strategies are quite flexible. The cage-closure could be end up with the reaction at the north or south part, or [1+1] coupling between the north and south moieties. Sometimes, high overall yield could be obtained starting from commercial available materials. In addition, hemicryptophanes are chiral cages because of the inherent chirality of the CTV, and many enantiopure hemicryptophanes have been successfully obtained. Furthermore, water-soluble compounds, capsules constructed by dynamic reversible bonds/interactions, and metal/non-metal functionalized cages represent also important developments in the synthesis of hemicryptophanes.

(2) In terms of their application in recognition, the hemicryptophanes are a versatile class of host molecules that can encapsulate various substrates, including neutral or charged guests, chiral or achiral molecules. The rigid CTV scaffold provides a well-preorganized cavity, of which size and shape can be adjusted by changing the linkages between the CTV and south units. The south moiety is also modulable and can lead to cage molecules with ditopic recognition properties. Thus, elegant heteroditopic recognition of ion pairs and zwitterions has been successfully achieved. Other exciting progresses include the use of water-soluble cages for the recognition of choline in pure water and the exclusive enantioselective complexation of carbohydrates.

(3) Despite the hemicryptophane enters the field of molecular machinery very recently, some appealing results have been achieved. For instance, hemicryptophane oxidovanadium complexes exhibit a reversible change in its propeller motion of the vanatrane structure uniquely controlled by the solvent, establishing an atrane-based molecular chiral switch displaying stimuli-responsive properties. The relatively rigid scaffold of the CTV and the multiple functionalizations of the linkages and south moieties imply that hemicryptophanes frequently display unexpected molecular mechanical properties.

(4) With regard to the catalysis, the endohedral location of highly reactive sites in this special class of hemicryptophane cages has offered a lifelike biomimetic modeling of enzymes.

Benefiting from the easy functionalization of the south part with active species and their guest encapsulation properties, various efficient organo-and organometallic-hemicryptophane catalysts have been prepared. A stimulating step is the Verπade s encaμed hemicryptophane catalysts, whose basicity and reactivity can be controlled by designing the size and shape of the cavity. Another one is that hemicryptophane complexes have proven to be superior catalysts usually exhibiting high TONs, because of their relatively flexible structure compared with other macrocycles. The high stability of the catalysts protected by the cage structure, for instance, observed from the case of CO2 conversion, is also a key feature that can greatly improve their catalytic performance.

Albeit hemicryptophane chemistry has made great progress during the last decade, their potential in synthesis and applications are still waiting for being further explored. (i) More synthetic strategies can be involved for more efficient and greener cage constructions, such as combinatorial dynamic chemistry. 215-217 (ii) The characterization of the guest recognition mainly relies on NMR spectroscopy, which has a high detection limit and slow analysis speed.

More effective signaling groups can be incorporated into the cage allowing their use in living systems, [218][219][220] such as fluorescent bio-imaging or magnetic resonance imaging (MRI). (iii) The exploration of their molecular mechanical properties is relatively poor. Indeed, these cages may be able to build various stimuli-responsive host-guest systems based on self-assembly, similar to what has been studied with rotaxanes, pseudorotaxanes, catenanes or even supramolecular polymers. 96,98,[185][186][187][188][189]221 (iv) Although a few elegant enantiopure hemicryptophanes have been obtained, their application in enantioselective asymmetric catalysis has never been reported, underlining the interest of this challenging task. (v) The major challenge for chemists in supramolecular chemistry is always to run experiments in aqueous medium. 103,104 Especially, the results can be very exciting if the water-soluble hemicryptophanes achieved the above-mentioned outlook of applications in biological media.

(vi) The hemicryptophane cages may also be immobilized on various solid materials, such as zeolite, SiO2 or polymer, via covalent bonds or non-covalent interactions, which will open new research domains. 222 Therefore, we can confidently anticipate that the chemistry of hemicryptophanes will go far beyond from what has been reported herein and will be an increasingly active field further contributing to the progresses of supramolecular chemistry.

Chapter 2. Objectives of This Thesis

As reviewed in Chapter 1, hemicryptophanes are a type of molecular cages that are useful in various applications, such as recognition, molecular machines and supramolecular catalysis. Despite the great progress during the last decade in hemicryptophane chemistry, their potential in synthesis and applications are still waiting for further exploration. Therefore, the major mission of this PhD thesis is to design and synthesize new hemicryptophane cages to either broaden their applications or to make the existing utilization more efficient. The final goal is to enhance the fundamental knowledge of hemicryptophanes in order to realize the targeted-function-directed molecular design, and apply them to other relevant cage hosts used in supramolecular chemistry.

(i) A targeted function: molecular recognition Hemicryptophanes are able to encapsulate zwitterions or ion pairs due to their heteroditopicity (Sections 1.4.2.2 and 1.4.2.3). To this end, additional factors that contribute to their binding performances can be incorporated, for instance the preparation of fluorescent cages, the introducing of additional weak binding interactions, and construction of cages by new building blocks. As enantiopure hemicryptophanes can stereoselectively complex carbohydrates (Section 1.4.2.4), more sophisticated structures bearing multiple types of chirality can be designed and prepared.

(ii) A targeted function: molecular machines Although it is not obvious to design molecular machines by cage molecules and only two cases were reported with hemicryptophanes (Section 1.5), one can expect that the cage is behaving as a type of molecular machines if it is able to switch between bistable states according to molecular motion.

(iii) A targeted function: supramolecular catalysis The vanadium(V)@hemicryptophane complexes were reported as supramolecular catalysts for sulfoxidation (Section 1.6.2.1). The bukyl aromatic binaphthol groups can be introduced into the cages to increase the hydrophobicity of the cavities leading to efficient supramolecular catalyst with high turnover numbers. These supramolecular vanadium(V) catalysts might be further used for catalytic lignin models oxidation. Azaphosphatrane-based hemicryptophanes were developed as organocatalysts for CO2 activitation previously due to the hydrogen-bonding donor ability of + P H group (Section 1.6.1.2). They might be developed as hydrogen-bonding catalysts for the activation of carbonyl groups.

(iv) Beyond hemicryptophanes: cages constructed by self-assemby

The final stage of this thesis is to apply the fundamental knowledge achieved from hemicryptophanes to more general cages constructed by self-assembly. The building blocks for self-assembly will be selected from those moieties of the reported hemicryptophanes, for instance, azaphosphatrane units. It should be noted that Chapters

Part II. Host-Guest Chemistry of Hemicryptophanes

Introduction

The design of artificial molecular receptors is very attractive as they can mimic biological systems such as enzymes. [1][2][3][4][5] A large number of bio-inspired compounds have been designed

and their recognition properties towards guests of biological interest have been studied.

Among the classes of molecular containers, such as calixarenes, resorcinarenes, curcubiturils, or cyclodextrines, 6 cryptophanes and hemicryptophanes both based on cyclotriveratrylene (CTV) unit have recently received a growing interest. 7,8 Cryptophanes are homotopic host compounds and have been shown to efficiently complex small molecules like methane or epoxides, or atoms like xenon. The related hemicryptophanes combining a CTV unit with another C3 symmetrical moiety are ditopic hosts presenting recognition properties towards biological molecules like carbohydrates, ammonium and zwitterionic neurotransmitters. 9 For example, we have recently demonstrated that using 1 H NMR and ITC techniques, a water-soluble hemicryptophane host is able to selectively recognize choline. 9h Despite the high efficiency and good selectivity of hemicryptophanes as receptors, the development of fluorescent hemicryptophanes for molecular recognition studies has never been described to date. However, it should be noted that fluorescence spectroscopy appears as an efficient method for the detection of biological molecules due to its high sensitivity, simple manipulation and facile visualization of bio-processes.

Scheme 3.1

The biological process involved in the generation of choline phosphate (a) and the guests studied in this work (b).

It is known that phosphorylated molecules play a crucial role in many biological processes. 10,11 In particular choline phosphate, generated by the conversion of choline and ATP under the choline kinase along with the production of ADP (Scheme 3.1a), is an important biological phosphorylated compound. It is an essential intermediate in the biosynthetic pathway of phosphatidylcholine, a major component of the membrane of all eukaryotic cells. 12,13 Thus, both effective complexation and optical detection of choline phosphate may have application as inhibitor or indicator in biological environment, allowing therefore a better understanding of this biosynthetic pathway. Moreover, the selective sensing of choline phosphate among choline may be developed as a method to monitor choline kinase activity in real time. Nevertheless, to the best of our knowledge, there is no fluorescent sensor capable of selective recognition of choline phosphate.

Scheme 3.2 Synthesis of the fluorescent Zn(II)@1 complex.

As literatures have revealed that metal-based sensors are particularly relevant for the sensing of phosphorylated molecules, 14 we decided to combine the recognition properties of hemicryptophanes with those of Zn(II) complexes to design a heteroditopic host for the recognition of zwitterionic choline phosphate (Scheme 3.2). It is anticipated that (i) the CTV unit of Zn(II)@1 will bind the ammonium part of choline phosphate, (ii) the Zn(II) center will stabilize the phosphate part and (iii) the naphthalene fluorophores which are used as hydrophobic waρρs connectinμ the Zn II bindinμ moiety to the CTV unit, wiρρ conλer fluorescent properties of the host structure.

Results and discussion

Ligand 1 was first synthesized in four steps, from vanillic alcohol, with 4% overall yield, according to a previous procedure. 15 Then the Zn(II) cation was coordinated by the tris(2-aminoethyl)amine (tren) unit via a reaction between ligand 1 and Zn(ClO4)2 in a CHCl3/CH3OH mixture (1/1, v/v) (Scheme 3.2). The 1 H NMR spectrum of the Zn(II)@1 exhibits broad signals at room temperature (298 K), probably because of the conformational rigidification of the whole structure induced by the metal complexation (Figure 3.1). Variable temperature 1 H NMR experiments in the range of 298-373 K were then performed, and they

show that the signals became increasingly narrow and well defined as the temperature raised.

In particular, at 373 K, a set of expected sharp peaks with a C3v symmetrical conformation was well displayed.

The complexation of choline phosphate 2 by Zn(II)@1 was studied by evaluating the fluorescent changes of a 5 µM solution of Zn(II)@1 upon progressive addition of the guest in DMSO containing 2% water. As shown in Figure 3.2a, addition of choline phosphate 2 resulted in significant fluorescence quenching of the host at 350 nm with 5 equivalents reaching the end of titration. A binding constant of 4.2×10 5 M -1 was obtained according to a 1:1 model confirmed by Job plot (Figure S3.1a). Choline 3 could also give rise to obvious fluorescence quenching of Zn(II)@1 while 90 equiv. of 3 were needed to reach the end of titration (Figure S3.1b and S3.2). In addition, a much smaller binding constant compared with choline phosphate 2 was achieved (7.0×10 3 M -1 ). The fluorescence quenching of the host induced by guest 2 or 3 could be attributed to the promotion of the photo-induced electron transfer (PET) process from the tren nitrogens to the naphthalene fluorophores because of the weakening of the tren-Zn(II) bonds after guest coordination. 14f It should be noted that in spite of a moderate binding between Zn(II)@1 and choline 3, the host could fully distinguish choline phosphate from choline since as shown in Figure 3.2b, 2 equiv. of choline phosphate 2 lead to remarkable fluorescence quenching of the host (75%), while only 9% quenching is generated by 2 equiv. of choline 3. This high selectivity of Zn(II)@1 towards 2 over 3 is very meaningful since the two biologically important compounds simultaneously participate in one crucial process of metabolism (Scheme 3.1a). Moreover, this selectivity was also maintained in a more competitive solvent. In DMSO/H2O (80/20, v/v), the marked fluorescence quenching of the host induced by choline phosphate 2 also occurred and a binding constant of 4.1×10 3 M -1 , larger than that with choline (1.2×10 2 M -1 ), was presented (Figure S3. 3). This result also underlines that the Zn(II)@1 cage is very efficient for the sensing of choline phosphate even in competitive media. We then decided to investigate whether the heteroditopicity of the host played a crucial role in the recognition process or if the complexation was only driven by either phosphate-zinc or cation-interaction. Thus, the bindinμ experiments oλ Zn II @1 with butylphosphate 4 and butyl-trimethylammonium 5, which only contain one kind of the recognized units, were carried out. As shown in Figure 3.2b, when in the presence of 2 equiv.

of whatever 4 or 5, a much smaller fluorescence quenching of Zn(II)@1 was observed (75%, 48% and 3% quenching induced by guests 2, 4 and 5, respectively), indicating that only the guest bearing both the phosphate and ammonium parts allows an efficient fluorescence quenching.

The corresponding titration experiments of host 1 with 4 and 5 were also performed and binding constants of 6.3×10 4 M -1 and 2.2×10 3 M -1 were respectively achieved, which are distinctly smaller than that obtained with the zwitterionic choline phosphate 2 (4.2×10 5 M -1 ), again emphasizing the synergistic effects of both the CTV and Zn(II) moieties in the complexation (Figure S3.4).

Previously, our group also reported two other heteroditopic hemicryptophane hosts for the recognition of zwitterions. 9d,9e Both of the two previous receptors showed the largest binding constant for taurine 6, up to 5.0×10 5 M -1 (Scheme 3.1b). imply that the exchange between the free and complexed choline phosphate appears slow on the NMR time scale at room temperature while it is fast at high temperature (353 K). It is interesting to note that the four new peaks respectively at -0.50, 0.61, 1.32 and 1.79 ppm display almost the same integration ratio (1:1:1:1). Indeed, these four new peaks in the up-field region of the spectrum can be attributed to the four diastereotopic protons of methylene group of the encaged choline phosphate which suffer from a shielding effect by the naphthalene linkers. The complexed choline phosphate is encapsulated in a chiral environment, hence any points of the cavity are chirotopic. 16 As a consequence, methylene groups of choline phosphate also become diastereotopic after inclusion giving rise to the four new peaks. Even though the latter are quite weak and broad, some clear cross-peaks between the four diastereotopic hydrogens were also observed in the COSY NMR spectrum (Figure S3.9). Thus, both the low chemical shifts of these shielded protons and the chiralisation-like behavior 17 of the guest strongly suggest that the choline phosphate is fully encaged inside the molecular cavity of Zn(II)@1. Interestingly, a similar but less extent NMR titration behavior also occurred with choline 3. At room temperature, progressive addition of choline to 31 P NMR titration experiments were also carried out to investigate the interaction mechanism. After addition of Zn(II)@1 to choline phosphate 2 in DMSO-d6/D2O (80/20, v/v), the signal composed initially of only one sharp peak splits into two peaks with opposite direction of chemical shifts: one narrow down-field shifted peak and a broad up-field shifted signal (Figure S3.12). The former strongly favored after addition of 0.5 equiv. of host was attributed to the encapsulated choline phosphate, whereas the latter whose intensity decreased was assigned to the free guest. These results support the encapsulation event between the host and guest and the slow complexation process on the NMR time scale at room temperature, which are in good agreement with those obtained from 1 H NMR titrations.

Finally, we examined the interactions involved in the recognition process by Density Functional Theory (DFT) calculations. In the fully optimized geometry of the complex, choline phosphate is encapsulated inside the Zn(II)@1 cavity (Figure 3.4). 18 The phosphate unit of the guest is linked to the zinc atom through a coordination bond (Zn … O distance: 1.9 Å). The distances between the aromatic rings of both the CTV unit and the naphthalene linkers of the host, and the ammonium moiety of the guest suggest that they interact through several CH … interactions (several distances between 2.8 and 3.3 Å). Thus, both the CTV and Zn(II) units contribute to the efficient and selective binding of choline phosphate, emphasizing the heteroditopic character of the host. Interestingly, C-H … interactions also occur between the methylene groups of the guest and the naphthalene linkers (several distances between 2.8 and 3.3 Å), accounting for the high-field shifts of these protons observed in 1 H NMR titrations, and also highlighting their diastereotopic behavior.

Conclusion

We have described a hemicryptophane cage combining a CTV unit and a Zn(II) metal center holding fluorescent properties. This fluorescent hemicryptophane has been developed as the first fluorescent sensor for zwitterionic choline phosphate in competitive media. The heteroditopic character of the host towards the guest was evidenced since the guest bearing both the ammonium and phosphate parts can give rise to the most significant fluorescence quenching and largest binding constant. Moreover, it was found that the exchange between the free and complexed guest is slow on the NMR time scale at room temperature while it is fast at higher temperature (353 K). NMR experiments also indicate the formation of an inclusion complex between the cage and the guest, and a chiralisation-like behavior of the achiral choline phosphate occurs inside the cavity. The exact binding mode has been examined by DFT calculations. Studies of stereoselective recognition properties of chiral zwitterions using enantiopure fluorescent metal-based hemicryptophanes are in progress.

Experimental section

Materials and instrumentation

All solvents used were of commercial grade. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance spectrometer operating at 500.10 MHz and 125.76 MHz for 1 H NMR and 13 C NMR spectra, respectively. 1 H NMR chemical shifts (δ) are reported in ppm. Fluorescence spectra were carried out with a Horiba-Jobin Yvon spectrofluorimeter. Mass spectra were recorded by the Centre de Spectrométrie de Masse, Institute of Chemistry, Lyon. DFT calculations were performed by Vincent Robert.

Synthesis and characterization

Hemicryptophane 1 was synthesized according to our previously reported procedure. 15a Zn(II)@1 complex was prepared as follow: to a solution of 1 (90.3 mg, 0.082 mmol) in 6 mL CHCl3, 20 µL triethylamine was added under argon followed by addition of the solution of Zn(ClO4)2(H2O)6 (30.5 mg, 0.082 mmol, 1.0 equivalent) in 6 mL CH3OH. After stirring the reaction mixture at room temperature for 2 hours, a large amount of precipitate appeared.

The precipitate was collected, washed thoroughly with Et2O and dried under vacuum to give the final product as a white solid (70.8 mg, yield 63%). The ligand 1 is soluble in most of the common solvents, for example CH2Cl2, CHCl3, acetone and DMSO. However, the Zn(II)@1 complex is only soluble in DMSO, and moderate soluble in acetone. (m, 12H). 13 C NMR (125.7 MHz, 298 K, CDCl3) δ 156. 8, 148.7, 146.5, 133.6, 133.2, 131.9, 129.3, 128.9, 127.2, 126.9, 126.5, 119.4, 116.7, 113.7, 107.3, 67.6, 67.5, 56.0, 52.9, 47.7, 36.7 (d, 3H, J = 13.5 Hz); 4.28 (bs, 12H); 3.88 (bs, 6H); 3.70 (s, 9H); 3.50 (d, 3H, J = 13.5 Hz); 2.97 (bs, 12H). 13 C NMR (125.7 MHz, 298 K, DMSO-d6) δ 156. 6, 148.4, 146.5, 133.9, 133.0, 132.0, 129.4, 128.4, 127.4, 119.3, 116.4, 107.4, 66.9, 66.3, 57.2, 54.6, 51.0, 49.4, 35. In The continuous variation method was used for determining the binding stoichiometry. 19 In this method, solutions of the host and guest at the same concentration (5µM) were prepared in DMSO containing 2% H2O. Then the two solutions were mixed in different proportions maintaining a total volume of 3 mL and a total concentration of 5 M. After incubating the mixture for 30 s, the spectra of the solutions for different compositions were recorded.

Job plot

Fluorescence spectroscopic titration

2 mL Zn(II)@1 complex solution (5µM) was taken into the cuvette, and then certain equivalents of a concentrated guest solution (0.5 mM or 5 mM) were added stepwise with a syringe. As a very small volume of guest solution was added, the final amount of the solution was almost unchanged (2 mL). The mixed solution was incubated for 30 s and then irradiated at 300 nm. The corresponding emission values at 350 nm during titration were then recorded.

1 H NMR spectroscopic titration

Computational method

Ab initio evaluations were performed using the Gaussian 03 package17 within a restricted DFT framework. 18 In order to access geometrical information upon the host-guest species, full geometry optimizations were performed using DFT calculations. A combination of BP86

function and an all electron 6-31G* basis set including polarization functions has proven to be very satisfactory for similar issues. [4] We checked using the hybrid B3LYP function that our results do not suffer from the arbitrariness of the exchange correlation function.

Abstract

The recognition properties of heteroditopic hemicryptophane hosts towards anions, cations, and neutral pairs, combining both cation and anion interaction sites, were investigated to probe the complexity of interfering weak intermolecular interactions. It is suggested from NMR experiments, and supported by CASSCF/CASPT2 calculations, that the binding constants of anions can be modulated by a factor of up to 100 by varying the fluorination sites on the electron-poor aromatic rings. Interestingly, this subtle chemical modification can also reverse the sign of cooperativity in ion-pair recognition. Wavefunction calculations highlight how short-and long-range interactions interfere in this recognition process, suggesting that a disruption of anion interactions can occur in the presence of a cobound cation. Such molecules can be viewed as prototypes for examining complex processes controlled by the competition of weak interactions.

Introduction

The Complex systems arouse great interest in physics, biology, and chemistry. 1 Nonlinearity of equations or responses to stimuli and inputs is one of the origins of complexity. In chemistry, heteroditopic molecular receptors that can simultaneously bind cationic and anionic guests appear as particularly interesting platforms to examine and ultimately control such complex processes; the response of a given host towards different guest molecules can differ from the linear combinations of the separate unit responses. 2 12 Such ion-pair receptors combine two different binding sites for the cation and the anion in a single molecular cavity, and one can anticipate a modulation of the cooperativity through chemical engineering. However, a delicate balance between long-and short-distance interactions must be established to achieve this goal. If the host has been carefully designed, a positive cooperative effect can be observed; an additional or enhanced long-range electrostatic interaction between ions is likely to improve affinity. Conversely, mismatched distances between the cationic and anionic binding sites can lead to negative cooperativity, possibly disrupting the short-range interactions. Among these noncovalent interactions, cation interactions have been extensively solicited. 13,14 They allow for the recognition of cationic guests through attractive interactions with the electron-rich aromatic rings of the host.

Anion interactions, which involve electron deficient aromatic rings, have received little attention in this context. 15 20 The combination of cation and anion interactions in the recognition of ion pairs by using a specifically designed molecular cavity would provide a playground to decipher the interfering weak interactions that control the sign of cooperativity in recognition processes. Hemicryptophanes appear to be a relevant class of host molecules for addressing this issue. 21 These molecular receptors are able to complex various guest compounds such as zwitterions and ion pairs, taking advantage of the ditopic character of the host cavity. 22 30 For instance, hemicryptophane 1 (Figure 4.1) was found to bind simultaneously to anionic and cationic species, exhibiting a strong positive cooperative effect. 30 To extend the series, starting with electron-rich aromatic rings as in compound 1, we decided to synthesize and investigate the recognition properties of two new hemicryptophane cages, 2 and 3, bearing fluorinated aromatic rings close to the anionic binding site. This should allow 1) an increase in the anion attractive interactions, thus reinforcing the binding ability of anions, and 2) the assessment of the consequences on cooperativity. The recognition properties were found to largely depend on the position of the fluorine atoms in the aromatic linkers, that is, anion binding constants were significantly increased and decreased in 2 and 3, respectively. Quantum chemistry [density functional theory (DFT) and complete active space self-consistent field (CASSCF and subsequent CASPT2)] calculations were performed to grasp the weak interactions involved in that recognition process and to rationalize the experimental results. For ion-pairs recognition, the cooperativity switched from positive to negative, that is, host 1 displayed high positive cooperativity, whereas that for host 2 was moderate, and a strong negative cooperative effect was observed with host 3. Thus, depending on the nature of the guest and the location of the fluorine atoms, the cooperativity can be modulated, providing a unique platform to study the interfering short-and long-range interactions.

Results and discussion

Hemicryptophanes 2 and 3 with respective arbitrariρy desiμned down and up λρuorine atoms in the aromatic linkers, respectively (Figure 4.1), were synthesized following a procedure similar to that described for hemicryptophane 1 (Scheme 4.1). 31 The reaction of vanillyl alcohol with 1,2-dibromoethane followed by protection with ). 32 The binding constants Ka are reported in Figure 4.2 (see also Table S4.1 in the Experimental Section). The three hosts display a similar trend; the spherical halide anions are bound with the following affinity F -> Cl -> Br -> I -, as expected from the hydrogen-bond-accepting ability of these guests. This is also consistent with the fact that H2PO4 -is better coordinated than HSO4 -. Compared to the less basic H2PO4 - anion, the most basic anion AcO -shows a slightly more complicated behavior, as expected from the hydrogenbond-accepting ability, with host 3 and the acetate anion displaying a slightly higher binding constant than H2PO4 -. However, a weaker affinity is observed with S4.1), can be observed. The crucial role played by the location of the fluorine atoms on the binding affinity of the anions prompted us to carefully investigate the role of the anion interactions in the recognition process. Indeed, we hypothesized that the free energy of binding corresponds to the sum of three different types of interactions: 1) the steric repulsion between the guest and the linkers, 2) hydrogen bonding between the anions and the amide groups, and 3) the anion interactions between the aromatic rings of the linkers and the anions. We considered that the steric hindrance related to the introduction of the fluorine atom can be neglected, because of the similar van der Waals radius of hydrogen and fluorine atoms. Thus, this first contribution is supposed to remain constant throughout the series, (i.e. for a given anion), the other interactions (hydrogen bonding and anion shouρd account λor the observed differences in the binding affinities. Thus, a deeper inspection of these interactions was undertaken by means of combined DFT and multireference wavefunction-based calculations.

Starting from the DFT-optimized structures, the chlorine anion was displaced along the C3 axis of the host by using simplified structures as the receptor. In this respect, CASSCF and subsequent CASPT2 calculations were performed to capture dispersion-origin and H-bond interactions (see the Experimental Section). Irrespective of the positions of the fluorine atoms, the C3 axis is maintained, which is a common feature with the naked host. Z stands for the guest position along the C3 axis of the host and ZDFT corresponds to the position in the DFT-optimized geometry. Starting from these geometries, the chlorine anion was displaced along the C3 axis and the CAS [8,8]PT2 energy was calculated, setting a reference of Z = 10 Å.

The CAS [8,8] First, the minimum position is relatively insensitive (Z ZDFT = 0.04 Å) to the presence and positions of the fluorine atoms. This is to be contrasted with the interaction energies. At this stage, let us recall that our calculations recover only the gasphase enthalpic contribution of the Gibbs energy. For hosts 1 and 3, the calculations are in good agreement with the experimental results and suggest the existence of a much stronger combination of anion and hydrogen-bond interactions with hemicryptophane 3 than with host 1. Thus, our calculations reveal that the fluorinated aromatic linker should interact much more strongly with the anion than the naπed ρinπer, which is fully consistent with the higher binding constant observed with host 3. Similar calculations indicate that anion interactions are stronger with host 3 than with host 2, which is consistent with the experimental results.

However, the experimental results unambiguously demonstrated that host 2 displays the worst binding properties towards anions of the three hosts. Therefore, our calculations fail to fully rationalize the low binding constants observed in that case. Nevertheless, all of the calculations were performed in the gas phase, and it has been shown that the energy of the anion interaction strongly differs in gas or solid phase from that in solution. A recent publication from Ballester et al. estimates their values as approximately 4 kJ mol -1 in solution, whereas values up to 20 kJ mol -1 are proposed in the solid or gas phases. 16 Thus, solvation effects should be taken into account in the study of the controversial anion interaction.

Besides, the Gibbs energy in the complexation process is more sensitive to the solvent reorganization, a contribution that has not been evaluated. 33 There is no doubt that upon anion interactions and H-bond formation, entropic changes are expected to compete with the enthalpic contribution arising from these weak interactions.

According to our previous study with host 1, hosts 2 and 3 should be able to complex ion pairs; ammonium and anions are expected to bind respectiveρy to the north CTV, cycρotriveratryρene and south triamide parts oλ hemicryptophanes 2 and 3. 30 We first investigated the binding properties of 2 and 3 towards cationic guests, without any anion trapped inside the cavity. The tetramethylammonium picrate salt M4NPic was chosen because 1) the picrate anion cannot bind to the NH groups of host 1-3, and 2) compared to other tetraalkyl ammonium, tetramethyl ammonium exhibits the highest binding constant with host 1 (380 M -1 ). 30 In aρρ cases, the Job s pρot evidences the formation of 1:1 host guest complexes. Upon addition of hosts 2 or 3, the protons of the tetramethyl ammonium display upfield shifts, suggesting the encapsulation of the M4N + cation in the CTV unit. Modeling of the titration curves with WinEQNMR2 afforded binding constants of 167±11 and 1600±120

M -1 with hosts 2 and 3, respectively. This trend is similar to that obtained for the recognition of anion.

As hosts 2 and 3 are able to complex anions and cations at the two ends of their cavity, we decided to examine their ability to complex ion pairs, and the nature (positive or negative) of the resulting cooperative effect. Owing to the low solubility of the Me4N + halide salts, we first prepared [2•Me4N + ] or [3•Me4N + ] complexes from the soluble Me4NPic guest, and then n-Bu4NX was added as the source of the halide anion guest. Picrate and tetra-n-butylammonium ions do not enter the hemicryptophane cavity (vide infra). Following this procedure, we obtained the apparent binding constants Ka λor the complexation of the anions in the presence of a co-bound counter ion, Me4N + , which allowed us to estimate a cooperativity effect (Figure 4.4 and Table S4.2). From the additional electrostatic interaction between the anion and the cation already trapped inside the cavity, one anticipates a positive cooperative effect. With host 2, a moderate positive cooperative effect is observed, with a cooperativity λactor K a/Ka ρower than that obtained with host 1. Indeed, host 2 exhibits lower affinities for cations than host 1. Consequently, fewer cation@2 species are present in solution when the anion is added, giving a lower positive cooperative effect. Surprisingly, a lower binding constant with host 3 is observed when one equivalent of the cation is already encaged; the binding constant of 3 for Cl -decreases from 1440 to 640 M -1 . This observation is rather puzzling, as host 3 exhibits a much higher affinity for cations and anions when the recognition experiments are run independently. This unexpected observation is probably the manifestation of a destructive interference between two recognition processes. In the absence of a host, the Me4N + •••Cl -distance was estimated by using DFT calculations to be 3.59 Å. To estimate the impact of the presence of a cation species, the energy changes at the optimal Z ZDFT value (ca. 0.4 Å, see Figure 4.3) were quantified by placing a positive point charge on the C3 axis at Z ZDFT=3.59 Å. We felt that there was no need to further explore the anion cation interaction, considering the aforementioned simplification of hosts 1 and 3. As above, CAS [8,8] was converged and the CASPT2 energies were evaluated. From these complementary calculations, the recognition ability for the chlorine anion is more affected with host 3 by approximately 1.1 kJ mol -1 than with host 1. Host 3 suffers from a partial disruption of the anion interactions as soon as the chlorine atom gets involved in an electrostatic interaction with a cation, dragging the electronic density away λrom the cloud.

This study not only confirms the tremendous importance of such weak interactions, but also suggests the destructive nature of interfering mechanisms. Further experimental evidence for this intriguing observation supported by theoretical calculations was finally given by substituting chlorine for bromine. For host 3, a stronger negative cooperative effect was observed (Figure 4.4b); the binding constant decreased from 620 to 5 M -1 . The enhanced polarizability results in stronger anion interactions, which, in turn, are expected to be affected to a greater extent by the presence of a cation species. These observations underline the complexity of cooperative effects in polytopic receptors.

Depending on the balance of the main interactions (cation anion, cation , anion , and hydrogen bonding) involved in the recognition process, the optimal position of the cation and anion can change slightly, inducing a dramatic switch in the nature of the cooperativity.

Conclusion

In conclusion, we have described the synthesis of two new hemicryptophane hosts, 2 and 3, bearing fluorinated aromatic linkers. Their complexation properties were investigated and compared to host 1, which lacked fluorine atoms in the aromatic linkers. The binding affinity toward anions was found to strongly rely on the location of the fluorine atoms on the linker, highlighting the difficulty in anticipating and understanding the complex role of anion and H-bond interactions in recognition processes. Furthermore, the nature of the cooperativity involved in the recognition of ion pairs can be modulated from positive to negative by chemical engineering. This switch in the cooperativity emphasizes the complexity of such polytopic receptors in which interfering interactions occur. We believe that the current

Experimental section

Materials and instrumentation

All reactions were carried out under argon by means of an inert gas/vacuum double manifold and standard Schlenk techniques. Pyridine, DMF, chloroform and methanol were dried prior to use over molecular sieves. Dichloromethane was dried and degassed on a solvent station by passage through an activated alumina column followed by an argon flush.

1 H and 13 C spectra were recorded at 500.1 MHz and 125.7 MHz respectively, and are reported relative to the residual protonated solvent signal ( 1 H, 13 C). Mass spectra were recorded by the Centre de Spectrométrie de Masse, Institute of Chemistry, Lyon. Compound 5 was prepared according to the published procedure. 31 DFT calculations were performed by Vincent Robert.

Synthesis and characterization

Synthesis of compound 2. Compound 8a (2.51 g, 1.78 mmol) was dissolved in formic acid (2.5 L) and the reaction mixture was stirred at room temperature for one week. The solvent was removed under reduced pressure and the residue was partitioned between chloroform (100 mL) and 10% aq. K2CO3 solution. The aqueous phase was extracted 2 times with chloroform (100 mL) and the combined organic phases were dried over Na2SO4, filtered and evaporated to give a brown oil. This procedure was carried out a second time with 2.89 g (2.05 mmol) compound 8a. Both crude compounds were purified by column chromatography over silica gel (CHCl3:MeOH, 150:2→150:10, v:v) to give 2 as a beige solid (1.20 g, 28% yield).

1 H NMR (CDCl3, 298K, 500.1 MHZ): δ 7.13 (t, 3H, J = 5.9 Hz); 6.96 (s, 3H); 6.82 (s, 3H); 6.15 (d, 6H, J = 9.2 Hz); 4.76 (d, 3H, J = 13.8 Hz); 4.40-4.42 (m, 6H); 4.20-4.26 (m, 12H); 3.82 (s, 9H); 3.55 (d, 3H, J = 13.8 Hz); 3.17 (s, 6H). 13 C NMR (CDCl3, 298K, 125.7 MHZ): δ 169. 9, 161.6, 159.4, 148.6, 146.2, 133.3, 131.7, 117.1, 113.6, 106.0, 98.7, 68.4, 68.2, 60.7, 55.9, 36.4, 30.8 Synthesis of compound 3. The procedure is identical to the one followed for compound 2. The reaction was carried out with 2. 8, 155.7, 148.9, 146.4, 133.9, 133.6, 133.4, 131.8, 117.5, 114.0, 110.6, 72.0, 68.6, 61.3, 56.0, 42.0, 36.4 Synthesis of compound 6a. 2,6-difluoro-4-methoxybenzylamine (4. 75 g, 27 mmol) and nitrilotriacetic acid (1,67 g, 8.8 mmol) were added to pyridine (60 mL) and then heated at 50°C for 20 minutes. Triphenylphosphite (8.5 mL, 32 mmol) was added dropwise and the solution is then stirred at 100°C for 17 h. Volatiles were evaporated. The residue was taken up with chloroform (75 mL) and washed with 10% aq. NaHCO3 and 75 mL distilled water. The organic phase was dried over Na2SO4, filtered and evaporated. The crude compound was dissolved with acetone and precipitated with pentane leading to a pure white solid (5.93g, 99% yield). 1 H NMR (CDCl3, 298K, 500.1 MHZ): δ 7.17 Synthesis of compound 6b. The procedure is identical to the one followed for the synthesis of 6a with 3,5-difluoro-4-methoxybenzylamine (5.0 g, 29 mmol), nitrilotriacetic acid (1,76 g, 9.0 mmol) and triphenylphosphite (8.32 mL) and gave a white solid (4.48 g, 75% yield). 1 H NMR (CDCl3, 298K, 500.1 MHZ): δ 7.53 (bs, 3H); 6.82 (d, 6H, J = 8.5 Hz); 4.34 (d, 6H, J = 5.9 Hz); 3.99 (s, 9H); 3.42 (s, 6H). 13 C NMR (CDCl3, 298K, 125.7 MHZ): δ 170. 7, 155.6, 135.7, 133.3, 111.3, 61.8, 60.6, 42.3 3328, 3216, 3060, 2948, 2842, 1656, 1520, 1442, 1246, 1039 cm -1 .

Synthesis of compound 8a. Under argon, compound 6a (5.87g, 8.94 mmol) was partially dissolved in dry dichloromethane (100 mL) and the solution was cooled to -78°C. A solution of 1M boron tribromide in dichloromethane (53 mL, 53 mmol) was added dropwise for 1 h and the solution was allowed to slowly warm up at room temperature over the night.

Methanol was then added until the gas emission stopped, and the pH was adjusted to 8 with 10% aqueous NaHCO3. The aqueous phase was then extracted with ethyl acetate (200 mL) for 3 times. The combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum to give a beige solid 7a which was then used without purification (5.21 g, 95% yield). Compound 7a was placed with compound 5 (5.19 g, 8.41 mmol), cesium carbonate (12.2 g, 37.3 mmol) 9, 162.0, 159.7, 149.8, 147.4, 132.2, 120.5, 114.3, 112.1, 105.9, 98.9, 98.6, 97.7, 68.7, 67.7, 67.3, 62.3, 59.8, 55.9, 30.6, 25.5, 19.5. ESI-HRMS m/z: calcd for C72H85F6N4O18 [M+H] + 1407.5758, found 1407.5729. IR (KBr) ῡ = 3309, 3066, 2940, 2871, 1639, 1591, 1510, 1265, 1151, 1072, 1036 cm -1 .

Synthesis of compound 8b. The procedure for the demethylation of compound 6b was the same as those used for compound 6a with 3.78 g (5.76 mmol) starting material and 33 mL of a solution of BBr3 in CH2Cl2 and gave 2.43 g beige compound 7b (69% yield). This compound was then reacted with compound 5 (5.85 g, 17 mmol) and Cs2CO3 (5. 66 g, 17 mmol) with the same procedure followed as those for compound 7a leading to the formation of compound 8b (3.04 g, 56% yield). 1 H NMR (CDCl3, 298K, 500.1 MHZ): δ 7.62 (bs, 3H); 6.91-6.93 (m, 9H); 6.82 8, 155.7, 149.9, 147.6, 134.5, 134.0, 132.1, 120.6, 114.6, 112.3, 111.3, 111.2, 97.8, 72.6, 68.8, 68.5, 62.4, 60.3, 56.0, 30.7, 25.5, 19.6

1 H NMR titration

Job plot

The continuous variation method was used for determining the binding stoichiometry. 34 In this method, solutions of the host and guest at the same concentration were prepared in CDCl3. Then the two solutions were mixed in different proportions maintaining a constant volume and concentration. After incubating the mixture for 30 s, the spectra of the solutions for different compositions were recorded. Quantum chemistry calculations were performed to explore the origin of the binding association differences observed in the hemicryptophanes recognition. First, density functional theory (DFT) was used to generate optimal geometries of the 3 hosts and the encapsulated chlorine guest. 35 Full geometry optimizations were performed using a combination of B3LYP functional and 6-31+G** basis set.

Computational details

Ion-interactions result from charge density fluctuations (i.e. dispersion interactions) within a given system in the presence of charges. Besides, one would like to seize the importance of charge reorganization in the N-H bond involved in possible H-bond formation with the chlorine anion. Multi-reference calculations are particularly attractive since one can effectively account for these physical phenomena. Thus, complete active space self-consistent field (CASSCF) calculations were then performed including 8 electrons in 8 molecular orbitals (MOs) on simplified structures of hosts (CAS [8,8]). The active space was converged onto the 6

MOs of the benzyl ring and the σ σ* pair of the NH bond. We checked that the mostly chlorine-localized MOs remain almost doubly occupied and need not to be included in the active space. Subsequent second-order perturbation theory treatment (CASPT2) was carried out to account for the so-called dynamical correlation effects. Using this strategy, one can accurately take into account the charge density fluctuations accounting for the H-bond and anion-interactions. Assuming a foxed geometry of the host, the energetics was followed as a function of the chlorine ion position Z along the C3 axis. Since our purpose was to concentrate the numerical effort on the -* charge fluctuations and the hydrogen bond, extended basis set was used for the aromatic ring, namely ANO-RCC 4s3p2d1f for C and N, 2s1p for H, while the other atoms were depicted using ANO-RCC double-zeta+polarization (DZP) basis sets. This combination of basis sets has been recently used successfully in various weak interactions inspections (VR2, VR3). Finally, the Cl anion was depicted with a 4s3p1d ANO-RCC basis set. All our calculations were performed using the MOLCAS 7.2 suite of program (VR 4).

Abstract

The synthesis, characterization and chiroptical properties of a new class of hemicryptophane cages combining both a bowl shaped cyclotriveratrylene (CTV) unit and a tris(2-pyridylmethyl)amine (TPA) moiety are reported. Interestingly, changing the linkers between these two units allows for the modification of the size and shape of the cavity. The synthesis is straightforward and efficient, providing gram-scale of cage compounds. The racemic mixture of each hemicryptophane can be readily resolved by chiral HPLC, giving an easy access to the enantiopure molecular cages of which absolute configurations have been assigned by ECD spectroscopy. These new hemicryptophanes represent available chemical platforms ready to use for various purposes due to the versatile metal complexation properties and applications of the TPA unit.

Introduction

Molecular cages have attracted considerable attention in the last two decades, leading to great applications in recognition, catalysis, separation and reactive species stabilization. 1 In particular, biomimetic chiral cages arouse a growing interest because of the important role of chirality in nature. 2 One prominent example is substrate binding and transformation by enzyme, displaying high chemoselectivity, regioselectivity and stereospecificity. 3 Among the chiral cages, hemicryptophanes, which combine a cyclotriveratrylene (CTV) unit with another C3-symmetric moiety, exhibit remarkable properties in molecular recognition and supramolecular catalysis. 1a The promising applications of hemicryptophanes benefit from the rigid bowl shape of the inherently chiral CTV unit as well as the feature of variability and easy functionalization of the other C3-symetrical moiety.

To construct novel hemicryptophane scaffolds, typical tripodal building blocks, such as tris(2-aminoethyl)-amine (tren) 4 and trialkanolamine units, 5 have been introduced as the other moiety connected with the CTV unit. The usefulness and easy availability should be considered when choosing this C3-symmetric group. In this regard, tris(2-pyridylmethyl)amine (TPA) unit appears promising. Indeed, TPA is a very useful ligand in coordination chemistry, which can coordinate with various metals, such as Fe, 6 Cu, 7 Zn, 8 Co, 9 Mn, 10 Ru, 11 Rh, 12 Ni, 13 and Ln, 14 and the resulting complexes have been extensively used in recognition, 15 catalysis, 6-7,10b,11b,12 chiroptical molecular switches, 16 and enantiomeric excess (ee) determination. 8a,8b,17 For instance, complex [Fe-(TPA)(MeCN)2](ClO4)2 combined with photocatalyst riboflavin tetraacetate was used as a readily accessible and efficient catalyst system for the visible-light-driven aerobic C-H bond oxidation of alkyl benzene to ketones and carboxylic acids. 6a The copper complexes of TPA derivatives have widely catalyzed the reactions of atom transfer radical cyclization (ATRC), 7a atom transfer radical addition (ATRA), 7b and atom transfer radical polymerization (ATRP). 7c Moreover, Anslyn and Giulia et al. adopted Zn(II) or Cu(II) complexes of TPA derivatives for rapid determination of ee of alcohols, carboxylic acids, amines, and amino acids. 8a,8b,17 This application originates from the propeller-like arrangement of TPA ligands around the metal center. The handedness of this helicity of the TPA analogues can also be controlled by the presence of a stereogenic center in the ligand backbone which realizes redox-triggered chiroptical switches, as reported by the group of Canary. 16 In line with the versatile nature of TPA complexes and their potential applications, we hereby report on the design and synthesis of a class of TPA-based hemicryptophanes (Figure 5.1). The obtained racemic mixture can also be readily resolved by chiral HPLC to give the enantiopure form in a relatively large-scale. Electronic circular dichroism (ECD) spectroscopy was used to determine the absolute configuration of each hemicryptophane enantiomer. To the best of our knowledge, the synthesis of enantiopure TPA-based cage molecules is unprecedented and these enantiopure hemicryptophanes are promising chemical platforms capable of complexation of various metals for different purposes and applications.

Results and discussion

The structures of the enantiomeric hemicryptophanes M-1 and P-1 (Figure 5.1) present the following features: (i) Firstly, the bowl-shaped CTV unit allows the formation of a well-defined chiral cavity; (ii) the naphthalene fluorophores, used as hydrophobic walls connecting the TPA and CTV units, confer fluorescence properties to the host; (iii) as mentioned above, the TPA moiety is able to coordinate with various metals giving rise to chemical platforms for further applications. Two routes can be followed to obtain hemicryptophane compounds: either a [1+1] coupling reaction between a CTV moiety and another C3 symmetrical unit to afford the expected cage, or a triple macrocylization reaction to build the CTV core in the last step of the synthesis. 1a We anticipated that the protonation of the TPA unit in formic acid could lead to some preorganization of the precursor for the cyclization, thus we decided to adopt the second strategy. 1a,1b,5a As the TPA constitutes the lower part of this precursor, the first aim was to prepare the TPA-trichloride 8 (Scheme 5.1). 18 Starting from 2,6-pyridinedicarboxylic acid 2, 2,6-pyridinedicarboxylate In order to achieve the hemicryptophane precursor 13, the phenol 12 was synthesized according to the pathway described in Scheme 5.2. Firstly, 2,6-dihydroxynaphthalene was mono-protected with an allyl group via its reaction with 1.0 equiv. of allyl bromide in acetone in the presence of K2CO3 to give allyloxyphenol 9 in 29% yield. Then, phenol 9 reacted with compound 10, obtained in 3 steps as described previously, 5a in the presence of Cs2CO3 in DMF at 80 o C to give 11 in 78% yield. Compound 11 was subsequently deprotected using Pd(II) complex in a H2O/THF mixture at 80 o C to generate the phenol 12 in 88% Yield.

Scheme 5.2 Synthesis of the phenol derivative 12.

With 8 and 12 in hand, hemicryptophane precursor 13 was prepared in one step (98% yield) by heating the two compounds in DMF at 90 o C for 3 days in the presence of Cs2CO3 as a base (Scheme 5.3). The intramolecular cyclization of 13 performed in formic acid led to low yields because of purification issues: several side products were very difficult to separate from the cage compounds. Finally, the use of stoichiometric amounts of Lewis acid Sc(OTf)3 in CH3CN at 65 o C provided rac-hemicryptophane (±)-1 with a yield of 49%.

Scheme 5.3 Synthesis of the racemic mixture of hemicryptophane (±)-1.

Given the modular feature of this synthetic pathway, we decided to change the naphtyl linkers to phenyl ones in order to prepare the hemicryptophane analogue (±)-16 presenting a smaller cavity (Scheme 5.4). Compound 14 was first obtained following the known procedure. 5a After achieving the hemicryptophane precursor 15 from 14, we observed that the macrocyclization of 15 in formic acid gave the racemic mixture of 16 in an extremely high yield (90%). In particular, hemicryptophane 16 can be isolated by simple precipitation in CH2Cl2/Et2O without the need of column chromatography purification. The preorganization of the precursor of cyclization in formic acid can account for the remarkable yield obtained.

Moreover, as the yield of each previous step is relatively high, gram-scale synthesis of (±)-16 was achieved. This constitute an important step for the future development of this class of host compounds as sensors or catalysts considering the common limitation related to the difficulty of accessing cage compounds on a large scale. 1a Scheme 5.4 Synthesis of the racemic mixture of hemicryptophane (±)-16.

The 1 H NMR spectra of (±)-1 and (±)-16 indicate that the molecules are, on average, of C3 symmetry in solution (Figure 5.2). They display the usual features of the structure of the CTV unit, i.e. two singlets for the aromatic protons, one singlet for the OCH3 groups, and the characteristic AB system for the ArCH2 bridges. 1a,1b The protons on aromatic TPA and linkers, and the multiplets for the OCH2 linkers were carefully assigned by 2D NMR (see 5.5.3). and their protons assignment. ▼ = CHDCl2; ▲ = Et2O.

Conclusion

In summary, we have described the synthesis of two hemicryptophanes (1 and 16) belonging to a new class of TPA-based hemicryptophane cages. As TPA unit can complex various metals, these hemicryptophanes are chemical platforms available for various purposes and applications. Moreover, the naphthalene linkers in hemicryptophane 1 confer fluorescence properties to the host structure. Despite the 14 steps involved in the synthesis of each cage, all the reactions are quite straightforward with relatively high yields. In particular, benefiting from a remarkable 90% yield of a triple macrocyclization reaction, gram-scale synthesis of hemicryptophane 16 was achieved. The racemate of each hemicryptophane can be readily resolved by chiral HPLC to give the enantiopure cages of which absolute configurations have been assigned by ECD spectroscopy. Currently, the preparation of metal complexes for these new cages, such as Zn(II), Cu(I) and Fe(II), and their applications in molecular recognition and supramolecular catalysis are being investigated and will be reported in due course.

Experimental section

Materials and instrumentation

All reactions were carried out under argon by means of an inert gas/vacuum double manifold and standard Schlenk techniques. Dichloromethane was dried and degassed on a solvent station by passage through an activated alumina column followed by argon flush.

Other solvents were dried prior to use over molecular sieves.

Synthesis, resolution and characterization

Synthesis of 8 and 9. Compound 8 was prepared starting from 2,6-pyridinedicarboxylic acid 2 according to the reported procedures. 18,20 Compound 9 was synthesized according to the published procedure. 21

Synthesis of 11.

A solution of 9 (100 mg, 0.500 mmol), 10 (172 mg, 0.500 mmol), and Cs2CO3 (244 mg, 0.750 mmol) in DMF (4 mL) was stirred for 2 days at 80 o C under argon. Then AcOEt (30 mL) and 10% aqueous NaOH (30 mL) were added. The organic layer was separated, and the aqueous phase was extracted with AcOEt (2 × 30 mL). The combined organic layers were washed with 10% aqueous NaOH (2 × 30 mL) and dried over Na2SO4. After filtration, the organic solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel with a 400 : 3 mixture of CH2Cl2 : MeOH as eluent to give compound 11 as a light yellow solid (180 mg, 0.39 mmol, 78% yield). 1 H NMR (CDCl3, 298K, 500.1 MHz): δ 7.65 (dd, J = 8.9, 1.9 Hz, 2H); 7.21-7.14 (m, 4H); 7.00-6.93 (m, 3H); 6. 19-6.11 155.1 (9), 149.8, 147.7, 133.4, 131.9, 129.9, 129.8, 128.3, 128.2, 120.6, 119.3(1), 119.2(8), 117.7, 114.2, 112.1, 107.4, 107.3, 97.6, 69.0, 68.8, 68.0, 66.6, 62.4, 56.0, 30.7, 25.5, 19.5 ppm. ESI-HRMS m/z: found 487.2077, calcd for C28H32NaO6 [11+Na] + 487.2091.

Synthesis of 12.

In a 25 mL round bottom flask, 11 (750 mg, 1.62 mmol), Pd(OAc)2 (7.3 mg, 0.033 mmol), PPh3 (28.5 mg, 0.110 mmol), NHEt2 (25.1 mmol), H2O (2 mL) and THF (8 mL) were mixed and stirred at 80 o C under argon for 4 h. Then the mixture was cooled to r.t., and the solvents were removed under vacuum. AcOEt (10 mL) was first added and then removed under vacuum twice. AcOEt (200 mL) and H2O (100 mL) were then added. After thoroughly mixing, the organic layer was separated, and the aqueous phase was extracted with AcOEt (2 × 30 mL). The combined organic layers were dried over Na2SO4, and the organic solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel with a 20 : 3 mixture of CH2Cl2 : AcOEt as eluent to give compound 12 as a light yellow solid (600 mg, 1.41 mmol, 88% yield). 1 13 C NMR (CDCl3, 298K, 125.7 MHz): δ 155. 1, 152.0, 149.7, 147.7, 131.8, 130.0, 129.6, 128.5, 127.8, 120.6, 119.6, 118.1, 114.1, 112.1, 109.7, 107.2, 97.7, 68.8, 67.9, 66.5, 62.4, 56.0, 30.7, 25.5, 19.5 ppm. ESI-HRMS m/z: found 447.1763, calcd for C25H28NaO6 [12+Na] + 447.1778.

Synthesis of 13.

In a 50 mL round bottom flask, 8 (100 mg, 0.230 mmol), 12 (321 mg, 0.757 mmol), Cs2CO3 (337 mg, 1.04 mmol), and DMF (10 mL) were mixed and stirred at 90 o C for 3 days. Then the mixture was cooled to r.t., and DMF was removed under vacuum. CH2Cl2 (200 mL) and H2O (200 mL) were then added. After thoroughly mixing, the organic layer was separated, and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were dried over Na2SO4, and the organic solvent was removed under vacuum.

The crude product was purified by column chromatography on silica gel with a 18 : 1 mixture of CH2Cl2 : MeOH as eluent to give hemicryptophane precursor 13 as a yellow solid (330 mg, 0.207 mmol, 90% yield). 1 13 C NMR (CDCl3, 298K, 125.7 MHz): δ 159. 1, 156.7, 155.3, 155.0, 149.8, 147.7, 137.3, 131.9, 129.9, 129.8, 128.3, 121.8, 120.6, 119.6, 119.3, 119.1, 114.2, 112.1, 107.8, 107.3, 97.6, 70.8, 68.8, 67.9, 66.6, 62.4, 60.3, 56.0, 30.7, 25.5, 19.5

Synthesis of hemicryptophane (±)-1.

A solution of hemicryptophane precursor 13 (100 mg, 63.0 µmol) in CH3CN (18 mL) was added dropwise (4 hours) under argon at 65 °C to a solution of Sc(OTf)3 (44 mg, 88 µmol) in CH3CN (46 mL). The mixture was stirred under argon at 65 °C for 24 hours. The solvent was then evaporated. The crude product was purified by column chromatography on silica gel with a 200 : 5 : 1 mixture of CHCl3 : MeOH : triethylamine as eluent to give hemicryptophane (±)-1 as a light yellow solid (40 mg, 88 µmol, 49% yield). The crude product could be also used directly for the following resolution procedure.

Chiral HPLC analysis for (±)-1. On a Chiralpak IA column (250 × 4.6 mm), with 1 mL min -1 as flow-rate, heptane/EtOH/CH2Cl2/TEA (20/40/40/0.1) as mobile phase, UV detection at 254 nm, Rt(M-1) = 4.7 min, Rt(P-1) = 5.6 min, k(M-1) = 0.59, k(P-1 = . , = . and Rs = . .

Resolution of hemicryptophane (±)-1.

The crude product of (±)-1 (320 mg) was dissolved in 25 mL of CH2Cl2. On a Chiralpak IA column (250 × 10 mm), with 5 mL min -1 as flow-rate, hexane/EtOH/CH2Cl2/TEA (20/40/40/0.1) as mobile phase, UV detection at 254 nm, 210 injections of 120 µL were stacked every 3.5 minutes. Both enantiomers were collected and the solvent was then evaporated. The first eluted enantiomer (( ), M-1, 84 mg) was obtained with 99% ee, and the second one ((+), P-1, 73 mg) with 90% ee. P-1: [∝] : +38 (c = 0.114; CH2Cl2); M-1: [∝] : -35 (c = 0.114; CH2Cl2). 1 H NMR (CD2Cl2, 298K, 500.1 MHz): δ 7.48 (t, J = 7.7 Hz, 3H); 7.36-7.28 (m, 12H); 7.10-7.08 (m, 6H); 6.96 (s, 3H); 6.86 (s, 3H); 6.81 (d, J = 2.3 Hz, 3H); 6.76 (dd, J = 8.9, 2.5 Hz, 3H); 5.24 (s, 6H); 4.80 (d, J = 13.7 Hz, 3H); 4. 30-4.19 (m, 12H); 4.01 (s, 6H);

Abstract

The synthesis of eight enantiopure molecular cages (four diastereomeric pairs of enantiomers) comprising a helically chiral cyclotriveratrylene (CTV) unit, three axially chiral binaphthol linkages and three centrally asymmetric carbons of a trialkanolamine core, is described. These new cages constitute a novel family of hemicryptophanes, which combine three classes of chirality. Their absolute configuration was successfully assigned by a chemical correlation method to overcome the signals overlap in the ECD spectra of the binaphtol and CTV units. Stereoselective recognition of glucose and mannose derivatives was investigated with these new chiral cages. Excellent enantio-selectivity and diastereo-selectivity were reached, since in some cases, both exclusive enantio-and diastereo-discrimination have been observed. In addition, compared with the most relevant hemicryptophanes, these new cages also exhibit improved binding affinities.

Introduction

Chirality plays an important role in living systems from the double helical strand of DNA to the confined chiral space of the enzyme cavities. Almost all natural products are chiral. 1 The application, control or monitoring of chirality via the principles of a supramolecular approach constitute a modern multidisciplinary field of research in chiral supramolecular science. 2 Various artificial and biomimetic compounds have been synthesized not only for fundamental purposes but also for a number of practical applications, such as asymmetric catalysis, 3 material science, 4 chiral recognition 5 and absolute configuration assignment. 6 To mimic more sophisticated chiral structures, bioinspired enantiopure cages have also been reported. 7 However, the synthesis of such chiral architectures remains challenging, in particular for highly engineered cages bearing multiple classes of stereogenic elements, because of their high complexity.

Among the chiral cage derivatives, cryptophanes and hemicryptophanes, both based on the cyclotriveratrylene (CTV) moiety have aroused a growing interest. 8 Due to the bowl shape of the CTV unit, cryptophanes and hemicryptophanes are inherently chiral with helical chirality. 9 Cryptophanes, which combine two CTV units, present complexation properties toward small molecules or atoms. 8a,10 Hemicryptophanes, associating a CTV unit with another different C3 symmetrical moiety, were found to act as selective molecular receptors or supramolecular catalysts. New stereocenters have also been incorporated into the hemicryptophane cages, giving rise to various efficient and stereoselective hosts, for instance, for chiral zwitterions, 11 ammoniums 12 and carbohydrates. 13 Until now, the most sophisticated hemicryptophanes hold two types of chirality, helical and central chirality, leading to two diastereomeric pairs of enantiomers. 14 Herein, we report on the design and synthesis of a family of enantiopure hemicrytophanes bearing three types of stereogenic elements (Figure 6.1), helical, axial and central chirality, which respectively results from the CTV, binaphthol and trialkanol moieties. Hence, four diastereomeric pairs of enantiomers are expected. We believe that the various stereogenic units as well as their different chirality should strongly affect the size and shape of the inner space of the hemicryptophane cavity, and therefore, have a dramatic influence on their stereoselective recognition properties. However, it should be noted that besides the high synthetic challenge, the binaphthol linkages also make it difficult to determine the absolute configuration of the hemicryptophanes using conventional methods, such as electronic circular dichroism (ECD), because of the signal overlap between binaphthol and CTV moieties. Hence in the present work, we shall mainly address the following three issues: (i) to design a synthetic pathway to obtain the eight stereoisomers; (ii) to develop a method to assign the absolute configuration of each enantiopure hemicryptophane; (iii) to investigate their stereoselective recognition properties towards carbohydrates and compare their binding performance with those of the previously reported relevant hemicryptophanes.

Results and discussion

The synthetic route for obtaining a pair of two diastereomers is shown in Scheme 6.1.

Firstly, compound 2, obtained via a previously reported two step procedure, 14a was reacted with (S)-binaphthol in acetone using K2CO3 as a base to give the mono-protected binaphthol S-3. The enantiopure epoxide S-S-4 was synthesized by a regioselective nucleophilic substitution reaction of its phenol unit with commercially available (S)-(-)-glycidyl nosylate in DMF. Compound S-S-4 was then treated with an excess of ammonia to give the primary amine S-S-5, followed by addition of 2 equiv. of S-S-4 in methanol producing the trialkanolamine SSS-SSS-6. Finally, intramolecular cyclization of trialkanolamine SSS-SSS-6

was achieved using a stoichiometric quantity of Lewis acid Sc(OTf)3 in acetonitrile under moderate dilution conditions to afford the hemicryptophanes mixture. The diastereomeric pair M-SSS-SSS-1 and P-SSS-SSS-1 was separated by column chromatography on silica gel followed by preparative TLC and isolated in 30% and 13% yields, respectively. The yields of M-and P-isomers are not equal, and a diastereoselectivity around 2:1 was observed, indicating the stereocontrol induced by the binaphthol and trialkanol moieties. 14b A diastereomeric ratio higher than 99:1 was obtained after separation, since no signal corresponding to the other diastereomer could be detected on the 1 H NMR spectra. Similar )

Wavelength (nm)

P-(R,R,R)-(S,S,S) M-(S,S,S)-(R,R,R)

The assignment of the absolute configuration of enantiopure CTV derivatives is usually achieved by ECD thanks to the sign of the band around the 1 LA transition (240 nm). If the enantiopure hemicryptophane gives rise to a characteristic positive-negative bisignate from low to high energies (270-230 nm), a P-configuration is indicated, otherwise a M-configuration. 14a The ECD spectra of the eight stereoisomers were then recorded in CH3CN at 298 K. As shown in Figure 6.2, the spectra of each pair of enantiomers exhibit a perfect mirror image. All of them present a similar behavior that consists of one main exciton pattern centered at 239 nm. However, it was found that the sign of this intense band was strictly determined by the configuration of the binaphthol moiety rather than the CTV. For instance, all the isomers bearing (R)-binaphthol give rise to a negative sign for this band, whereas (S)-binaphthol-based isomers correspond to a positive sign. Indeed, the signals of the binaphthol completely overlap that of the CTV, preventing any assignment of the configuration. Facing this failure, we then developed a novel chemical correlation method to determine the absolute configuration of these new compounds. Scheme 6.2 Synthetic pathway to P-SSS-SSS-1 used for the assignment of the absolute configuration of the hemicryptophanes by chemical correlation.

Based on the retrosynthesis, we proposed that the enantiopure hemicryptophane 1 may also be obtained from the enantiopure tris-binaphtol 12 and CTV-tribromide 13, via a [1+1] macrocyclization reaction (Scheme 6.2). The first key issue is to prepare the two important enantiomerically pure intermediates 12 and 13. The racemate 13, obtained by known procedures, 15 was readily resolved by means of chiral HPLC in gram scale and the absolute configuration of the two enantiomers P-13 and M-13 has been successfully assigned by ECD spectra (Figure S6.1). 16 We then devised a synthetic pathway to access the enantiopure compound 12. As shown in Scheme 6.2, (S)-binaphthol was first mono-protected by reaction with iodomethane in acetone, in the presence of K2CO3. The resulting mono-phenol S-7

reacted with (S)-(+)-glycidyl nosylate to give S-S-8. Ring opening of the epoxide by ammonia was then performed in MeOH, providing the primary amine S-S-9 in quantitative yield.

Heating 9 with 2 equiv. of 8 at 50°C for 5 days afforded SSS-SSS-10. Deprotection of the methoxy groups by an excess of a solution of lithium diphenylphosphide 11 in THF (1 M) at 60 °C gave rise to the triphenol SSS-SSS-12.

The subsequent [1+1] macrocyclization has to be performed at low temperature with reaction time no longer than two days to prevent the racemization of enantiopure 13. 16 In addition, the concentration of the reaction solution should be optimal to avoid polymerization or low reaction rate. Thus, the macrocyclization step between SSS-SSS-12 and P-13 was performed at 25°C, leading to hemicryptophane P-SSS-SSS-1 in 25% yield (Scheme 6.2). Comparing the1 H NMR spectra of enantiopure P-SSS-SSS-1 with those of the diastereomeric pair P-SSS-SSS-1/M-SSS-SSS-1 obtained in the last step of the synthesis in Scheme 6.1, the cage with the P-configuration was identified, and accordingly, the other is Structures of carbohydrate guests.

M-SSS-SSS-1. Moreover,
We have previously reported the enantio-and diastereo-selective recognition of glucopyranosides by hemicryptophane 14 (Figure 6.3a), where the host-guest association relies on hydrogen bonding and C-H••• interactions. 13a,17 As the introduction of the axially chiral binaphthol units should strongly modify the shape of the inner cavity, we thus decided to study the recognition properties of the enantiopure hemicryptophanes 1 toward carbohydrates. Binding constants with two n-octyl-pyranoside anomers of glucose (Oct Gρc and Oct Gρc , and mannose Oct Man and Oct Man Fiμure 6.3b), were determined from NMR time scale (Figure S6.5). During the titration, both the OMe and the aromatic protons of the CTV are shifted, underlining the interactions of this unit with the guest. The anomeric proton of the carbohydrtae also exhibits slight highfield shift, which may be related with the vicinity of this proton with the aromatics of the host. In contrast, we did not observe any changes of the protons of the octyl-chain, suggesting that this moiety do not interact with the host. Complexation induced shifts of the CTV-OMe signal were plotted as a function of the guest/host ratio and modeled with the HypNMR2008 software, 18 using a 1:1 model according to job s pρot Fiμure S6.6-6.8). 19 The resulting binding constants Ka are reported in Table 6.1

M-RRR-SSS-1 -b -b 50 -b P-SSS-RRR-1 -b -b 100 -b M-RRR-14 c 123 126 -b -b P-RRR-14 c -b 115 -b -b M-SSS-14 c 155 184 -b -b P-SSS-14 c -b -b -b -b
a Ka was determined by fitting 1 H NMR titration curves (CDCl3, 500 MHz, 298 K) on OMe protons with HypNMR2008; estimated error 10%. For hosts

M-RRR-RRR-1, P-SSS-SSS-1, M-SSS-SSS-1 and

P-RRR-RRR-1, no complexation was detected. b No complexation detected. c From ref. 13a.

From Table 6.1, several trends can be observed. (i) Concerning the stereorecognition of glucose derivatives with 1, excellent diastereoselectivity is obtained, since only the stereoisomers M-SSS-RRR-1 and P-RRR-SSS-1 exhibit binding properties. In addition, depending on the enantiomer of M-SSS-RRR-1 or P-RRR-SSS-1 used, the / seρectivity can be reversed. Good enantioselectivity was also achieved in the recognition of the anomer Oct Gρc Ka(P-RRR-SSS-1)/Ka(M-SSS-RRR-1) = 6.0), associated with an improvement of the binding constant compared to those of the previous hosts 14 (537 M -1 vs 184 M -1 ). (ii) In contrast to hosts 14, which showed no aλλinity λor mannose derivatives, μood / seρectivity is reached with M-SSS-RRR-1, M-RRR-SSS-1 and P-SSS-RRR-1, which onρy recoμnize Oct Man. It is also interesting to note that only P-RRR-SSS-1 binds Oct Man with a bindinμ constant oλ 8 M -1 , indicating an exclusive enantio-differentiation compared to M-SSS-RRR-1. (iii) these cages are able to discriminate glucose from mannose derivatives and the selectivity observed is not correlated to the different intrinsic abilities of the guests to be involved in intermoρecuρar hydroμen bonds Oct Man > Oct Man > Oct Gρc > Oct Gρc . 20 For instance, with P-RRR-SSS-1, the bindinμ constants decrease λoρρowinμ the order Oct Gρc > Oct Man > Oct Gρc > Oct Man, hiμhρiμhtinμ the speciλic host-guest interactions involved in the recognition process.

Conclusion

In summary, we have described the synthesis of eight enantiomerically and diastereomerically pure cage compounds combining three classes of chirality on seven stereogenic units: the helical chirality of the CTV unit, the axial chirality of the binaphthol linkages and the central chirality of the asymmetric carbons on the trialcohol unit. Albeit the multiple chirality in the engineered structure makes it difficult in the assignment of the absolute configuration of CTV with conventional methods, a chemical correlation strategy was developed, to successfully determine the configuration of the eight hemicryptophane stereoisomers. The stereoselective recognition properties toward glucose and mannose derivatives with these new enantiopure cages were investigated. It was found that the recognition behaviour strongly depends on the configuration of the cages, and from moderate to exclusive guest diastereo-and enantio-discrimination were observed. In particular, compared with the structurally relevant hemicryptophanes, these new cages exhibit an improved binding performance, such as the stereoselectivity and also binding affinity.

Considering the sophisticated cage structures, the novel method of configuration assignment, and excellent stereorecognition properties, we do believe that the current research will contribute significantly to the burgeoning field of chiral supramolecular science.

Experimental section

Materials and instrumentation

All solvents used were of commercial grade and were dried prior to use over molecular sieves. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance spectrometer operating at 500.10 MHz and 125.76 MHz for 1 H NMR and 13 C NMR spectra, respectively. 1 H NMR chemical shifts (δ) are reported in ppm and referenced to the protonated residual solvent signal. Mass spectra were recorded by the Centre de Spectrométrie de Masse, Institute of Chemistry, Lyon. Specific rotations (in deg cm 2 g -1 ) were measured in a 1 dm thermostated quartz cell on a Jasco-P1010 polarimeter. Circular dichroism spectra were recorded on a CD6

Jobin-Yvon dichrograph.

Synthesis and Characterization

S-3/R-3:

A solution of K2CO3 (0. 75 g, 5.4 mmol) and (S/R)-(-/+)-, -Bi(2-naphthol) (1. 29 g, 4.5 mmol) in acetone (50 mL) was stirred at room temperature for 1 h under argon. Then 30 mL acetone solution of compound 2 (1. 54 g, 4.5 mmol) was added in one portion. After reflux under argon for 48 h, the solvent was evaporated. The mixture was then dissolved in CH2Cl2, and washed with distilled water for 3 times. The organic phase was dried over anhydrous Na2SO4, filtrated and evaporated. After column chromatography over silica gel (first with CH2Cl2 as eluent, then use CH2Cl2/AcOEt 95:5), 1.20 g (49%) S-3/R-3 was obtained as a white solid. 1 H NMR (CD2Cl2, 298K, 500.1 MHz): δ 7. 97 (dd, J = 4.3, 9.05 Hz, 1H); 7.94-7.91 (m, 2H); 7.88 (d, J = 8.2 Hz, 1H); 7.49 (dd, J = 1.5, 9.1 Hz, 1H); 7.41 (t, J = 7.1 Hz, 1H); 7.39-7.29 (m, 3H); 7.22-7.17 (m, 2H); 7.05 (d, J = 8.5 Hz, 1H); 6.79 (d, J = 8.2 Hz, 1H); 6.75 (s, 1H); 6.63 (dd, J = 1.5, 8.1Hz, 1H); 5.95 (d, J = 5.4 Hz, 1H); 4.67-4.65 (m, 2H); 4.51-4.56 (m, 1H); 4.38 (d, J = 11.6 Hz, 1H); 4.28-4.32 (m, 1H); 4.16-4.19 (m, 1H); 4.06-4.11 (m, 1H); 3.93-3.88 (m, 1H); 3.51-3.55 (m, 1H); 3.34 (d, J = 3.7 Hz, 3H); 1.73-1.58 (m, 6H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 155. 7, 151.9, 149.1, 146.7, 134.1, 134.0, 131.7, 130.4, 130.0, 129.6, 129.0, 128.1, 128.0, 126.9, 126.3, 124.9, 124.7, 124.3, 123.1, 120.3, 118.1, 117.8, 116.7, 115.4, 113.0, 111.6, 97.8, 68.7, 68.2, 67.9, 62.1, 55.1, 30.7, 25.6, 19.5

S-S-4/R-R-4:

To NaH (90 mg, 3.75 mmol) (60% suspension in oil), a solution of S/R-3 (1.05 g, 1.91 mmol) in DMF (22 mL) was added at room temperature. After stirring under argon for 60 min, a solution of S/R-(+/-)-glycidyl nosylate (621 mg; 2. 40 mmol) in DMF (8 mL) was added.

The mixture was stirred at room temperature under argon for 24 h. Then the reaction was quenched by adding saturated NH4Cl solution and the resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous Na2SO4, filtrated and evaporated. After column chromatography over silica gel (CH2Cl2/AcOEt 100:7.5), 1.10 g (95%) S-S-4/R-R-4 was obtained as a white solid. 4.67-4.64 (m, 2H); 4.39-4.31 (m, 3H); 4.23 (dd, J = 2.9, 11.6 Hz, 1H); 3.99 (t, J = 5.0 Hz, 2H); 3. 95-3.87 (m, 2H); 3.75 (s, 3H); 3.56-3.51 (m, 1H); 2.98-2.95 (m, 1H); 2.54 (t, J = 4.8 Hz, 1H); 2.31 (dd, J = 2.6, 5.1 Hz, 1H); 1. 88-1.56 (m, 6H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 154. 3, 154.0, 149.5, 147.6, 133.9, 131.8, 129.6, 129.6, 129.5, 129.4, 128.0, 126.3, 126.3, 125.2, 123.8, 120.4, 120.3, 120.3, 116.2, 115.8, 113.7, 112.0, 97.8, 70.2, 68.7, 68.7, 68.1, 62.1, 55.7, 50.2, 43.9, 30.7, 25.6, 19.5. ESI-HRMS for S-S-4 m/z: found 629.2486, calcd for C38H38NaO7 [M+Na] + 629.2510.

ESI-HRMS

S-R-4/R-S-4:

The procedure was similar as that of S-S-4/R-R-4 using the starting materials with the corresponding chirality in 90% yield. 4, 154.1, 149.5, 147.6, 134.0, 131.7, 129.6, 129.6, 129.5, 129.5, 128.0, 126.4, 126.3, 125.2, 125.2, 123.9, 123.8, 120.4, 120.4, 120.3, 116.2, 115.9, 113.7, 112.0, 97.8, 70.4, 68.8, 68.7, 68.1, 62.1, 55.8, 50.1, 44.1, 30.7, 25.6, 19.

SSS-SSS-6/RRR-RRR-6:

To a solution of 7N NH3 in methanol (36 mL, 252 mmol), compound 4 (350 mg, 0.58 mmol) was added. After stirring at 50 °C for 12 h under argon, the solvent was evaporated. 10 mL pentane was added and evaporated for 3 times to fully remove the residue NH3. Then 2.0 equivalent of 6 (700 mg, 1.16 mmol) and 60 mL MeOH were added under argon. The solution was stirred at 60 °C for 5 days. After evaporation of the solvent, the crude product was purified by column chromatography over silica gel (first with CH2Cl2/AcOEt 98:2, then use pure AcOEt), 660 mg (62%) SSS-SSS-6/RRR-RRR-6 was obtained as a white solid. 3 Hz, 1H); 7.21 (t, J = 7.9 Hz, 1H); 7. 16-7.11 (m, 2H); 7.03 (d, J = 8.5 Hz, 1H); 6.83 (s, 1H); 6.68 (d, J = 7.3 Hz, 1H); 6.44 (d, J = 8.1 Hz, 1H); 4.66-4.64 (m, 2H); 4.37 (d, J = 11.6 Hz, 1H); 4.27-4.20 (m, 2H); 3.95-3.88 (m, 4H); 3.69-3.67 (m, 4H); 3.54-3.51 (m, 1H); 2.98-2.97 (m, 1H); 2.89 (bs, 1H); 1. 85-1.54 (m, 7H); 1.35 (d, J = 11.9 Hz, 1H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 154. 2, 154.1, 149.5, 147.5, 133.9, 133.9, 131.7, 129.5, 129.5, 129.4, 128.0, 127.9, 126.3, 125.2, 125.1, 123.8, 123.6, 120.6, 120.3, 119.7, 116.4, 115.1, 113.8, 112.0, 97.8, 71.1, 68.8, 68.7, 68.0, 66.3, 62.1, 56.0, 55.7, 30.7, 25.6, 19.5

SSS-RRR-6/RRR-SSS-6:

The procedure was similar as that of SSS-SSS-6/RRR-RRR-6 using the starting materials with the corresponding chirality in 56% yield. 4.66-4.63 (m, 2H); 4.36 (d, J = 11.6 Hz, 1H); 4.29-4.22 (m, 2H); 3.91-3.89 (m, 3H); 3.76-3.75 (m, 2H); 3.68 (s, 3H); 3.55-3.50 (m, 1H); 3.08-3.07 (m, 1H); 2.77 (bs, 1H); 1. 85-1.57 (m, 8H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 154. 2, 154.1, 149.5, 147.5, 133.9, 133.9, 131.8, 129.6, 129.5, 128.0, 126.4, 126.3, 125.2, 125.1, 123.9, 123.7, 120.5, 120.3, 120.1, 116.2, 115.8, 113.8, 112.0, 97.8, 72.0, 68.7, 68.7, 68.0, 66.6, 62.1, 56.6, 55.7, 30.7, 25.6, 19.5

Hemicryptophanes P-SSS-SSS-1 and M-SSS-SSS-1:

A solution of SSS-SSS-6 (200 mg, 109 µmol) in CH3CN (30 mL) was added dropwise (4 hours) under argon at 65 °C to a solution of Sc(OTf)3 (75 mg, 152.3 µmol) in CH3CN (80 mL). The mixture was stirred under argon at 65 °C for 24 hours. The solvent was then evaporated. A column chromatography (SiO2, CHCl3/MeOH 20:0.1) for the crude product gave the pure product P-SSS-SSS-1 (22 mg, 13%) and diastereomerically enriched M-SSS-SSS-1. Then a silica preparative TLC was performed for the crude M-SSS-SSS-1 with CHCl3/MeOH (20:0.1) to give 50 mg enantiopure M-SSS-SSS-1 in 30% yield. Both of the two enantiopure compounds are white solid after precipitation with MeOH. (d, J = 11.9, 8.2 Hz, 1H); 2.32-2.30 (m, 2H); 0.97 (t, J = 11.1 Hz, 1H); -0.19 (dd, J = 5.0, 11.4 Hz, 1H). 13 C NMR (CDCl3, 298K, 125.7 MHz): δ 155. 7, 154.3, 147.2, 146.4, 134.1, 134.0, 131.7, 131.1, 130.1, 129.0(2), 129.0(0), 128.5, 127.9, 127.6, 126.6, 126.4, 126.0, 124.9, 123.9, 123.0, 120.7, 119.5, 117.3, 115.1, 112.1, 111.8, 71.3, 67.8, 66.7, 66.4, 55.7, 5 3.0. 36.5 (d, J = 9.0 Hz, 1H); 7.39-7.29 (m, 3H); 7.24-7.19 (m, 2H); 7.09 (d, J = 8.5 Hz, 1H); 6.99 (d, J = 8.6 Hz, 1H); 6.82 (s, 1H); 6.73 (s, 1H); 4.67 (d, J = 13.9 Hz, 1H); 4.44-4.41 (m, 2H); 4.11-4.02 (m, 2H); 3.92-3.90 (m, 1H); 3.61 (bs, 1H); 3.54 (t, J = 7.3 Hz, 1H); 3.48-3.45 (m, 4H); 3.07 (bs, 1H); 1.33 (t, J = 12.6 Hz, 1H); 0.31 (dd, J = 4.8, 12 Hz, 1H). 13 C NMR (CDCl3, 298K, 125.7 MHz): δ 152. 7, 147.7, 146.3, 134.3, 134,3, 132.3, 131.8, 130.4, 129.6, 129.3, 129.2, 128.0, 127.9, 126.7, 126.4, 126.0, 125.1, 124.6, 123.6, 123.3, 119.1, 118.0, 115.2, 115.0, 71.7, 69.6, 67.1, 65.8, 56.5, 56.2, 36.4 : -35 (c = 0.097; CH2Cl2).

Diastereomer P-SSS-SSS-1:

Hemicryptophanes P-RRR-RRR-1 and M-RRR-RRR-1:

The procedure was similar as that of M-SSS-SSS-1/P-SSS-SSS-1 in the same yield except using the starting materials with the corresponding chirality. Because of the mirror image properties, the 1 H and 13 C NMR spectra are also exactly the same as those of M-SSS-SSS-1/P-SSS-SSS-1. : -516 (c = 0.116; CH2Cl2).

Diastereomer P-RRR-RRR

Hemicryptophanes P-SSS-RRR-1 and M-SSS-RRR-1:

A solution of SSS-SSS-6 (200 mg, 109 µmol) in CH3CN (30 mL) was added dropwise (4 hours) under argon at 65 °C to a solution of Sc(OTf)3 (75 mg, 152.3 µmol) 7.30-7.24 (m, 2H); 7.17-7.13 (m, 2H); 7.03 (d, J = 8.5 Hz, 1H); 6.78 (s, 1H); 6.68 (s, 1H); 4.71 (d, J = 13.8 Hz, 1H); 4.60-4.55 (m, 1H); 4.22-4.19 (m, 1H); 4.06-4.05 (m, 2H); 3.75 (s, 3H); 3.61 (dd, J = 3.7, 10.3 Hz, 1H); 3.48 (d, J = 13.9 Hz, 1H); 3.03 (dd, J = 5.7, 10.1 Hz, 1H); 2.61-2.48 (m, 1H); 1.10 (dd, J = 9.1, 13.4 Hz, 1H). 13 C NMR (CDCl3, 298K, 125.7 MHz): δ 154. 3, 147.7, 147.2, 134.1, 133.9, 132.2, 132.1, 129.5, 129.3, 129.1, 127.9, 127.6, 126.4(4), 126.4(0), 125.6, 125.4, 123.9, 123.7, 120.3, 120.0, 116.9, 115.5, 114.5, 113.7, 70.9, 68.4, 67.4, 56.9, 56.7, 36.4 4, 153.5, 148.4, 146.3, 134.3, 133.9, 133.0, 131.5, 129.7(4), 129.7(1), 129.4, 129.1, 128.1, 127.7, 126.7, 126.4, 125.7, 125.1, 124.3, 123.7, 122.0, 119.4, 116.8, 116.7, 115.8, 113.1, 71.9, 68.5, 68.4, 58.0, 54.9, 36.5. ESI-HRMS m/z: found 1530.6099, calcd for C99H88NO15 [M+H] + 1530.6148.

[∝] : -14 (c = 0.130; CH2Cl2).

Hemicryptophanes P-RRR-SSS-1 and M-RRR-SSS-1:

The procedure was similar as that of M-SSS-RRR-1/P-SSS-RRR-1 in the same yield except using the starting materials with the corresponding chirality. Because of the mirror image properties, the 1 H and 13 C NMR spectra are also exactly the same as those of M-SSS-RRR-1/P-SSS-RRR-1. : -4 (c = 0.120; CH2Cl2).

Diastereomer P-RRR-SSS-

S-7:

A solution of K2CO3 (0. 75 g, 5.4 mmol) and (S)-(-)-, -Bi(2-naphthol) (1.29 g, 4.5 mmol) in acetone (50 mL) was stirred at room temperature for 1 h under argon. Then 20 mL acetone solution of iodomethane (640 mg, 4.5 mmol) was added in one portion. After reflux under argon for 48 h, the solvent was evaporated. The mixture was then dissolved in CH2Cl2, and washed with distilled water for 3 times. The organic phase was dried over anhydrous Na2SO4, filtrated and evaporated. After column chromatography over silica gel (CH2Cl2 as eluent), 949 mg (70%) S-7 was obtained as a white solid. 3, 134.0, 133.8, 131.1, 129.7, 129.5, 129.1, 128.2, 128.1, 127.2, 126.4, 124.6, 124.5, 124.0, 123.3, 117.4, 115.1, 114.9, 113.6, 56.4.

ESI-HRMS

S-S-8:

To NaH (124 mg, 5.16 mmol) (60% suspension in oil), a solution of S-3 (901 mg, 3.0 mmol) in DMF (32 mL) was added at room temperature. After stirring under argon for 60 min, a solution of S-(+)-glycidyl nosylate (980 mg; 3. 78 mmol) in DMF (8 mL) was added. The mixture was stirred at room temperature under argon for 24 h. Then the reaction was quenched by adding saturated NH4Cl solution and the resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous Na2SO4, filtrated and evaporated. After column chromatography over silica gel (CH2Cl2 as eluent), 1.04 g (97 %) S-S-8 was obtained as a white solid. 1 H NMR (CD2Cl2, 298K, 500.1 MHz): δ 8.05 (d, J = 9.1 Hz, 1H); 8.00 (d, J = 9.0 Hz, 1H); 7. 93-7.91 (m, 2H); 7.51 (dd, J = 9.1, 11.4 Hz, 2H); 7.39-7.33 (m, 2H); 7.27-7.22 (m, 2H); 7.10 (dd, J = 8.6, 13.7 Hz, 2H); 4.26 (dd, J = 2.9, 11.7 Hz, 1H); 3.97 (dd, J = 5.4, 11.7 Hz, 1H); 3.81 (s, 3H); 3.00-2.97 (m, 1H); 2.58 (t, J = 4.8 Hz, 1H); 2. 34-2.33 (m, 1H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 154. 9, 154.1, 134.0, 133.9, 129.6, 129.5, 129.4, 129.1, 128.0, 126.4, 126.3, 125.2, 124.9, 123.9, 123.5, 120.7, 118.9, 116.0, 113.6, 70.3, 56.4, 50.2, 44.0. ESI-HRMS m/z: found 379.1296, calcd for C24H20NaO3 [M+Na] + 379.1305.

[∝]

: -62 (c = 0.122; CH2Cl2).

S-R-8:

The procedure was similar as that of S-S-8 using the starting materials with the corresponding chirality in 96% yield. 1 H NMR (CD2Cl2, 298K, 500.1 MHz): δ 8.05 (d, J = 9.1 Hz, 1H); 8.00 (d, J = 9.1 Hz, 1H); 7.92-7.91 (m, 2H); 7.52 (d, J = 9.1 Hz, 1H); 7.49 (d, J = 9.1 Hz, 1H); 7.39-7.33 (m, 2H); 7.27-7.22 (m, 2H); 7.11 (d, J = 8.5 Hz, 1H); 7.08 (d, J = 8.5 Hz, 1H); 4.21 (dd, J = 3.0, 11.6 Hz, 1H); 3.99 (dd, J = 5.4, 11.6 Hz, 1H); 3.82 (s, 3H); 2.98-2.95 (m, 1H); 2.60 (t, J = 4.8 Hz, 1H); 2. 38-2.37 (m, 1H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 154. 9, 154.1, 134.0, 133.9, 129.7, 129.5, 129.4, 129.1, 128.0, 126.4, 126.3, 125.2, 124.9, 123.9, 123.5, 120.7, 118.9, 116.1, 113.7, 70.5, 56.4, 50.1, 44.1. ESI-HRMS m/z: found 357.1479, calcd for C24H21O3 [M+H] + 357.1485.

[∝]

: -68 (c = 0.102; CH2Cl2).

SSS-SSS-10:

To a solution of 7N NH3 in methanol (36 mL, 252 mmol), compound 6 (300 mg, 0.84 mmol) was added. After stirring at 50 °C for 12 h under argon, the solvent was evaporated. 10 mL pentane was added and evaporated for 3 times to fully remove the residue NH3. Then 2.0 equivalent of 6 (600 mg, 1.68 mmol) and 70 mL MeOH were added under argon. The solution was stirred at 60 °C for 5 days. After evaporation of the solvent, the crude product was purified by column chromatography over silica gel (first with CH2Cl2/AcOEt 1:1, then use CH2Cl2/MeOH 100:3), 699 mg (76%) SSS-SSS-10 was obtained as a white solid. 154.1, 133.9, 133.8, 129.5, 129.4, 129.1, 128.0, 127.9, 126.4, 125.1, 124.9, 123.8, 123.5, 120.1, 119.0, 115.5, 113.8, 71.4, 66.3, 56.5, 56. : -111 (c = 0.115; CH2Cl2).

SSS-RRR-10:

The procedure was similar as that of SSS-SSS-10 using the starting materials with the corresponding chirality in 75% yield. 7, 154.1, 133.9, 133.8, 129.6, 129.5, 129.4, 129.1, 128.0, 127.9, 126.4, 126.3, 125.1, 124.9, 123.9, 123.5, 120.3, 119.0, 115.9, 113.6, 71.9, 66.7, 56.7, 56.5. ESI-HRMS m/z: found 1086.4555, calcd for C72H64NO9 [M+H] + 1086.4576.

[∝]

: -52 (c = 0.100; CH2Cl2).

Preparation of 11 (1M solution in THF):

Lithium (600 mg, 86.4 mmol) was added to 10 mL dried THF at room temperature under argon. The mixture was cooled down to 0 °C, and a solution of chlorodiphenylphosphine (3.7 mL, 20.6 mmol) in THF (10 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2h until it turned red.

SSS-SSS-12:

SSS-SSS-10 (163 mg, 0.15 mmol) was dissolved in THF (1.5 mL) and the solution was stirred at room temperature for 5 min under argon. A 1M solution of lithium diphenylphosphide 11 in THF (3.6 mL, 3.6 mmol) was added slowly and the mixture was heated at 60°C for 12 h. Afterwards, another 3.6 mL 11 was added and kept the reaction for another 6h. Then, the reaction was cooled to room temperature and a saturated solution of NaHCO3 was added until a neutral pH was exhibited. CH2Cl2 (100 mL) was added and the solution was stirred vigorously for half an hour. The two layers were then separated and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic solutions were washed with water (200 mL), dried over anhydrous Na2SO4, filtrated and evaporated. The 1, 153.1, 134.4, 134.0, 129.6, 129.5, 129.3, 128.4, 128.3, 128.2, 126.6, 126.4, 125.3, 124.6, 123.9, 122.7, 120.2, 118.8, 116.7, 115.7, 72.1, 66.0, 57.4 = -76 (c = 0.096; CH2Cl2).

SSS-RRR-12:

The procedure was similar as that of SSS-SSS-12 using the starting materials with the corresponding chirality in 35% yield. 1, 153.1, 134.4, 134.0, 129.7, 129.6, 129.3, 128.4, 128.3, 126.6, 126.3, 125.4, 124.6, 124.0, 122.7, 120.5, 118.8, 117.2, 115.6, 72.6, 66.5, 58 CH2Cl2 was added to the reaction, followed by washing with brine (100×5) to remove DMF and Cs2CO3. The organic phase was dried over anhydrous Na2SO4, filtrated and evaporated.

The crude product was purified by column chromatography on silica gel to give the corresponding P-SSS-SSS-1 (37 mg, 25%) (with CH2Cl2 as eluent) or P-SSS-RRR-1 (6.0 mg, 4%) (first with CH2Cl2 as eluent, then use CH2Cl2/MeOH 80/1).

Absolute configuration assignment

P-(S,S,S)-(S,S,S) M-(S,S,S)-(S,S,S)

M-(R,R,R)-(R,R,R) P-(R,R,R)-(R,R,R) P-(S,S,S)-(R,R,R) M-(S,S,S)-(R,R,R) M-(R,

1H NMR titration

Job plot

The continuous variation method was used for determining the binding stoichiometry. 19 In this method, stock solutions (1.0 mM in CDCl3) of 1 and of the guest were prepared and mixed in NMR tubes in different ratios. In this way, relative concentrations were varied continuously but their sum was kept constant (1.0 mM). 1 H NMR spectra were recorded for each sampρe and vaρues oλ host s chemicaρ shift δobs were measured. Job s pρots were obtained by plotting (δobs δfree) versus , where δfree is the chemical shift of the proton in the free host.

The stoichiometry of the complexes was obtained from the value of the molar fraction which corresponds to the maximum of the curve: a 1:1 complexation is obtained for max = 0.5.

Abstract

A class of hemicryptophane cages that adopt imploded conformations in solution and in the solid state is described and studied by NMR and X-ray crystallography. We show that the degree of collapse of the molecular cavity can be controlled by changing the stereochemistry of the chiral elements of the hemicryptophanes, leading to a modulation of their physical and chemical properties. Upon the binding of an oxidovanadium unit, the collapsed molecular cavity can inflate to give an expanded conformation. Removal of the vanadium core by an ancillary complexing ligand restores the initial folded structure. Thus coordination/de-coordination of metal ion controls the dynamic motions of the cage leading to a reversible nanomechanical process. This controlled motion between a collapsed and expanded cavity can be seen as that of a breathable molecular cage.

Introduction

There is an increased interest in the synthesis and development of systems able to perform a defined function at the molecular level. 1 For instance, molecular machines can produce quasi-mechanical movements (output) in response to specific stimuli (input). Currently, synthetic systems mimicking the ability of brakes, 2a gears, 2b propellers, 2c ratchets, 2d rotators, 2e scissors, 2f muscles, 2g,h gyroscopes, 2i walkers, 2j and motors 2k-n have been widely devised and studied. Among them, catenanes and rotaxanes are well known molecular systems that are frequently used as supramolecular forces in the design of molecular devices. 1j,k Remarkable molecular motion of molecular strands from folding to unfolding states has been also achieved using coordination/de-coordination of metal ions. 3 Recently, besides the properties of recognition, catalysis, and reactive species stabilization, molecular cages have received a growing interest in constructing molecular machines. 4 For instance, hemicryptophanes have been used to achieve nanomechanical processes mimicking the function of gyroscopes or molecular propellers. 2c,4i Although nice examples of size and shape modifications of molecular cavity in self-assembled or covalent cages have been recently described, 5 control of the dynamic motion in molecular cages from fully folded to extended states is still a challenge.

We previously reported the synthesis of a new family of enantiopure hemicryptophane cages bearing three types of stereogenic elements, helical, axial and central chirality, which respectively result from the cyclotriveratrylene (CTV), binaphthol and trialkanolamine moieties, giving rise to four pairs of enantiomers (Figure 7.1a). 6 Herein, we report how these chiral units modulate the shape and size of the inner cavity and the consequences on their physical and chemical properties. We found that these molecular cages collapse in solution and that the resulting imploded form can re-inflate upon the complexation of an oxidovanadium unit. This conformational change between the collapsed and expanded form is reversible, leading to a synthetic molecule simulating the breathing motion upon the binding-unbinding of an external stimulus. Insights into the conformations of the cavities of the four diastereomers of 1 in solution were obtained by 1 H NMR, 13 C NMR, COSY, HSQC and HMBC experiments (see 7.5.5). In the 1 H NMR spectra, we can observe the high-field shifted signals of the NCH2 protons (Figures 7.1 and S7.2), with a shielding order P-SSS-SSS-1 (δ = 0.20 ppm) > M-SSS-SSS-1 (0.30 ppm) > M-SSS-RRR-1 (0.97 ppm) ≈ P-SSS-RRR-1 (1.08 ppm). These high-field shifted signals are consistent with imploded conformations as viewed in the crystal structure (Figure 7.2). To ppm

Results and discussion

P-SSS-SSS-1/M-RRR-RRR-1 M-SSS-SSS-1/P-RRR-RRR-1 P-SSS-RRR-1/M-RRR-SSS-1 M-SSS-RRR-1/P-RRR-SSS-1 (a) (b)

further demonstrate the concave conformation of each cage in solution, ROESY experiments were performed (Figures S7. 3-S7.6). Cross-peaks between the protons of the trialkanolamine core and the aromatic and methoxy protons of the CTV unit directly evidence short distances between the two moieties (< 5 Å) and are indicative of the imploded conformations of these host molecules in solution. The inter-proton distance between the most shielded NCH2 proton and its closest CTV aromatic-H (see Figure 7.1a and Experimental section) was calculated, Several physical properties of these cages are directly related to the hierarchical modulation in the size and shape of their inner cavities. With the increase of the implosion degree from M-SSS-RRR-1 to P-SSS-SSS-1, (i) the 1 H NMR signal of the alcohol proton becomes sharper and sharper (Figure 7.1a), (ii) their exchange with MeOD reveals increasingly difficult (Figure S7.9), and (iii) the migration properties of these compounds on TLC plates appears easier (Rf equals to 1.00, 0.47, 0.29 and 0.30 for P-SSS-SSS-1, M-SSS-SSS-1, P-SSS-RRR-1 and M-SSS-RRR-1, respectively, Figure 7.1b). All these observations indicate that the alkanolamine core of the most imploded cage P-SSS-SSS-1, which occupies the inner cavity, is well protected by the CTV shelter, significantly reducing its interaction with the surrounding environment.

Coordination/de-coordination of metal ions can allow for dynamic motions and reversible nanomechanical processes of molecular compounds, 3 we thus prepared the oxidovanadium(V)-1 hemicryptophane complexes which were also developed as efficient oxidation catalysts recently (see Chapter 8). 8 The reaction of each cage diastereomer with 1.0 equiv. of vanadium(V) reagent was carried out at room temperature in CDCl3 and monitored by 1 H NMR (Figure S7.10 and S7.11). Interestingly it was found that the reaction rate with the most imploded cage P-SSS-SSS-1 is 10-fold slower than those of the other three diastereomers, suggesting a higher energy barrier for the reorganization of the structure for vanadium complexation. In addition, in the 1 H NMR spectrum of the vanadium@P-SSS-SSS-1 complex in CDCl3, the chemical shifts of the NCH2 protons are in the region of 1.28-1.78 ppm (Figure S7.12). Compared to those of the free ligand ( 0.20 and 0.95 ppm), these protons show an obvious down-field shift. ROESY experiments performed on this complex reveal no NOE correlation between the trialkanolamine unit and the CTV moiety (Figure S7.13). These results are in agreement with strong conformational changes leading to the inflation of the molecular cavity through vanadium complexation (Figure 7.3).

Figure 7.3

Graphical representation of the hemicryptophane cage switching between its bi-stable states, i.e. imploded and inflated conformations, with external inputs. This switching can be done at least for three cycles. The new inflated vanadium complex is able to further encapsulate the ammonium guest, while the parent imploded ligand cannot.

Furthermore, tetramethyl ammonium (Me4N + ) can be efficiently bound by the vanadium@M-SSS-RRR-1 cage with a binding constant of 547 M 1 (Figure S7.14), 8 evidencing the presence of a well defined cavity in the complex. An MM3 model of vanadium@M-SSS-RRR-1 with Me4N + encapsulated inside the cavity was prepared using SCIGRESS software (Figure S7.15). 9 Results show that the distance d between the more shielded NCH2 proton and its closest CTV aromatic-H, as indicated in Figure 7.1, has been expanded from 3.86 Å to 13.57 Å. In contrast, when similar experiments were performed with Me4N + and any of the free molecular hosts 1, no characteristic complex induced shift of the Me4N + signal was observed, even after several days. These results demonstrate that the inner cavity of the vanadium cage complex is accessible, whereas there is no available molecular cavity in the parent free host. Thus, it appears clearly that the vanadium acts as an inflator to fully inflate the imploded cages.

To test the reversibility of the inflation-deflation dynamic process, we studied the binding-unbinding properties of the hemicryptophanes 1 with vanadium(V) oxytriisopropoxide. To remove the oxidovanadium moiety from the cage ligand, an excess of triethanolamine (TEA) was added to a solution of vanadium@M-SSS-SSS-1 in CDCl3. The NMR spectrum showed that vanadium was fully de-coordinated from the cage ligand, followed by immediate collapse, proving that the imploded structure of the free ligand is much more stable than its globular form. Subsequent addition to this solution of an excess of vanadium(V) oxytriisopropoxide, recovered the initial shape of the vanadium@hemicryptophane complex. This switch between the imploded and inflated bi-stable states has been performed at least for three cycles in the case of M-SSS-RRR-1 7.3 and S7.16). Therefore, through the input of vanadium reagent or TEA as a stimulus, the hemicryptophane cage can artificially breathe.

(Figures

Conclusion

In summary, we have described herein a class of imploded hemicryptophane cages. The level of collapse, which can be indicated by the inter-proton distances between the CTV and trialkanolamine units, have been measured based on NOE cross-peaks of the ROESY spectra.

It was found that the imploded degree of the cages can be controlled by varying the stereochemistry of the constructing units. Stereomodulation of the inner cavity also results in the regulation of their corresponding physical and chemical properties. For instance, the reaction between vanadium(V) oxytriisopropoxide and the most imploded cage P-SSS-SSS-1

suffers from a slower reaction rate compared to the other three diastereomers. Interestingly, vanadium complexation re-inflates the cage from its imploded conformation to a globular form, and the resulting vanadium core can also be removed from the inner cavity according to external coordination with TEA. Thus, this system is capable of switching between the imploded and expanded bi-stable states via external inputs, leading to a molecular breathing motion. This class of molecular cage is for the first time exploited as a novel mode of switching that is worthy of being explored for potential applications.

Experimental section

Materials and instrumentation

All solvents used were of commercial grade and were dried prior to use over molecular sieves. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance spectrometer operating at 500.10 MHz and 125.76 MHz for 1 H NMR and 13 C NMR spectra, respectively. 1 H NMR chemical shifts (δ) are reported in ppm and referenced to the protonated residual solvent signal. The method for measurement of the interproton distances was proposed by Sebastiano Di Pietro. X-ray data were collected, solved and refined by Heinz Gornitzka.

Crystal data

Table S7.1 Crystal data and refinement for compound Spectra of V@M-SSS-RRR-1 obtained from (d) by the same procedure as that from (b) to (c); (f) Spectra of the ligand M-SSS-RRR-1 obtained by adding an excess of TEA to (e); and (g) Spectra of V@M-SSS-RRR-1 obtained from (f) by the same procedure as that from (b) to (c).

M-RRR-RRR-1•2(CHCl3)•(Et2O).

Measurement of the interproton distances

Briefly, for two dipolar coupled nuclei A and B (Scheme S7.1), the rate constant RAB is inversely proportional to the sixth power of their inter-proton distance rAB: = Where k is a constant which is determined by the parameters of the NMR experiment. If we select another two coupled nuclei C and D in the same cage as the reference, we can exploit the following relationship, since the k value will be cancelled.

= × √ 6

Hence, from this equation, if we determine the rate constants RAB and RCD, and if the reference distance rCD is known, we can calculate the unknown distance rAB. The reference nuclei C and D have to be chosen from the rigid part of the cage to possess an invariable distance, which can be measured directly from the crystal structure. For RAB and RCD, by inputting the relative volumes of both cross and diagonal peaks of the interacting nuclei, the mixing time of the experiment, and the peak volumes of the same couple of nuclei measured at zero mixing time (all the magnetization is in the diagonal peaks), the routine EXSYcalc can output the corresponding rate constant via an eigenvalues eigenvector method. 10 Scheme S7.1 Graphical representation illustrates the desired interproton distance between HA and HB, the reference distances between H1 and H2 on the binaphthol, and between Ha and He on the CTV.

Herein, the distance between H1 and H2 on the binaphthol unit (2.29 Å) or that between the diastereotopic Ha and He (1.60 Å) on the CTV were chosen as the references (Scheme S7.1). The Table of Contents in each chapter has been presented in the corresponding chapter cover.

NMR characterization

The cited references are listed at the end of each chapter.

Abstract

Five sets of oxido-vanadium(V) complexes, including both cages and open structures, were prepared and tested in catalytic oxidation of sulfides. It was found that the hemicryptophane complexes comprising simultaneously cyclotriveratrylene (CTV), binaphthol and oxido-vanadium(V) moieties are the most efficient supramolecular catalysts. The specific shape of the confined hydrophobic space above the metal center leads to a strong improvement of the yield, the selectivity and the rate of the reaction, compared to the other catalysts investigated herein. A remarkable turnover number (TON) of 10000 was obtained, which can be attributed both to the high reactivity and to the stability of the catalyst. Similar as enzymes, kinetic analysis shows that the mechanism of oxidation with the supramolecular catalysts obeys the Michaelis-Menten model, with initial rate saturation upon increasing substrate concentration. This enzyme-like behavior is also supported by the competitive inhibition and substrate size-selectivity observed, underlining the crucial role played by the cavity.

Introduction

Molecular cages, bearing a well-defined cavity with suitable endohedral functionalities, are very attractive since they can mimic biological systems, such as enzymes, to realize supramolecular catalysis of various reactions in their confined space. 1 These cage catalysts are capable of surrounding the surfaces of the reactants imposing specific orientation and conformation of the substrate in the vicinity of the catalytic site, leading to new and original reactivity. 2 Importantly, the goal of using such systems as true synthetic analogues of enzymes requires not only a high selectivity but also the enhancement of the reaction rates, like in enzymatic reactions. 3 However, product inhibition using supramolecular catalysts is commonly observed, since the high affinity of the product with the cavity can prevent further catalytic cycles. 4 Consequently, relatively large catalyst loadings are frequently required and low turnover numbers (TONs) are usually obtained. This issue has become one of the biggest challenges in supramolecular catalysis. 4a A pioneering work presenting high-turnover catalysis with supramolecular catalysts was reported by Raymond and Bergman groups in 2011. 5 They incorporated a ruthenium(II) cation into a supramolecular assembly, which was active in the isomerization of allyl alcohols with turnovers reaching 1070. Recently, using the same assembly, high TONs (> 300) were also reached in alkyl-alkyl reductive elimination catalyzed by the encapsulated gold(III) or platinum(IV) complex. 2j

Although tremendous advances have been made in the development of self-assembled hosts for guest encapsulation and transformation, it should be noted that covalent cages present several advantages, such as their stability and easier endohedral functionalization. 2n-p,6 Among the covalent cage compounds, hemicryptophanes, which are constructed from a cyclotriveratrylene (CTV) moiety and another different C3 symmetrical unit, have recently received a growing interest. The endohedral functionalization of their cavities via covalent bonds is versatile, giving rise to various excellent supramolecular catalysts presenting improved selectivity, reactivity, TON and/or stability compared to the related model catalysts which lack a cavity. 7 For instance, an oxido-vanadium(V) active site was attached inside the hydrophobic cavity of hemicryptophanes (complexes in Set III, Figure 8.1), which were efficient in oxidation of the hydrophobic sulfide substrate into the hydrophilic sulfoxide product with 180 turnovers. 7e In the present work, we have designed hemicryptophane derivatives containing binaphthol moieties (complexes in Set II, Figure 8.1), aiming at constructing more hydrophobic cavities.

In addition, compared with the catalysts in Set III, the location of the bulky binaphthol units in the linkers can isolate more efficiently the heart of the cavity from the bulk solution, thus the effect of the confinement in stabilizing a transition state should be more pronounced. We have also prepared the oxido-vanadium(V) complexes of the related open structure (complexes in Set IV and V) and of cages with smaller cavity size (cage complexes in Set I) to demonstrate the necessity of having a cavity and the essential role of its size. Sulfoxidation, an important oxidation reaction due to the importance of sulfoxides in the synthesis of pharmaceutical and agrochemical products, 8 was chosen as the model reaction. It was found that the new hemicryptophane complexes (Set II) combining both a CTV moiety and binaphthol units are most efficient for the oxidation of thioanisol, exhibiting a TON of 10000, a remarkable TON for a supramolecular cage catalyst. Mechanism studies show that the catalytic behaviors exhibit the Michaelis-Menten kinetics, competitive inhibition and substrate size-selectivity, suggesting that the reaction occurs inside the cavity of the hemicryptophanes.

Results and discussion

Design and synthesis

Scheme 8.1 Synthesis of the complex (S,S,S)-(S,S,S)-1.

The synthesis of the oxido-vanadium complexes 3 and 5 have been previously reported. 7e,9

Complexes 2 and 4 were obtained from the corresponding stereoisomers 10 by reaction with vanadium(V)-oxytriisopropoxide in CHCl3 at room temperature (r.t.) with excellent yields (> 90%). The was subsequently deprotected to generate the phenol derivative (S,S,S)-(S,S,S)-11, followed by a [1+1] reaction with 1,3,5-tris(bromomethyl)benzene in DMF under high dilution conditions to give the cage (S,S,S)-(S,S,S)-12. Compared to our previously reported synthesis of compound 11 based on the deprotection of methoxy groups, 10 this new pathway gives higher yield (56% vs. 33%) and displays an easier purification step. Finally, the oxido-vanadium complex (S,S,S)-(S,S,S)-1 was obtained by the reaction of 12 with 1.0 equiv.

of vanadium(V)-oxytriisopropoxide in CHCl3. Derivative (S,S,S)-(R,R,R)-12 was obtained following the same procedure starting from enantiopure binaphthol S-6 and (R)-( )-glycidyl nosylate. However, the subsequent complexation of vanadium failed to give the desired complex, even in the presence of an excess of vanadium(V)-oxytriisopropoxide, probably because of the more hindered conformation of the cavity.

Catalytic properties

These complexes were first tested in the oxidation of thioanisole into sulfoxide, using cumene hydroperoxide (CHP) as terminal oxidant with 1.5 mol% of catalyst loading in CH2Cl2 at 0 °C. The results at 180 min and their kinetics are shown in Table 8. Using tert-butyl hydroperoxide (TBHP) as a terminal oxidant led to similar trends in reactivity (Figure S8.3). Therefore, the order of the catalytic activity, i.e. Set II > Set I > Set III > Set IV ≈ Set V, emphasizes that onρy the caμes containinμ simuρtaneousρy CTV, binaphthoρ and oxido-vanadium moieties can serve as highly efficient supramolecular catalysts. The specific shape of the confined hydrophobic space above the metal center efficiently isolates the substrate from the surrounding solvent and expels the hydrophilic product, leading to a strong improvement of the activity. 2 Moreover, the stablization of the transition state with catalysts 2 may also account for this improvement since the oxygen transfer will give a partial positive charge on the sulfur atom in the transition state which can be better stablized by the numerous aromatic rings of the cage. a Conditions: 1.5 mol% catalyst, 1.0 equiv. of CHP, CH2Cl2, 0 °C, 180 min. b Yield and selectivity were determined by HPLC with benzophenone as internal standard. Selectivity is defined as the yield/conversion ratio.

To have more accurate evaluation on the ratio of the kinetic constants, the catalyst amount was decreased to 1.0 mol% while keeping other conditions identical and using CHP as oxygen source. As shown in Figure 8.2, the reaction rate with P-(S,S,S)-(S,S,S)-2 is much faster than with other catalysts, and 91% yield has been reached within 120 min. Based on the initial rate, the kinetic constant with P-(S,S,S)-(S,S,S)-2 was estimated to be 3-, 5-and 33-fold higher than with (S,S,S)-(S,S,S)-1, M-(S,S,S)-3 and (S,S,S)-(S,S,S)-4, respectively, again emphasizing the efficiency of the new hemicryptophane complexes.

Yield (%)

As the confinement can strongly improve the reaction rate and no product inhibition effect was exhibited, we wonder if the new hemicryptophane complexes in Set II can overcome the issue of low TON which is commonly observed in supramolecular catalysis. 5 Thus, the oxidation of thioanisol was carried out with M-(S,S,S)-(R,R,R)-2 at a low loading (0.01%) at r.t.

As shown in Figure 8.3, a yield of 85% was obtained within 10 h, and a rarely observed remarkable TON up to 10000 was reached after 13 h. A turnover frequency (TOF) of 1200 h -1 further indicates the high catalytic activity of this family of confined catalysts. Albeit the catalyst loading is extremely low, the high selectivity for the reaction was also retained (> 90%), suggesting the stability of the catalyst. To further evaluate this stability, catalytic cycles using the same catalyst (0.1 mol%) for oxidation of thioanisol in CH2Cl2 at room temperature was performed. It was found that no noticeable alteration in catalytic activity over four-cycle experiments was observed (Figure S8.4), emphasizing the high stability of the encaged catalyst. Obviously, the constraint cage structure protects the metal active site from degradation as we, and also other groups, have previously reported. 5,7d

Mechanism investigation.

To understand whether the reaction catalyzed by hemicrytophane catalysts is similar to enzymatic catalysis, more detailed investigations, Michaelis-Menten kinetics, were explored.

In enzymatic reactions, a substrate and enzyme typically participate in a reversible equilibrium with an enzyme-substrate complex, and usually rate saturation at high substrate concentrations can be observed. evaluated that the rate acceleration, Kcat/Kuncat, is larger than 1.12 核10 7 , being an enzyme-like remarkable value. Another characteristic aspect of enzymatic catalysis is the possible inhibition of the enzyme active site with a suitable nonreactive molecule. A bound inhibitor can exclude substrate from the cavity, thereby inhibiting the activity of the enzyme. The Me4N + cation was expected to be encapsulated by the hemicryptophane cage because of the possible cation-interactions between this cationic guest and the numerous aromatic rings of the cage. 11 As shown in

Conclusion

In summary, using the oxidation of sulfide as a model reaction, we have described herein five sets of oxido-vanadium(V) complexes, including both cages (Sets I-III) and open (Sets IV and V) structures. It was found that the complexes (Set II) simultaneously holding CTV, binaphthol and oxido-vanadium groups are the most efficient catalysts because of the construction of the hydrophobic cavity with the right size, which is suitable to accommodate and convert the sulfide substrates, and to expel the product from the inner cavity. The oxidation of thioanisol, using the catalysts of Set II, displayed reaction rates 3-, 5-and 33-fold faster than those obtained with catalysts of Sets I, III and IV, respectively. The specific shape of the confined hydrophobic space above the metal center induced by the bulky binaphthol linkages, leads to strong improvement of the yield, the selectivity and also the catalytic activity. Hence, the present case constitutes a rare example of supramolecular catalysts that exhibit extremely high levels of efficiency with 10000 turnovers. The catalytic reaction obeys the Michaelis-Menten model of enzyme kinetics, and competitive inhibition of this reaction was observed using Me4N + as an inhibitor. The substrate size-selectivity of the cage catalysts further indicate that the reaction occurs inside the cavity of the hemicryptophane hosts mimicking enzymatic functions. Catalytic activities of these new supramolecular catalysts toward other reactions benefiting from the encapsulated vanadium(V) active sites, like oxidation of lignin models, are in progress in our laboratory.

Experimental section

Materials and instrumentation

All solvents used were of commercial grade and were dried prior to use over molecular sieves. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance spectrometer operating at 500.10 MHz and 125.76 MHz for 1 H NMR and 13 C NMR spectra, respectively. 1 H NMR chemical shifts (δ) are reported in ppm and referenced to the protonated residual solvent signal. Mass spectra were recorded by the Centre de Spectrométrie de Masse, Lyon.

HPLC analyses were performed on an Agilent-1100 apparatus (binary pump, autosampler, column, thermostat, and diode array detector) using Chiralpack IC (0.46 × 25 cm) column.

Synthesis and characterization

S-7/R-7:

A solution of K2CO3 (3.7 g, 27 mmol) and (S)-(-)-, -Bi(2-naphthol) (6.0 g, 20.9 mmol) in acetone (45 mL) was stirred at room temperature for 1 h under argon. Then 5 mL acetone solution of allyl bromide (2.8 g, 23 mmol) was added in one portion. After reflux under argon for 48 h, the solvent was evaporated. The mixture was then dissolved in CH2Cl2, and washed with distilled water for 3 times. The organic phase was dried over anhydrous Na2SO4, filtrated and evaporated. After column chromatography over silica gel (CH2Cl2/petroleum ether 3:2), 4.8 g (70%) S-7 was obtained as a white solid. .3, 134.0, 133.8, 133.2, 130.8, 129.7, 129.6, 129.1, 128.2, 128.1, 127.1, 126.4, 124.6(9), 124.6(5), 124.2, 123.2, 117.4, 116.9, 116.0, 115.4, 115.1, 69.8 9, 126.3, 125.2, 125.0, 123.8, 123.6, 120.5, 119.6, 116.3, 115.8, 115.3, 70.2, 69.8, 50.2, 44.0. ESI-HRMS m/z: found 405.1455, calcd for C26H22NaO3 [M+Na] + 405.1461.

S-R-8:

The procedure was similar as that of S-S-8 using the starting materials with the corresponding chirality in 90% yield. , 126.3(4), 126.3(1), 125.3, 125.1, 123.9, 123.6, 120.6, 119.7, 116.4, 115.9, 115.3, 70.4, 69.8, 50.1, 44.1. (75 mL, 525 mmol), (S,S,S)-(S,S,S)-8 (450 mg, 1.18 mmol) was added. After stirring at 50 °C for 12 h under argon, the solvent was evaporated. 10 mL pentane was added and evaporated, which was repeated for 3 times to fully remove the residue NH3. Then 2.0 equiv. of (S,S,S)-(S,S,S)-8 (900 mg, 2.35 mmol) and 150 mL MeOH were added under argon. The solution was stirred at 60 °C for 5 days. After evaporation of the solvent, the crude product was purified by column chromatography over silica gel (CH2Cl2/MeOH 200:3), 820 mg (60%) (S,S,S)-(S,S,S)-10 was obtained as a white solid. 2, 128.0, 127.9, 126.3(4), 126.3(2), 125.1(5), 125.0(6), 123.7(3), 123.6(9), 120.0, 119.9, 116.6, 115.7, 115.3, 71.2, 70.0, 66.3, 56.2. ESI-HRMS m/z: found 1064.5011, calcd for C78H70NO9

ESI-HRMS

[M+H] + 1164.5045.

(S,S,S)-(R,R,R)-10: The procedure was similar as that of (S,S,S)-(S,S,S)-10 using the starting materials with the corresponding chirality in 64% yield.

(S,S,S)-(R,R,R)-12:

The procedure was similar as that of (S,S,S)-(S,S,S)-12 using the starting materials with the corresponding chirality in 43% yield. 129.8(9), 129.8, 128.1(1), 128.0(6), 126.9, 126.7, 125.4, 125.2, 124.5, 124.3, 121.2, 120.7, 116.0, 115.6, 72.2, 71.1, 66.6, 64.3 (14.2 µL, 60.4 µmol) was added to the solution, which was further stirred for 1 h. After evaporation of the solvent, the mixture was dissolved in 10 mL CH2Cl2. The solution was filtered by syringe filter (pore size: 0.45 µm), followed by evaporation to give the complex (S,S,S)-(S,S,S)-1 (67 mg, 91%) as a dark green solid. 154.0, 153.3, 136.8, 134.4, 134.0, 129.9, 129.8, 129.5, 129.3, 128.1, 127.9, 127.0, 126.8, 126.4, 125.2, 125.1, 124.4(2), 124.3(6), 121.4, 120.7, 116.5, 114.2, 83.1, 71.6, 69.3, 57. (S,S,S)-(R,R,R)-1: A similar procedure as that of (S,S,S)-(S,S,S)-1 has been used for the synthesis of (S,S,S)-(R,R,S)-1 using the corresponding ligand. However, the reaction failed to give the desired complex as the 1 H NMR spectrum is too complicated to analyze. The different behavior from the synthesis of (S,S,S)-(S,S,S)-1 probably because of its more hindered conformation of the cavity. Scheme S8.1 Synthesis of the oxido-vanadium(V) hemicryptophane complexes 2.

P-(S,S,S)-(S,S,S)-2:

The ligand of P-(S,S,S)-(S,S,S)-2 complex was synthesized according to our previous procedure. 10 To 3 mL CHCl3, the ligand of P-(S,S,S)-(S,S,S)-2 (10 mg, 6.5 µmol) was added. The solution was stirred at room temperature for 5 min. Then vanadium(V) oxytriisopropoxide (4.8 µL, 19.6 µmol) was added to the solution, which was further stirred for 1 h. After evaporation of the solvent, the mixture was dissolved in 5 mL CH2Cl2. The solution was filtered by syringe filter (pore size: 0.45 µm), followed by evaporation to give the

Introduction

The confinement of catalytic sites in well-defined cavities arises a growing interest since it can mimic the binding pocket of enzyme and thus induce new reactivities and selectivities. 1

Among the hosts presenting a well-defined cavity and capable of metal complexation, hemicryptophanes combining a cyclotrivertylene (CTV) moiety with another C3 symmetrical unit, constitute a novel class of supramolecular catalysts. 2 Indeed, depending on the catalytic sites encaged in the molecular cavity, improvement of the stability of the catalyst, rate and selectivity of the reaction can be observed. 3 For instance, encapsulation of an oxido-vandium site in a hemicryptophane core led to supramolecular catalyst 1 (Figure 9.1) for the oxidation of sulfide into sulfoxide: a strong improvement of the catalytic activity was achieved when compared to the model catalyst 2 which lacks a cavity. 4 Furthermore, we have recently showed that such oxido-vanadium model complex, similar as 2, exhibits good activity in the oxidation of lignin model, and an original two-electron-process was evidenced both experimentally and theoretically. 5 Such development of new catalytic processes for valorization of nonfood biomass polymers to chemicals and fuels is of great interest. 6 Indeed, Lignin is a nonfood biomass polymer composed by an irregular polymer presenting methoxy-substituted phenolic subunits. 7 However, this polymer is relatively complex and the different linkages are difficult to chemically breakdown. 8 Among the strategies that have been used, 9 the aerobic oxidation of this robust bio-polymer appears particularly promising. 10 Thus, considering the effect of confinement on the catalytic activity of oxido-vandium in the oxidation of sulfide, 4 and the good activity of this oxido-vanadium model in the oxidation of lignin, 10 we decided to examine the catalytic activities of the encaged vanadium complex 1 for the valorization of nonfood biopolymers. Merging supramolecular catalysis and lignin oxidation was expected to give rise to original complex systems with improved catalytic activity and/or selectivity.

Herein, we report the use of the cage complex 1 as a supramolecular catalyst for aerobic oxidation of lignin models. The encapsulation was found to improve the catalytic activity of the trapped vanadium site associated with the phenomenon of diastereoselective conversion of chiral substrates.

Results and discussion

We first tested the catalytic activity of the cage and model catalysts for aerobic oxidation of a simple diol substrate 3 (Table 9.1). Although this substrate cannot be considered as a lignin model, we chose this reaction in order to investigate the ability of the confined catalyst to perform such reaction on an easier oxidable compound and to have a preliminary result on the comparative efficiency of these systems. Reactions were carried out at 80°C in DMSO-d6 using 0.1 mol % of a catalyst. The yield and conversion were determined by 1 H NMR using mesitylene as an internal standard (Figure S9.1). We observed that after 18h, a conversion of 61% was reached with the cage catalyst 1, corresponding to a TON of 610. This represents a relatively high TON for a supramolecular catalyst considering the product inhibition frequently observed in supramolecular catalysis (Table 9.1). 11 A good selectivity was also achieved with this encapsulated complex, similar to that of the model one: over-oxidation was avoided since the aldehyde was obtained as a major product with an aldehyde/acid ratio of 10/1.3. Moreover, the encaged catalyst 1 displays a better catalytic activity than the mode 2, with conversions of 61% and 44%, respectively. Thus, it appears that for this simple diol substrate 3, the confinement has improved the reactivity and also retained the selectivity of the catalyst. This encourages us to examine the catalytic activity of this complex for substrate 6, which is usually employed as a lignin model. 10a a Determined by 1 H NMR using mesithylene as an internal standard.

We then tested the catalytic properties of the hemicryptophane catalyst 1 and the model catalyst 2 for the aerobic oxidation of 6. Yields and conversions were first determined by 1 H NMR spectroscopy using mesitylene as an internal standard (Figure S9.2). Reactions were performed in DMSO-d6 at 110°C with 1 mol % of a catalyst loading for 20 h (optimized conditions). Lowering the reaction time to 5 h at 110°C or the temperature to 100°C for 13 h decreased significantly the conversion (with each catalyst for either condition, conversions < 15%). Almost no catalytic activity was observed in CD3CN under reflux for 20h. We were pleased to observe that under the optimized conditions, the cage complex 1 gave better yields in products 4 and 7 (37% and 20%, respectively) than its model 2 (28% and 15%, respectively) (Table 9.2), again indicating that the confinement improved the reaction rate. However, because of signals overlap, this NMR method does not allow an accurate measurement of the yield of product 5 as well as the conversion. Thus we turn our attention in GC method to study more accurately the cage effect. a Cannot be accurately determined. b Determined by 1 H NMR using mesitylene as an internal standard. c Determined by GC using mesitylene as an internal standard.

Full assignment of the signals of 4-8 in the GC chromatogram was successfully achieved, allowing obtaining the yield of each product as well as the conversion (Figure S9.3). This GC analysis is consistent with the NMR data: the cage catalyst 1 give a better conversion than the model 2 (87% and 67%, respectively), as a consequence, better yields in products 4 and 7 were achieved: 38% and 17% respectively with the former vs 30% and 13% with the latter. Thus it appears that the supramolecular catalyst 1 does not suffer from product inhibition, as the observation for oxidation of 3, and a good conversion can be reached with a low loading for a cage catalyst.

As the substrate 6 was used as a 1/3.5 mixture of two diastereomers which can be distinguished by GC chromatogram showing two separate peaks, and the catalyst 1 is used as a single isomer, we expected that diastereoselective conversion of the substrates may be observed. 12 The GC analysis reveals that with the model catalyst 2, the initial ratio was almost retained at the end of the reaction (from 1/3.5 to 1/3.4), showing that the reaction rates are very similar for the two diastereomers (Figure S9.4). In contrast, this ratio changed to 1:1.4

with the cage complex 1, evidencing that the rate for one diasteromer is faster than for the other. The different catalytic behaviors of catalysts 1 and 2 may also reflect the fact that diastereoselective host-guest combination between the substrates and the cage catalyst may have occurred that can affect the catalytic rate. 12 Thus, it appears that the cage structure induced an improvement of the diastereoselectivity of the reaction, as previously observed with encaged Verkade superbase in a hemicryptophane core when used as catalyst in a Diels-Dalder basico-catalyzed reaction.

Conclusion

In conclusion, an oxido-vanadium complex trapped inside a hemicryptophane cavity has been used as a supramolecular catalyst for the aerobic oxidation of lignin model. Compared to the model catalyst with an open structure, an improvement of the catalytic activity associated with a diastereomerically selective conversion has been observed. Good TON was reached considering the supramolecular feature of catalyst 1. This underlines that this class of supramolecular catalysts benefits from its flexibility to prevent product inhibition, as previously observed for other hemicryptophane catalytic systems. Following this communication, our future work will seek to expand the scope of lignin substrates with the hemicryptophane catalyst to comprehensively understand the confinement effect.

Experimental section

Materials and instrumentation

Unless specified otherwise, all reactions were carried out under nitrogen using Schlenk techniques. Deuterated solvents were purchased from Cambridge Isotope Laboratories. 1 H NMR spectra were obtained at room temperature on a Bruker AVANCE 300 spectrometer, with chemical shifts referenced to the residual solvent signals. GC-MS anaρysis was performed using a Hewlett-Packard 6890 GC system equipped with a HewlettPackard 5973 mass selective detector.

Catalytic procedure

Catalytic oxidation of substrate 3. In a 25 mL Schlenk flask, substrate 3 (23.5 mg, 0.110 mmol), and 0.1 mol % 1 (0.18 mg, 1.10 × 10 -4 mmol) or 2 (0.13 mg, 1.10 × 10 -4 mmol) were dissolved in 0.8 mL of DMSO-d6. The reaction was heated to 80 o C with constant stirring for 18 h. At the end of the reaction, the Schlenk flask was cooled down to room temperature. 0.4 mL of DMSO-d6 containing 1,3,5-trimethylbenzene (6.0 uL, 0.043 mmol) as an internal standard was added. The reaction mixture was transferred to a NMR tube and 1 H NMR spectrum was recorded. The yields of 4 and 5, and the conversion of 3 were calculated based on the corresponding integration against that of the internal standard.

Catalytic oxidation of substrate 6. In a 25 mL Schlenk flask, substrate 6 (25.0 mg, 0.110 mmol), and 1 mol % 1 (1.75 mg, 1.10 × 10 -4 mmol) or 2 (1.28 mg, 1.10 × 10 -4 mmol) were dissolved in 0.8 mL of DMSO-d6. The reaction was heated to 120 o C with constant stirring for 20 h. At the end of the reaction, the Schlenk flask was cooled down to room temperature. 0.4 mL of DMSO-d6 containing 1,3,5-trimethylbenzene (6.0 uL, 0.043 mmol) as an internal standard was added. The reaction mixture was transferred to a NMR tube and 1 H NMR spectrum was recorded. The yields of 7, 8, 10 and 11 were calculated based on the corresponding integration against that of the internal standard. The yield of 9 and the conversion of 6 cannot be determined due to signals overlap. To address the scope of the azaphosphatranes as hydrogen bonding moieties, their ability to activate C=O bonds was first evaluated in the model reaction of lactide ROP. Indeed, as the pKa values of azaphosphatranes are larger than 32 in CH3CN, [START_REF] Brotin | [END_REF] their corresponding protonated azaphosphatrane salts are very weak acids. As a consequence, the latter can be used in partnership with basic cocatalysts such as Sp, PMP, or CyNMe2 (pKa < 22 in CH3CN), 25 without any proton exchange.

The effect of phosphonium substituents (R: Me, iPr, CH2C6H4-p-OMe) was screened using protonated Verkade's bases [1a-1c•H] + •X (Scheme 10.1). In addition, two hindered and lipophilic anions, bis(trifluoromethane)sulfonimide (X: NTf2 ) and tetrakis [3,5-bis(trifluoromethyl)phenyl]borate (X: BArF ), were used as non-coordinating counterions to ensure the solubility of the cationic catalysts in dichloromethane, and to favour their interactions with the monomer.

Results and discussion

Synthesis

New azaphosphatranes [1a-1c•H] + •Cl (Scheme 10.1) were obtained according to a two-step published procedure. [START_REF] Collet | Comprehensive Supramolecular Chemistry[END_REF] consistent with C3-symmetrical structures for the azaphosphatrane units. One doublet due to the acidic proton could be observed between 5.27 and 5.85 ppm, with a J constant between 491 and 502 Hz. The 31 P NMR spectra show the characteristic signal of an azaphosphatrane, with chemical shifts varying between 9.0 and 11.6 ppm, similar to their chloride analogues.

X-ray diffraction

Crystallographic structures of azaphosphatranes with different aliphatic R substituents and different anions have been reported since the late 1980s. 1,29 These structures unambiguously show the hybridization of the phosphorus and nitrogen atoms within these rigid globular In the [1b Thus, the inspection of these two azaphosphatranes in the solid state showed that the globular rigid structures can provide a + P H group as a main hydrogen-bond donor, possibly assisted by the three surrounding C H bonds from the aliphatic substituents R.

Intermolecular hydrogen-bonds

The accepted mechanism for the ring-opening polymerization of cyclic esters promoted by hydrogen bonding relies on the simultaneous formation of two distinct hydrogen-bonded complexes (Figure 10.2) in both initiation and propagation steps. 12,13 Indeed, when the carbonyl group of the monomer is interacting with the hydrogen-bond-donor catalyst (i. This mechanism requires the formation of specific hydrogen bonds between the desired partners. If stronger hydrogen bonds can form between other partners (e.g., between the two catalysts), then the efficiency of the catalysis can be dramatically reduced. 18b To evaluate the hydrogen bonding between partners, and the ability of different catalyst combinations to promote the ROP reaction, geometry optimizations at the PM3 level were undertaken on a mixture of [1b•H] + with L-lactide (desired hydrogen bonds), and on mixtures of [1b•H] + with the different cocatalysts (undesired hydrogen bonds) (see Figure 10.3, right).

A hydrogen bond between the P + H bond and the carbonyl group of lactide (O-1 P-1: 2.75 Å) was observed, without any steric hindrance between the two partners (Figure 10.3, left). In contrast, the formation of a hydrogen-bonded complex between CyNMe2 and [1b•H] + is prevented by strong steric hindrance between the aliphatic substituents of the two partners. The bulkier tertiary amines, i.e., PMP and ( )-sparteine, cannot form hydrogen bonds between their nitrogen atom and the + P H bond (see Experimental section in this chapter). Based on semi-empirical calculations, the chosen azaphosphatranes and tertiary amines should not inhibit the catalytic reaction through undesired hydrogen bonding between the catalyst molecules. However, in the key step of the mechanism, two hydrogen-bonded complexes are formed in close proximity. So the bulkiness of all of the partners could play a role in the efficiency of the initiation and propagation steps. This point will be considered in the following reactivity section.

Catalytic properties in the ROP of lactide

The organocatalyzed ROP of DL-lactide was carried out in dry dichloromethane under the usual conditions (20 °C, 24 h, 4 Å molecular sieves, 30 [LA] = 1 M), in the presence of the hydrogen-bonding systems (donor + acceptor; 5 or 10 mol%), and 4-biphenylmethanol (BMP) as the initiator (5 or 10 mol%). 12 Due to its known efficiency in the ROP of LA, ( )-sparteine (Sp) was systematically used as the hydrogen-bond acceptor catalyst, while pentamethylpiperidine (PMP) and CyNMe2 were tested with some of the azaphosphatranes.

Preliminary experiments indicated that each component of the catalytic system [azaphosphatrane, tertiary amine, initiator, or molecular sieves (4 Å)] did not trigger the ROP independently. Only Sp gave a conversion of about 10% in the presence of the initiator and in the absence of a hydrogen-bond donor. 18b

The reaction mixtures were analysed by 1 H NMR spectroscopy to establish the percentage conversion. The crude polyesters were analysed by size-exclusion chromatography (SEC) to determine the molar mass (Mn) and dispersity (Ð), and by mass spectrometry to establish the chain-end fidelity and distribution (see Experimental section). In accordance with a living-like mechanism through H-bonds, the average molar masses were close to the theoretical ones, and the dispersity was narrow (Ð = 1.03 1.09). MALDI-TOF analysis confirmed these data, and showed that the side-reaction of polyester transesterification was very limited

The conversion ranged from 40 to 53% when the catalytic systems were at 5 mol%, and it reached 74 81% when the hydrogen-bonding systems were used at 10 mol% catalyst loading (Table 10.2). Compared to the leading system (thiourea + Sp) 14 which gives 100% conversion, the catalytic efficiency of these combinations is somewhat lower. Two hypotheses can be proposed: either the hydrogen-bond donor properties of azaphosphatranes towards C=O are moderate, or the steric hindrance of the azaphosphatranes can preclude their approach towards the (alcohol/hydrogen-bond acceptor) complex, a crucial step for the propagation.

Concerning the strength of the hydrogen bond between lactide and the azaphosphatranes, titrations monitored by 1 H and 31 P NMR spectroscopy (CDCl3) revealed changes in chemical shift that were too small for the corresponding binding constants to be determined accurately.

This fact also indicates that the hydrogen bonding between the two species is weak (K < 1 M 1 ), and weaker than previously reported. 14,18b,18c,20a So both moderate hydrogen-bond activation of the C=O group and steric hindrance from the azaphosphatranes can account for the conversions being 74 81% after 24 h. It is interesting that for each cation we tested in these ROP reactions, the nature of the phosphonium counterion (X : NTf2 or BArF ) had no impact on the conversion. This might be due to the noncoordination of the ion pairs in each case. Furthermore, variation of the phosphonium substituents (R: Me, iPr, CH2C6H4-p-OMe) has no noticeable effect, as conversions are similar in all entries of Table 10.2. This is in sharp contrast with our previous results related to the use of azaphosphatranes as phase-transfer catalysts or organocatalysts for CO2 conversion. 6 10 In both these previous cases, [1a•H] + •Cl was found to be a much less efficient catalyst than its aromatic or neopentylsubstituted counterparts, steric hindrance accounting for the higher stability of these latter two. Thus, the mild conditions used here in this ROP reaction allow the simplest system (i.e., [1a•H] + •X ) to show catalytic activity comparable to that of more hindered systems, paving the way for the use of this easily accessible compound in other reactions involving C=O activation. However, when the azaphosphatrane-based hemicryptophane cage (Figure 10.4) was used as catalysts (conditions:

5 mol% catalyst, BArF counterion, Sp, 5 mol% BMP, DL-Lactide 1 M in CH2Cl2, 20 °C, 24 h), only 10% of conversion was observed, indicating that the steric hindrance induced by the cage is too significant, which prevents the three reactants simutaneouly close to the catalytic site to afford the catalytic reaction.

Conclusion

New azaphosphatranes with lipophilic hindered anions (NTf2 or BArF ) were synthesized.

Crystallographic analysis and semiempirical calculations revealed that the phosphonium group is located in a hydrophobic cavity on top of a globular structure. Thus, the + P H bond can interact with the C=O group of lactide, but undesired hydrogen bonding with the tertiary amine cocatalysts does not take place, due to steric hindrance. A shape memory phenomenon was observed during guest displacement due to its faster kinetics relative to those of structural reconfiguration.

Introduction

Self-assembly is an efficient tool for the construction of diverse functional architectures. 1 One subset of these, metal organic polyhedral complexes, have proven useful in a range of applications, including molecular recognition, 2 chirality sensing, 3 gas separation, 4 stabilization of reactive species, 5 and catalysis. 6 The strategy of subcomponent self-assembly 7 allows the preparation of a variety of capsules with different shapes and sizes, which bind a diverse collection of guests. 8 Most such capsules contain cavities surrounded by aromatic panels. 7a-d The elaboration of the cavity microenvironment, through incorporation of functional moieties, 7e,7f represents an attractive means by which specific substrate encapsulation might be achieved.

Azaphosphatranes, the conjugate acids of Verkade superbases, 9 are attractive functional moieties for incorporation into the faces of tetrahedral capsules. Their polarized + P H groups enable them to be employed as catalysts for CO2 activation and lactide ring-opening polymerization. 10 Although both of these applications benefit from the hydrogen-bond donor ability of the + P H group, their use as anion receptors has not been reported. Importantly, these cationic species can be rendered water-soluble via selection of a suitable counterion, potentially enabling their use as anion binders in water, the development of which has been identified as a key challenge in supramolecular chemistry. 11

Scheme 11.1 Subcomponent self-assembly of cage 1 in acetonitrile.

Here we report a new azaphosphatrane-functionalized tetrahedron 1, (Scheme 11.1) assembled from cationic triamine subcomponent A. The design of 1 was based on the following four principles. First, the cationic nature of the azaphosphatranes together with the metal ions provide an overall +12 charge, offering a strong electrostatic driving force for anion binding. Second, the cationic framework also inductively increases the affinity of the + P H hydrogen bond donor for anionic species. 12 Third, the counterion SO4 2-was chosen to maximize the water solubility of 1. Fourth, methylene groups between the phenyl rings and azaphosphatrane nitrogen atoms were introduced to enhance cage flexibility, enabling the cavity to adapt to fit a diverse array of anions.

Results and discussion

We first prepared cage We then attempted the preparation of a water-soluble cage by employing SO4 - counterions. 13 The Cl -of A was exchanged to SO4 -(Scheme S11.2). However, the subsequent reaction of A•[SO4]0.5 (4 equiv) with FeSO4 (4 equiv) and 2-formylpyridine (12 equiv) failed to give the expected cage complex (Figure S11.37). We infer that the hydrophilic character of 52, S11.62 and S11.65). The two cage isomers were observed to interconvert taking at least two weeks at 298 K to reach equilibrium, which was monitored by both 1 H and 31 P NMR. For instance, for the self-assembly with NO3 -as a template, a gradual conversion from T-1 to C3-1 was observed with the ratio changing from 58:42 at 24 h to 10:90 at 215 h (Figure 11.3, S11.50 and S11.52). This indicates that NO3 -⊂T-1 is kinetically metastable while NO3 -⊂C3-1 is thermodynamically favorable. After two weeks at 298 K, the ratio of NO3 -⊂T-1:NO3 -⊂C3-1 became constant with a value of 5:95. This value remained unchanged on varying the initial concentration. The free energy of activation for interconversion was then determined from 1 H NMR experiments, and calculated to be 105 kJ mol -1 at 298 K from NO3 -⊂T-1 to NO3 -⊂C3-1 with a rate constant of (2.95 ± 0.08) × 10 -6 s -1 (Figure S11.67). were observed to be both kinetically and thermodynamically favored products compared to BF4 -⊂C3-1 and I -⊂C3-1, respectively, giving ratios of 90:10 and 56:44 at equilibrium after two weeks. The free energies of activation at 298 K for the conversion from X -⊂C3-1 to X -⊂T-1 (X - = BF4 -or I -) are 105 kJ mol -1 and 106 kJ mol respectively (Figures S11.68 and S11.69), similar to the value in the case of NO3 -. Considering these values are very close to the previously reported energy barriers of interconversion between homochiral and heterochiral M4L6 tetrahedral isomers (around 102 kJ mol -1 ) 15 and noting that no disassembled products were observed during the conversion, we infer that the cage transformation occurs via a partial reconfiguration mechanism, which is also the pathway with the minimum energy barrier: only one azaphosphatrane face among the four is (partially) released followed by inversion and reassembly; during the whole process, the cage framework maintains a degree of structural integrity. 16 Based on the crystal structure of OTf -⊂1 in Figure 11.1, we prepared an MM3 model of NO3 -⊂C3-1 using SCIGRESS software (Figure 11.4). 17 The modelling studies support a configuration where all Fe II centers maintain the same Δ or Λ stereochemistry. The trigonal planar NO3 -is located in the plane formed by the three endo + P H groups with hydrogen bonding interactions. The bulky methylene groups of the exo-azaphosphatrane occupy the rest of the cavity. Consequently, its + P H is also available to form hydrogen bonds with the surrounding water. The volume of the preorganized planar cavity approximates 59 Å 3 (69% occupancy for NO3 -, Figure S11.70), significantly smaller than that of OTf -⊂T-1 (166 Å 3 ). This modelling also emphasizes why the assembled cage driven by NO3 -, rather than BF4 -(Figure 1 H NMR spectra of 1 templated by ClO4 -, ReO4 -, PF6 -, OTf -, NTf2 -or CB11H12 -in water show only one set of ligand signals (Figure S11.38 and S11.39), indicating the exclusive formation of the T-cage. This is also consistent with the highly symmetric 13 C and 31 P NMR spectra (Figure S11. 40 and S11.41) as well as 2D NMR spectra (Figure S11. 43-S11.48). Especially, the 1 H 19 F HOESY spectra of OTf -/PF6 -⊂T-1•[SO4]5.5 exhibit strong NOE correlations between the F atoms of the encapsulated guest and the + P H of the azaphosphatranes, underlining the hydrogen bonding interactions (Figures S11.42, S11.47 and S11.48).

Although the cage is unstable in the absence of a template anion, competitive guest exchange offers a way of measuring the relative binding affinities of the different anions. We first chose the 19 F NMR spectrum of OTf -⊂1•[SO4]5.5 as the reference and monitored the decrease of the encapsulated OTf -and increase of the free OTf -upon addition of a competitive anion. Results show that the binding affinities of PF6 -, ReO4 -and ClO4 -are 17, 1.9 and 0.03-fold relative to that of OTf -, respectively (Figures S11.71-S11.73). No obvious OTf - displacement was observed upon addition of NO3 -, BF4 -, I -, NTf2 -or CB11H12 -. 18 We then chose the 1 H NMR spectrum of NTf2 -⊂1•[SO4]5.5 as the reference to classify the relative binding affinities of theses latter anions. It was observed that 1.7 equiv of CB11H12 -completely displaced the encapsulated NTf2 -, (Figure S11.74), while a larger excess of BF4 -or I -was needed, with BF4 -binding stronger than I -(Figure S11. 75 and S11.76). NO3 -was unable to displace the bound NTf2 -. Combining all these results, we can establish the following anion binding hierarchy: PF6 -> ReO4 -> OTf -> ClO4 -> CB11H12 -> NTf2 -> BF4 -> I -> NO3 -. This hierarchy cannot be rationaρized by Rebeπ s % ruρe due to the λρexibiρity oλ the cavity. 19 Moreover, it can be noted that the binding affinity for ReO4 -is higher than those for most of other anions, indicating that the cage may be a promising receptor for perrhenate or the physicochemically similar pertechnetate in water, which is useful in the context of radiopharmaceuticals and nuclear waste treatment. 11d

Despite the BF4 -templated assembly existing in two distinct cage isomers in equilibrium (T-1 ⇌ C3-1), it was noted that during the titration of BF4 -into NTf2 -⊂T-1, only BF4 -⊂T-1 was observed within 5 h, while BF4 -⊂C3-1 appeared thereafter, indicating a short-term shape memory effect (Figure 11.5). Further experiments showed that after addition of 2 equiv of BF4 - to the solution containing a 5:95 ratio of NO3 -⊂T-1:NO3 -⊂C3-1, a 5:95 ratio of BF4 -⊂T-1:BF4 -⊂C3-1 was observed immediately following the competitive anion displacement (Figure S11.77). Over time, BF4 -⊂C3-1 gradually converted to BF4 -⊂T-1 to reach equilibrium.

These results indicate that two successive processes have occurred: the fast kinetics of the direct guest displacement giving a shape memory phenomenon followed by the slow kinetics of BF4 -templated isomeric reconfiguration. Importantly, benefiting from the larger population of BF4 -⊂C3-1 (95%) after anion exchange from NO3 -⊂C3-1, we clearly observed NOE correlations between the bound BF4 -and the methylene protons of the exo-azaphosphatrane of BF4 -⊂C3-1 in the 1 H 19 F HOESY spectrum (Figure S11.78), which we were unable to observe directly in the BF4 --driven assembly (population of BF4 -⊂C3-1 < 25%), further verifying the accuracy of the assigned structure.

Conclusion

In summary, this study has demonstrated the feasibility of introducing azaphosphatranes into polyhedral complexes using subcomponent self-assembly, and also proved for the first time the utility of azaphosphatranes as anion binding moieties. Due to the designed flexibility, the assembled tetrahedron with acidic protons located inside encapsulates various anions in water with volumes ranging from 35 to 219 Å 3 via hydrogen bonding and electrostatic interactions. Moreover, structural adaptation was observed during cage formation in response to the size and shape of the external template anions exhibiting a X -⊂T-cage or a X -⊂C3-cage. The two cage isomers may coexist in solution and interconvert. Shape memory phenomena were observed during guest displacement due to its faster kinetics compared to that of isomeric reconfiguration. Future work will seek to use this tailored cage as an organocatalyst in supramolecular catalysis benefiting from the azaphosphatrane catalytic sites, for instance for CO2 conversion.

Experimental section 11.5.1 Materials and instrumentation

Unless otherwise specified, all reagents were purchased from commercial sources and used as received. NMR spectra were recorded using a Bruker 400 MHz Avance III HD Smart Probe (routine 1 H NMR), DCH 500 MHz dual cryoprobe (high-resolution 13 C), and DPX S5 500 MHz BB ATM ( 1 H, 13 C, 19 F and 31 P NMR and 2D experiments). Chemical shifts for 1 H, 13 C, 19 F and 31 P NMR are reported in ppm on the δ scale. DOSY experiments were performed on a Bruker DPX S5 500 MHz BB ATM spectrometer. Maximum gradient strength was 6.57 G/cmA. The standard Bruker pulse program, ledbpgp2s, employing a stimulated echo and longitudinal eddy-current delay (LED) using bipolar gradient pulses for diffusion was utilized.

Rectangular gradients were used with a total duration of 1.5 ms. Gradient recovery delays were s. Individuaρ rows oλ the S quasi-2D diffusion databases were phased and baseline corrected. X-ray data were collected, solved and refined by Tanya K. Ronson.

Flash column chromatography was performed using Silica Gel high purity grade (pore size 60 Å, 230-400 mesh particle size, Sigma-Aldrich). TLC analyses were performed on Merck TLC Siρica Geρ F Gρass pρates. Product spots were visuaρized under UV ρiμht max = 254 nm). All anhydrous reactions were carried out in oven-dried glassware and under an inert atmosphere of nitrogen. All reactions were stirred with magnetic followers. Centrifugation of samples was carried out using a Grant-Bio LMC-3000 low speed benchtop centrifuge. Low 298K, 125.7 MHz): 174.7 (Ca), 158.3 (Cn), 155.8 (Ce), 149.5 (Cl), 139.6 (Cc), 137.2 (Cm), 131.2 (Cb), 130.2 (Cg), 129.7 (Cd), 121.4 (Cf), 49.8 (Ch), 45.6, 37.8 (Ci and j) 129.9, 129.6, 117.3, 51.0, 47.5, 39.3. 31 (25.9 mg, 48.0 mol, 4 equiv.), FeSO4(H2O)7 (13.3 mg, 48.0 mol, 4 equiv.) and 2-formylpyridine (15.4 mg, 144 mol, 12 equiv.) were dissolved in D2O (4 mL). Then 1 equiv of template anion (12 mol) from the salt of NaBF4, KNO3, KI, KClO4, NaReO4, KPF6, NaOTf, LiNTf2 or CsCB11H12, was added. The reaction mixture was kept at 25 o C under nitrogen. The resulting purple solution of X ⊂1•[SO4]5.5 was used directly for the following anion displacement and shape memory phenomena.

It was found that for the assembly of the cage without additional template anions, no cage was λormed. When usinμ the tempρate anions with voρumes Å 3 , such as ClO4 , ReO4 , PF6 , OTf , NTf2 or CB11H12 , X ⊂T-1•[SO4]5.5 was formed after one night. However when using the tempρate anion with voρumes Å 3 , such as BF4 , NO3 or I , both X ⊂T-1•[SO4]5.

X-ray crystallography

Data were collected using a Bruker D8 VENTURE equipped with high-briρρiance I S Cu-K radiation .

Å , with ω and ψ scans at 180(2) K. Data integration and reduction were undertaken with SAINT and XPREP. [START_REF] Brotin | [END_REF] Subsequent computations were carried out using the WinGX-32 graphical user interface. 25 Multi-scan empirical absorption corrections were applied to the data using SADABS. [START_REF] Brotin | [END_REF] Structures were solved by direct methods using SHELXT [START_REF] Collet | Comprehensive Supramolecular Chemistry[END_REF] then refined and extended with SHELXL-2013. [START_REF] Collet | Comprehensive Supramolecular Chemistry[END_REF] In general, non-hydrogen atoms with occupancies greater than 0.5 were refined anisotropically. Carbon-bound hydrogen atoms were included in idealized positions and refined using a riding model.

Phosphorus-bound hydrogen atoms were first located in the difference Fourier map before refinement. Disorder was modelled using standard crystallographic methods including constraints, restraints and rigid bodies where necessary. Crystallographic data along with specific details pertaining to the refinement follow. Crystallographic data have been deposited with the CCDC (CCDC 1529220). Nevertheless, the quality of the data is far more than sufficient to establish the connectivity of the structure. The asymmetric unit was found to contain one half of a Fe4L4 assembly and associated counterions and solvent molecules. Due to the less than ideal resolution, bond lengths and angles within the two crystallographically unique organic ligands were restrained to be similar to each other and thermal parameter restraints (SIMU, RIGU) were applied to all atoms except for iron.

The anions within the structure show evidence of substantial disorder. Three triflimide anions were modelled as disordered over two or three locations and several anions were modelled with partial occupancies. The encapsulated triflate was disordered around a symmetry position and modelled as a rigid group. Substantial bond length and thermal parameter restraints were applied to facilitate a reasonable refinement of the disordered anions.

Further reflecting the solvent loss and poor diffraction properties there is a significant amount of void volume in the lattice containing smeared electron density from disordered solvent and 3.7 unresolved anions per Fe4L4 complex (included as triflate in the formula).

Consequently the SQUEEZE 27 function of PLATON 28 was employed to remove the contribution of the electron density associated with these remaining anions and further highly disordered solvent.

Volume calculations

In order to determine the available void space within 1 in the complex OTf ⊂T-1, VOIDOO calculations 29 based on the crystal structure were performed. The volume of 1 within NO3

⊂C3-1 was similarly calculated from the MM3 model. In both cases a virtual probe with a radius of 1.4 Å (set by default, water-sized) was employed, and the standard parameters tabulated below were used, following the previously published procedure. 30 Maximum number of volume-refinement cycles: 30

Minimum size of secondary grid: 3

Grid for plot files:

Competitive binding studies

A 3.0 mM stock solution of the templated cage OTf /NTf2 ⊂1•[SO4]5.5 in D2O was prepared through the procedures described in Section 11.5.2.4 in this Chapter. Then its concentration was adjusted to be around 1.0 mM through dilution with D2O, using t-BuOH as the internal standard. This solution was used directly for probing the relative binding strength of anions inside the cavity relative to OTf or NTf2 by recording 19 F NMR or 1 H NMR spectra. For each anionic guest, different equivalents were added to the reference solution in order to obtain an accurate average relative binding affinity. After each addition of the guest anion to the reference, the mixture was kept at 298 K for at least 12 h prior to recording the spectra to make sure the exchange between anions had reached the equilibrium.

In solution, there is the following equilibrium:

[ ] + [ ] ⇄ [ ] + [ ]
The relative binding constant (Krel) is calculated by the following equation:

= = [ ] [ ] × [ ] [ ]
Here Krel is the relative binding constant; Ka 2 is the binding constant for guest 2 and Ka 1 is the binding constant for guest 1. In the 19

Shape memory phenomenon

NO3 -driven assembled cages were used to investigate the shape memory phenomena by addition of the competitive anion BF4 in D2O. As described above, two weeks after initial mixture of the building blocks, the assembly driven by NO3 gave two cage isomers of NO3

⊂T-1 and NO3 ⊂C3-1 in a ratio of 5 : 95, as shown in the 1 H NMR spectrum (i) of Figure S11.77a. After addition of BF4 to the solution, the 1 H NMR spectrum changed immediately, giving a spectrum corresponding to the mixture of BF4 ⊂T-1 and BF4 ⊂C3-1 in a ratio of 5 : 95.

This indicates that guest displacement is relatively rapid. Afterwards, it was observed that in time, the concentration of BF4 ⊂T-1 gradually increased while that of BF4 ⊂C3-1 decreased.

This interconversion from BF4 ⊂C3-1 to BF4 ⊂T-1 suggests that after anion displacement, the assembly follows the kinetics of BF4 -driven assembly, rather than that driven by NO3 -. The observed behavior occurs also because the kinetics of guest displacement are faster than the kinetics of cage isomer reconfiguration. Therefore during the whole process, we first observed the shape memory phenomenon induced by guest displacement, followed by the BF4 -driven cage isomeric interconversion.

Part VI. Conclusion

In this PhD thesis, the advances in hemicryptophane chemistry have been thoroughly reviewed in Chapter 1. A brief history about its development is first given in the introduction part. Then synthetic methods and applications in recognition, molecular machines and supramolecular catalysis are successively described. Based on the inborn advantages of hemicryptophanes compared to other cages that were widely used in supramolecular chemistry as well as the limitation in the current development, in Chapter 2, we have proposed the objectives of this thesis. The major mission of this PhD work is to design and synthesize new hemicryptophane cages to either broaden their applications or to make the existing utilization more efficient. The final goal is to enhance the fundamental knowledge of hemicryptophanes in order to realize the targeted-function-directed molecular design, and apply them to other relevant cage hosts. These include the preparation of a series of new heteroditopic hemicryphtophanes bearing new building blocks, the synthesis of enantiopure cages having up to three types of chirality, and the preparation of metal@hemicryptophane complexes and self-assembled molecular capsules, all of which have been designed as recognition receptors, molecular machines, or supramolecular catalsysts. These two chapters constitute the first part of this thesis (Part I). analysis and semiempirical calculations revealed that the phosphonium group is located in a hydrophobic cavity on top of a globular structure. Thus, the + P H bond can interact with the C=O group of lactide, but undesired hydrogen bonding with the tertiary amine cocatalysts is unable to take place due to steric hindrance. The ability of azaphosphatranes to activate C=O groups in the ring-opening polymerization of lactide is promising, as the conversion reached 74 81% under classical conditions.

The works in

In this PhD thesis, my goal is not limited to the hemicryptophane cages, a more prospective view focusing on cages constructed by self-assembly has been opened, as described in Chapter 11 (Part V). In collaboration with Prof. Jonathan R. Nitschke at the University of Cambridge, we have demonstrated the feasibility of introducing azaphosphatranes into tetrahedron complexes using subcomponent self-assembly, and also proved for the first time the utility of azaphosphatranes as anion binding moieties. Due to the designed flexibility, the assembled tetrahedron is able to encapsulate various anions in water with volumes ranging from 35 to 219 Å 3 via hydrogen bonding and electrostatic interactions. Moreover, structural adaptation was observed during cage formation in response to the size and shape of the external template anions exhibiting a X -⊂T-cage or a X -⊂C3-cage. The two cage isomers may coexist in solution and interconvert. Shape memory phenomena were finally observed during guest displacement due to its faster kinetics compared to that of isomeric reconfiguration. We belive that this endohedrally functionalized assembled cage will have the great potential in supramolecular catalysis.

  La deuxième partie (Part II) s intéresse particuρièrement aux hémicryptophanes conçus pour la reconnaissance moléculaire. Chaque chapitre de la partie II inclue donc la synthèse et les propriétés de nouvelles molécules cages. Ainsi, le chapitre 3 (Chapter 3) décrit la synthèse d un hémicryptophane λρuorescent composé d une unité CTV, de μroupes naphtyρe dans ρes trois bras et d un site coordinant un atome de Zn II . Une teρρe moρécuρe s est avérée être un capteur très efficace de la choline phosphate dans un milieu compétitif pour la complexation. Le caractère hétéroditopique de ρ association a été étudié à la fois par fluorescence et par RMN. Dans le chapitre 4 (Chapter 4) nous comparons ρ eλλet de ρa λρuoration des μroupements aromatiques portés par ρes trois bras d un hémicryptophane sur ρa reconnaissance de paires d ions. Comme nous ρ avions anticipé, ρa λρuoration conduit à des constantes d associations plus fortes grâce à une augmentation des interactions anion-. Deux caμes portant une sous-unité tris(2-pyridylmethyl)amine (TPA) sont λont ρ objet du chapitre Chapter 5). Elles se distinguent par des bras phényle ou naphtyle et leurs énantiomères ont pu être séparés par HPLC chirale. Enfin le chapitre 6 (Chapter 6) présente la synthèse en version énantiopure de huit stéréoisomères d un nouveρ hémycryptophane possédant sept centres stéréoμènes de trois types diλλérents. L attribution de ρeurs conλiμurations absoρues ont pu être déterminées par corrélation chimique et leurs propriétés de reconnaissance des sucres a été examinée. La troisième partie (Part III) est composée du chapitre 7 (Chapter 7) et s intéresse à ρ appρication des caμes énantiopures décrites dans ρe chapitre (Chapter 6) dans le domaine des machines moρécuρaires. Nous y décrivons ρe mouvement de "respiration initié par da coordination/décoordination d un atome de vanadium s accompaμnant du passaμe d une cavité à volume réduit (implosée) à une cage déployée (gonflée). Dans la quatrième partie (Part IV), nous présentons trois études dans le domaine de la catalyse supramoléculaire. Les résultats présentés dans le chapitre 8 (Chapter 8) montrent que les complexes de vanadium(V) des cages obtenues dans le chapitre 7 (Chapter 7) sont des catalyseurs efficaces de la réaction de sulfoxydation. L eλλet de conλinement a été démontré par comparaison entre ρ activité du cataρyseur supramoρécuρaire et ceρρe de son homoρoμue ouvert ne comportant pas le CTV. En comparaison avec des résultats précédents, la présence des binaphtyle dans les bras permet une amélioration des rendements, de la sélectivité et de Résumé XII ρ activité cataρytique. Ces mêmes compρexes de vanadium V dérivés d hémicryptophanes se sont avérés capabρe de cataρyser ρ oxydation de ρa ρiμnine avec une activité cataρytique une disatéréosélectivité bien supérieure aux cataρyseurs modèρes ouverts. Ces résuρtats λont ρ objet du chapitre 9 (Chapter 9). Comme nous le montrons dans le chapitre 10 (Chapter 10), nous avons tenté d utiρiser des dérivés azaphosphatrane d hémicryptohanes comme organo-catalyseurs de la réaction de polymérisation par ouverture du lactide. Dans ce cas, une inhibition du catalyseur supramoléculaire a été observée alors que le catalyseur modèle ouvert s est avéré pρus perλormant et nous a permis de proposer un mécanisme pour cette réaction.

  ) sont publiés et les chapitre 9 (Chapter 9) vont être soumis pour publication.

Figure 1 . 1

 11 Figure 1.1 Cyclotribenzylene and cyclotriveratrylene (CTV, X = Y = OCH3); (b) Cryptophane-E.[START_REF] Brotin | [END_REF]

Figure 1 . 2

 12 Figure 1.2 (a) Hemicryptophanes 1-6 synthesized between 1982 and 2005. (b) Structures of Kuck's hemicryptophanes based on the TBTQ unit.

Figure 1 . 3

 13 Figure 1.3 Synthesis strategies for the preparation of hemicryptophane hosts: (a) by formation of the CTV unit; (b) by [1+1] coupling of north and south parts; (c) by closure reaction at the south part (X, Y and F are suitable functions).

Scheme 1 . 3

 13 Scheme 1.3 Synthesis of Hemicryptophanes 22 and 24.

Scheme 1 . 5

 15 Scheme 1.5 Synthesis of Hemicryptophanes 31a-c. Rivera et al. developed a very efficient and straightforward method, featuring the one-pot assembly of molecular architectures by Ugi-type multiple multicomponent macrocyclization of trifunctional building blocks, for the synthesis of the hemicryptophane 33 bearing

epoxide 37

 37 is synthesized by a regioselective nucleophilic substitution reaction of 36 on (R)-(-)-glycidyl nosylate in DMF. Then an excess of ammonia is added to the methanol solution of 37 to give the primary amine 38. The hemicryptophane precursor 39 is obtained by a trimerization reaction of 38 with 2 equiv. of the epoxide 37 in methanol followed by an acetylation reaction to decrease the polarity and facilitate the purification. An intramolecular cyclization of 39 is then accomplished using Sc(OTf)3 as Lewis acid in CH3CN to produce hemicryptophanes M-(R,R,R)-40 and P-(R,R,R)-40 in their diastereomerically pure form with yields of 22% and 17%, respectively after separation by column chromatography. Finally, the synthesis of hemicryptophanes M-(R,R,R)-41 and P-(R,R,R)-41 is achieved quantitatively from the corresponding hemicryptophane 40 by hydrolysis with methanolic NaOH. Starting from the (S)-(+) enantiomer of glycidyl nosylate, the other diastereoisomeric pair, P-(S,S,S)-41 and M-(S,S,S)-41, were also successfully prepared using the same synthetic pathway.The determination of the absolute configuration of the four stereoisomers of 41 was achieved using ECD spectroscopy. The P-configuration of the enantiopure hemicryptophane gave rise to a characteristic positive-negative bisignate (from low to high energies, 270-230 nm). In turn, the M-configuration is assigned to the hemicryptophane that gives a negative-positive bisignate, as observed in Figure1.4.60

Figure 1 . 4

 14 Figure 1.4 ECD spectra of the four stereoisomers of hemicryptophane 41 in CH2Cl2 at 20 o C.

(

  withdrawing or electro-donating groups), it can either interact with anions, cations or neutral guests by anion-, cation-or CH-interactions, respectiveρy. The λoρρowinμ examples are representative of the variety of strategies used for the construction of hemicryptophanes from a tripodal benzenic platform.

Scheme 1 . 10 64 Scheme 1 . 11

 11064111 Scheme 1.10 Synthesis of Hemicryptophanes M-(S,S,S)-56 and P-(S,S,S)-56.The absolute configurations of the stereoisomers M-(S,S,S)-56, P-(S,S,S)-56, M-(R,R,R)-56and P-(R,R,R)-56 were assigned using the chemical correlation method. For this, the authors synthesized the stereoisomers of 56 by the [1+1] coupling of diastereomerically and enantiomerically pure CTV 57 suitably substituted with BINOL arms, with 1,3,5-tris(bromomethyl)benzene as shown in Scheme 1.11 for M-(S,S,S)-56.64

Scheme 1 . 15

 115 Scheme 1.15 Synthesis of Hemicryptophanes M-76 and P-76. Hemicryptophanes based on a macrocyclic arylamide platform. Wang et al. synthesized hemicryptophanes 85a and 85b starting from the CTV tribromides 18a and 18b (Scheme

Scheme 1 . 19

 119 Scheme 1.19 Synthesis of Hemicryptophane 105.

77 Scheme 1 . 20 1 . 3 . 1 . 7

 771201317 Scheme 1.20 Synthesis of C60-CTV tris-adducts 3 and 4. 1.3.1.7 Hemicryptophanes constructed from a diphenylglycoluril unit Nolte et al. reported in 1989 the preparation of one of the first hemicryptophane structures.The cage molecule (5) was constructed from the CTV scaffold and a diphenylglycoluril southern unit that did not satisfy the expected C3 symmetry, giving rise to a molecular cage with a free functionalized arm. The strategy used is depicted in Scheme 1.21: vanillin reacts first with 1,6-dibromohexane to give 107, which then reacts with diphenylglycoluril to give the precursor 108a with four n-hexyl arms terminated with vanillyl groups. Reduction with NaBH4 affords the corresponding benzylic alcohol derivative 108b, which is treated in formic acid to produce the expected hemicryptophane 5.28

Figure 1 . 5

 15 Figure 1.5 Structures of hemicryptophanes built on [4Fe-4S] clusters.

Figure 1 . 6

 16 Figure 1.6 Hemicryptophane 113g obtained by complexation of iron ion: (a) X-ray molecular structure, (b) different linkages used in the construction of complexes 113a-h.

114

  Scheme 1.22 Formation of Hemicryptophane capsule Et4N + @116. Subsequently, the authors reported the assembled hemicryptophane capsule 116 with the same modules 114 and 115 triggered by amine using dynamic boronate esterification. 94 As shown in Scheme 1.23, upon addition of Et3N to the CD3OD/CD3CN solution of 114 and 115, the N B bonds are first formed together with the association of two modular compounds to generate the intermediate 117. Then, the cage 117 is subjected to a solvolysis reaction to produce the CD3O-attached 116 with the encapsulation of Et3NH + . The addition of Bu3N also

  Jabin et al. combined the trisamine-calix[6]arene 86 with the CTV-tricarboxylic acids 88 or 89 to generate [1+1] hemicryptophanes (Scheme 1.24).

Scheme 1 . 26

 126 Scheme 1.26 Synthesis of the Water-soluble Hemicryptophane 125.

Figure 1 . 7

 17 Figure 1.7 Structures of hemicryptophane superbases and the non-caged models.

Figure 1 . 9 X

 19 Figure 1.9 X-ray molecular structure of Fe(III)@101 complex.

  11), obtained by slow evaporation from a CH3CN solution, exhibited a preorganized cavity constructed by the CTV and the tren moieties.144 A molecule of CH3CN is entrapped inside the moρecuρar cavity stabiρized by hydroμen bondinμ and CH••• interactions.54

Figure 1 . 12

 112 Figure 1.12 Crystal structures of 15b, 31a, 105 and V(V)@P-(S,S,S)-41.

Figure 1 .

 1 Figure 1.13 A proposed binding mode between hemicryptophane 1 and MeNH3 + .

  displayed significant highfield shifts due to the shielding effect of the aromatic cavity, in agreement with the formation of inclusion complexes. The binding constants were thus determined based on the 1:1 stoichiometry indicated by Job s pρot, and showed reρativeρy hiμh values (10 4 -10 5 M -1 ) with an order BnNH3 + > MeNH3 + > t-BuNH3 + > n-PrNH3 + . A combination of a stabilizing hydrogen bonding network between the encapsulated ammonium and the tren moiety, and a good fit allowing both favourabρe CH••• interactions within the aromatic cavity and minimization of steric repulsions, can account for these results. In addition, the ability of hemicryptophane 15a to complex ammonium neurotransmitters was also investigated. A binding constant of 2.5 x 10 4 M -1 was measured with dopamine as guest molecule, highlighting the potential use of hemicryptophane hosts for the recognition of neurotransmitters. A binding mode between 15a and dopamine has been proposed by DFT calculations (Figure1.14a).

Figure 1 .

 1 Figure 1.14 (a) DFT optimized structure of dopamine@15a, and the structure of dopamine. (b) DFT optimized structure of choline@123, and the structures of choline, betaine aldehyde and glycine betaine.

Figure 1 .

 1 Figure 1.15 A proposed binding mode between hemicryptophane 91 and RNH3Cl.

Figure 1 .

 1 Figure 1.16 (a) Anion binding constants of hemicryptophane 14 in the absence or presence of 1 equiv. of Me4N + . Cooperativity factors are given in parentheses. (b) DFT-optimized structure of Me4NCl@14.

(

  estimated error 10%). c Packing coefficient based on a cavity volume of 169 Å 3 .

Figure 1 .

 1 Figure 1.18 DFT-optimized structures of (a) taurine@14, and (b) taurine@54.

Figure 1 .

 1 Figure 1.19 DFT-optimized structure of (R)-carnitine@PL-67.

  carbohydrates) and apolar surfaces (through C-H••• interactions with the aromatic rings of the host molecule).

Figure 1 . 20

 120 Figure 1.20 Structures of carbohydrate guests.

  a 7:1 enantioseρectivity λor Oct Gρc and excρusive enantioseρective recoμnition λor Oct Gρc are respectively observed, indicating the perfect enantio-discrimination induced by the inherent chirality of the M-enantiomer. Next, the authors also tested the recognition of the same sugar derivatives with the four stereoisomers of hemicryptophane 41 (Scheme 1.7) to investigate more accurately the control of the inherent chirality of the CTV on the enantioselective recoμnition. In this case, modest to hiμh diastereoseρectivity in λavor oλ Oct Gρc over Oct Gρc for the four isomers of 41 is reported. In addition, in most cases the exclusive binding of the M-enantiomers is observed, in accord with the above results, demonstrating the crucial role of the inherent chirality of the CTV, by comparison with the central chirality of the trialkanol amine moiety.

  8 for M-(S,S,S)-29, and exclusive binding for P-(S,S,S)-29. According to the authors, the binding sites being similar in hosts 14 and 29, conformational changes induced by the addition of the methyl groups account for both the improvement of the binding affinity and the change in selectivity. A marked, or even exclusive, enantioselectivity in favor of the M-configurated hosts is also observed, such as the bindinμ oλ Oct Gρc with P-(S,S,S)-29 and M-(R,R,R)-29, which is consistent with the results obtained with 14.

  1 H NMR NOESY experiments of 85b in CDCl3/CS2 revealed the existence of NOE cross-peaks between some protons in CTV and cyclic triimine, indicating the close contact between the two cyclic units. Addition of 1 equiv. of C60 or C70 caused the disappearance of these NOE signals, suggesting the encapsulation of the fullerenes in the molecular cavity of 85b. DOSY experiments performed with 85b showed a significant decrease of the diffusion coefficients of the host molecule in the presence of C60 or C70, in accord with the increase of the apparent size of 85b resulting in an extended conformation of the linkers after fullerene binding. Vapor pressure osmometry (VPO) experiments in toluene

  Generally, the following three criteria are required for the design of molecular gyroscopic systems: (i) rotary elements (rotators) should be attached to a static framework (stator); (ii) steric contacts, internal rotation barriers, and interaction with solvent should be minimized to allow low-barrier rotary motion; and (iii) rotating groups should be isolated and/or well-separated from each other.

Figure 1 .

 1 Figure 1.21 Gyroscope-inspired hemicryptophane 105 possessing two rigid stator and three rotator groups. Dmochowski et al. reported the gyroscope-inspired scaffold shown in Figure 1.21, in which the CTV and trisbenzylamine units of hemicryptophane 105 serve as the two-component stator bridged by three p-phenylenes, which are rotators. 52 The X-ray molecular structure of 105 showed an empty tribenzylamine hemicryptophane cavity because of the compact size of the cage. This absence of encapsulated solvent molecules that could hinder p-phenylene rotation, suggests a high freedom degree of rotation for the three rotators. The 1 H NMR experiments performed in the 180-300 K temperature range allowed determining the energy barrier of 9.2 kcal mol -1 for the rotation of the p-phenylene groups at the coalescence temperature (203 K). To investigate the conformational fluctuations of the rotators and stator, molecular dynamic simulations were carried out, which reveal the existence of weak steric hindrance between neighboring p-phenylenes, accounting for the measured energy barrier for rotation. Hence, this work presents a rigid hemicryptophane framework bearing close multiple rotators, which constitutes a molecular gyroscopic system. It should be noted that in spite of the fact that the correlared despite rotation of the aromatic rings was not observed and the control of the direction of the motion was not achieved, this gyroscope-inspired hemicryptophane is an important step towards the control of the direction and the coupling of rotators within molecular systems.

Figure 1 . 22

 122 Figure 1.22 Vanatrane structure and its Δ and Λ forms viewed down the N-V bond.

Figure 1 . 23

 123 Figure 1.23 Plot of the Λ/Δ ratio (from 1 H NMR data) vs. time for the ΔΛ stereoconversion of (a) V(V)@M-(S,S,S)-41 and (b) V(V)@P-(S,S,S)-41, after alternating dissolution in C6D6 and CDCl3.Martinez et al. investigated the oxidovanadium hemicryptophane complex V(V)@41 including the vanatrane structure (Scheme 1.28). Because of the atrane structure of the vanadyl moiety, they identified in the 1 H NMR spectra the two diastereomers V(V)@M-(S,S,S-Λ -41 and V(V)@M-(S,S,S-Δ -41 in the 1:0.35 ratio in CDCl3, respectively.139,156

Figure 1 . 24

 124 Figure 1.24 Changes of the cumulative TON for catalysts PH + @15a and PH + @126a as a function of time. Reaction conditions: styrene oxide (50.0 mmol), catalyst (0.05 mmol), CO2 (1 bar) and 100 o C.

Figure 1 . 25

 125 Figure 1.25 Time course of oxidation of thioanisole catalyzed by catalysts V(V)@M-(S,S,S)-41 and V(V)@(S,S,S)-126a. Conditions: 10 mol% catalyst, 1.0 equiv. of CHP, CH2Cl2, 0 o C.

Figure 1 . 26

 126 Figure 1.26 Time course of oxygenation of CyH catalyzed by Cu(II)@15a, Cu(II)@126 and Cu(ClO4(H2O)6. Conditions: MeCN (250 µL), CyH (3.2 µL, 30 µmol), H2O2 (300 µmol), catalyst (0.3 µmol), 35 o C).

Preface

  figure below). One common feature among the obtained racemic cages is that they all show heteroditopic properties, which are promising in the complexation of achiral zwitterions or ion pairs, as described in Chapters 3, 4 and 5. The enantiopure cages have been used for stereorecognition of carbohydrates, as discussed in Chapter 6.

Contents 3 . 1 78 3. 3

 31783 Abstract .......................................................................................................................78 3.2 Introduction ................................................................................................................Results and discussion .............................................................................................79 3.4 Conclusion ..................................................................................................................83 3.5 Experimental section .................................................................................................83 3.6 References ...................................................................................................................89

Figure 3 .

 3 Figure 3.1 1 H NMR spectra of Zn(II)@1 at different temperature in DMSO-d6. For the proton assignment, see Scheme 3.2.

Figure 3 . 2

 32 Figure 3.2 (a) Fluorescence titrations of 5 µM Zn(II)@1 excited at 300 nm with choline phosphate 2 in DMSO containing 2% water. Inset: the fluorescence intensity at 350 nm as a function of the equivalents of added choline phosphate 2. (b) Normalized spectra of 5 µM Zn(II)@1 upon addition of 2 equiv. of different guests in DMSO containing 2% water.

  9e Hence, we decided to study the fluorescent response of the present cage Zn(II)@1 for this competitive zwitterion. It was found that taurine 6 only gave rise to negligible fluorescence quenching of Zn(II)@1 in DMSO containing 2% water (Figure3.2b and FigureS3.5), highlighting(i) the high sensing selectivity of this new host for choline phosphate 2 and (ii) the possibility to tune the structure of hemicryptophane hosts in order to complex selectively a zwitterionic guest of biological interest. In this case, the specificity probably arise from the high binding affinity of Zn(II) moiety towards phosphorylated molecules. 14b,14d Indeed, the fluorescent sensing of choline phosphate using the ligand 1 was also investigated, and only very small fluorescent changes were observed (FigureS3.6), emphasizing the crucial role of Zn(II) moiety in this recognition process.More insights into the interaction mechanism were obtained from a series of NMR experiments. Progressive additions of choline phosphate 2 to a solution of Zn(II)@1 in DMSO-d6/D2O(80/20, v/v) at room temperature lead to more complicated signals for aromatic protons (down-field region) and to new peaks (up-field region) that cannot be assigned to the free choline phosphate 2, indicating the existence of multiple conformers in solution for the host-guest complex(Figure 3.3a and Figure S3.7). Heating the host-guest mixture up to 353 K resulted in the disappearance of these additional signals and the appearance of sharp and well defined peaks for the whole spectrum(Figure 3.3b and Figure S3.8). A subsequent return to room temperature for the mixture restored the initial spectrum(Figure S3.8). These results

  Zn(II)@1 in DMSO-d6/D2O(80/20, v/v) gave rise to new peaks in the up-field region of the 1 H NMR spectra (0.5-2.0 ppm), indicating a slow complexation exchange on the NMR time scale (Figure S3.10), whereas at higher temperature (353 K), the gradual shifts of the initial signals and the absence of new peaks during titrations suggest a fast exchange on the NMR time scale (Figure S3.11).

Figure 3 .

 3 Figure 3.3 1 H NMR spectra of 1 mM Zn(II)@1 in the absence and presence of 5.0 equiv. of choline phosphate 2 in DMSO-d6/D2O (80/20, v/v) at 298 K (a) and at 353 K (b). The four new peaks respectively at -0.50, 0.61, 1.32 and 1.79 ppm in Figure 3.3a are attributed to the four diastereotopic protons of the methylene groups of the encaged choline phosphate 2.

Figure 3 . 4

 34 Figure 3.4 DFT optimized structure of the complex between Zn(II)@1 and choline phosphate 2.

  4. ESI-MS m/z: found 1199.4224 [M 2+ + Cl -] + ; calcd for C69H73N4O9: 1199.4274. IR ῡ = 3237, 2934, 1612, 1507, 1483, 1263, 1218, 1282, 1085 cm -1 . M.p. > 350 °C (decomp.).

Figure S3. 1

 1 Figure S3.1 Fluorescence Job plot of Zn(II)@1 with choline phosphate 2 (a) and choline 3 (b).

Figure S3. 2

 2 Figure S3.2 Fluorescence titrations of 5 µM Zn(II)@1 with choline 3 excited at 300 nm in DMSO containing 2% water. Inset: the intensity at 350 nm as a function of the added choline 3.

Figure S3. 3

 3 Figure S3.3 Fluorescence titrations of 5 µM Zn(II)@1 with choline phosphate 2 (a) and choline 3 (b) excited at 300 nm in DMSO/H2O (80/20, v/v). Inset: the intensity at 350 nm as a function of the guest.

Figure S3. 4

 4 Figure S3.4 Fluorescence titrations of 5 μM Zn(II)@1 excited at 300 nm with guest 4 (a) and guest 5(b) in DMSO containing 2% water. Insets: the intensity at 350 nm as a function of the guest.

Figure S3. 5

 5 Figure S3.5 Fluorescence titrations of 5 μM Zn(II)@1 excited at 300 nm with taurine 6 in DMSO containing 2% water.

Figure S3. 6

 6 Figure S3.6 Fluorescence titrations of 5 μM ligand 1 excited at 300 nm with choline phosphate 2 in DMSO containing 2% water.

Figure S3.7 1 H

 1 Figure S3.7 1 H NMR titrations of 1 mM Zn(II)@1 with choline phosphate 2 at 298 K in DMSO-d6/D2O(80/20, v/v). H atoms in blue are the four diastereotopic protons of the encaged 2. 0.5 mL Zn(II)@1 complex solution was taken into the NMR spectroscopy tube, and then certain equivalents of a concentrated guest solution were added stepwise with a syringe. As a

Figure

  Figure S3.8 1 H NMR titrations of 1 mM Zn(II)@1 with choline phosphate 2 at 353 K and then return to 298 K in DMSO-d6/D2O (80/20, v/v).

Figure S3. 9

 9 Figure S3.9 The up-field region of the COSY spectrum for the mixture of Zn(II)@1 and 5 equiv. of choline phosphate 2 in DMSO-d6/D2O (80/20, v/v).

Figure

  Figure S3.10 1 H NMR titrations of 1 mM Zn(II)@1 with 3 at 298 K in DMSO-d6/D2O (80/20, v/v). H atoms in blue are attributed to the diastereotopic protons of methylene and N(CH3)3 of the encaged 3.

Figure S3.11 1 H

 1 Figure S3.11 1 H NMR titrations of 1 mM Zn(II)@1 with 3 at 353 K in DMSO-d6/D2O (80/20, v/v).

Figure

  Figure S3.12 31 P NMR titrations of 1 mM 2 with Zn(II)@1 at 298 K in DMSO-d6/D2O(80/20, v/v).

Figure 4 . 1 .

 41 Figure 4.1. Structures of hemicryptophanes 1, 2, and 3.

Scheme 4 . 1

 41 Scheme 4.1 Synthesis of hemicryptophanes 2 and 3. (a) K2CO3, EtOH, 50 °C, 6 h, 48%; (b) DHP, APTS, THF/CH2Cl2, r.t., 3 h, 96%; (c) 2,6-difluoro-4-methoxybenzylamine or

The complexation properties of 2 and 3

 3 toward different anions were investigated in CDCl3 by means of 1 H NMR titrations, with n-tetrabutyl ammonium as the counter ion. In all cases, only one set of signals was observed for the guest and for the receptor, indicating fast exchange conditions on the NMR timescale. The 1 H NMR experiments provide information on the geometry of the complexes in chloroform solutions (Figure S4.2): 1) the NH protons display a strong downfield shift upon progressive addition of the guest, evidencing hydrogen bonding between the anionic guest and the amide groups of the host; 2) the protons of the aromatic linkers are significantly shifted upfield (0.05 ppm), indicating that the anion faces the system oλ the ρinπers no shiλt was observed for the n-Bu4N + protons, thereby indicating that no host guest interaction between hosts 2 or 3 and n-Bu4N + occurs. Taken together, these chemical-shift changes indicate that the anion is bound to the south part of the receptor through both hydrogen bonding with the amide functional groups and anion interactions with the aromatic rings of the linkers. Complexation-induced shifts of the aromatic protons of the linkers or those of the C(O) CH2 N groups were plotted as a function of the guest/host ratio, and the resulting curves were fitted with WinEQNMR2 software, using a 1:1 model, in agreement with the results of the Job s pρot experiments Fiμures S4.3 and S4.4

hosts 1 and 2 . 1 .

 21 Symmetry consideration can account for this weaker association constant; contrary to the V-shaped AcO -anion, the tetrahedral H2PO4 -anion can bind simultaneously to the three hydrogen atoms of the amide functions in 1 and 2. Nevertheless, the most striking feature is the remarkable change in the binding constant induced by the introduction of the two fluorine atoms in the aromatic linkers. If host 1, lacking fluorine atoms, is chosen as a reference, a strong enhancement or decrease of the association constant is observed for a given anion, depending on the position of the two additional fluorine atoms. If the fluorine atoms are down (host 2), binding constants are significantly lower than that obtained with host If the λρuorine atoms are up host 3), the complexation properties toward anions are strongly increased, up to 20 times higher compared to the benchmark host 1. Thus, it appears that the location of the fluorine atoms on the aromatic rings strongly affect the binding properties of the host. As their positions are modified, a dramatic change in the binding constant, up to a 100-fold increase (see for instance with AcO -as the guest, Table

Figure 4 . 2

 42 Figure 4.2 Comparison of association constants Ka for anion guests with hosts 1-3, obtained by modeling the titration curves with WinEQNMR2. 31

  molecular orbitals (MOs) are shown in Figure S4.5. They correspond to the six MOs that are mostly * in character on the benzyl ring and the δN-H δN-H* pair on the N H bond. Figure 4.3 shows the CASPT2 potential-energy curves for the three host guest associations.

Figure 4 . 3

 43 Figure 4.3 CASPT2 energies (kJ mol -1 ) as a function of the Z-ZDFT (Å) displacement of the Cl ion along the C3 axis of the hemicryptophane cavities. The reference energy was chosen for Z-ZDFT= 10 Å, a distance for which the highlighted interactions are very small.

Figure 4 . 4

 44 Figure 4.4 Association constants for a) Cl and b) Br with hosts 1, 2, and 3 without Me4N + inside the cavity (Ka, in blue) and with one equivalent of Me4N + inside (Ka', in red). The cooperativity ΔΔG o is also given (green).

  the better use and understanding of anion interactions and facilitate the design of more sophisticated systems bearing multiple weak interactions for cooperative molecular recognition.

  6 g (1.85 mmol) and then with 2.80 g (2.0 mmol) starting material 8b but the reaction time is only 3 days. Both crude compounds were purified by column chromatography over silica gel (CHCl3:MeOH, 150:2→150:108, v/v) to give 3 as a beige solid (1.03 g, 51% yield). 1 H NMR (CDCl3, 298K, 500.1 MHZ): δ 7.60 (t, 3H, J = 5.9 Hz); 6.87 (s, 3H); 6.80 (s, 3H); 6.63(d, 6H, J = 8.2 Hz); 4.71 (d, 3H, J = 13.8 Hz); 4.48 (m, 6H); 4.43-4.45 (m, 3H); 4.21-4.31 (m, 6H); 4.09-4.13 (m, 3H); 3.80 (s, 9H); 3.51 (d, 3H, J = 13.8 Hz); 3.44 (m, 6H). 13 C NMR (CDCl3, 298K, 125.7 MHZ): δ 170.

  (bs, 3H); 6.46(d, 6H, J = 9.5 Hz); 4.43 (d, 6H, J = 5.3 Hz); 3.81 (s, 9H); 3.29 (s, 6H). 13 C NMR (CDCl3, 298K, 125.7 MHZ): δ 169.8, 162.1, 160.7, 105.6, 98.0, 59.7, 55.8, 31.1. ESI-HRMS m/z: calcd for C30H31F6N4O6 [M+H] + 657.2142, found 657.2126. IR (KBr) ῡ =3302, 3074, 2948, 1643, 1591, 1549, 1506, 1143, 1070 cm -1 .

  and 50 mL DMF. The reaction mixture was heated to 80°C for 17 h. After cooling to room temperature, water (200 mL) was added and the aqueous phase was extracted with ethyl acetate (200 mL) for 3 times. The combined organic phases were washed with 10% aq. NaOH (200 mL) and distilled water (200 mL), dried over Na2SO4, filtered and evaporated. Purification of the crude by column chromatography over silica gel (CH2Cl2 → CH2Cl2:MeOH, 95:5, v:v) gave compound 8a as a brown oil (5.45 g, 46% yield). 1 H NMR (CDCl3, 298K, 500.1 MHZ): δ 7.15 (t, 3H, J = 5.5 Hz,); 6.91-6.95 (m, 9H); 6.53(d, 6H, J = 9.3 Hz); 4.75(d, 3H, J = 11.9 Hz); 4.71 (m, 3H); 4.47 (d, 3H, J = 11.9 Hz); 4.43 (d, 6H, J = 5.3 Hz); 4.35 (m, 12H); 3.93 (m, 3H); 3.88 (s, 9H); 3.57-3.59 (m, 3H); 3.27 (s, 6H); 1.64-1.90 (m, 18H).13 C NMR (CDCl3, 298K, 125.7 MHZ): δ 169.

( d ,

 d 6H, J = 8.2 Hz); 4.74(d, 3H, J = 11.7 Hz); 4.71 (m, 3H); 4.45-4.49 (m, 9H); 4.32-4.35 (m, 12H); 3.94 (m, 3H); 3.85 (s, 9H); 3.55-3.58 (m, 3H); 3.39 (s, 6H); 1.63-1.90 (m, 18H). 13 C NMR (CDCl3, 298K, 125.7 MHZ): δ 170.

Figure S4.1 1 H

 1 Figure S4.1 1 H NMR spectra (500.1 MHz, CDCl3, 298 K) of hemicryptophanes 2 and 3.

Figure

  Figure S4.2 1 H NMR (CDCl3, 298 K, 500 MHz) titration experiment of host 2 (3.7 mM) with Bu4NCl: (a) 0 eq. of Bu4NCl; (b) 0.6 eq. of Bu4NCl ; (c) 1.7 eq. of Bu4NCl; (d) 5.1 eq. of Bu4NCl; (e) 11.3 eq. of Bu4NCl.

  Figure S4.3 1 H NMR (CDCl3, 500 MHz, 298 K) titration curves for different anions with 5.0 mM hosts 2 (a) and 3 (b) (+ : H2PO4 -, ■ : Br -, □ : Cl -, • : HSO4 -, ○ : I -, × : Ac, ▲ : F -).

Figure S4. 4 1

 4 Figure S4.4 1 NMR Job plot of 3 with TBACl (a) and tetramethylammonium picrate (b).

Figure S4. 5

 5 Figure S4.5 MOs: CAS[8,8]SCF MOs of a simplified structure of host 2 and Cl anion guest. Similar pictures are obtained for hosts 1 and 3.

Figure 5 . 1

 51 Figure 5.1 Design of the new enantiopure TPA-based hemicryptophanes which are available chemical platforms able to coordinate with various metals for different applications.

3 Scheme 5 . 1

 351 Scheme 5.1 Synthesis of TPA-trichloride 8.

Figure 5 .

 5 Figure 5.2 1 H NMR spectra (500.1 MHz, CD2Cl2, 298 K) of hemicryptophanes (±)-1 (a) and (±)-16 (b)and their protons assignment. ▼ = CHDCl2; ▲ = Et2O.

  is very useful in chiral recognition, asymmetric catalysis, and chirality sensing,2 we attempt the resolution of the racemate of hemicryptophanes 1 and 16 by chiral HPLC. In the case of (±)-1, the two enantiomers were separated on a Chiralpak IA column (250 × 4.6 mm) with an enantioselectivity of 1.52 and a resolution of 2.3, using heptane/ethanol/CH2Cl2/triethylamine (20/40/40/0.1) as the mobile phase. At preparative scale, after multiple injections on a Chiralpak IA column (250 × 10 mm), around 80 mg of each enantiomer were obtained in 12 h with ee values of 99% and 90% for the first and second eluted compounds, respectively. For (±)-16, with the same eluent on a Chiralpak ID column, the enantioselectivity is 1.51 and the resolution is 4.6 for the analytical separation, and around 50 mg of each enantiomer with both ee values > 99% were obtained in 3 h. The absolute configuration of each enantiopure hemicryptophane was determined by ECD spectroscopy recorded in CH2Cl2 at 298 K.19 As shown in Figure5.3, in both cases, the spectra of the first eluted enantiomers exhibit a characteristic positive-negative bisignate curve from 230-250 nm corresponding to the M-configuration; The second eluted enantiomers show similar but inverted signals, thus allowing the assignment of the P-configuration.19

Figure 5 . 3

 53 Figure 5.3 Experimental ECD spectra in CH2Cl2 at 298 K of: (a) (+)-(P)-1 (blue) and (-)-M-1 (green), and (b) (+)-(P)-16 (blue) and (-)-M-16 (green).

  1 H and13 C NMR spectra were recorded at 500.1 and 125.7 MHz, respectively. The HRMS-ESI mass spectra were recorded in positive-ion mode (or negative) on a hybrid quadrupole time-of-flight mass spectrometer with an electrospray ionization (ESI) ion source. Specific rotations (in deg cm 2 g -1 ) were measured in a 1 dm thermostated quartz cell on a Jasco-P1010 polarimeter. Circular dichroism spectra were recorded on a CD6 Jobin-Yvon dichrograph. Resolution of the racemic hemicryptophanes was performed by Marion Jean and Nicolas Vanthuyne.

  (m, 1H);5.50 (dd, J = 17.3, 1.4 Hz, 1H); 5.35 (dd, J = 10.5, 1.2 Hz, 1H); 4.76 (d, J = 11.7 Hz, 1H); 4.72 (t, J = 3.6 Hz, 1H); 4.66(d, J = 5.3 Hz, 1H); 4.50-4.47 (m, 5H); 3.98-3.91 (m, 1H); 3.90 (s, 3H); 3.60-3.56 (m, 1H); 1.93-1.62 (m, 6H) ppm.13 C NMR (CDCl3, 298K, 125.7 MHz): δ 155.2(5),

Figure S5. 3

 3 Figure S5.3 COSY spectrum (CD2Cl2, 500.1 MHz, 298K) of hemicryptophane 1.

Figure S5. 4

 4 Figure S5.4 HSQC spectrum (CD2Cl2, 500.1 MHz, 298K) of hemicryptophane 1.

Figure S5. 5

 5 Figure S5.5 HMBC spectrum (CD2Cl2, 500.1 MHz, 298K) of hemicryptophane 1.

Figure S5.6 1 H

 1 Figure S5.6 1 H NMR spectrum (CD2Cl2, 500.1 MHz, 298K) of hemicryptophane 16.

Figure S5. 7

 7 Figure S5.7 13 C NMR spectrum (CD2Cl2, 125.8 MHz, 298K) of hemicryptophane 16.

Figure S5. 8

 8 Figure S5.8 COSY spectrum (CD2Cl2, 500.1 MHz, 298K) of hemicryptophane 16.

Figure S5. 9

 9 Figure S5.9 HSQC spectrum (CD2Cl2, 500.1 MHz, 298K) of hemicryptophane 16.

Figure S5. 10

 10 Figure S5.10 HMBC spectrum (CD2Cl2, 500.1 MHz, 298K) of hemicryptophane 16.

Figure 6 . 1

 61 Figure 6.1 Structures of enantiomers M-SSS-SSS-1 and P-RRR-RRR-1. Varying the chirality of CTV, binaphthol or trialkanol moieties, gave rise to the other three pairs of enantiomers P-SSS-SSS-1/M-RRR-RRR-1, M-SSS-RRR-1/P-RRR-SSS-1 and M-RRR-SSS-1/P-SSS-RRR-1.

Scheme 6 . 1

 61 Scheme 6.1 Synthetic route for obtention of hemicryptophane diastereomers M-SSS-SSS-1 and P-SSS-SSS-1.

Figure 6 . 2

 62 Figure 6.2 Experimental ECD spectra (CH3CN, 298 K) of the four enantiomeric pairs of hemicryptophane 1.

  as the NMR spectra and TLC migration properties of enantiomers are identical, this experiment also allows the assignment of the configuration of their mirror images M-RRR-RRR-1 and P-RRR-RRR-1. Hence, a single chemical correlation experiment assigns the absolute configuration of four hemicryptophane cages (FigureS6.2). It can be noticed that no racemization of CTV-13 occurred during the reaction as only one diastereomer is observed when the 1 H NMR spectra of the crude product and of the pure diastereomeric pair are compared(Figure S6.3). LCMS analyses further demonstrate the configuration assignment and the lack of racemization(Figure S6.4). The similar synthesis with enantiopure (S)-binaphthol, (R)-(-)-glycidyl nosylate and P-13 was then carried out to produce P-SSS-RRR-1, which allows the assignment of the configuration of the other four enantiopure hemicryptophanes.

Figure 6 . 3

 63 Figure 6.3 (a) Structures of hemicryptophane enantiomeric pair M-SSS-14/P-RRR-14. Varying the chirality of CTV or trialcohol moiety afforded the enantiomeric pair P-SSS-14/M-RRR-14. (b)

  . ESI-HRMS for S-3 m/z: found 573.2236, calcd for C35H34NaO6 [M+Na] + 573.2248. ESI-HRMS for R-3 m/z: found 573.2225, calcd for C35H34NaO6 [M+Na] + 573.2248.

  298K, 500.1 MHz): δ 8.03 (d, J = 9.0 Hz, 1H); 7.99 (d, J = 9.0 Hz, 1H); 7.92 (t, J = 9.2 Hz, 2H); 7.59 (d, J = 9.1 Hz, 1H); 7.45 (d, J = 9.0 Hz, 1H); 7.39-7.33 (m, 2H); 7.26-7.20 (m, 2H); 7.13-7.09 (m, 2H); 7.85 (d, J = 1.8 Hz, 1H); 6.71 (dd, J = 1.8, 8.2 Hz, 1H); 6.50 (d, J = 8.2 Hz, 1H);

  for R-R-4 m/z: found 629.2485, calcd for C38H38NaO7 [M+Na] + 629.2510.

  1 H NMR (CD2Cl2, 298K, 500.1 MHz): δ 8.04 (d, J = 9.0 Hz, 1H); 8.00 (d, J = 9.0 Hz, 1H); 7.93 (t, J = 8.6 Hz, 2H); 7.61 (d, J = 9.1 Hz, 1H); 7.46 (d, J = 9.0 Hz, 1H); 7.40-7.35 (m, 2H); 7.27-7.21 (m, 2H); 7.15-7.10 (m, 2H); 6.87 (d, J = 1.6 Hz, 1H); 6.72 (dd, J = 1.6, 8.2 Hz, 1H); 6.53 (d, J = 8.1 Hz, 1H); 4.69-4.66 (m, 2H); 4.41-4.35 (m, 3H); 4.20 (dd, J = 2.9, 11.5 Hz, 1H); 4.01 (t, J = 5.1 Hz, 2H); 3.98-3.90 (m, 2H); 3.76 (s, 3H); 3.57-3.53 (m, 1H); 2.97-2.95 (m, 1H); 2.57 (t, J = 4.7 Hz, 1H); 2.35 (dd, J = 2.6, 5.0 Hz, 1H); 1.89-1.55 (m, 6H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 154.

5 .

 5 ESI-HRMS for S-R-4 m/z: found 629.2480, calcd for C38H38NaO7 [M+Na] + 629.2510. ESI-HRMS for R-S-4 m/z: found 629.2479, calcd for C38H38NaO7 [M+Na] + 629.2510.

1 H

 1 NMR (CD2Cl2, 298K, 500.1 MHz): δ 8.00 (d, J = 9.0 Hz, 1H); 7.91 (d, J = 8.2 Hz, 1H); 7.80 (d, J = 9.0 Hz, 1H); 7.73 (d, J = 8.1 Hz, 1H); 7.40 (d, J = 9.0 Hz, 2H); 7.35 (t, J = 7.4 Hz, 1H); 7.25 (t, J = 7.

  1 H NMR (CD2Cl2, 298K, 500.1 MHz): δ 7.98 (d, J = 9.0 Hz, 1H); 7.90 (d, J = 8.1 Hz, 1H); 7.83 (d, J = 9.1 Hz, 1H); 7.72 (d, J = 8.2 Hz, 1H); 7.43 (d, J = 9.1 Hz, 1H); 7.40 (d, J = 9.0 Hz, 1H); 7.37-7.34 (m, 1H); 7.23-7.17 (m, 2H); 7.14-7.03 (m, 3H); 6.83 (d, J = 1.8 Hz, 1H); 6.67 (dd, J = 1.8, 8.2 Hz, 1H); 6.40 (d, J = 8.1 Hz, 1H);

  . ESI-HRMS for SSS-RRR-6 m/z: found 1836.8216, calcd for C114H118NO21 [M+H] + 1836.8191. ESI-HRMS for RRR-SSS-6 m/z: found 1836.8117, calcd for C114H118NO21 [M+H] + 1836.8191.

1 H

 1 NMR (CDCl3, 298K, 500.1 MHz): δ 8.65 (d, J = 9.2 Hz, 1H); 8.08 (d, J = 8.2 Hz, 1H); 8.04 (d, J = 9.2 Hz, 1H); 7.77 (d, J = 8.1 Hz, 1H); 7.69 (t, J = 7.2 Hz, 1H); 7.63 (d, J = 9.2 Hz, 1H); 7.23 (t, J = 8.1 Hz, 2H); 7.07 (t, J = 7.3 Hz, 1H); 6.91 (s, 1H); 6.81 (s, 1H); 6.77 (d, J = 8.6 Hz, 1H); 6.74 (d, J = 8.5 Hz, 1H); 5.64 (d, J = 9.3 Hz, 1H); 4.82 (d, J = 13.7 Hz, 1H); 4.64 (t, J = 11.3 Hz, 1H); 4.53 (t, J = 10.0 Hz, 1H); 4.17 (t, J = 13.3 Hz, 2H); 4.08 (s, 3H); 3.59 (d, J = 13.8 Hz, 1H); 3.01 (d, J = 11.5 Hz, 1H); 2.88

- 1 :

 1 ESI-HRMS m/z: found 1530.6079, calcd for C99H88NO15 [M+H] + 1530.6148. [∝] : 41 (c = 0.087; CH2Cl2). Diastereomer M-RRR-RRR-1: ESI-HRMS m/z: found 1530.6095, calcd for C99H88NO15 [M+H] + 1530.6148. [∝]

  in CH3CN (80 mL). The mixture was stirred under argon at 65 °C for 24 hours. The solvent was then evaporated. A first silica preparative TLC (CHCl2/MeOH 20:1) for the crude product gave the diastereomeric pair mixture with no other impurities. Then a second silica preparative TLC was performed for the mixture with CHCl3/MeOH (20:1) to give 19 mg enantiopure P-SSS-RRR-1 in 11% yield and 40 mg M-SSS-RRR-1 in 24% yield. Both of the two compounds are white solid after precipitation with MeOH. Diastereomer P-SSS-RRR-1: 1 H NMR (CDCl3, 298K, 500.1 MHz): δ 8.02 (d, J = 9.0 Hz, 1H); 7.92 (t, J = 8.7 Hz, 2H); 7.82 (d, J = 8.9 Hz, 2H); 7.46 (d, J = 9.1 Hz, 1H); 7.37 (t, J = 7.1 Hz, 1H);

1 H

 1 NMR (CD2Cl2, 298K, 500.1 MHz): δ 8.12 (d, J = 9.1 Hz, 1H); 7.96-7.93 (m, 2H); 7.89 (d, J = 8.2 Hz, 1H); 7.55 (d, J = 9.2 Hz, 1H); 7.41-7.38 (m, 1H); 7.36-7.28 (m, 3H); 7.25-7.22 (m, 1H); 7.13 (d, J = 8.5 Hz, 1H); 7.03 (d, J = 8.5 Hz, 1H); 5.00 (s, 1H); 3.85 (s, 3H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 156.0, 151.

  m/z: found 301.1214, calcd for C21H17O2 [M+H] + 301.1223. [∝] = 39 (c = 0.116; CH2Cl2).

1 H

 1 NMR (CD2Cl2, 298K, 500.1 MHz): δ 8.02 (d, J = 9.0 Hz, 1H); 7.92 (d, J = 8.2 Hz, 1H); 7.83 (d, J = 9.1 Hz, 1H); 7.76 (d, J = 8.2 Hz, 1H); 7.45 (d, J = 9.0 Hz, 1H); 7.37 (t, J = 7.2 Hz, 1H); 7.32 (d, J = 9.1 Hz, 1H); 7.28-7.24 (m, 2H); 7.17 (t, J = 8.5 Hz, 1H); 7.10 (d, J = 8.5 Hz, 1H); 7.02 (d, J = 8.5 Hz, 1H); 3.95 (dd, J = 3.5, 9.9 Hz, 1H); 3.68-3.67 (m, 4H); 3.00-2.99 (m, 1H); 2.69 (bs, 1H); 1.52 (d, J = 10.3 Hz, 1H); 1.38 (d, J = 10.3 Hz, 1H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 154.7,

  1 H NMR (CD2Cl2, 298K, 500.1 MHz): δ 7.99 (d, J = 9.0 Hz, 1H); 7.92 (d, J = 8.2 Hz, 1H); 7.87 (d, J = 9.1 Hz, 1H); 7.75 (d, J = 8.1 Hz, 1H); 7.44 (d, J = 9.0 Hz, 1H); 7.39-7.36 (m, 2H); 7.26 (t, J = 7.6 Hz, 1H); 7.20 (t, J = 7.1 Hz, 1H); 7.12-7.10 (m, 2H); 7.03 (d, J = 8.5 Hz, 1H); 3.80-3.78 (m, 2H); 3.72 (s, 3H); 3.13-3.12 (m, 1H); 2.71 (bs, 1H); 1.70-1.57 (m, 2 H). 13 C NMR (CD2Cl2, 298K, 125.7 MHz): δ 154.

  crude product was purified by column chromatography on silica gel (first with CHCl3/MeOH 100/1, then use 20/1) to give SSS-SSS-12 as a beige solid (52 mg, 33%). 1 H NMR (DMSO-d6, 298K, 500.1 MHz): δ 9.27 (s, 1H); 8.03 (d, J = 9.1 Hz, 1H); 7.94 (d, J = 8.1 Hz, 1H); 7.63 (d, J = 8.5 Hz, 2H); 7.56 (d, J = 9.1 Hz, 1H); 7.34 (t, J = 7.2 Hz, 1H); 7.26-7.22 (m, 2H); 7.16-7.14 (m, 2H); 7.03 (d, J = 8.5 Hz, 1H); 6.87-6.85 (m, 1H); 3.96 (s, 1H); 3.87 (dd, J = 3.3, 9.9 Hz, 1H); 3.57 (dd, J = 3.9, 9.8 Hz, 1H); 2.84 (s, 1H); 1.26 (t, J = 12.7 Hz, 1H); 0.92 (d, J = 12.2 Hz, 1H). 13 C NMR (DMSO-d6, 298K, 125.7 MHz): δ 155.

  1 H NMR (DMSO-d6, 298K, 500.1 MHz): δ 9.25 (s, 1H); 8.03 (d, J = 9.0 Hz, 1H); 7.94 (d, J = 8.1 Hz, 1H); 7.68 (d, J = 8.8 Hz, 1H); 7.64-7.62 (m, 1H); 7.54 (d, J = 9.0 Hz, 1H); 7.34 (t, J = 7.3 Hz, 1H); 7.27-7.23 (m, 2H); 7.04-7.01 (m, 3H); 6.84 (d, J = 7.3 Hz, 1H); 4.08 (s, 1H); 3.74-3.64 (m, 2H); 3.03 (s, 1H); 1.42 (t, J = 11.3 Hz, 1H); 1.26 (d, J = 11.7 Hz, 1H). 13 C NMR (DMSO-d6, 298K, 125.7 MHz): δ 155.

. 1 .

 1 ESI-HRMS m/z: found 1044.4054, calcd for C69H58NO9 [M+H] + 1044.4106. macrocyclization: A solution of Cs2CO3 (187 mg, 574 µmol) and compound SSS-SSS-12 or SSS-RRR-12 (100 mg, 96 µmol) in DMF (90 mL) was stirred at 25 o C for 15 min under argon. Then 90 mL DMF solution of enantiopure P-13 (77 mg, 105 µmol) was added dropwise. The reaction solution was stirred at 25 o C for 48 h. Afterwards, 200 mL

Figure S6. 1

 1 Figure S6.1 Experimental ECD spectra in CH3CN at 25°C of compound 13; red: first eluted enantiomer P-13 (C = 2.39×10 -4 M -1 ); red: second eluted enantiomer M-13 (C = 3.56×10 -4 M -1 ).

Figure S6. 2 A

 2 Figure S6.2 A chart showing that with one single chemical correlation experiment, the absolute configuration of four hemicryptophane stereoisomers can be determined.

Figure S6.3 1 H

 1 Figure S6.3 1 H NMR spectra (CD2Cl2, 500.1 MHz, 298K) of P-SSS-SSS-1, M-SSS-SSS-1 and the crude product obtained by the reaction of P-13 and SSS-SSS-12. It can be observed that in the 1 H NMR spectrum of crude product, only the signals of P-SSS-SSS-1 are present.

Figure S6. 4

 4 Figure S6.4 Chromatograms of the hemicryptophane diastereomers P-SSS-SSS-1 and M-SSS-SSS-1, and of the crude product of P-SSS-SSS-1 obtained from chemical correlation synthesis; The Mass for each fraction has been indicated. Separation parameters: column: phenomenex-synergi-4µ-Hydro-RP (250×4.6 mm); eluent: CH3CN/H2O, gradient change from 70/30 v/v to 100/0 v/v; flow rate: 0.75 mL/min; UV detection at 250 nm.

Figure S6. 5

 5 Figure S6.5 Partial 1 H NMR spectra (CDCl3, 500.1 MHz, 298K) of host P-RRR-SSS-1 (1 mM) upon addition of different equiv. of OctαMan. 1 H NMR titrations: Solutions of hemicryptophane hosts (1.0 mM in CDCl3, 500 L) were titrated in NMR tubes with small aliquots of concentrated solutions (20 mM in CDCl3) of guests. Complexation induced shifts Δδ of the OMe protons of the host were measured after

Figure

  Figure S6.6 1 H NMR titration curves (CDCl3, 500.1 MHz, 298K) for the complexation of glucoside by host 1 (experimental and calculated chemical shifts are shown as points and lines, respectively).

Figure S6.7 1 H

 1 Figure S6.7 1 H NMR titration curves (CDCl3, 500.1 MHz, 298K) for the complexation of mannoside by host 1 (experimental and calculated chemical shifts are shown as points and lines, respectively).

Figure S6. 8 In

 8 Figure S6.8 Job's plot of P-RRR-SSS-1 with OctαMan in CDCl3.

  Crystals of M-RRR-RRR-1•2(CHCl3)•0.5(Et2O) suitable for X-Ray diffraction analysis were obtained by slow evaporation from a concentrated solution of the cage in CHCl3/Et2O. The structure of hemicryptophane M-RRR-RRR-1 exhibits a C3 symmetry with an unexpected imploded conformation where the trialkanolamine core is collapsed within the CTV unit obstructing the inner cavity (Figures 7.2 and S7.1). 7 The three OH groups point outward λorminμ hydroμen bonds with the two cρosest O atoms oλ the binaphthoρ μroups O•••O distances, 2.77-2.94 Å), whereas the NCH2 protons, directed toward the CTV unit, interact with the aromatic rings (distances between the axial proton of NCH2 and the closest CTV aromatic ring, 3.08-3.53 Å).

Figure 7 . 1

 71 Figure 7.1 (a) Partial 1 H NMR spectra (500.1 MHz, 298 K) of the four diastereomeric pairs of hemicryptophane 1 in CDCl3 and their protons assignment. ▲ = water; ► = grease. The high-field shifted NCH2 protons are highlighted. The distance d between the more shielded NCH2 proton and its closest CTV aromatic-H has been illustrated, which is used for the evaluation of the cage collapse degree. (b) TLC migration properties of 1 (silica, eluent: CH2Cl2/MeOH = 200/3). The symbolisms used are the abbreviation names of each hemicryptophane isomers, for instance, PSS represents P-SSS-SSS-1.

1 ( 3 .

 13 giving a distance for P-SSS-SSS-1/M-RRR-RRR-1 in the range of 3.03-3.08 Å, in agreement with that measured from the crystal structure(3.08-3.53 Å). Moreover, the implosion degree indicated by the calculated H•••H distances for each cage follows the same trend as that of the chemical shifts of the shielded NCH2 protons: P-SSS-SSS-1 (average: 3.06 Å) > M-SSS-SSS-21 Å) > P-SSS-RRR-1 (3.86 Å). The measurement for M-SSS-RRR-1 failed due to peaks overlap of the two NCH2 signals. These results suggest that the size and shape of the cavity can be modulated by the chirality of its constitutive chiral units. Notably, this imploded conformation is also retained in other solvents such as toluene-d8 and DMSO-d6 and at higher temperature (up to373 K, Figures S7.7 and S7.8).

Figure 7 . 2

 72 Figure 7.2 Crystal structure of M-RRR-RRR-1. Solvent molecules are omitted for clarity. Dashed lines in the left figure represent the distance between the two neighboring binaphthyl groups, and those in the right figure represent the distances between the axial proton on NCH2 and its closest aromatic-H on CTV or between the O atom on OH and its two closest binaphthyl O atoms.

3 Figure S7. 3

 33 Figure S7.3 An overlap between the full COSY (red) and ROESY (blue and green) spectra of P-SSS-SSS-1/M-RRR-RRR-1 in CDCl3 (500.1 MHz, 298 K); Cross-peaks of 1-8 indicate the correlations between the upper and lower parts of the cage, suggesting its imploded conformation.

Figure S7. 4

 4 Figure S7.4 ROESY spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-SSS-1/P-RRR-RRR-1; The NOE cross-peaks between the NCH2 proton of trialkanolamine and benzene-H or OMe on the CTV have been indicated.

Figure S7. 5

 5 Figure S7.5 ROESY spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-RRR-1/M-RRR-SSS-1. The NOE cross-peaks between the NCH2 proton of trialkanolamine and benzene-H or OMe on the CTV have been indicated.

Figure S7. 6

 6 Figure S7.6 ROESY spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-RRR-1/P-RRR-SSS-1. The NOE cross-peaks between the NCH2 proton of trialkanolamine and benzene-H or OMe on the CTV have been indicated.

Figure S7.7 1 H

 1 Figure S7.7 1 H NMR (500.1 MHz, 298K) of P-SSS-SSS-1 in (a) DMSO-d6 and (b) toluene-d8.

Figure S7.8 1 H

 1 Figure S7.8 1 H NMR spectra of P-SSS-SSS-1 at different temperature in toluene-d8 (500.1 MHz); ■ and▲represent the aromatic binaphthol protons and the axially oriented NCH2 protons in the cage.

Figure S7.9 1 H

 1 Figure S7.9 1 H NMR spectra (500.1 MHz, 298 K) of P-SSS-SSS-1 (a) and M-SSS-SSS-1 (b) upon addition of different equiv. of MeOD. represents MeOH.

Figure S7.10 1 H

 1 Figure S7.10 1 H NMR spectra (CDCl3, 500.1 MHz, 298K) of the hemicryptophane ligands and their corresponding vanadium(V) complexes; Each complex was obtained via the reaction of the ligand with 1.0 equiv. of vanadium(V) oxytriisopropoxide in CDCl3 for 10 min, followed by evaporation.

Figure S7. 11

 11 Figure S7.11 Time course of the 1 H NMR spectra (500.1 MHz, 298K) for the reaction of P-SSS-SSS-1 with 1.0 equiv. of vanadium(V) oxytriisopropoxide in CDCl3 at r.t. ,  and  represent the species of the ligand, the vanadium(V) complex and the Cl2CHCHCl2, respectively. The intensity of the reference in each spectrum has been adjusted equally. The yield at each time has been indicated.

Figure

  Figure S7.12 (a) 1 H NMR spectra (CDCl3, 500.1 MHz, 298K) of P-SSS-SSS-1 and its vanadium(V) complex. (b) COSY spectrum (CDCl3, 500.1 MHz, 298K) of V@ P-SSS-SSS-1. (c) HSQC spectrum (CDCl3, 500.1 MHz, 298K) of V@ P-SSS-SSS-1.

Figure S7. 13

 13 Figure S7.13 ROESY spectra (CDCl3, 500.1 MHz, 298K) of V@P-SSS-SSS-1. No NOE cross-peak between the NCH2 proton of trialkanolamine and benzene-H or OMe on the CTV was observed.

Figure S7.14 1 H

 1 Figure S7.14 1 H NMR titrations (500.1 MHz, 298 K) of Me4N + Pic -(0.5 mmol/L) in CD2Cl2 upon addition of different equiv. of the host V@M-SSS-RRR-1; ▼ represents the signal of Me4N + protons.

Figure S7. 15

 15 Figure S7.15 MM3-optimized molecular model of vanadium@M-SSS-RRR-1 with Me4N + encapsulated inside the cavity.

Figure S7.16 1 H

 1 Figure S7.161 H NMR spectra of M-SSS-RRR-1 or V@M-SSS-RRR-1 (CDCl3, 500.1 MHz, 298 K) that illustrate the three cycles between the bi-stable states, i.e. the imploded and inflated conformations.

( a )

 a Spectra of V@M-SSS-RRR-1; (b) Spectra of the ligand M-SSS-RRR-1 obtained by adding an excess of TEA to (a); (c) Spectra of V@M-SSS-RRR-1 obtained by adding an excess of vanadium(V) oxytriisopropoxide to (b), followed by the manipulations of filtration, evaporation, dissolution and re-filtration. The purpose of the first filtration is to remove the precipitate formed by TEA and vanadium(V) oxytriisopropoxide, and the second filtration is to remove the vanadium aggregated particles; (d) Spectra of the ligand M-SSS-RRR-1 obtained by adding an excess of TEA to(c);(e)

17

 17 Figure S7.171 H NMR spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-SSS-1/M-RRR-RRR-1.

  Figure S7.171 H NMR spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-SSS-1/M-RRR-RRR-1.

Figure

  Figure S7.18 13 C NMR spectrum (CDCl3, 125.8 MHz, 298K) of P-SSS-SSS-1/M-RRR-RRR-1.

Figure S7. 19

 19 Figure S7.19 COSY spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-SSS-1/M-RRR-RRR-1.

Figure S7. 20

 20 Figure S7.20 HSQC spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-SSS-1/M-RRR-RRR-1.

Figure S7. 21

 21 Figure S7.21 HMBC spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-SSS-1/M-RRR-RRR-1.

Figure

  Figure S7.22 1 H NMR spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-SSS-1/P-RRR-RRR-1.

Figure S7. 23

 23 Figure S7.23 13 C NMR spectrum (CDCl3, 125.8 MHz, 298K) of M-SSS-SSS-1/P-RRR-RRR-1.

Figure S7. 24

 24 Figure S7.24 COSY spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-SSS-1/P-RRR-RRR-1.

Figure S7. 25

 25 Figure S7.25 HSQC spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-SSS-1/P-RRR-RRR-1.

Figure S7. 26

 26 Figure S7.26 HMBC spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-SSS-1/P-RRR-RRR-1.

Figure S7.27 1 H

 1 Figure S7.27 1 H NMR spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-RRR-1/M-RRR-SSS-1.

Figure

  Figure S7.28 13 C NMR spectrum (CDCl3, 125.8 MHz, 298K) of P-SSS-RRR-1/M-RRR-SSS-1.

Figure S7. 29

 29 Figure S7.29 COSY spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-RRR-1/M-RRR-SSS-1.

Figure S7. 30

 30 Figure S7.30 HSQC spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-RRR-1/M-RRR-SSS-1.

Figure S7. 31

 31 Figure S7.31 HMBC spectrum (CDCl3, 500.1 MHz, 298K) of P-SSS-RRR-1/M-RRR-SSS-1.

Figure

  Figure S7.32 1 H NMR spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-RRR-1/P-RRR-SSS-1.

Figure S7. 33

 33 Figure S7.33 13 C NMR spectrum (CDCl3, 125.8 MHz, 298K) of M-SSS-RRR-1/P-RRR-SSS-1.

Figure S7. 34

 34 Figure S7.34 COSY spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-RRR-1/P-RRR-SSS-1.

Figure S7. 35

 35 Figure S7.35 HSQC spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-RRR-1/P-RRR-SSS-1.

Figure S7. 36

 36 Figure S7.36 HMBC spectrum (CDCl3, 500.1 MHz, 298K) of M-SSS-RRR-1/P-RRR-SSS-1.

Figure 8 . 1

 81 Figure 8.1 Structures of the five sets of oxido-vanadium(V) complexes.

1 H

 1 NMR spectra of each isomer of complexes 2 and 4 are consistent with a C3 symmetry. The synthetic route for the vanadium complexes in set I, such as (S,S,S)-(S,S,S)-1, is shown in Scheme 8.1. Firstly, the enantiopure binaphthol 6 was mono-protected with an allyl group via the reaction of S-6 with 1 equiv. of allyl bromide in acetone in the presence of K2CO3 to give S-7. The enantiopure epoxide (S,S)-8 was obtained by a regioselective nucleophilic substitution reaction of S-7 on commercially available (S)-(+)-glycidyl nosylate in DMF. An excess of ammonia in methanol was then reacted with (S,S)-8 to give the primary amine (S,S)-9. The C3 symmetrical allyl-protected trialkanolamine (S,S,S)-(S,S,S)-10 was obtained by a trimerization reaction of 9 with 2 equiv. of 8 in MeOH for 5 days. Compound 10

  1 and FigureS8.1, respectively. It can be seen that(i) with CHP as oxidant, all the supramolecular complexes in Set II are very efficient giving rise to high yields from 85% (P-(S,S,S)-(R,R,R)-2) to 93% (P-(S,S,S)-(S,S,S)-2) (Table8.1, entries 2-5). The excellent selectivity is (> 91%) evidenced by the typical kinetic curves of both yield and conversion of P-(S,S,S)-(S,S,S)-2 that are almost identical (FigureS8.2). (ii) In addition, the yields obtained with hemicryptophane catalysts 2 (entries 2-5) are also significantly higher than those obtained with the corresponding model catalysts 4, which lack a cavity (entries 8 and 9), and the performances of catalysts 4 and 5 are very close, indicating that the cage structure is essential for efficient sulfoxidation. (iii) Noticeably, the hemicryptophane catalysts 2 are more effective than the smaller cage catalyst 1 (entry 1), highlighting the important role of the cavity size. (iv) Furthermore, the yields with the new hemicryptophane catalysts in Set II are much higher than those with the previous hemicryptophane catalysts in Set III (entries 6 and 7). The improvement of the hydrophobicity and the more pronounced confinement effect induced by these specific bulky binaphthol linkages could account for the enhancement of the reaction rates and yields. (v) It is also interesting to note that the kinetic curves, monitoring the yields as a function of time, are very close to each other among the catalysts in each set (FigureS8.1).

Figure 8 . 2

 82 Figure 8.2 Oxidation of thioanisol with four typical catalysts: (S,S,S)-(S,S,S)-1 in Set I, P-(S,S,S)-(S,S,S)-2 in Set II, M-(S,S,S)-3 in Set III and (S,S,S)-(S,S,S)-4 in Set IV (1.0 mol% catalyst, 1.0 equiv. of CHP, 0 o C, CH2Cl2).

Figure 8 . 3

 83 Figure 8.3 Oxidation of thioanisol catalyzed by catalyst M-(S,S,S)-(R,R,R)-2 (0.01 mol% catalyst, 1.0 equiv. of CHP, r.t., CH2Cl2).

  2g As shown in Figure8.4a, when the substrate concentration was increased while maintaining constant amounts of hemicryptophane catalyst M-(S,S,S)-(R,R,R)-2 and oxidant, initial rate saturation was observed, consistent with the Michaelis-Menten rate profile. Strict compliance was further confirmed by re-plotting the data to give the Lineweaver-Bruck plot in Figure8.4b with an excellent fit (R 2 = 0.99). The slope and y-intercept gave Km = 18.72 mM and Vmax = 4.08 × 10 -2 mM s -1 . The latter value was used to calculate a turnover rate, Kcat (Vmax/[Catalyst]), of 3.71 × 10 -2 s -1 . To determine the rate enhancement, Kcat/Kuncat, the background experiment, the oxidation of thioanisol by CHP under the same conditions without any catalyst, was performed. It was observed that after 7 days, the conversion is < 2%, giving rise to a Kuncat of < 3.3×10 -9 s -1 . Therefore, it can be

Figure 8 . 4

 84 Figure 8.4 (a) Initial rate dependence on the concentration of thioanisol in CH2Cl2 with 1.1 mM hemicryptophane catalyst M-(S,S,S)-(R,R,R)-2 and 110 mM CHP at 0 o C. (b) The corresponding Lineweaver-Burke line plotted by 1/rate as a function of 1/[Thioanisol].

Figure 8 . 5

 85 Figure 8.5 (a) Graphical representation of catalysis inhibition by Me4N + . (b) Oxidation of thioanisol in the absence or presence of Me4N + catalyzed by M-(S,S,S)-(R,R,R)-2 of Set II or (S,S,S)-(R,R,R)-4 of Set IV (1.5 mol% catalyst, 1.0 equiv. of CHP, 0 o C, CH2Cl2).

Figure S8. 5 ,

 5 Figure S8.5, upon progressive addition of a concentrated solution of the host M-(S,S,S)-(R,R,R)-2 to a solution of guest Me4NPic in CD2Cl2, the 1 H NMR signals of the protons of Me4N + display up-field shifts, which can be attributed to the shielding effect induced by guest encapsulation. Modelling the titration curve with HypNMR2008 afforded a binding constant of 547 M 1 for the 1:1 host-guest complex (Figure S8.5). 12 Hence Me4N + was considered as the competitive inhibitor, and oxidation of thioanisol in the presence of Me4N + catalyzed by either the cage M-(S,S,S)-(R,R,R)-2 or the model (S,S,S)-(R,R,R)-4 catalyst was carried out. Me4N + Pic (1.33 catalyst equiv.) was added to the reaction mixture since this concentration corresponds to its solubility limit in CH2Cl2 at r.t., and also, based on the binding constant, on average more than half of the cavities can be occupied by the Me4N + guest. As expected, the catalytic activity of the cage M-(S,S,S)-(R,R,R)-2 strongly decreased in the presence of Me4N + , whereas that of the model compound (S,S,S)-(R,R,R)-4 almost remained constant (Figure 8.5). Indeed, the reaction rate became 3.5-fold slower in the

Figure 8 . 6

 86 Figure 8.6 Oxidation of thioanisol (substrate A), benzylphenyl sulfide (substrate B), or naphthylmethyl phenyl sulfide (substrate C) with catalyst M-(S,S,S)-(R,R,R)-2 in Set II or (S,S,S)-(S,S,S)-1 in Set I (1.5 mol% catalyst, 1.0 equiv. of CHP, 0°C, CH2Cl2).

10 :

 10 m/z: found 405.1456, calcd for C26H22NaO3 [M+Na] + 405.1461. To a solution of 7N NH3 in methanol

1 :

 1 . ESI-HRMS m/z: found 1158.4543, calcd for C78H64NO9 [M+H] + 1158.4576. To 15 mL CHCl3, (S,S,S)-(S,S,S)-12 (70 mg, 60.4 µmol) was added. The solution was stirred at room temperature for 5 min. Then vanadium(V) oxytriisopropoxide

Figure S8. 2

 2 Figure S8.2 Time course of oxidation of thioanisol with hemicryptophane catalyst P-(S,S,S)-(S,S,S)-2 (conditions: 1.5 mol% catalyst, 1.0 equiv. of CHP, 0 o C, CH2Cl2).

Figure S8. 3

 3 Figure S8.3 Time course of oxidation of thioanisol with typical catalysts in different sets (conditions: 1.5 mol% catalyst, 1.0 equiv. of TBHP, 0 o C, CH2Cl2).

Figure S8. 4

 4 Figure S8.4 Changes of the cumulative TON over four-cycle experiments catalyzed by M-(S,S,S)-(R,R,R)-2 with the development of time (conditions: 0.1 mol% catalyst, 1.0 equiv. of CHP, r.t., CH2Cl2; after each cycle, 1.0 equiv. of reaction substrate and CHP were reloaded; TON was calculated from the yield).

Figure S8.5 1 H

 1 Figure S8.5 1 H NMR spectra (500 MHz, 298 K) of Me4N + Pic -(▼) in CD2Cl2 upon progressive addition of different equivalents of the host M-(S,S,S)-(R,R,R)-2 (left side) and its titration curve fitted by HypNMR2008 (right side).

Figure S8. 6

 6 Figure S8.6 Time course of oxidation of benzylphenyl sulfide with typical catalysts (conditions: 1.5 mol% catalyst, 1.0 equiv. of CHP, 0 o C, CH2Cl2).

Figure S8. 7

 7 Figure S8.7 Time course of oxidation of benzylphenyl sulfide with hemicryptophane catalyst M-(S,S,S)-(R,R,R)-2 (conditions: 1.5 mol% catalyst, 1.0 equiv. of CHP, 0 o C, CH2Cl2).

Figure S8. 8

 8 Figure S8.8 Time course of oxidation of naphthylmethyl phenyl sulfide with typical catalysts (conditions: 1.5 mol% catalyst, 1.0 equiv. of CHP, 0 o C, CH2Cl2).

Figure S8. 9

 9 Figure S8.9 Time course of oxidation of naphthylmethyl phenyl sulfide with hemicryptophane catalyst M-(S,S,S)-(R,R,R)-2 (conditions: 1.5 mol% catalyst, 1.0 equiv. of CHP, 0 o C, CH2Cl2).

Figure S8. 10

 10 Figure S8.10 (a) Initial rate dependence on the concentration of benzylphenyl sulfide in CH2Cl2 with 1.1 mM hemicryptophane catalyst M-(S,S,S)-(R,R,R)-2 and 110 mM CHP at 0 o C. (b) The corresponding Lineweaver-Burke line plotted by 1/rate as a function of 1/[benzylphenyl sulfide].

  Development of new catalytic processes for valorization of nonfood biomass polymers to chemicals and fuels is of great interest. In this communication, we have the first time demonstrated the aerobic oxidation of lignin model by a supramolecular cage catalyst, constructed by a hemicryptophane framework incorporated with an oxido-vanadium site inside the cavity. Compared to the model catalyst with an open structure, the cage catalyst exhibited an improvement of the catalytic activity without product inhibition phenomena. A diastereoselective conversion for a mixture of chiral lignin substrates has been observed, indicating either a diastereoselective recognition between the substrates and the cage catalyst or stabilistaion of the transistion states.

Figure 9 . 1

 91 Figure 9.1 Structures of the cage and model complexes 1 and 2.

Figure S9.1 1 H

 1 Figure S9.1 1 H NMR spectrum (DMSO-d6, 300 MHz, 298K) of the reaction mixture of catalytic oxidation of 3 by the cage catalyst 1 at 80 o C in DMSO-d6 for 18 h. The yields of 4 and 5, and the conversion of 3 were calculated based on the integrations against that of the internal standard. Similar spectrum with different integration ratios was obtained for the same substrate catalyzed by the model catalyst 2 under the same conditions.

Figure S9.2 1 H

 1 Figure S9.2 1 H NMR spectrum (DMSO-d6, 300 MHz, 298K) of the reaction mixture of catalytic oxidation of 6 by the cage catalyst 1 at 110 o C in DMSO-d6 for 20 h. The yields of 4, 7, 8 and MeOH (9) were calculated based on the integrations against that of the internal standard. Due to signals overlap, the yield of 5 and the conversion of 6 cannot be determined. Similar spectrum with different integration ratios was obtained for the same substrate catalyzed by the model catalyst 2 under the same conditions.

Figure S9. 3

 3 Figure S9.3 GC analytical spectrum of the reaction mixture of catalytic oxidation of 6 by the cage catalyst 1 at 110 o C in DMSO-d6 for 20 h, with the full assignment of all the signals of 4-8.

Figure S9. 4

 4 Figure S9.4 GC analysis showing that after 20 h of catalytic oxidation of 6 catalyzed by the cage catalyst 1, obvious variation in the raito between the two diastereomeric pairs of enantiomers has been observed (from 1:3.5 to 1:1.4); while when catalyzed by the model catalyst 2, no obvious change occurred (from 1:3.5 to 1:3.4).

  Scheme 10.1 Azaphosphatranes [1a-1c•H] + •X -(X: NTf2, BArF) and hydrogen-bond acceptors [(-)-sparteine, pentamethylpiperidine, and CyNMe2] involved in the ring opening of DL-lactide.

  compounds. Monocrystals of [1b•H] + •NTf2 and [1b•H] + •BArF were grown by slow evaporation from methanol solutions. The bond lengths and bond angles of these two compounds were found to be similar to those obtained for [1b•H] + •aluminatrane . 29d Detailed bond lengths and close contacts are listed in the Experimental secontion of this Chapter and summarized in Table 10.1. In particular, the + P H bond length is 1.300 Å for [1b•H] + •NTf2 , and 1.277 Å for [1b•H] + •BArF . The phosphorus atom is also surrounded by three sp 2 -hybridized Neq atoms ( + P Neq bond lengths of 1.658 1.681 Å), and a fourth sp 3 -hybridized nitrogen atom Nax ( + P Nax bond length of 1.981 Å for both crystals).

Figure 10 . 1

 101 Figure 10.1 Selected contacts in crystal cells: [1b•H] + •NTf2 -(left) and [1b•H] + •BArF -(right). For the [1b•H] + •NTf2 crystal (Figure 10.1, left), each cation is mainly in close contact with its NTf2 anion through C H•••F C (2.567 2.85 Å), C H•••O=S (2.517 2.90 Å), and C H•••N (2.601 Å) interactions. The anions also experienced C F•••F C interactions (2.84 3.09 Å). Remarkably, the + P H bonds are located near their benzylic substituents [ + P H•••H C distances: 1.928 (H12), 2.042 (H7), and 2.130 (H15) Å], and embedded into a hydrophobic cavity with no other close contacts.

  e., azaphosphatranes [1a 1c•H] + •X ), and at the same time the hydrogen-bond-acceptor catalyst (i.e., a tertiary amine) is also hydrogen bonded to the initiator or the end of the growing chain (both alcohols), then both the nucleophile and the electrophile are activated, and could react at room temperature.

Figure 10 . 2

 102 Figure 10.2 Proposed H-bonding activation using the [1a-c•H] + •X -and tertiary amine (NR 2 R 3 R 4 ) couple catalysts for the consensual ROP mechanism (R 1 OH as the initiator or the growing chain).

Figure 10 . 3

 103 Figure 10.3 Energy-minimized structures (PM3 level, HyperChem 8.0) between [1b•H] + and: (i) L-lactide (left) and (ii) CyNMe2 (right).

  c•H] + •X -in presence of acceptors, in the ROP of lactide. a,b

Figure 10 . 4

 104 Figure 10.4 Structure of the azaphosphatrane-based hemicryptophane catalyst.

  The ability of azaphosphatranes to activate C=O groups in the ring-opening polymerization of lactide is promising, as the conversion reached 74 81% under classical conditions, even with the simplest azaphosphatrane catalyst. Again, this ROP model reaction offered a wealth of learning opportunities for the further exploration of azaphosphatranes in hydrogen-bonding catalysis. Future modifications of the azaphosphatrane structures should improve their ability to promote other transformations through the formation of multiple hydrogen bonds.Anion binding in water templated the self-assembly of an endohedrally functionalized Fe II 4L4 tetrahedron from azaphosphatrane-based subcomponents. This new water-soluble cage is flexible and able to encapsulate anions with volumes ranging from 35 to 219 Å 3 via hydrogen bonding and electrostatic interactions. It structurally adapts in response to the size and shape of the template anions, adopting a conformation either where all four azaphosphatrane + P H vectors point inward or else in which one points outward and the other three inward. The two cage isomers coexist in solution in some cases and interconvert.

  Figure 11.1, 1 has a face-capped tetrahedral framework with approximate T-symmetry. Both enantiomers ΔΔΔΔ and ΛΛΛΛ) are present in the unit cell. The + P H groups of the azaphosphatrane units point inward into cavity, where a disordered triflate anion is encapsulated. The Fe II centers are separated by an average of 14.7 Å, and the volume of the central cavity approximates 166 Å 3 (51% occupancy for OTf -, Figure S11.70).

Figure 11 . 1

 111 Figure 11.1 Crystal structure of OTf -⊂1, which shows a T-symmetric cage. Disorder, unbound counterions, nonacidic hydrogen atoms, and solvents are omitted for clarity.

SO4 2 -

 2 prevents it acting as a template for the formation of 1.14 Therefore, a series of other anions with different shapes and volumes, listed in Figure11.2, were added to the aqueous reaction mixture to investigate their template effects (1 equiv of anion was added in each case with regard to the final cage).

Figure 11 . 2 1 (

 1121 Figure 11.2 Schematic representation of the two cage isomers X -⊂T-1 and X -⊂C3-1 obtained by self-assembly in water driven by 1 equiv of template anion. The tripods colored orange in the faces of the tetrahedra represent endo-azaphosphatrane ligands with the + P-H oriented inward, while the one colored cyan represents exo + P-H. All of the anions listed in Figure 11.2, with volumes ranging from 35 Å 3 (I -) to 219 Å 3 (CB11H12 -), were observed to serve as competent templates for 1, indicating that its cavity adapted readily to guests having different sizes and shapes. In particular, cage 1 manifested this adaptability in a novel way: for the smaller template anions with volumes 53 Å 3 , part of the population of 1 consisted of a C3-symmetric isomer (C3-1) in which one of the azaphosphatrane + P H groups was oriented away from the inner cavity (defined as exo) with the other three pointed inward (defined as endo); while a T-symmetric isomer (T-1) constructed by four endo + P H groups constituted the other part of the population. For the larger anionic templates with volumes Å 3 , the T-symmetric isomer (T-1) was observed exclusively. The 1 H NMR spectra of 1 templated by BF4 -, NO3 -or I -in water show five sets of ligand signals (Figures S11.49), in which one set belongs to T-1, while the other four sets in a 1:1:1:1 integrated ratio belong to C3-1 (for full structural assignment, see Figure S11.53). The corresponding 31 P NMR spectra exhibit three peaks, one for T-1 and two in a 3:1 ratio for C3-1(Figures S11.52, S11.62 and S11.65). The two cage isomers were observed to interconvert

Figure 11 . 3

 113 Figure 11.3 Time evolution of the ratio between NO3 -⊂T-1•[SO4]5.5 () and NO3 -⊂C3-1•[SO4]5.5 (▲) at β98 K by monitoring the integration of the corresponding imine peaks in the 1 H NMR spectra (D2O, 500 MHz, 298 K). DOSY shows that the two species give the same diffusion coefficient. In the cases of BF4 -and I -(Figures S11.61, S11.62, S11.64 and S11.65), BF4 -⊂T-1 and I -⊂T-1

S11. 63 )

 63 or I -(Figure S11.66), predominantly favors the C3-isomeric conformation.

Figure 11 . 4

 114 Figure 11.4 MM3-optimized molecular model of NO3 -⊂C3-1, based on the crystal structure of OTf -⊂1 in Figure 11.1. Nonacidic hydrogen atoms are omitted for clarity. The exo-azaphosphatrane ligand is colored cyan.

Figure 11 . 5

 115 Figure 11.5 Schematic representation of two successive processes: fast kinetics of guest displacement of NTf2 -or NO3 -by BF4 -giving shape memory phenomena followed by slow kinetics of isomeric reconfiguration.

1 1 [

 11 Scheme S11.1 Synthetic route for the preparation of azaphosphatrane-based subcomponents A•NTf2, A•PF6 and A•OTf.

Figure S11.1 1 H

 1 Figure S11.1 1 H NMR (CD3CN, 500 MHz, 298 K) spectrum of 1•[NTf2]12.

Figure S11. 2

 2 Figure S11.2 31 P-decoupled 1 H NMR (CD3CN, 500 MHz, 298 K) spectrum of 1•[NTf2]12.

Figure S11. 3

 3 Figure S11.3 13 C NMR spectrum (CD3CN, 125.8 MHz, 298K) of 1•[NTf2]12.

Figure S11. 4

 4 Figure S11.4 1 H-decoupled 31 P NMR spectrum (CD3CN, 202.4 MHz, 298K) of 1•[NTf2]12.

Figure S11.5 19 F

 19 Figure S11.5 19 F NMR spectrum (CD3CN, 470.4 MHz, 298K) of 1•[NTf2]12.

Figure S11.6 1 H

 1 Figure S11.6 1 H-1 H COSY spectrum (CD3CN, 500 MHz, 298K) of 1•[NTf2]12.

Figure S11. 7

 7 Figure S11.7 1 H-13 C HSQC spectrum (CD3CN, 500 MHz, 298K) of 1•[NTf2]12.

Figure S11.8 1 H

 1 Figure S11.8 1 H-13 C HMBC spectrum (CD3CN, 500 MHz, 298K) of 1•[NTf2]12.

Figure S11. 9

 9 Figure S11.9 1 H-31 P HSQC spectrum (CD3CN, 500 MHz, 298K) of 1•[NTf2]12.

Figure S11.10 1 H

 1 Figure S11.10 1 H DOSY spectrum (CD3CN, 500 MHz, 298K) of 1•[NTf2]12. The diffusion coefficient of 1•[NTf2]12 in CD3CN was measured to be 8.25 × 10 -6 cm 2 s -1 .

Figure S11. 11

 11 Figure S11.11 High-resolution ESI-mass analysis of 1•[NTf2]12 showing the +6 and +5 peaks.

Figure S11. 12

 12 Figure S11.12 Low-resolution ESI-mass spectrum of 1•[NTf2]12.

Figure

  Figure S11.13 1 H NMR (CD3CN, 500 MHz, 298 K) spectrum of 1•[PF6]12.

Figure

  Figure S11.14 31 P-decoupled 1 H NMR (CD3CN, 500 MHz, 298 K) spectrum of 1•[PF6]12.

Figure

  Figure S11.15 13 C NMR spectrum (CD3CN, 125.8 MHz, 298K) of 1•[PF6]12.

Figure S11. 16

 16 Figure S11.16 1 H-decoupled 31 P NMR spectrum (CD3CN, 202.4 MHz, 298K) of 1•[PF6]12.

Figure S11. 17

 17 Figure S11.1719 F NMR spectrum (CD3CN, 470.4 MHz, 298K) of 1•[PF6]12.

19 F

 19 Figure S11.1719 F NMR spectrum (CD3CN, 470.4 MHz, 298K) of 1•[PF6]12.

Figure

  Figure S11.18 1 H-1 H COSY spectrum (CD3CN, 500 MHz, 298K) of 1•[PF6]12.

Figure S11. 19

 19 Figure S11.19 1 H-13 C HSQC spectrum (CD3CN, 500 MHz, 298K) of 1•[PF6]12.

Figure

  Figure S11.20 1 H-13 C HMBC spectrum (CD3CN, 500 MHz, 298K) of 1•[PF6]12.

Figure S11. 21

 21 Figure S11.21 1 H-31 P HSQC spectrum (CD3CN, 500 MHz, 298K) of 1•[PF6]12.

Figure S11.22 1 H

 1 Figure S11.22 1 H DOSY spectrum (CD3CN, 500 MHz, 298K) of 1•[PF6]12. The diffusion coefficient of 1•[PF6]12 in CD3CN was measured to be 8.35 × 10 -6 cm 2 s -1 .

Figure S11. 23

 23 Figure S11.23 High-resolution ESI-mass analysis of 1•[PF6]12 showing the +6 and +5 peaks.

Figure S11. 24

 24 Figure S11.24 Low-resolution ESI-mass spectrum of 1•[PF6]12.

  ppm. 31 P NMR (CD3CN, 298K, 202.4 MHz): δ -17.9 ( + P-Hk) ppm. 19 F NMR (470.4 MHz, 298 K, CD3CN): δ -. encapsuρated OTf , -. λree OTλ ) ppm. ESI-MS m/z 411.1 [M+3OTf ] +9 , 481.1 [M+4OTf ] +8 , 571.1 [M+5OTf ] +7 ,691.2 [M+6OTf ] +6 , 859.2 [M+7OTf ] +5 , 1111.2 [M+8OTf ] +4 , 1531.3 [M+9OTf ] +3 .

Figure

  Figure S11.25 1 H NMR (CD3CN, 500 MHz, 298 K) spectrum of 1•[OTf]12.

Figure S11. 26

 26 Figure S11.26 31 P-decoupled 1 H NMR (CD3CN, 500 MHz, 298 K) spectrum of 1•[OTf]12.

Figure S11. 27

 27 Figure S11.27 13 C NMR spectrum (CD3CN, 125.8 MHz, 298K) of 1•[OTf]12.

Figure S11. 28

 28 Figure S11.28 31 P NMR spectrum (CD3CN, 202.4 MHz, 298K) of 1•[OTf]12.

Figure S11.29 19 F

 19 Figure S11.29 19 F NMR spectrum (CD3CN, 470.4 MHz, 298K) of 1•[OTf]12.

Figure S11. 30

 30 Figure S11.30 1 H-1 H COSY spectrum (CD3CN, 500 MHz, 298K) of 1•[OTf]12.

Figure

  Figure S11.31 1 H-13 C HSQC spectrum (CD3CN, 500 MHz, 298K) of 1•[OTf]12.

Figure S11. 32

 32 Figure S11.32 1 H-13 C HMBC spectrum (CD3CN, 500 MHz, 298K) of 1•[OTf]12.

Figure

  Figure S11.33 1 H-31 P HSQC spectrum (CD3CN, 500 MHz, 298K) of 1•[OTf]12.

Figure

  Figure S11.34 1 H DOSY spectrum (CD3CN, 500 MHz, 298K) of 1•[OTf]12.The diffusion coefficient of 1•[OTf]12 in CD3CN was measured to be 8.25 × 10 -6 cm 2 s -1 .

Figure S11. 35

 35 Figure S11.35 High-resolution ESI-mass analysis of 1•[OTf]12 showing the +6 and +5 peaks.

Figure S11. 36 5 Scheme S11. 2

 3652 Figure S11.36 Low-resolution ESI-mass spectrum of 1•[OTf]12. 11.5.2.3 Synthesis of subcomponent A•[SO4]0.5

  P NMR (D2O, 298K, 202.4 MHz): δ -12.0 ppm. ESI-HRMS m/z: found 490.2842, calcd for C27H31N7O6P [M] + 490.2843. 11.5.2.4 Preparation of cage X -⊂1•[SO4]5.5 in water A•[SO4]0.5

  5 and X ⊂C3-1•[SO4]5.5 were observed after one night. The two species then slowly interconverted taking almost 2 weeks to reach equilibrium.

Figure S11. 39

 39 Figure S11.39 31 P-decoupled 1 H NMR (D2O, 500 MHz, 298 K) spectrum of OTf -⊂T-1•[SO4]5.5.

Figure S11. 40

 40 Figure S11.40 13 C NMR (D2O, 125.8 MHz, 298 K) spectrum of OTf -⊂T-1•[SO4]5.5.

Figure S11. 41

 41 Figure S11.41 1 H-decoupled 31 P NMR spectrum (D2O, 202.4 MHz, 298K) of OTf -⊂T-1•[SO4]5.5.

Figure S11.42 19 F

 19 Figure S11.42 19 F NMR spectrum (D2O, 470.4 MHz, 298K) of OTf -⊂T-1•[SO4]5.5.

Figure S11. 43

 43 Figure S11.43 1 H-1 H COSY spectrum (D2O, 500 MHz, 298K) of OTf -⊂T-1•[SO4]5.5.

Figure S11. 44

 44 Figure S11.44 1 H-13 C HSQC spectrum (D2O, 500 MHz, 298K) of OTf -⊂T-1•[SO4]5.5.

Figure S11. 45

 45 Figure S11.45 1 H-13 C HMBC spectrum (D2O, 500 MHz, 298K) of OTf -⊂T-1•[SO4]5.5.

Figure S11. 46

 46 Figure S11.46 1 H-31 P HSQC spectrum (D2O, 500 MHz, 298K) of OTf -⊂T-1•[SO4]5.5.

Figure S11.47 1 H- 31 F

 131 Figure S11.47 1 H-31 F HOESY spectrum (D2O, 500 MHz, 298K) of OTf -⊂T-1•[SO4]5.5.

Figure S11.48 1 H- 31 F

 131 Figure S11.48 1 H-31 F HOESY spectrum (D2O, 500 MHz, 298K) of PF6 -⊂T-1•[SO4]5.5.

Figure S11. 50

 50 Figure S11. 50 Time evolution of the ratio between NO3 -⊂T-1•[SO4]5.5 () and NO3 -⊂C3-1•[SO4]5.5 (▲) at β98 K monitored by 1 H NMR spectroscopy (D2O, 500 MHz, 298 K). Imine protons have been labelled in the spectra. DOSY spectrum shows that the two species give the same diffusion coefficient (1.4 × 10 -6 cm 2 s -1 ).

Figure S11. 51

 51 Figure S11.51 31 P coupled/decoupled 1 H NMR (D2O, 500 MHz, 298 K) spectrum of the assembly of NO3 -⊂1•[SO4]5.5 after 87 h in D2O, giving two isomeric cage species of NO3 -⊂T-1•[SO4]5.5 () and NO3 -⊂C3-1•[SO4]5.5 (▲), and the corresponding 1 H-31 P HSQC (D2O, 500 MHz, 298K) spectrum.

Figure S11. 52 .

 52 Figure S11.52. Time evolution of the ratio between NO3 -⊂T-1•[SO4]5.5 () and NO3 -⊂C3-1•[SO4]5.5 (▲) at β98 K monitored by 31 P NMR spectroscopy (D2O, 202.4 MHz, 298 K). Phosphorous peaks have been assigned in the spectra. The schematic inset at the left with two types of colors of + P-H (orange and purple) on the four faces of the tetrahedron illustrates the two sets of signals in the 31 P NMR spectra of NO3 -⊂C3-1•[SO4]5.5.

Figure S11. 53

 53 Figure S11.53 1 H NMR (D2O, 500 MHz, 298 K) spectrum of the assembly of NO3 -⊂1•[SO4]5.5 in D2O after 2 weeks which shows the percentage of NO3 -⊂C3-1•[SO4]5.5 among the two cage isomers is 95%. The protons of NO3 -⊂C3-1•[SO4]5.5 have been labelled and assigned in the spectrum; ♦ represents impurity.

Figure S11. 54

 54 Figure S11.54 1 H-1 H COSY spectrum (D2O, 500 MHz, 298K) of the assembly of NO3 -⊂1•[SO4]5.5 in D2O after weeks with the ratio of NO3 -⊂T-1•[SO4]5.5 : NO3 -⊂C3-1•[SO4]5.5 = 5 : 95.

Figure S11. 55

 55 Figure S11.55 1 H-P HMBC spectrum (D2O, 500 MHz, 298K) of the assembly of NO3 -⊂1•[SO4]5.5 in D2O after weeks with the ratio of NO3 -⊂T-1•[SO4]5.5 : NO3 -⊂C3-1•[SO4]5.5 = 5 : 95.

Figure S11. 56

 56 Figure S11.56 TOCSY spectrum (D2O, 500 MHz, 298K, mixing time: 50 ms) of the assembly of NO3 - ⊂1•[SO4]5.5 in D2O after 2 weeks with the ratio of NO3 -⊂T-1•[SO4]5.5 : NO3 -⊂C3-1•[SO4]5.5 = 5 : 95.

Figure S11. 57

 57 Figure S11.57 TOCSY (D2O, 500 MHz, 298K, mixing time: 100 ms) of the assembly of NO3 - ⊂1•[SO4]5.5 in D2O after 2 weeks with the ratio of NO3 -⊂T-1•[SO4]5.5 : NO3 -⊂C3-1•[SO4]5.5 = 5 : 95.

Figure S11. 58

 58 Figure S11.58 NOESY spectrum (D2O, 500 MHz, 298K) of the assembly of NO3 -⊂1•[SO4]5.5 in D2O after 2 weeks with the ratio of NO3 -⊂T-1•[SO4]5.5 : NO3 -⊂C3-1•[SO4]5.5 = 5 : 95.

Figure S11. 59

 59 Figure S11.59 1 H-13 C HSQC spectrum (D2O, 500 MHz, 298K) of the assembly of NO3 -⊂1•[SO4]5.5 in D2O after 2 weeks with the ratio of NO3 -⊂T-1•[SO4]5.5 : NO3 -⊂C3-1•[SO4]5.5 = 5 : 95.

Figure S11. 60

 60 Figure S11.60 Aromatic region of 1 H-13 C HMBC (D2O, 500 MHz, 298K) of the assembly of NO3 - ⊂1•[SO4]5.5 in D2O after 2 weeks with the ratio of NO3 -⊂T-1•[SO4]5.5 : NO3 -⊂C3-1•[SO4]5.5 = 5 : 95.

Figure S11. 61

 61 Figure S11.61 Time evolution of the ratio between BF4 -⊂T-1•[SO4]5.5 () and BF4 -⊂C3-1•[SO4]5.5 (▲) at 298 K monitored by 1 H NMR spectroscopy (D2O, 500 MHz, 298 K). Imine protons have been labelled in the spectra. DOSY spectrum shows that the two species give the same diffusion coefficient (1.4 × 10 -6 cm 2 s -1 ).

Figure S11. 62

 62 Figure S11.62 Time evolution of the ratio between BF4 -⊂T-1•[SO4]5.5 () and BF4 -⊂C3-1•[SO4]5.5 (▲) at 298 K monitored by 31 P NMR spectroscopy (D2O, 202.4 MHz, 298 K). Phosphorous peaks have been assigned.

Figure S11. 63

 63 Figure S11.63 MM3-optimized molecular model of BF4 -⊂C3-1, based on the single-crystal X-ray structure of OTf -⊂T-1. Nonacidic hydrogen atoms are omitted for clarity. The exo-azaphosphatrane is colored cyan.

Figure S11. 64

 64 Figure S11.64 Time evolution of the ratio between I -⊂T-1•[SO4]5.5 () and I -⊂C3-1•[SO4]5.5 (▲) at 298 K monitored by 1 H NMR (D2O, 500 MHz, 298 K). Imine protons have been labelled in the spectra.DOSY spectrum shows that the two species give the same diffusion coefficient (1.4 × 10 -6 cm 2 s -1 ).

Figure S11. 65

 65 Figure S11.65 Time evolution of the ratio between I -⊂T-1•[SO4]5.5 () and I -⊂C3-1•[SO4]5.5 (▲) at 298 K monitored by 31 P NMR spectroscopy (D2O, 202.4 MHz, 298 K). Phosphorous peaks have been assigned.

Figure S11. 66

 66 Figure S11.66 MM3-optimized molecular model of I -⊂C3-1, based on the single-crystal X-ray structure of OTf -⊂T-1. Nonacidic hydrogen atoms are omitted for clarity. The exo-azaphosphatrane is colored cyan and the central iodide is yellow.

Figure S11. 69

 69 Figure S11.69 Kinetic study of interconversion of I -⊂T-1•[SO4]5.5 ⇌ I -⊂C3-1•[SO4]5.5. (a) The plot between Y and the time t, where Y is calculated by Eq 1 at the right part; the corresponding slope is the rate constant k1, as indicated in Figure S69b; the time after 40 h of assembly was chosen as "t = 0"; k-1, G1 ǂ and G-1 ǂ were determined by either Eq 2 or Eq 3. (b) Activation energy diagram of I - ⊂T-1•[SO4]5.5 ⇌ I -⊂C3-1•[SO4]5.5.

Formula 3 Specific 5

 35 C190.50H184F40.50Fe4N40O31.50P5.50S10.50, M 5037.63, Orthorhombic, space group F d d d (#70), a 18.6629(8), b 64.266(3), c 85.271(4) Å 3 , V 102273(8) Å 3 , Dc 1.309 g cm -3 , Z 16, crystal size 0.210 by 0.170 by 0.080 mm, colour purple, habit block, temperature 180(2) Kelvin, λ(CuK ) 1.54178 Å, (CuK ) 3.746 mm -1 , T(SADABS)min,max 0.5665, 0.7488, 2θmax 89.05, hkl range -16 16, -43 58, -77 72, N 53746, Nind 10071(Rmerge 0.0349), Nobs 8700 (I > 2σ(I)), Nvar 1652, residuals* R1(F) 0.1078, wR2(F 2 ) 0.2780, GoF(all) 1.085, Δ min,max -0.644, 0.937 e -Å -3 . *R1 = Σ||Fo| -|Fc||/Σ|Fo| for Fo > 2σ(Fo); wR2 = (Σw(Fo 2 -Fc 2 )2/Σ(wFc 2 ) 2 ) 1/2 all reflections w=1/[σ 2 (Fo 2 )+(0.1114P) 2 +3339.7393P] where P=(Fo 2 +2Fc 2 )/were grown by diffusion of diethyl ether into an acetonitrile solution of a mixture of 1•[OTf]12 and 1•[PF6]12. The crystals employed immediately lost solvent after removal from the mother liquor and rapid handling prior to flash cooling in the cryostream was required to collect data. Despite these measures and the use of a high intensity laboratory source few reflections at greater than 1.1 Å resolution were observed.

Figure

  Figure S11.70 VOIDOO-calculated void space as shown (green mesh) within the crystal structure of OTf -⊂T-1 (left) and within the MM3-optimized structure of NO3 -⊂C3-1 (right) in the absense of the encapsulated anions.

F 5 Figure S11. 71 19 F

 57119 Figure S11.71 Competitive titration of PF6 -into a solution of OTf -⊂1•[SO4]5.5 in D2O monitored by 19 F NMR spectroscopy (D2O, 470.4 MHz, 298K). Each spectrum was recorded after 12 h since the addition of PF6 -to the solution to reach equilibrium. The relative binding constant for PF6 -versus OTf - was calculated to be 17.

Figure S11. 72 19 F

 7219 Figure S11.72 Competitive titration of ReO4 -into a solution of OTf -⊂1•[SO4]5.5 in D2O monitored by 19 F NMR spectroscopy (D2O, 470.4 MHz, 298K). Each spectrum was measured after 12 h since the addition of ReO4 -to the solution to reach equilibrium. The relative binding constant for ReO4 -versusOTf -was calculated to be 1.9.

Figure S11. 73 19 F 5 Figure S11. 74

 7319574 Figure S11.73 Competitive titration of ClO4 -into a solution of OTf -⊂1•[SO4]5.5 in D2O monitored by 19 F NMR spectroscopy (D2O, 470.4 MHz, 298K). Each spectrum was measured after 12 h since the addition of ClO4 -to the solution to reach equilibrium. The relative binding constant for ClO4 -versus OTf -was calculated to be 0.03.

Figure S11. 75 1 H

 751 Figure S11.75 Competitive titration of BF4 -into a solution of NTf2 -⊂1•[SO4]5.5 in D2O monitored by 1 H NMR spectroscopy (D2O, 400 MHz, 298K). Each spectrum was measured after 12 h since adding BF4 -to the solution to reach equilibrium. Results show that 6.0 equiv of BF4 -are not enough to fully displace the encapsulated NTf2 -, indicating the weaker binding of BF4 -than that of NTf2 -.

Figure S11. 76

 76 Figure S11.76 Competitive titration of I -into a solution of NTf2 -⊂1•[SO4]5.5 in D2O monitored by 1 H NMR spectroscopy (D2O, 400 MHz, 298K). Each spectrum was measured after 12 h since adding I -to the solution to reach equilibrium. Results show that the binding of I -relative to NTf2 -is much weaker than that of BF4 -.

Figure S11. 77

 77 Figure S11.77 (a) Shape memory phenomena observed by 1 H NMR spectroscopy (D2O, 500 MHz, 298K). (b) Assignment of the methylene protons of the exo-azaphosphatrane in cage BF4 - ⊂C3-1•[SO4]5.5 to its 1 H NMR spectrum by (b) partial 1 H-31 P HMBC and 1 H-1 H COSY experiments.

Figure S11. 78

 78 Figure S11.78 1 H-19 F HOESY (D2O, 500 MHz, 298K) spectrum of BF4 -⊂C3-1•[SO4]5.5 (95% population) obtained by competitive anion displacement from 95% NO3 -⊂C3-1•[SO4]5.5 solution. Clear NOE correlations have been observed between BF4 -and the methylene protons of the exo-azaphosphatrane in the spectrum.In order to assign the C3-1 structure induced by NO3 , BF4 or I , we investigated by 1 H-19 F

  Part II mainly focus on the host-guest chemistry of hemicryptophanes. This begins with a fluorescent hemicryptophane cage combining a CTV unit and a Zn(II) metal center, as described in Chapter 3. This fluorescent hemicryptophane was developed as the first fluorescent sensor for a zwitterion, choline phosphate, in competitive media. The heteroditopic character of the host towards the guest was thoroughly investigated by both fluorescence and NMR spectroscopy. The exact binding mode has been examined by DFT calculations. In Chapter 4, two new hemicryptophane hosts bearing fluorinated aromatic linkers were synthesized to investigate their complexation properties of ion pairs. The introduction of fluorine atoms around the aromatic linkers was expected to improve the anion binding abilities of the host, therefore affecting their ion pair binding performance. The binding affinity toward anions was found to strongly rely on the location of the fluorine atoms on the linkers, highlighting the complexity of anion interactions. The cooperativity involved in the recognition of ion pairs was found to be able to modulate from positive to negative by this chemical engineering. These observations have been supported by CASSCF/CASPT2 calculations. Encouraged by the two efficient heteroditopic hemicryptophanes in the recognition of zwitterions and ion pairs, in Chapter 5, two new heteroditopic hemicryptophanes bearing TPA units were synthesized: one with phenyl rings as linkers and the other with naphthalene rings. As TPA unit is able to complex various metals, these hemicryptophanes are chemical platforms available for various purposes and applications. The naphthalene linkers in one cage also confer fluorescence properties to the host structure, and gram-scale synthesis of the other cage was also achieved. The racemate of each hemicryptophane was finally resolved by chiral HPLC, and their enantiopure versions have been obtained. We anticipate their promising applications, for instance for heteroditopic recognition of chiral zwitterions. Due to the strong interest in chirality as well as the consideration of their importance, in Chapter 6, eight enantiopure cages were designed and synthesized combining three classes of chirality on seven stereogenic units: the helical chirality of the CTV unit, the axial chirality of the binaphthol linkages, and the central chirality of the asymmetric carbons on the trialcohol unit. Albeit the multiple chirality in the engineered structure makes difficult the assignment of the absolute configuration of CTV with conventional methods, a chemical correlation strategy was developed, to successfully determine the configuration of the eight hemicryptophane stereoisomers. The stereoselective recognition properties toward glucose and mannose derivatives with these new enantiopure cages were investigated, and from moderate to exclusive guest diastereo-and enantio-discrimination were observed. As described in Section 1.5, hemicryptophanes have also been developed as molecular machines, which include only two examples. Despite this area in hemicryptophane chemistry is not fruitful, in Chapter 7 (Part III), the breathing motion of a series of enantiopure cages was explored. In fact, we observed that the cages obtained in Chapter 6 adopt imploded conformation in both solution and solid states and a hierarchical imploded degree between the four cage diastereomers was exhibited. The hierarchical implosion also results in the regulation of their corresponding physical and chemical properties. For instance, the reaction between vanadium(V) oxytriisopropoxide and the most imploded cage suffers from a slower reaction rate compared to the other three diastereomers. Interestingly, vanadium complexation re-inflates the cage from its imploded conformation to a globular form, and the resulting vanadium core can also be removed from the inner cavity according to external coordination with TEA. Thus, this system is capable of switching between the imploded and expanded bistable states via external inputs, leading to the molecular breathing motion. In Part IV, three works related to the supramolecular catalysis with functionalized hemicryptophanes have been discussed. Benefiting from the obtained vanadium(V) complexes in Chapter 7, using the oxidation of sulfide as a model reaction, in Chapter 8, we described in total five sets of oxido-vanadium(V) complexes, including both cages and open structures. It was found that the complexes simultaneously holding CTV, binaphthol and oxido-vanadium groups are the most efficient catalysts because of the construction of the hydrophobic cavity with the size appropriate to accommodate and convert the sulfide substrates, and to expel the products from the inner cavity. This case constitutes a rare example of supramolecular catalysts that exhibit extremely high levels of efficiency with 10000 turnovers. The catalytic reaction obeys the Michaelis-Menten model of enzyme kinetics, and competitive inhibition was observed using Me4N + as an inhibitor. The substrate size-selectivity of the cage catalysts further indicate that the reaction occurs inside the cavity of the hemicryptophane hosts mimicking enzymatic functions. In Chapter 9, we further tested the catalytic lignin oxidation properties of these developed vanadium(V) hemicryptophane catalysts in collaboration with the group of Prof. R. Tom Baker at the University of Ottawa. This would be the first example of lignin oxidation by supramolecular catalysts. Compared to the model catalyst with an open structure, an improvement of the catalytic activity associated with a diastereo-selective conversion has been observed. Good turnover number was also reached considering the supramolecular feature of the catalyst. In Chapter 10, in collaboration with the group of Dr. Brigitte Bibal at the University of Bordeaux, we attempted to develop the azaphosphatrane-functionalized hemicryptophanes as hydrogen-bonding organocatalysts for the ring-opening polymerization of lactide. Although we observed a low reactivity with hemicryptophane cages, it was found that the model catalysts with lipophilic hindered counteranions (NTf2 or BArF ) show good catalytic behavior. Crystallographic

  Rivera et al. applied the Ugi-type multiple multicomponent macrocyclization to the synthesis of hemicryptophane 49.59 Following the same synthesis pathway described for hemicryptophane 33 (Scheme 1.6) and adding the triisocyanide 48 to CTV 32, they obtained the cage compound 49 bearing a C3 symmetry tricarboxamide platform (Scheme 1.8).

Scheme 1.8 Synthesis of Hemicryptophane 49. Scheme 1.9 Synthesis of hemicryptophane 54.

1 H NMR titration was first used for characterizing the

	biological processes. 162 However, most of them are chiral amine derivatives that lead to the
	formation of diastereomeric host-guest complexes in the recognition experiments run with
	racemic host compounds. To this end, enantiopure hemicryptophanes have been synthesized
	and used successfully in the recognition of chiral ammonium guests. Enantiopure
	tren-hemicryptophanes, M-(S,S,S)-30, P-(S,S,S)-30, M-(R,R,R)-30 and P-(R,R,R)-30, were tested
	in the stereoselective recognition of norephedrine and ephedrine in CDCl3/CD3OD solution. 151
	1 H NMR titration experiments were performed showing the formation of 1:1 and 1:2
	host-guest complexes. The authors explained the 1:2 stoichiometry with the fact that both the
	tren and CTV moieties are able to bind ammonium guests according to hydrogen bonding
	and cation-interactions, as previousρy observed in the recoμnition oλ dopamine and choρine
	with 15a and 123 respectively. Examination of the binding constants reported in Table 1.1
	shows that these hosts are able to complex ephedrine and norephedrine with high binding
	constants, and in addition, most of the host diastereomers discriminate norephedrine from
	ephedrine, exhibiting larger affinity towards the former. Furthermore, remarkable
	enantioselectivities in favour of the P-(S,S,S) enantiomer over M-(R,R,R) are displayed for
	both guests.
	host-guest association, where significant high-λieρd shiλts oλ the μuest s protons were observed
	attributed to the shielding effect of the aromatic environment. At lower temperature (270 K),
	under slow exchange conditions on the NMR time-scale, a new signal appeared in the
	high-field region corresponding to the included choline ammonium. In addition, DFT
	calculations are consistent with the 1 H NMR data and confirm the location of the ammonium
	part of the guest in the vicinity of the CTV unit (Figure 1.14b). A binding constant of 2300 M -1
	was determined by isothermal titration calorimetry (ITC). Surprisingly, no association was
	observed by ITC for betaine aldehyde and glycine betaine guest molecules, highlighting the
	high specificity and selectivity of hemicryptophane 123 towards choline.
	The complexation of choline emphasized the use of hemicryptophanes for the recognition
	of compounds of biological interest in water. More importantly, the recognition of
	neurotransmitters is very meaningful since many of them are involved in important

Table 1 .1 Association Constants of Enantiopure Receptors 30 with Ephedrine or Norephedrine a

 1

		Norephedrine	Ephedrine
		β1 (M -1 ) b	β2 (M -1 ) b	β1 (M -1 ) b	β2 (M -1 ) b
		1:1 host-guest	1:2 host-guest	1:1 host-guest	1:2 host-guest
	(M-(R,R,R))-30	-c	1.39 10 7	-c	4.60 10 6
	(M-(S,S,S))-30	1.52 10 5	2.64 10 9	4.71 10 4	2.18 10 8
	(P-(S,S,S))-30	3.99 10 3	2.18 10 7	8.06 10 3	2.52 10 7
	(P-(R,R,R))-30	2.50 10 5	1.95 10 9	1.65 10 4	7.92 10 7
	a β1 and β2 values were determined by fitting the 1 H NMR titration curves of the methyl protons
	of the guests using hypNMR2008 software 163 (CDCl3/CD3OD 95/5, 500 MHz, 298 K). b

1.4.2.2 Recognition of ion pairs

	In 2008, Jabin et al. reported a heteroditopic hemicryptophane cage that displays versatile
	host-guest properties towards organic associated ion pair salts (Figure 1.15). 70 Upon the
	addition of an excess of RNH3Cl (R = Et or Pr) to a solution of 91 in CDCl3, high-field shifted
	signals of the alkyl chain of the ammonium ions were observed, indicating that the
	ammonium ions are located inside the cavity of the calixarene. In addition, the amide protons
	close to the calixarene subunit also show a significant downfield shift, suggesting a strong
	hydrogen bonding interaction with the Cl anion. Hence, hemicryptophane 91 behaves as a
	heteroditopic receptor because of the simultaneous endo-complexation of cation and anion.

Table 1 .

 1

	2 Association Constants Ka of hemicryptophane 14 with
	neurotransmitters and related guests (CD3CN/D2O 9:1)
	Guest a	Ka (M -1 ) b	Vvdw (Å 3 )	pc (%) c
	H3N + CH2SO3 -	-	82	48
	Taurine	14000	99	59
	Homotaurine	530	116	69
	Glycine	-	69	41
	-Alanine	8500	86	51
	GABA	510	104	61
	Betaine	80	121	78
	(CH3)3N + CH2CH2COO -	-	138	82
	Choline phosphate	-	160	94

a Picrate salts. b Ka values were determined by DOSY NMR experiments except for (CH3)3N + CH2CH2COO -for which Ka

was determined by 1 H NMR titration using WinEQNMR2 sofware 169

Table 1 .3

 1 Association Constants Ka and Complexation Induced Shifts (CIS)

	Δδmax Measured by 1 H NMR Titration of Guests with Host 54 (CD3CN/D2O 8:2;
	500 MHz; 298 K)
	Guest	Ka (M -1 ) a	Vvdw (Å 3 ) b	Δδmax NCH2 + (ppm)	Δδmax CH2X -(ppm)
	-Alanine	1.5 ± 0.1 10 4	86	-0.41	-0.25
	Taurine	5.0 ± 0.4 10 5	99	-0.39	-0.20
	GABA	2.3 ± 0.1 10 5	103	-0.41	-0.20
	Homotaurine	1.1 ± 0.2 10 5	116	-0.31	-0.07

a Ka

values were determined by fitting 1 H NMR titration curves using WinEQNMR2 software 169 . b Van der Waals volume were calculated according to the method of Abraham et al. 170

Table 1 . 5

 15 Binding Constants Ka (M -1 ) for the 1:1 Complexes Formed Between Different Enantiopure Hemicryptophane Hosts and Carbohydrate Guests a,b

	Host	OctαGlc Oct Glc OctαMan Oct Man OctαGal	Oct Gal	Ref.
	M-14	216	64		155

  The binding properties of the stereoisomers of hemicryptophane 56 were compared to those of the model open-shell compounds 57 (Scheme 1.11).64 The cage derivatives 56 exhibit lower binding constants than 57, probably because of the lack of OH groups able to induce hydrogen bonding with the alcohol functions of the carbohydrate guests. The affinity towards carbohydrates follows the same order with hemicryptophane 56 and model host 57:

	S,S)-29	595	1660					56
	P-(S,S,S)-29	-c	183					56
	P-(R,R,R)-29	34	384					56
	M-(R,R,R)-29	56	192					56
	M-(S,S,S)-30	213	378	1410	804	29	13	57
	P-(S,S,S)-30	141	400	1648	387	112	68	57
	P-(R,R,R)-30	95	722	1544	967	142	59	57
	M-(R,R,R)-30	83	270	2511	641	22	-c	57
	M-(S,S,S)-56	41	-c	-c	61			64
	P-(S,S,S)-56	174	-c	-c	118			64
	P-(R,R,R)-56	29	72	182	458			64
	M-(R,R,R)-56	223	287	55	40			64
	P-(R,R,R)-57	177	359	616	204			64
	M-(R,R,R)-57	122	457	1174	375			64
	M-(S,S,S)-57	161	403	393	288			64
	P-(S,S,S)-57	98	334	749	197			64

a Ka was determined by fitting 1 H NMR titration curves (CDCl3, 500 MHz, 298 K) with HypNMR2008; estimated error 10%.

b

The blank cells indicate no measurement for this host and guest.

c No complexation detected.

Table 1 .

 1

6 Diels-Alder Reaction Between 3-Hydroxy-2-pyrone and N-Methylmaleimide or Dimethylfumarate with Catalysts P@15a and P@126a. dienophile catalyst compound (%) a de (%) b N-methylmaleimide P@126a 127 (99) 43 c N-methylmaleimide P@15a 127 (100) 77 c dimethylfumarate P@126a 128 (95) 20 dimethylfumarate P@15a 128 (<1) -

a

Table 1 .

 1

	133a	22	35	2.2
	133a	132	16
	133b	22	18	1.8
	133b	132	10
	133c	22	27	1.8
	133c	132	15
	133d	22	6.2	2.6
	133d	132	2.4
	133e	22	9.2	3.5
	133e	132	2.6
	133f	22	4.4	0.8
	133f	132	5.4

7 Zinc-Catalyzed Hydrolysis of Alkyl Carbonates 133a-f. a Substrate Ligand kobs (10 -3 h -1 ) k(22)/k(120) a Conditions: 85 M substrate, 5.0 equivalents EtN(i-Pr)2, 10 equivalents D2O and 0.1 equivalent catalyst in DMSO-d6 at 295 K.

Table 1 . 8

 18 Ruthenium Catalyzed Oxidation Reactions. a

	Catalyst	Substrate	Aldehyde Yield (%)	Carboxylic acid Yield (%)
	RuCl2@132	1-octanol	18	82
	RuCl2@22	1-octanol	90	0
	RuCl2@132	benzyl alcohol	52	48
	RuCl2@22	benzyl alcohol	91	9
	RuCl2@132	4-methoxybenzyl alcohol	55	41
	RuCl2@22	4-methoxybenzyl alcohol	94	6
	RuCl2@132	4-nitrobenzyl alcohol	27	10
	RuCl2@22	4-nitrobenzyl alcohol	88	12
	RuCl2@132	2-dodecanol	68 b	-
	RuCl2@22	2-dodecanol	26 b	-

a Conditions: alcohol (0.1 mmol), catalyst (5 mol%), Ce(NH4)2(NO3)6 (4eq.), in CH3CN/H2O (1/0.3). b Product is 2-dodecanone.

A Fluorescent Heteroditopic Hemicryptophane Cage for the Selective Recognition of Choline Phosphate

  European Journal(2016, 22, 8038 8042). The numbers of compounds, figures, schemes and tables have been renumbered in each chapter from the beginning, and the numbers of compounds between chapters have no relationship. Table of Contents in each chapter has been presented in the corresponding chapter cover. The cited references are listed at the end of each chapter.

	Chapter 3. This Chapter is based partially on the following manuscript-
	Dawei Zhang, Guohua Gao, Laure Guy, Vincent Robert, Alexandre Martinez,
	Jean-Pierre Dutasta
	Chem. Commun. 2015, 51, 2679-2682.

3, 4 and 6 are respectively based particially on my following publications: Chemical Communications (2015, 51, 2679 2682), ChemPhysChem (2015, 16, 293 2935), The Journal of Organic Chemistry (DOI: 10.1021/acs.joc.7b00559) and Chemistry -A The work in this chapter was carried out at the ENS-Lyon.

  . ESI-MS m/z: found 1101.5350 [M+H] + ; calcd for C69H73N4O9: 1101.5372. IR ῡ = 2931, 1606, 1508, 1263 cm -1 . M.p. > 310 °C (decomp.).

	Zn(II)@1 complex: 1 H NMR (500.1 MHz, 298 K, DMSO-d6) δ 7.43-7.63 (broad, 12H); 7.20 (s,
	3H); 7.05-7.11 (broad, 9H); 4.66 (d, 3H, J = 13.3 Hz); 4.21-4.43 (broad, 12H); 4.03 (broad, 3H);
	3.93 (broad, 3H); 3.69 (s, 9H); 3.47 (d, 3H, J = 13.4 Hz); 2.96-3.18 (broad, 12H). 1 H NMR (500.1
	MHz, 373 K, DMSO-d6) δ 7.57 (bs, 9H); 7.32 (bs, 3H); 7.03-7.10 (m, 12H); 4.68

. ESI-HRMS m

  /z: calcd for C57H55F6N4O12 [M+H] + 1101.3715, found 1101.3673. IR (KBr) ῡ = 3406, 3068, 2937, 1639, 1590, 1510, 1444, 1265 1149 cm -1 .

  . ESI-HRMS m/z: calcd for C57H55F6N4O12 [M+H] + 1101.3715, found 1101.3669. IR (KBr) ῡ = 3423, 3068, 2935, 1656, 1514, 1444, 1336, 1265 1039 cm -1 .

  . ESI-HRMS m/z: calcd for C30H31F6N4O6 [M+H] + 657.2142, found 657.2126. IR (KBr) ῡ =

  . ESI-HRMS m/z: calcd for C72H85F6N4O18 [M+H] + 1407.5758, found 1407.5729. IR (KBr) ῡ =3309, 3066, 2940, 2871, 1639, 1591, 1510, 1265, 1151, 1072, 1036 cm -1 .

Table S4 . 1 .

 S41 Association constants Ka of hosts 1-3 with anion guests obtained by modeling the titration curves with WinEQNMR2.32

		Ka (M -1 )	Ka (M -1 )	Ka (M -1 )
		host 1	host 2	host 3
	F -	120 ± 5	61 ± 3	2330 ± 100
	Cl -	103 ± 4	27 ± 5	1440 ± 70
	Br -	64 ± 3	12 ± 2	620 ± 13
	I -	41 ± 3	13 ± 1	270 ± 8
	AcO -	60 ± 3	11 ± 1	1140 ± 60
	HSO4 -	42 ± 5	18 ± 1	400 ± 16
	H2PO4 -	230 ± 20	21 ± 1	830 ± 110

Table S4 .2. Association

 S4

	F	61 ± 3	-	-	2330 ± 100	-	-	3
	Cl	27 ± 5	58 ± 1	2	1440 ± 70	640 ± 70	0.44	15
	Br	12 ± 2	42 ± 1	3.5	620 ± 13	< 5	< 0.01	9
	AcO	11 ± 1	27 ± 2	2.5	1140 ± 60	145 ± 15	0.13	5

constants of hosts 2 and 3 with anions in the absence (Ka) and presence (Ka') of one equivalent of Me4N + inside the cavity, and the cooperativity factors of hosts 1-3 with anion guests.

Ka (M -1 ) 2 Ka' (M -1 ) 2 Ka'/Ka 2 Ka (M -1 ) 3 Ka' (M -1 ) 3 Ka'/Ka 3 Ka'/Ka 1

  H NMR (CDCl3, 298K, 500.1 MHz): δ 7.60 (dd, J

	= 15.1, 8.3 Hz, 2H); 7.18-7.08 (m, 4H); 7.00-6.93 (m, 3H); 5.10 (s, 1H); 4.76 (d, J = 11.7 Hz, 1H);
	4.72 (t, J = 3.7 Hz, 1H); 4.50-4.43 (m, 5H); 3.99-3.94 (m, 1H); 3.90 (s, 3H); 3.61-3.57 (m, 1H);
	1.93-1.63 (m, 6H) ppm.

  ppm. ESI-HRMS m/z: found 1621.7043, calcd for C96H102N4NaO18 [13+Na]

+ 1621.7081.

Table 6 . 1

 61 Binding constants Ka (M -1 ) for the 1:1 complexes formed between the different isomers of hosts 1 or 14 and the carbohydrate guests. a

	Host	OctαGlc Oct Glc OctαMan Oct Man
	M-SSS-RRR-1	105	83	58	-b
	P-RRR-SSS-1	89	537	135	48

  . ESI-HRMS for SSS-SSS-6 m/z: found 1836.8142, calcd for C114H118NO21 [M+H] + 1836.8191. ESI-HRMS for RRR-RRR-6 m/z: found 1836.8235, calcd for C114H118NO21 [M+H] + 1836.8191.

  . ESI-HRMS m/z: found 1530.6080, calcd for C99H88NO15 [M+H] + 1530.6148. [∝]

	: 547 (c =
	0.092; CH2Cl2).
	Diastereomer M-SSS-SSS-1: 1 H NMR (CDCl3, 298K, 500.1 MHz): δ 8.05 (d, J = 9.0 Hz, 1H);
	7.97 (d, J = 9.1 Hz, 1H); 7.90 (t, J = 8.2 Hz, 2H); 7.59

  . ESI-HRMS m/z: found 1530.6079, calcd for C99H88NO15 [M+H] + 1530.6148. [∝]

  . ESI-HRMS m/z: found 1044.4064, calcd for C69H58NO9 [M+H] + 1044.4106. [∝]

3.08-3.53Å 2.77-2.94Å 2.74-2.96Å

Table 8 . 1

 81 Oxidation of thioanisol with CHP in the presence of catalyst. a

	Entry	Catalyst	Yield (%) b

  . ESI-HRMS m/z: found 349.1196, calcd for C23H18NaO2 [M+Na] + 349.1199. To NaH (131 mg, 3.28 mmol) (60% suspension in oil), a solution of S-7 (622 mg, 1.91 mmol) in DMF(22 mL) was added at room temperature. After stirring under argon for 60 min, a solution of S-(+)-glycidyl nosylate (621 mg, 2.40 mmol) in DMF (8 mL) was added. The mixture was stirred at room temperature under argon for 24 h. Then the reaction was quenched by adding saturated NH4Cl solution and the resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over

	anhydrous Na2SO4, filtrated and evaporated. After column chromatography over silica gel
	(CH2Cl2 as eluent), 730 mg (100 %) S-S-8 was obtained as a white solid. 1 H NMR (CD2Cl2,
	K,	. MHz δ .	d, J = 9.0 Hz, 2H); 7.92 (d, J = 8.2 Hz, 2H); 7.50 (d, J = 9.1 Hz, 1H); 7.47
	(d, J = 9.1 Hz, 1H); 7.36 (q, J = 6.7 Hz, 2H); 7.25 (t, J = 8.1 Hz, 2H); 7.12 (t, J = 8.3 Hz, 2H);
	5.85-5.79 (m, 1H); 5.07-5.04 (m, 2H); 4.59-4.58 (m, 2H); 4.26 (dd, J = 2.6, 11.6 Hz, 1H); 3.98 (dd, J
	= 5.4, 11.6 Hz, 1H); 3.0 (bs, 1H); 2.59 (t, J = 4.7 Hz, 1H); 2.34 (dd, J = 2.5, 4.8 Hz, 1H). 13 C NMR
	(CD2Cl2,	K,	. MHz δ	.	,	.	,	.	,	.	,	. ,	. ,	. ,	.	,
	129.2(5), 127.

S-S-8:

Table 9 .1. Oxidation of 3 by catalysts 1 and 2.

 9

				Yield (%) a
	Catalyst	Conversion (%) a
			4	5
	1	61	44	6
	2	44	34	4

Table 9 . 2

 92 Oxidation of 6 by catalysts 1 and 2.

						Yield (%) a
	Catalyst	Method	Conversion (%)
				4	5	7	8	9
		1 H NMR b	-a	37	-a	20	14	3
	1
		GC c	87	38	15	17	12	-a
		1 H NMR b	-a	28	-a	15	12	2
	2
		GC c	67	30	12	13	12	-a

Table 10 . 1

 101 Main short contacts ([Å]) in [1b•H] + •NTf2 -and [1b•H] + •BArF -monocrystals.

		Distance + P-H to H-CNsubstituent (Å)	Cation-anion Contacts (Å)	Other close contacts (Å)
	[1b•H] + •N Tf2 -	1.928, 2.042, 2.130	2.57-2.85 (C-H ... F-C), 2.601 (N -... H-C), 2.52-2.77 (C-H ... O-S)	2.84-3.09 (C-F ... F-C) 2.52-2.77 (C-H ... H-C)
	[1b•H] + • BArF -	2.044, 2.052, 2.060	2.53-2.85 (C-H ... F-C)	2.81-3.00 (C-F ... F-C), 2.50-2.83 (C-H ... H-C)

Table 10 . 2

 102 Catalytic properties of H-bond donors [1a-

4.0x10 6 6.0x10 6 8.0x10 6 0-50 equiv. Intensity (a.u.) Wavelength (nm)

H NMR titrations in CDCl3 at

K. Only one set of signals of the host was observed upon progressive addition of carbohydrate guests, evidencing that the recognition process is fast on

Acknowledgements I Acknowledgements Acknowledgements II Cochrane and Sandrine for NMR support; Dr. Thierry Brotin and Dr. Yann Bretonniere for the

Abstract

The first fluorescent hemicryptophane cage was synthesized and developed as an efficient and selective sensor for choline phosphate. The heteroditopic character of the host in the recognition process was evidenced. NMR experiments highlight a full encapsulation of the guest, inducing the chiralisation-like behavior of the achiral choline phosphate.

Supplementary figures

Chapter 7. Breathing Motion of a Modulable Molecular

Cavity

This Chapter is based partially on the following manuscript-Dawei Zhang, James Robert Cochrane, Sebastiano Di Pietro, Laure Guy, Heinz Gornitzka, Jean-Pierre Dutasta, and Alexandre Martinez Chem. Eur. J. 2017, 23, 6495-6498. The work in this chapter was carried out at the ENS-Lyon.

Supplementary figures

Preface

In Chapter 7 of Part III, a series of vanadium(V)@hemicryptophane complexes bearing binaphthol groups as linkers have been prepared leading to a breathing motion at the molecular level. We notice that these vanadium@hemicryptophane complexes bearing inflated cavities are interesting supramolecular catalysts due to the oxidation properties of vanadium(V) as well as the well-defined hydrophobic cavities above the metal centers.

Therefore, Chapter 8 describes the utilization of these vanadium complexes as supramolecular catalysts for sulfoxidation. Moreover, in collaboration with Prof. R. Tom Baker at the University of Ottawa, these vanadium complexes were also used for the oxidation of lignin models, as the results discussed in Chapter 9.

Previously our group reported several azaphosphatrane-based hemicryptophanes, such as the one above, and they were found to be efficient catalysts for CO2 conversion benefiting from the hydron-bonding donor ability of + P H group (Section 1. 6.1.2). We propose that this unit might be also efficient hydrogen-bonding organocatalysts for activation of carbonyl Chapter 8. Tailored Oxido-Vanadium(V) Cage

Complexes for Selective Sulfoxidation in Confined

Spaces

This Chapter is based partially on the following manuscript-Dawei Zhang, Kelsey Jamieson, Laure Guy, Guohua Gao, Jean-Pierre Dutasta, Alexandre Martinez Chem. Sci., 2017, 8, 789-794. The work in this chapter was carried out at the ENS-Lyon. Scheme S8.2 Synthesis of the oxido-vanadium(V) complexes 4.

Supplementary figures

P-(S,S,S)-(S,S,S)-2 M-(S,S,S)-(S,S,S)-2 P-(S,S,S)-

Abstract

The hydrogen-bonding activation of C=O bonds by azaphosphatranes was explored in a model reaction, i.e., the ring-opening polymerization of lactide. The polymerization process was controlled, and allowed the preparation of polylactides with narrow dispersity under mild conditions (20 o C, 24 h, 10 mol% catalyst loading). Interestingly, the steric hindrance of azaphosphatranes, as globular rigid structures, prevents any undesired interaction with the tertiary amine cocatalysts, as shown by X-ray analysis and semi-empirical calculations. In contrast to their organocatalytic activity in the CO2/epoxide reaction, all of the phosphonium derivatives tested were found to be efficient catalysts in this ROP benchmark reaction.

Introduction

Proazaphosphatranes, first described by Verkade and coworkers more than 20 years ago, show remarkable properties as basic or nucleophilic catalysts in numerous reactions. 1 3 Compared to these Verkade's superbases, their azaphosphatrane conjugate acids, resulting from protonation at the phosphorus atom of the proazaphosphatrane, have received little attention. Nevertheless, protonated azaphosphatranes have several interesting features as potential catalysts for various reactions related to their charge, the relative ease and modular character of their syntheses, their robustness, and the positively polarized proton located on the phosphorus atom. Two synthetic applications of these molecules have been reported by Verkade's group: one involves their use as procatalysts in the conversion of bromo-alkanes to alkenes under the action of sodium hydride, 4 the second one involves their ability to act as promoters of the Michael and Strecker reactions. 5 Martinez et al. have also reported the use of these azaphosphatranes as highly active and robust phase-transfer catalysts, and as organocatalysts for the synthesis of cyclic carbonates from CO2 and epoxides. 6 10 In the latter reaction, the mechanism was shown to involve an initial activation step of the epoxide through formation of a hydrogen bond with the + P H group of the azaphosphatrane. This recent result encouraged us to further explore the use of this original cation as an organocatalyst in the activation of C=O groups.

Indeed, the activation of carbonyl bonds by hydrogen-bond donor compounds is still a blossoming field of research, as a result of current challenges in asymmetric catalysis and ring opening polymerization (ROP). 11 Notably, the organocatalyzed ROP of cyclic esters by a hydrogen-bonding system (donor + acceptor) has become a model reaction to evaluate the activity of new hydrogen-bond-donor catalysts, and test their ability to activate C=O bonds, even in the presence of a hydrogen-bond acceptor (HBA) cocatalyst. 12 Since the pioneering work of Hedrick et al. based on the Takemoto's catalyst, 13 hydrogen-bond donor catalysts such as thiourea derivatives, 14 fluorinated alcohols, 15 phosphoric acids, 16 sulfonamides, 17 amides, 18 thiazolines, 19 and phenols, 20 as well as protonated amines 21 and quaternary ammonium compounds 22 have been evaluated in the ROP of lactide (LA) as a model monomer.

These hydrogen-bonding systems can be either bifunctional or dual systems, as the hydrogen-bond donor is used in the presence of a tertiary amine which acts as a DL-Lactide was recrystallized three times in toluene and freshly sublimated.

Dichloromethane was dried over calcium hydride and distilled. 4-biphenylmethanol was purified by precipitation in pentane. Commercially available Proazaphosphatranes, ( )-sparteine, PMP, CyNMe2, LiNTf2 and NaBArF were used as received. The synthesis of azaphosphatranes [1a-1c•H] + •Cl was achieved according to the literature. 26 28 The anion exchanges were adapted from our previously published procedure.

Synthesis of Azaphosphatranes [1a-1c•H] + •BArF -:

The corresponding phosphonium chloride [1a 1c•H] + •Cl (400 mg) was dissolved in deionized water/ethanol (1:1; 2 mL), and a solution of NaBArF (1.1 equiv.) in deionized water/ethanol (1:1; 2 mL) was added dropwise.

A white precipitate was formed instantaneously. The reaction mixture was stirred for 1 h at room temperature. The solid was then collected by filtration, washed with deionized water (3 × 1 mL) and water/ethanol (1:1; 3 × 1 mL), and dried under vacuum, yield 76 100 %. following equation can be obtained:

[1a•H]

Eq 1 Eq 2 Here [A] eq and [B] eq in Eq 2 are the concentrations of two cage isomers at the equilibrium, which can be determined by 1 H NMR spectroscopy. Therefore, at different time t , the corresponding value of k1t can be calculated based on the right part of Eq 1. If we establish Y = k1t, Then k1 can be determined by linear fit between Y and t. Based on Eq 2, k-1 could be also calculated from k1 and K 0 .

From Eying equation, the free activation energy △G ǂ can be calculated as follows:

Eq 3

Here T is 298 K. Therefore, according to the values of k1 and k-1, the corresponding activation energies of △G1 ǂ and △G-1 ǂ for interconversion can be determined.

It should be noted that △G1 ǂ is the free energy of activation for the conversion from T-1 to C3-1, and k1 is the corresponding rate constant; while △G-1 ǂ is the free energy of activation for the conversion from C3-1 to T-1, and k-1 is the corresponding rate constant.