Entre L'universite De Lyon

E T L'

Universite De

Maria Curie-Sk

Odowska De

Claude Bernard Lyon

Asymetrycznej ) Katalizy

Directeurs

Dr E Framery

Prof K M Pietrusiewicz

B Andrioletti

C Goux-Henry

S Juge

P Kie

Basi Ski

B Marciniec

K M Pietrusiewicz

Bernard Lyon

Uniwersytet Marii

Curie-Sk Odowskiej

Wydzia Chemii

Karolina Wójcik

D-Glukozamina Jako

" Zielony

" Substrat

W Syntezie

Dr Eric K Micha Pietrusiewicz

Framery

Claude Universite

Bernard -Lyon

Secrétaire Général

M François-Noël

Gilly M Le Professeur

Hamda Ben

Hadid M Le Professeur

Philippe Lalle

M Le Professeur

Germain Gillet

M Alain Helleu

Composantes Sante

J Etienne

G Kirkorian

D Bourgeois

La Mme

C Professeure

Vinciguerra

Y Matillon

a X = O, R = H, Ph b X = N, R = H R = Ph C X = N

Ome

R = Ph D X = N

Np Ome

THESE EN COTUTELLE

Keywords: D-glucosamine, "Green chemistry", allylic alkylation, hydrogenation, organocatalysis, PEG, Silica supported catalysts, SAPC, homogeneous catalysis, heterogeneous catalysis D-glucosamine, "Green chemistry", allylic alkylation, hydrogenation, organocatalysis, PEG, Silica supported catalysts, SAPC, homogeneous catalysis, heterogeneous catalysis

Green chemistry" is a multi-disciplinary concept that has emerged over the past two decades, considering chemical research and engineering that encourages the design of products and processes that minimize the use and generation of hazardous substances.

Anastas and Warner 1 formulated the twelve principles of green chemistry in 1998, which help to explain what the definition means in practice.

COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE

Atom economy:

Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product.

Less hazardous chemical synthesis:

Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment.

Designing safer chemicals:

Chemical products should be designed to preserve efficacy of function while reducing toxicity.

Safer solvents and auxiliaries:

The use of auxiliary substances (e.g. solvents or separation agents) should be made unnecessary whenever possible and innocuous when used.

Design for energy efficiency:

Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure.

Use of renewable feedstocks:

A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable.

Reduce derivatives:

Unnecessary derivatization (use of blocking groups, protection/ deprotection and temporary modification of physical/ chemical processes) should be minimized or avoided if possible.

9. Catalysis: Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.

10. Design for degradation: Chemical products should be designed so that at the end of their function they do not persist in the environment and break down into innocuous degradation products.

Real-time analysis for pollution prevention:

Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances.

12. Inherently safer chemistry for accident preventions: Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions and fires.

These principles identify catalysis as one of the most important tools for realization of assumptions of "green chemistry"2 . Developing green chemistry methodologies is a challenge that makes need to design chemical products and processes that reduce or eliminate the use and generation of hazardous substances. Industrial catalysis can be divided into heterogeneous and homogeneous catalysis.

Homogeneous catalysis by transition metals is a fundamental methodology used for production of fine chemicals, specially because of its efficiency, reproducibility, high selectivity and mild reaction conditions. Many bonds like C-C, C-H, C-N, C-S or C-O bonds can be accomplished with high yield and enantioselectivity in case of chiral compounds. However using this method we will encounter few obstacles. High catalyst performance requires careful choice of resources (activating metals and chiral ligands, use of harmless solvents and reagents). Other drawback are undesired by-products and difficulties with separation of catalyst from reaction mixture.

Nowadays, mostly chosen methodologies for solving this problem is heterogeneous catalysis. Supporting organometalic complexes in inorganic or organic matrix make recovery and reuse of the catalyst to be easy, but also reduce metallic impurities left in the final products. Heterogeneous catalysts have a longer lifetime for the storage and increased temperatures, they are less susceptible to various forms of pollution and higher resistance to poisons. Finally by choosing appropriate support and its bonding to the support they are able to provide very good activity and selectivity of the catalyst.

Very important is also design and application of new catalysts which are achieving goals of lower energy requirements, catalytic versus stoichiometric amounts of materials, increased selectivity, and decreased use of processing and separation agents.

One of the simplest ways to obtain chiral ligands is to transform or derivatize natural chiral compounds, thus making tedious optical-resolution procedures unnecessary. In the past few years, carbohydrate derivative ligands have been used in vide range of catalytic asymmetric reactions with impressive results. Carbohydrates have many advantages. They are readily available from environmentally friendly feedstocks, they are highly functionalized, and have several stereogenic centers.

Thesis Objectives

One of the objectives of this thesis was to synthesize conformationally restricted derivative of D-glucosamine: 1,2--glucodiamine that could be used as structurally well defined and coming from natural feedstock analogous of trans-1,2cyclohexadiamine.

Secondly this work assumed to use of such derivative as a starting material in synthesis of chiral ligands, catalysts and organocatalysts.

In order to use them in different catalytic homogeneous reactions such as allylic alkylation, hydrogenation or organocatalysis.

Furthermore one of the stipulated aims was preparation of immobilized Dglucosamine based ligands that could be use in heterogeneous catalysis.

No previous explore was made in area of SAPC (Supported Aqueous Phase Catalyst) system catalysed reaction of Suzuki Miyaura cross coupling, thus, in this study, we were interested in developing methodology which will allows to prepare in simple way immobilized system that could be easy recover and reuse.

The final objective was to synthesize ligands for heterogeneous catalysis which could be used in biphasic systems or could be grafted in inorganic matrix and easy recovered from reaction mixture.

CHAPTER 1

Bibliography Introduction

BIBLIOGRAPHY

The chemistry of simple sugars was developed in the end of nineteenth century by Emil Fischer [START_REF] Frieder | Collection of Emil Fischer Papers[END_REF] , and the ring structures were determined in the interwar years by Haworth 4 and coworkers. Since then carbohydrate received attention of scientists and knowledge about their biological activity was successively enlarged. However their synthetic utility was omitted in favor of aminoacids, vitamins, terpenes or alkaloids. Recently situation change and during last decade use of the carbohydrates as ligands become more popular and developed. Their role has been also expanded to using them as chiral auxiliaries, reagents, and organocatalysts 5 . Finally they start to be used in many asymmetric processes in field of pharmaceutical [START_REF] Shukla | For recent reviews see[END_REF] and agrochemical industry 7 but also in production of flavors and fragrances 8 .

In synthetic point of view carbohydrates are excellent starting materials. Most of them are easily available, cheap and they offer a ready source of enantiomerically pure compounds.

Another advantage is their stereochemical diversity. Presence of several highly functionalized stereogenic centers gives scientists scope for preparing unique ligands structures which can be used in many asymmetric processes. Only inconvenience in using those molecules could be that only one of enantiomer is easy available when L-sugars are prohibitively expensive. This problem can be easily solved by using pseudoenantiomers.

One of the widely used carbohydrates is D-glucosamine (Figure 1. 1). This amino sugar is obtained by hydrolysis of the polysaccharides like chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and many higher organisms. Easy availability of biomass used to obtain Glucosamine make it to be inexpensive material which price is around 1€ for 5 gram (Acros Organics).

Because of the fact that D-glucosamine can be easily functionalized and modified, several types of ligands have been prepared in recent decades.

Large numbers of 'D-glucosamine cores' have been developed and used as ligands for different kind of catalytic reactions both in homogeneous and heterogeneous catalysis. This article aims to give an overview of D-glucosamine based ligands, organocatalysts and reagents with pyranose substructure. Furanose, acyclic and heterocyclic structures will not be discussed.

Organization of Chapter 1

This Chapter is separated in two main parts:

Homogeneous catalysis

Firstly compounds used in homogeneous catalysis will be presented and their use as ligands, organocatalysts and reagents. Review is organized according to the type of ligands, and take into account fires nature of donor atom (P, N, S, O). In subchapters when large amount of different ligands with the same type of chelation was known in literature, first all ligands are presented followed by their use in catalytic reactions.

Heterogenous catalysis

Ligands are organized by technique of immobilization of ligand. Firstly ligands grafted in organic matrix of polystyrene will be presented and after ligands used in biphasic media.

Homogeneous catalysis

1 That compound was used also in [Rh]-catalysed hydroformylation in a biphasic and homogeneous medium with low chemoselectivity of the desired branched product (16% of conversion, n/iso-selectivity 82 : 18), and enantiomeric excesses were not determined (Scheme 1.2). Ligands Lig2a,g containing alkyl substituents on nitrogen atom have been found to be totally ineffective. Other ligands formed products of hydrovinylation, with low to moderate enantiomeric excesses up to 64% (Scheme 1.3).

Phosphites and aminophosphine ligands

Monophosphites ligands Lig3 and aminophosphine ligand Lig4 with glucopyranoside backbone were prepared by RajanBabu and coworkers (Figure 1.4) 10,11 . and had been Best results were achieved with ligand Lig3b containing in its structure (R)-BINAP moiety, 2-methoxy-6-[(S)-1-methylallyl]naphthalene was formed with 94% of yield and 63% ee (Scheme 1.3).

R R MeO MeO R = H (S) R = H (S)

Lig2f 93% 45%ee Lig2b 62% 32%ee

Lig3b 94% 63%ee Lig2e 81% 64%ee

Lig3b 95% 62%ee Lig4 19% 54%ee R = i-Bu (S)
Lig3b 99% 38%ee Lig2e 36% 61%ee Scheme 1.3 Asymmetric hydrovinylation reactions.

Bidentate ligands

Phosphines ligands

Recently Ruffo et al. 12 developed a strategy for preparing ligands Lig5a-e with structure similar to already known ligands in which trans-cyclohexanediamine 13 core was replaced by D-glucosamine ring (Figure 1.5).

These ligands have been successfully used in reactions for the carbon-carbon bonds formation such as the asymmetric allylic alkylation of meso-2-cyclopenten-1,4-diol biscarbamate promoted by palladium, afforded product with excellent yields 99% and enantioselectivities up to 98% (Scheme 1.4) . Authors found that the most successful ligand Lig5c is effective for the addition of both ZnMe 2 and ZnEt 2 to a class of enones possessing only aliphatic substituents with minimal steric profiles. In general, for all substrates this ligand provided better yields (up to 95%) and enantioselectivities (up to 95%).

Phosphinites ligands

RajanBabu et al. 14 These ligands have been successfully applied in the [Rh]-catalysed asymmetric hydrogenation of alkenes which are aromatic and heteroaromatic derivatives of alanine The widely available 2-deoxy-2-acetamido-glucose system Lig6 was found to be an effective ligand for the production of D-amino acids with excellent enantioselectivities up to 98% ee. One of the limitations of those ligands prepared from the chiral pool is that they can catalysed only the formation of one enantiomer.

(Table 1.2). R NHAc COOR' R NHAc COOR' L*Rh + (COD)X - H 2 * ligand X R R' ee(%) (S)

N/N ligands

Milner et al. 15 presented Schiff-base ligands derived from salicylaldehyde or pyridine-2carboxaldehyde. Boysen et al. 17 developed new type of carbohydrate-based bis(oxazoline) ligands Lig9 All ligands Lig7-9 found application in the asymmetric copper(I) catalysed cyclopropanation of haloalkenes ( Boysen, Synlett,, 2008, 1483-1486. obtained when hindered as pivaloylated substituent was introduced; the major cis diastereomer was generated with 94% ee using ligand Lig9c. (Table 1.3). With benzylidene-protected ligands Lig9e-k, authors observed steric and electronic effects of the 3-O substituent in carbohydrate ring. Small acetyl group gave far better results than those obtained with more bulky acyl residues and ether groups irrespective of their steric demand. The major trans diastereomer was formed in 93% ee using ligand Lig9f with acetyl substituent in 3-O position. Authors explain that phenomenon to be caused by conformational effect chair-like conformation which gives best results in combination with the rather small 3-O acetyl group. Peracetylated ligands Lig9b adopting a twist-like conformation, led to better results with bulky pivalate residues.

(Figure 1.9). O O N O O N OR RO RO OR RO OR O O O O O O N O O N OR RO Ph Ph e R = H f R = Ac a R = H b R = Ac Lig9 i R = Me j R = Bn c R = Piv d R = TMS g R = Bz h R = Piv k R = TES
Ligand Lig9b in combination with copper was investigated also in Henry reaction 18 with a wide range of aromatic, aliphatic and heteroaromatic aldehydes to afford the corresponding nitroalkanols with high enantioselectivity (up to 99%) in excellent yields (up to 95%) (Table 1.4).

O N O O R Ph b R = Me c R = i-Pr d R = i-Bu e R = t-Bu f R = Ph g R = Bn Lig10a
Figure 1.10 Phosphine oxazoline ligands Lig10.

Diéguez and Pàmies 21 had designed a new family of carbohydrate based oxazoline ligands

Lig11-Lig15a-g in with phosphite group carrying biphenyl residues with bulky substituents or naphtyl residues to position 3 in carbohydrate ring (Figure 1.11). [Pd] Allylic alkylation. P/N ligands are well designed for allylic alkylation and most of them find application in this area. Ligands Lig10-15 had been employed successfully in [Pd]-catalysed enantioselective allylation of dimethylmalonate to symmetrically and nonsymmetrically substituted allyl acetates 19,20a,b,21a yielded products in high enantioselectivities up to 98 % ee (for phosphine ligand Lig10a) (Scheme 1.5).

O O O N O O R Ph P O O O O O O R R' R' R R" R" O O R"' R"' O O a R = R' = t-Bu, R" = H b R = t-Bu, R' = OMe, R" = H c R = TMS, R' = R" = H d R = R' = Me, R" = H e R = R' = R" = H f (S); R = t-Bu, R' = R" = Me g (R); R = t-Bu, R' = R" = Me = Lig11 R = Ph Lig12 R = i-Pr Lig13 R = t-Bu Lig14 R = Me Lig15 R = Bn f (S) R"' = H g (R) R"' = H j (S) R"' = TMS k (R) R"' = TMS =

OAc

R R R' R R COOMe MeOOC R' R R COOMe MeOOC R' (S) R = Ph, R' = H (R) R = Ph, R' = H Lig10a 94% 98%ee R = R' = Ph Lig10a 83% 88%ee R = R2 = Me Lig10a 81% 92%ee + Lig10b 98% 93%ee Lig10c 99% 90%ee Lig10d 82% 95%ee Lig10f 74% 94%ee Lig11a 100% 92%ee Lig12a 91% 86%ee Lig14a 100% 85%ee Lig18a 100% 80%ee [Pd]
Scheme 1.5 Asymmetric allylic substitution reactions.

For ligands containing phosphate moiety activities are higher when less sterically demanding substituents are presented (Me>Ph>i-Pr>t-Bu). Ligand Lig10b with the smallest substituent on oxazoline ligand (R = Me) proceed the best enantioselectivity (96% ee). The ligands having bulky substituents gave lower ees.

Chapter 1

Ligands were examined also with other various nucleophiles. Ligands Lig16 were tested in reaction of allylic alkylation with dimethyl malonate (Scheme 1.5). Best results were obtained for ligand Lig16d and that ligand was used in reaction with other nucleophiles (Table 1 .5). Good reactivities (up to 94%) and enantioselectivities (up to 93% ee) were generated with both bulky and substituted malonates. When benzylamine was used as a nucleophile, the highest enantiomeric excess (95% ee) was observed using the chiral ligand Lig10d (R = i-Bu). Almost the same level of enantioselectivity (94% ee) was achieved using for ligands Lig10b,11d. [Pd] Heck reaction D-glucosamine based phosphinite-oxazolines Lig10-15 were studied in Heck reactions 20a,21a,c with different substrates aryl triflates and led to good yields and enantioselectivities of products, however in many cases was observed also compound obtained by izomerizaron of desired product (Table 1 .6). 2,3-Dihydrofuran was transformed to 2-aryl-2,5-dihydrofuran using ligand Lig10g with 100% of yield, and 96% ee). When cyclopentene was used as starting material the most efficient worked ligand Lig11a, coupling product was obtained with 94% ee in 100% conversion. Many other substrates and aryl triflates were tested, however yields and enantioselectivities were worse than in presented cases.

OR

R' R' R' R' Nu NuH [Pd] *
X X R X R + A, X = O B, X = CH 2 X = O X = CH
[Ir] Hydrogenation D-glucosamine based oxazoline ligands Lig11-Lig15a-g with phosphite moiety were extensively studied in hydrogenation of minimally functionalized olefins 21d,f . Excellent ligands have been identified for a range of substrates, including disubstituted terminal olefins as well as trisubstituted olefins (Figure 1.13).

S) (R) Lig15c (100%), 99%ee (S) Lig15a (100%), 92%ee tBu (S) Lig15c (100%), 93%ee tBu (+) Lig15a (100%), 99%ee (
[Cu] Addition of diethylzinc to acyclic enones.

Ligands Lig17a,b, were tested in enantioselective 1,4-conjugate addition of diethylzinc to acyclic enones 22b . Authors dedicated more attention for testing ligand containing (S)-BINOL in its structure Lig17a. Moderate to high yields (up to 81%) and enantioselectivities (up to 78% ee) were obtained (Table 1 Recently Ruffo and Benessere 27 , presented ligands Lig22 in which oxygen in third position in carbohydrate ring was replaced with nitrogen (Figure 1. 16). [Pd] Allylic alkylation Compounds Lig19-22 were applied in reactions of allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. Two different ratios of palladium / ligand were investigated. In proportions of palladium / ligand 1 / 1 P,O-chelation type was observed (Scheme 1.6), and with ratio 1 / 2 ligands P,P-chelation took pace ( Scheme 1.7).

O N H S R"' PPh 2 R" = a R = Ac, OR' = -OAc b R = Ac, OR' = OAc c R = H, OR' = -OH d R = Ac, OR' = -OMe e R = Ac, OR' = -OMe f R = Ac, OR' = -OBn g R = Ac, OR' = -OBn R" = m R = Ac, OR' = -OAc h R = Ac, OR' = H i R = H, OR' = A = A A R" = R" = R" = o R = H, OR' = -OH n R = Ac, OR' = OAc s R = H, OR' = -OH, R" = N-morpholine p R = H, OR' = -OH r R = H, OR' = -OH, R'' = NMe 2 j R = Ac, OR' = -OAc, R'" = H k R = Ac, OR' = OAc, R"' = (S)-Et l R = Ac, OR' = -OAc, R"' = (R)-Et R" = Lig19
R = Ac, R' = OAc b R = Ac, R' = -OMe c R = Ac, R' = -OBn d R = Ac, R' = -Ot-Bu e R = Ac, R' = -OCy Lig21a,b,f,g,h f R = Ac, R' = A g R= H, R' = A h R = Ac, R' = B H A = B =
P O N H O O O O O OBn R MeO Ph 2 a R = o-C 6 H 4 -PPh 2 b R = Me c R = CH 2 Ph d R = CH 2 Cy e R = t-Bu f R = (R)-CHMe(Ph) Lig22 g R = (S)-CHMe(Ph) h R = CHPh i R = CMePh 2 j R = CHCy 2 k R = Ph l R = CH 2 C 6 F 5
For the first type of chelation (P,O) with phosphino-amido ligands Lig19 the best results were obtained for Lig19b containing acetyl group in -position on anomeric carbon (98% of yield and 83% ee for R enantiomer). Among phosphino-imino ligands Lig20 turned out to be the best Lig20d with sterically demanding tert-butyl function in anomeric position (98% of yield and 87% ee for S enantiomer) (Scheme 1. Palladium associated with a carbohydrate-based phosphine has been shown to have very high efficiency for the coupling reaction of iodides, chlorides and bromides with electronrich as well as electron-poor substituents and a wide range of boronic acids. The polyhydroxylated ligands led to more active catalysts than the peracetylated ligands, also in case of ligand Lig18p it was possible to recycle the catalyst.

N/O ligands

Bauer et al. 28 presented the synthesis of sulfonamides derived from D-glucosamine (Figure 1.17) and their application as ligands in titanium tetraisopropoxide promoted enantioselective addition of diethylzinc to different aldehydes (Table 1 .11).

O O O N H O H R S Ph O O R' N N Lig23a R = -OMe, R' = p-CH 3 -C 6 H 4 b R = -OMe, R' = p-CH 3 -C 6 H 4 c R = -OMe, R' = CH 3 d R = -OMe, R' = CF 3 e R = -OMe, R' = A f R = -OBn, R' = p-CH 3 -C 6 H 4 g R = -OMe, R' = 3,5-(CF 3 )-C 6 H 3 h R = -OMe, R' = B A = B = Figure 1.17 Sulfonamides ligands Lig23.
The catalytic activity of ligands Lig23a-f was tested using different aromatic and aliphatic aldehydes. Different aryl and heteroaryl bromides were used as the substrates and good yields up to 95% were obtained.

H O OH R R Zn(Et) 2 [Ti] Ligand R
Recently 30 D-glucosamine was used also in copper catalysed synthesis of primary aryl amines from aryl halides and ammonia (Table 1.13). Various aryl iodides and aryl bromides provided good to excellent yield of the corresponding primary amines.

N/N/N ligands

In 2007 Boysen et al. 32 prepared carbohydrate-derived pyridyl bis(thiazoline) ligands Lig25 (Figure 1.18).

Ligand Lig25a was used in cyclopropanation reactions. Different substrates were tested, however authors didn't success to obtaining good yields and enantioselectivities of products 32a . Ligand Lig25b, was applied in [Cu]-catalysed alkynylations of imines 32b . Excellent enantiomeric excess (99% ee) was achieved for the alkynylation of imines derived from 31 N. Khiar, B. Suárez, I. Fernández, Inorg. Chim. Acta, 2006, 359, 3048-3053. 32 M. Irmak, T. Lehnert, M. M. K. Boysen, Tetrahedron Lett., 2007, 48, 7890-7893, (b) M. Irmak, M. M. K. Boysen, Adv. Synth. Catal., 2008, 350, 403-405. benzaldehyde and aniline with phenylacetylene. Other products were obtained with low to good yields and moderate enantioselectivities (Table 1 .14). 20). Ligands were used in the [V]-promoted asymmetric oxidation of thioanisole (Table 1 Epoxides were the major products in all cases however many others byproducts were observed: corresponding substituted benzaldehyde usually diols, phenylacetaldehyde for styrenes and 1,2-dihydronaphthalene, and allylic oxidation products for 1-methylcyclohexene). In all cases high conversions were obtained (99%), when styrene was used as substrate enantioselectivity was low up to 54% ee, using cis--methylstyrene selectivity of cis product was high and desired diastereoisomer (1S,2R) was obtained with up to 86% ee.

AcO

R H N R' R" H N R1 R" R' [Cu] + Ligand R R' R" Yield (
O N O H O O OBn O H O N O H O O OBn O H R' R Lig27g t-Bu t-Bu Lig27 a R = R' = H b R = R' = t-Bu c R = H, R' = t-Bu d R = t-Bu, R' = H e R = t-Bu, R' = NO 2 f R = R' = I

Glucosamine derivatives as organocatalysts

Novel catalytic system which combines carbohydrate and amino acids moiety was subject of interest of three research groups: Machinami et al. 39 prepared organocatalysts Lig30a-d,

Agarwal and Peddinti40 , prepared D-glucosamine based organocatalysts whose include the prolinamides Lig30e-g and Pedatella et al. 41 prepared catalyst Lig30h (Figure 1. 22). Lig30 catalysts were investigated in aldol reaction of acetone and different benzaldehydes in the presence of water. (Scheme 1.10).

O N H O N H O N H 2 O N H 2 O R"O OR" R"O NHR OR' O O H OH O H NHR OMe i-Bu t-Bu Lig30 e R = A, R' ' = Me, R " = Bn f R = A, R' = R" = Bn g R = A, R' = Me, R" = E h R = B, R' = TBDPS, R" = H E a R = A b R = B c R = C d R = D A B C D t-Bu
H O O OH O OH O R R R + R = 4-NO 2 -(R) R = 4-NO 2 -(S) Lig30b 49% 50%ee R = 4-Br -(R) Lig30f 96% 93%ee R = 2-Cl -(R) Lig30f 96% 94%ee
Lig30f 98% 95%ee Lig30h 54% 70%ee + Scheme 1.10 Aldol reaction of aryl aldehydes with acetone 73.

D-glucosamine based prolinamides

Lig30e-h (Figure 1.22) with different substituents in carbohydrate ring, were used in the aldol reaction between aromatic ketones and aryl aldehydes under solvent free conditions (Table 1 .19). In case of Lig30e-h the corresponding aldol products with six-membered cyclic ketones as starting materials were obtained in excellent yields with high levels of anti diastereoselectivity (up to 99 : 1) and enantioselectivity (up to 99%). The best results were obtained when compound Lig30f was used as organocatalyst in the presence of benzoic acid as additive. Michael adducts were generated in high yields (up to 98%) with excellent diastereoselectivities (up to >99 : 1) and moderate enantiomeric ratios (up to 84 : 16) (Table 1.20).

Chapter 1 O X O H R O X OH R O X OH R + anti syn + Catalyst X R
Agarwal and Peddinti42 prepared amino organocatalysts Lig31a-f. Aldol reaction of cyclic ketones with substituted benzaldehydes however diastereoselectivities as well as enantioselectivities were worse than in case of ligands Lig30e-h (Figure 1.23). Kunz et al. 43 prepared series of bifunctional urea Schiff base organocatalysts (Figure 1. 24). Recently Chen et al. 44 In mostly cases reaction occurred with good yields of desired compound, but the ees value obtained were poor (Table 1 .22). When acetone was used as a substrate reaction occurred with good yields and moderate enantioselectivity up to 75% ee.. D-glucosamine was also tested in this reaction however enantioselectivity of corresponding product did not reach more than 10% ee (Table 1 .22).

O O H NH 2 Ph OMe O R'O R'O R'O NH 2 OR O R'O R'O R'O NH 2 OR Lig31a b R = Me, R' = Bn c R = Me, R' = 4-(t-Bt)benzyl d R = R' = Bn, e R = Me, R' = Bn f R = R' = Bn,
O R' AcO R"'O R R"O N H O N H N H O N OH PivO O O O R" R' Ph R B = A = Lig32 a R = A, R' = B, R" = R"' = Ac b R = B, R' = A, R" = R"' = Ac c R = A, R' = B, R" = (CO)(CH 2 ) 2 (CO)O(CH 2 ) 8 OTBDPS R"' = Ac d R = A, R' = B, R" = TBDPS R"' = -(CO)(CH 2 ) 9 OTBDPS e R = -SEt, R' = B, R' = A f R = -S(CH 2 ) 4 COOEt, R' = B, R" = A Figure 1.
N O O R OH N O O R" R R O Lig + R' R' ketone Catalyst R
Other carbohydrate-based bifunctional organocatalysts were prepared by Poletti et al. 45 (Figure 1.26) and used in nucleophilic addition to nitroolefins and imines. Best results were obtained for catalyst Lig34b. in reaction addition of acetylacetone to -nitrostyrene chemical yields up to 93% and enantioselectivities up to 89% were achieved These catalysts were also preliminarily investigated as promoters in the addition of diethyl malonate to the N-BOC imine of benzaldehyde, affording the product with low yields and moderate enantioselectivities up to 81% ee. (Scheme 1.12) 12 The addition of diethyl malonate to N-Boc imines.

CF 3 CF 3 N H N H X O RO R'O R"O NMe 2 Lig34 a X = O, R = R' = R" = Ac b X = O, R = R' = R" = TES c X = O, R,R' = PhCH, R"' = TES d X = O, R = R' = R" = H e X = O, R = R' = R"' = Me f X = S, R = R' = R"' = TES
(
NBOC COOEt EtOOC NBOC Lig34b 25% 81%ee Lig34f 23% 75%ee * Scheme 1.
In 2009 Boutureira et al 46 Compounds were tested as asymmetric epoxydation catalysts. Different kind of olefins were screened. In case of Lig35a-f obtained yields were moderate to good (up to 98%) but yields were not higher than 67% ee.

a R = Me, R' = p-CF 3 C 6 H 4 b R = Me, R' = p-ClC 6 H 4 c R = Me, R' = C 6 H 5 Lig35 d R = Me, R = p-MeOC 6 H 4 e R = Me, R' = p-Me 2 NC 6 H 4 f R = R' = Me g R = Bn, R' = Me a R = H b R = Bn Lig36 Lig37a R = H b R =Bn c R = Bz d R = Piv Lig37e R = -OMe f R = -OMe g R = -OBn

Glucosamine derivatives as reagents

Davis et al. 48 presented carbohydrate derived amino alcohols Lig38-39 (Figure 1.29).

NH 2 O O O O H Ph R N N O N R = -OMe Lig38a-m a N= NH 2 b N = NHEt c N = NEt 2 d N = NHPr e N = NPr 2 j N = k N = Lig39a,b,c,f,g,j,k f N = NHBn g N = NBn 2 h N = N(CH 2 OH) 2 i N = NHTs R = -OMe l N = Figure 1.29 Ligands Lig38-39.
Those compounds were employed in addition of diethyl zinc to aldehydes. No high results

were achieved with any of the substrates used. The highest enantiomeric excess was obtained for benzaldehyde as substrate using ligand Lig38k (65% ee) (Scheme 1.13).

H O R Et OH R Et OH R + (S) R = H (R) R = H Lig38a 66% 63%ee Lig38c 91% 53%ee Lig38e 96% 56%ee Lig38f 64% 35%ee R = CF 3 Lig38a 81% 50%ee Lig38e 88% 52%ee ZnEt 2 Lig38j 91% 55%ee Lig38k 93% 64%ee
Lig38j 90% 58%ee Lig38k 86% 65%ee Lig39a 68% 46%ee Scheme 1.13 Addition of diethyl zinc to different aldehydes.

The same ligands were also investigated in the Zn(OTf) 2 -mediated addition of alkynes to aldehydes 48b . Several alkynes as well as aliphatic and aromatic aldehydes were tested. In mostly cases reaction occurred with excellent enantioselectivities but more disappointing yields (Table 1.24 Ligands were used in Strecker reaction of benzaldimine, with disappointing results. In any case yield did not exceed more than 54% and enantioselectivity was not higher than 15% ee (Scheme 1.16).

). O R H R' OH R R' Zn(OTf) 2 Ligand R R' Yield (%) ee (%) Lig38k i-
O R' AcO R"O R TBDPSO N H O N H N H O R"' N OH PivO O O O R"O R' Ph R O R' AcO AcO R AcO R' = R = R" = (CO)(CH 2 ) 2 (CO)O(CH 2 ) 8 O(CO)Ps A R"' = Ph B R'" = Ps Lig41a R = A Lig41c R = B Lig41b R = A

NH

Ph NH 2 CN Ph (i) TMSCN Lig (ii) (CF 3 CO) 2 O Lig41a 30% 15%ee (S) Lig41b 35% 12%ee (R) Lig41c 54% 4%ee (S)
Scheme 1.16 Hydrocyanation of Imines (Strecker Reaction).

Biphasic catalysts

Ionic liquids are among the most promising green solvents [START_REF]Ionic Liquids in Synthesis[END_REF] . Their use does not required specific tagging of the catalyst, however ligands should be polar to increase affinity for the ionic liquids and avoids leaching of the catalyst into organic product phase.

Group of Ruffo prepared ligand Lig42 and use in reaction of allylic alkylation of meso-2cyclopenten-1,4-diol biscarbamate using 1-butyl-3-methylimidazolium tetrafluoroborate

(BMIM[BF 4 ]) as solvent. OBn O N N O H O H O H OH O O O N H NH O N O O H H t-Bu t-Bu (3R, 6S)

Ts

Ts Ts Run 1 99% 55%ee Run 2 99% 56%ee Run 3 99% 50%ee Run 3 99% 47%ee Lig42 [Pd] Scheme 1.17 Ligand use in ionic liquids.

Product was obtained with full conversion and 55% of ee.. Catalyst phase was recycled for further runs, four first cycles were reproducible, in further cycles both yield and enantioselectivity progressively decreased (Scheme 1.17).

Uemura and Ohe 50 prepared water soluble ligand L19, bearing a diethylaminomethyl group on the phenyl ring of the phosphinite moiety (Table 1 .25). His complex with palladium and [BF 4-] worked effectively as a catalyst and provided good enantiomeric excess in allylic alkylation and amination in water or an aqueous/organic biphasic medium.

The product could be easily separated from the water-soluble catalyst by phase separation. Reaction with dimethyl malonate in acetonitrile proceeded smoothly with 95% of yield and 92% ee. Excellent results were obtained also in THF, and it was possible to recycle catalyst to obtain 90% of yield and 89% of ee in second cycle. When benzylamine was used as a nucleophile in mixture acetonitryl and water, 84% of enantiomeric excess was obtained in first cycle and 77% ee in second cycle (Table 1 .25).

Conclusions

Daunting task hindered preparation of novel carbohydrates cores can seem polarity of unprotected starting material and wide reagent ranges or specialist conditions often required for synthesis. However this review show that easy availability of D-glucosamine together with its low cost, and presence five natural stereogenic centers makes it excellent choice in synthesis of new chiral ligands.

Over few past years D-glucosamine backbone was modified and functionalized in many ways by variation of stereogenic centers and steric properties to gave a large diversity of ligands, organocatalyst and reagents. They had been employed in many catalytic reactions like allylic alkylation, hydrogenation, hydrocyanation, Heck reactions or Suzuki-Miyaura cross-coupling to gave excellent yields. In case of asymmetric catalysis also high control of enantioselectivity was observed and selectivities achieved with glucosamine derivatives are comparable to those obtained with the more traditional derivatives from the chiral pool, what make them interesting alternatives. Despite the fact that many traditional structures of ligands have his equivalent based in carbohydrate, there is steel many ligands that can be replaced with ligands derived from natural chiral pool.

In literature many examples of use of glucosamine based ligands in homogeneous catalysis is described, nevertheless the productivity of catalysts needs to be further improved to achieve high turnover numbers and frequencies. This task can be accomplished by heterogenisation of catalyst.

Introduction

2 Ligands for homogeneous catalysis.

One of the aims of this thesis is to develop a strategy which will let incorporating in a sugar ring essential function of already known ligands derived from trans-cyclohexanediamine. Ligands containing trans-diamine function incorporated into frame of D-glucosamine are already known. Ruffo et al. 12,16,33,38 as well as RajanBabu et al. 37 In research made by our team 24,25 on ligands for allylic alkylation it was proved that anomeric -position plays an essential function in obtaining high enantiomeric excess.

NH 2 NH 2 O NH 2 NH 2 RO RO RO NH 2 RO O RO NH 2 OR NH 2 NH 2 1,2--glucodiamine 2 1,2-cyclohexanediamine
Combining those knowledge we decide to prepare series of D-glucosamine based ligands, containing two amino functions in first and second position of carbohydrate ring, in order to test them in catalytic reactions of allylic alkylation, hydrogenation and Michael addition.

Organization of Chapter 2

The synthesis of carbohydrate chiral pool: trans-1,2--glucodiamine will be presented at first. The next subsection will concern preparation of amino-and imino-type ligands for allylic alkylation. Furthermore catalyst designed for hydrogenation will be shown. Finally synthesis of thiourea organocatalysts will be described and their use in reaction of Michael addition. And in the end of this chapter, all conditions of reactions and detailed descriptions of compounds will be included in experimental part. 4,6 The second step was treatment of 5 with sodium azide in dry DMF at reflux for 3 hours. Next step was reduction of azide 3 to amino group in presence of hydrogen and palladium on carbon. After 14 hours in room temperature and filtration on celite 2-acetamido-3,4,6-tri-O-acetyl-1-amino-2-deoxy--D-glucopyronose 6 was obtained with 96% of yield (Scheme 2.3).

Results and discussion

Preparation of 1,2-diamino-D-glucosamine.

2-Acetamido

It has been known that direct cleavage of the acetamide bonds protected amines required harsh conditions such as refluxing in solutions of HCl 53 or Ba(OH) 2 54 , which are not compatible with sensitive functionality of carbohydrates. Trying to perform synthesis of compound 2, starting from 6 method described by Burk and Allen 55 was tested. According to authors some amides can be activated to hydrolysis by prior conversion to the N-BOC amide derivatives and following that selective hydrolysis of the amide with hydrazine leaves the N-tert-butoxycarbamate in place. However in case of carbohydrate 6 it was impossible for us to deprotect amino function, which probably resulted from the presence of free amino function in neighboring anomeric carbon (Scheme 2.3).

The same reaction starting from azido derivative 3 lead to product of deprotection 7 with rather low yield 38%. Another drawback of this reaction was activity of hydrazine, which next to acetyl form amido function removed acetyls of third and fourth hydroxyl groups and reacetylation was required.

To avoid such problems and problematic purification we prepare 3,4,6-tri-O-acetyl-1azido-2-(tert-butyl-carbamate)-2-deoxy--D-glucopyronose 8 with 73% of yield by changing acetamido group for tert-butoxycarbonyl (BOC) group according to methodology described by Lafont 56 . In next step BOC group was deprotected using trifluoroacetic acid 53 G. A. Dilbeck, L. Field, A. Gallo, R. J. Gargiulo, J. Org.Chem. 1978, 43, 4593-4596. 54 X. Hu, W. Zhang, I. Carmichael, A. S. Serianni, J. Am. Chem. Soc., 2010, 132, 4641-4652. 55 M. J. Burk, J. G. Allen J. Org. Chem., 1997, 62, 7054-7057. 56 D. Lafont, P. Boullanger, Tetrahedron: Asymmetry, 2006, 17, 3368-3379. in dichloromethane in room temperature overnight giving expected product 7 with 88% yield, and 64% after two steps (Scheme 2.3).

O

O A = (i) BOC 2 O, DMAP, THF, reflux (ii) NH 2 NH 2 . H 2 O, MeOH, r.t. (iii) TFA, rt. B = (i) BOC 2 O, DMAP, THF, reflux (ii) MeONa, MeOH, rt (iii) Ac 2 O, pyridine A A 38% DCM CF 3 COOH rt, overnight 88% EtOAc H 2 , Pt 2 O rt, 2 h 90% 3 6 8 7 2 overall yield 33% H 2 , Pd / C (10%) MeOH 14 h, rt, 96% B 73% Scheme 2.3 Synthesis of 3,4,6-tri-O-acetyl-1,2--glucodiamine 2.
In last step: hydrogenation using Platinum oxide57 for 2 hours in room temperature, diamino compound 2 was obtained with very good yield 90%, and overall yield 33% starting from carbohydrate 4 (Scheme 2.3).

Diamino compound 2 was used as starting material to obtain various ligands for allylic alkylation, hydrogenation, organocatalysis and oxidation.

During work on the preparation the Ligands were applied in Pd-catalyzed desymmetrization of meso-cyclopent-2-ene-1,4-diol with excellent conversions up to 99% and enantioselectivities up to 96% (Scheme 2.6).

O O O N H NH O O N O (3S, 6R) Ts Ts Lig44 (99%) 95%ee Lig45 (99%) 96%ee [Pd] (R) (S)
Ts Scheme 2. 6 The desymmetrization of meso-cyclopent-2-ene-1,4-diol.

"Trost type" ligands for allylic alkylation.

In In our team we decided to prepare ligands belong to family of "Trost ligand system" containing 1,2-diamino-D-glucosamine as chiral pool and two types of linkers: amido-or imino-linkers, and to test them in reaction of allylic alkylation with palladium.

Amide type ligand.

By coupling of compound Ligand L1 was characterized by many techniques: 1 H NMR, 13 C NMR, 31

Imine type ligand.

Ligand with similar structure containing imino function was prepared using condensation of anime Compound was isolated with 28% of yield, and its structure confirmed with 1 H NMR, 13 C NMR, 31 P NMR, IR, ESI-MS experiments (See experimental part).

Allylic alkylation with "Trost type ligand"

It has been applied to a large number of asymmetric allylic alkylations with substrates difficult to control with other systems 61,62 A wide variety of transition metals are known to catalyze this reaction, however the mostly studied were reactions with palladium. 61 For review, see: B. M. Trost, M. L. Crawley, Chem. Rev., 2003, 103, 2921-2943. 62 B. M. Trost, A. C. Krueger, R. C. Bunt, J. Zambrano, J. Am. Chem. Soc., 1996, 118, 6520-6521. The generally accepted mechanism for [Pd]-catalyzed allylic alkylation contain two key steps: oxidative addition of Pd species, "Pd (0) L2", to the allylic electrophile and followed by nucleophilic attack on the resulting Pd(II) allyl cation, to liberate the product and regenerate the Pd(0) complex (Scheme 2.10).

Chapter 2 X R R Nu R R Pd (0) R R X R R Pd (0) R R Nu Pd +(II) X - Nu - L L Pd (0)
Efficiency of ligand L1 was tested in the in reactions of allylic alkylation. Two typical racemic allylic substrates, 2-acetoxy-1,3-diphenyl-2-propene and 2-acetoxy- In case of 1,3-Diphenyl-3-acetoxyprop-1-ene, results of allylic alkylation are better comparing to results obtained by Trost (Table 2.2, entry 1,2). Increasing of yield from 24 to 39% was observed as well as increasing of enantioselectivity from 12 to 42% ee. When 4-acetoxy-2-pentene was used as starting material reaction occurred with excellent yield and enantioselectivity with "Trost ligand" (Table 2.2, entry 3), when carbohydrate ligand L1 was used as ligand no conversion was observed with neither of used conditions (Table 2.2, entry 4,5).

Despite of better results in case of 1,3-Diphenyl-3-acetoxyprop-1-ene in comparing with results of Trost ligand we decided to stop project and do not study reactivity of ligand L1 with other substrates. Obtained by us results were not satisfactory. Many other carbohydrate based ligands catalysed reaction of allylic alkylation with better yields and enantioselectivities (see Chapter 1 Scheme 1.5, Scheme 1.6, Scheme 1.7).

Chapter 2

Catalyst for hydrogenation.

BINAP-Ru(II) diaminecomplexes were used first time in 1995 by Noyori 63a . Since then they are shown to be efficient, catalyst in many organic transformations. They were used successfully in enantiomeric hydrogenation of simple aromatic 63b-e , heteroaromatic 63f,g , cyclopropyl 63h , dialkyl 63h , amino 63i,j , olefinic 63h,k , and -alkoxy ketones 63a,l . They show great efficiency in chemoselective hydrogenation C=O bonds in presence of C=C bond, also variety of functionalities such as F, Cl, Br, I, CF 3 , OCH 3 , OCH 2 C 6 H 5 , COOCH(CH 3 ) 2 , NO 2 , NH 2 , and NRCOR.

P P N N R' R" R"' R Ru Cl Cl H 2

BINAP-Ru(II) diaminecomplex

Using procedure establish by

Hydrogenation with BINAP-Ru(II) diaminencomplexes

Hydrogenation catalyzed by a BINAP/diamine-Ru II catalyst and an alkaline base is general solution for problem of asymmetric transformation of simple ketones with lack any Lewis basic functionality capable to interact with metal center. Various complexes (Figure 2.9) provided to be effective in hydrogenation of variety of ketones 63 .

Hydrogenation occurred by nonclasical metal-ligand bifunctional mechanism (Scheme 2.12) 63a,e . First complex I is converted into Ruthenium hydride II in presence of base and hydride source (H 2 and isopropanol). Catalytic cycle who carried out between II and III contain two transition states TS1 and TS2. Ru hydride in II reacts with a ketonic substrate via six membered transition state TS1, where hydridic Ru-H and protic N-H plays role in hydrogen delivery to ketones, forming alcoholic product directly, without formation of a metal alkoxide. Via transition state TS2 Ru-N dipolar bond splits III to restore hydride II, alternatively II may be regenerated by way of IV and V by action of protonic medium and base (Scheme 2.12). This [Ru]-complex obtained from R-BINAP and compound 2 was used in reaction of hydrogenation of acetophenone (Table 2.3). As a first choice potassium hydroxide was used as a base. In case of Noyori 63b complex with DPEN as diamine authors obtained full conversion and 87% ee (Table 2.3, entry 1). In the same conditions with complex containing 1,2--glucodiamine, no conversion was observed, even when time of reaction was elongated from 3 to 72 hours (

N N Ru R 3 P R 3 P Cl Cl N N Ru X(R 3 P) 2 H N N Ru X(R 3 P) 2 N N Ru X(R 3 P) 2 N N Ru X(R 3 P) 2 HH CO CO H H N N H OH Ru X(R 3 P) 2 H C Ru X(R 3 P) 2 H H N N H + H 2 H 2 H 2 H 2 H 2 H + H 2 H 2 + H 2 H 2 2 HCl H 2 base H 2 base X = H, OR, etc.

Thiourea organocatalysts for Michael addition

Organo-catalyzed asymmetric reactions are becoming an increasingly important field of organic synthesis 64 . First time thiourea organocatalyst based on cyclohexanediamine ring (Figure 2.12) was prepared by Jacobsen 65 and used in Strecker reaction. In 2003

Takemoto 66 use similar ligand in nucleophilic addition of nitroolefins, and one year later bifunctional dithiourea organocatalyst was prepared by Nagasawa 67 and used in Baylis-Hilman reaction. Since then library of those compounds has been enriched, and used successfully in many different kind of reactions 68 .

N H N H N H S S N H CF 3 CF 3 CF 3 CF 3 N H NRR' S N H CF 3 CF 3 R, R' = H, Bn, Me, i-Bu Figure 2.
12 Bifunctional thiourea organocatalysts based on cyclohexadiamine.

We decided to prepare three different D-glucosamine based thiourea organocatalysts.

Project was made in collaboration with professor Florence Popowycz and PhD student Marc Baron from team CASYEN from University Lyon 1 who carried out tests of reaction of Michael addition between chalcone and nitromethane.

Synthesis of D-glucosamine based thiourea organocatalysts

Three catalyst containing thiourea moiety were prepared. Starting from described above compound 8, where amino function was protected with BOC group, in two steps we prepared catalyst L3, by hydrogenation with platinum oxide, and condensation with thiocyano compound with 96% of yield. Compound that was used as starting material for preparation another catalyst L4. Deprotection of amino function followed by condensation with benzaldehyde and reduction of created imine to amine using thiocyanoborohydride in acidic conditions gave catalyst L4 containing thiourea moiety and benzyl function in neighboring amino functions. Last compound from series of thiourea organocatalysts is product of condensation of 1 equivalent of diamine 2 with two equivalents of dicyano compound to give catalyst L5 with 30% of yield after purification (Scheme 2.13).

Ligands L3-L5 were characterized by many techniques: 1 H NMR, 1 H-1 H COSY, 13 C NMR, 1 H-13 C HSQC, ESI-MS (See experimental part).

In Table 2 Spectra analysis allows to confirm the ligands structure and to check his purity. The sugar identity was confirmed by the typical pattern of glucosamine (Figure 2.13).

Michael addition with thiourea organocatalysts

Asymmetric Michael addition is one of the most useful methods in formation of C-C bonds, which provides easy access to important chiral building blocks and intermediates in synthesis. Thiourea compounds bearing 3,5-bis(trifluoromethyl)benzene and different substituted amino groups were revealed to be highly efficient catalysts in this kind of reactions [START_REF] Siau | For review on use thiourea organocatalyst in organocatalysis see[END_REF] .

Two different models are proposed in literature for hydrogen bonding activation of unsaturated ketone and nitronate anion by thiourea moiety. First mechanism correspond to dual activation model of Takemoto 70 , nitroate interacts with the protonated amine while the ketone binds the thiourea. Pápai71 proposed other system: thiourea stabilized the nitronate and ketone is activated by the protonated amine of the organocatalyst.

In order to evaluate D-glucosamine based bifunctional thiourea as organocatalysts, compounds L3-L5 were used in the Michael addition between nitromethane and chalcone (

Conclusions

Presently chemistry of carbohydrates is well known and developed. Attention of chemists all over the world is focused on those molecules, because of their biological activity and synthetic utility. They are easy available from biomass and are excellent natural chiral building blocks. The strategy of this work has involved the synthesis of carbohydratebased ligands, which can reproduce the structural and stereochemical motifs of already known and use in asymmetric catalysis ligands.

In the first place was established synthesis of trans-1,2--glucodiamine which with its structure is similar to one of the widely used building blocks in synthesis of chiral ligands:

trans-1,2-cyclohexanediamine. This newly synthesized molecule been used to prepare ligands and catalysts designed for asymmetric reactions: Amido-and imino-ligands were synthesized and tested in reaction of allylic alkylation with two different substrates. Also attempts have been made to prepare diamino carbohydrate complex with Ruthenium and BINAP which was tested in reaction of hydrogenation of acetophenone. Finally considering increasing interest in organocatalysis in last few years synthesis of new thiourea organocatalysts was developed, and obtained compounds were used in catalytic reaction of addition of nitromethane to chalcone.

Although there has been well developed synthesis of ligands for asymmetric catalysis there still remain great challenges including using natural sources like carbohydrates. The main objective of such studies have been to replace known ligands with ligands derived from D-glucosamine. The results obtained so far have been somewhat disappointing, but further development considering advantages of those catalysts is necessary.

Experimental part

All experiments involving organometalic catalysis were carried out in a Schlenk tube under inert atmosphere. Solvents were dried and distilled under argon before use. The reagents were purchased from commercial suppliers and used without further purification.

Conversion was determinated by GC using Shimadzu GC-14B apparatus with flame ionization detector (FID) and integrator Shimadzu C-R6A. the capillary column Quadrex OV1 (30cm x 0.25mm) was used and helium as a carried gas. The temperature of detector and the cell of injector was 250 o C. The inject volume was 1μL.

Enantiomeric excesses was determined by HPLC method, with Chiralpack AD column (25 cm x 4.6 mm) with amylose tris (3,5-dimethoxylphenylcarbamate) coated on silica as a support, in companion of Shimadzu SPD-6A pump and integrator Shimadzu C-R6A pump and integrator Shimadzu C-R6A. The mobile phase was ratio of hexane / i-propanol. The analyses were performed at room temperature with inject volume of 20μL. In Schlenk tube under argon atmosphere D-glucosamine hydrochloride (3 g, 13.9 mmol) was added to solution of sodium (0.64 g, 27.8 mmol) in methanol ( 25 Synthesis of 2-Amino-3,4,6-tri-O-acetyl-1-azido-2-deoxy--D-glucopyronose 7 55 Method A Azide compound 5 (1,00 g, 2.89 mmol, 1.0 equiv) and N,N-dimethyl-4-aminopyridine (0.10 g, 0.87 mmol, 0.3 equiv) were dissolved in THF (20 mL). Di-tert-butyl dicarbonate

Experiments dealing with synthesis of 1,2--glucodiamine

(1,89 g, 8.67 mmol, 3.0 equiv) was added, and the mixture was heated to reflux overnight.

After the solution was cooled to room temperature, methanol (20 mL) and hydrazine (0.62 mL, 12.7 mmol, 4.4 equiv) were added and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into dichloromethane, washed with 1N HCl, CuSO 4sat , and NaHCO 3sat , dried (Na 2 SO 4 ), and concentrated. Chromatography on silica using dichloromethane : methanol 20 : 1 gave 0.33 g (38%) of pure 7. Azide compound 5 (5,40 g, 14.5 mmol, 1.0 equiv) and N,N-dimethyl-4-aminopyridine (0.52 g, 4.7 mmol, 0.3 equiv) were dissolved in THF (20 mL). Di-tert-butyl dicarbonate Chapter 3

Method

(10.2 g, 48.8 mmol, 3.0 equiv) was added, and the mixture was heated to reflux for 4 h.

After the solution was cooled to room temperature, solvents were evaporated, mixture was dissolved in methanol (20 mL) added to solution of freshly prepared sodium metanolate.

After 2 hours in room temperature methanol was evaporated and mixture was drying in vacuum pump for another 3 hours. In 0 o C crude was dissolved in mixture of pyridine (17 1371, 1320, 1294, 1211, 1162, 1106, 1080, 1033, 1008, 966, 897, 862.

ESI full ms calcd. for C 17 H 26 N 4 NaO 9 (M + Na + ):453.1592, found 453.1601. General procedure for the asymmetric allylic alkylation with NaH / THF A THF (1 mL) solution of [Pd( 3 -C 3 H 5 )Cl] 2 (2 mol%) and ligand (4 mol%) were stirred for 0.5 hour under an argon atmosphere and then substrate (1 equiv) in THF (1 mL) was added. The mixture was stirred for 10 min and a solution of sodium dimethyl malonate, prepared from dimethyl malonate (3.0 equiv) and sodium hydride (3.0 equiv) in THF (2 mL), was canulated to Schlenk at room temperature. The reaction mixture was then stirred for 24 h at room temperature. After this time, solution was diluted with diethyl ether (5 mL) and wash with water (5 mL) and brine (5 mL). The combined organic layers were dried with MgSO 4 , the solvent was evaporated and the crude product was purified by chromatography eluting with hexane : ethyl acetate (10 : 1) .For Dimethyl (1,3-Diphenylprop-2-en-1-yl)malonate conversions were determined by GC and 1 H NMR analysis. Enantiomeric excess was determined by chiral HPLC (Cellulose 3 column). For (E)-dimethyl (1-methyl-2-butenyl)propanedioate conversions were determined by GC and 1 H NMR analysis.

Experiments dealing with synthesis of ligands for allylic alkylation.

Ligands for homogeneous catalysis

General procedure for the asymmetric allylic alkylation with Cs 2 CO 3 / DCM A solution of [Pd( 3 -C 3 H 5 )Cl] 2 (2 mol%) and ligand (4 mol%) in dichloromethane (1 mL)

were stirred for 30 min under an argon atmosphere and then 4-acetoxy-2-pentene (1 equiv) in dichloromethane (1 mL) was added. The mixture was stirred for 10 min at this temperature and dimethyl malonate (3.0 equiv), and cesium carbonate (3.0 equiv) were sequentially added. The reaction mixture was then stirred for 24 h at room temperature.

After this time, solution was diluted with diethyl ether (5 mL) and wash with water (5 mL)

and brine (5 mL). The combined organic layers were dried with MgSO 4 , the solvent was evaporated. Conversions were determined by GC and

Experiments dealing with synthesis catalyst for hydrogenation.

Synthesis of (R),(R,R)-10:

[RuCl 2 (C 6 H 6 )] 2 (15.5 mg, 0.031 mmol) and (R)-BINAP (41 mg, 0.066 mmol) were placed in a dry 50-mL Schlenk flask. DMF (1 mL) was added, the mixture was degassed by three vacuum argon cycles and stirred under argon at 100 o C for 10 min to form a reddish brown solution. After the solution was cooled to 25 o C, 1,2-diamino-D-glucosamine 2 (20 mg, 0.066 mmol) was added and the mixture was stirred for 3 h. The solvent was removed under reduced pressure for 30 min in 25 o C and then in 50 o C for one hour. The residue was dissolved in dichloromethane (1 mL) and turbidity was removed by filtration. The filtrate was concentrated to about 1 mL, then ether (2 mL) was added and a light brown powder was obtained. The supernatant was removed and the resulting solid was dried under reduced pressure to give 63 mg of 10 quantitative. General procedure for the hydrogenation reaction of acetophenone to 1-phenylethanol.

2-Propanol (5 mL) charged into a Schlenk flask and was degassed by three vacuum argon replacement cycles. Solid trans 10 (0.2 mol%) was dissolved in the 2-propanol and used as a catalyst stock solution. Acetophenone (1.0 equiv) and solid (CH 3 ) 3 COK (1 mol%) were placed in argoned steel autoclave. 2-Propanol (5 mL) and an aliquot of the catalyst solution were added to the autoclave under a stream of nitrogen. Hydrogen was introduced initially into the autoclave at a pressure of 10 atm and then reduced to 1 atm by carefully releasing the stop valve. After this procedure was repeated three times, the vessel was pressurized to desired pressure. The reaction mixture was vigorously stirred at room temperature to give 1-phenylethanol. After the hydrogen gas was carefully vented, the solvent was removed under reduced pressure. The conversions were determined by GC analysis, yields by isolation from reaction mixture using column chromatography (cyclohexane : ethyl acetate 20 : 1) and ee value were determined by HPLC (Cellulose 3 column) Analysis of substrates and products of catalysis were made using conditions: GC: Research on heterogenisation of homogeneous catalysts is extensively explored 77 . Many issues is discussing with included insuring high activity and selectivity in immobilization with avoid leaching of catalyst, improving enantioselectivity or increasing availability of cheaper chiral ligands. Immobilized catalysts have many advantages like easy separation and recover of the catalyst, or stabilization of highly reactive species that cannot exist in solution. Furthermore multifunctional catalysts can be obtained in which more than one active component is bound to a support. However using immobilized catalysts have also disadvantages. A common phenomenon is leaching of the metal and/or ligand and inhomogeneity due to different linkages between support matrix and complex. Also problematic features of homogeneous catalysts, such as corrosion, catalyst recovery and catalyst recycling, have so far not been overcome satisfactorily. Besides heterogeneous catalysts have lover catalytic activity comparing to their homogeneous counterparts caused by incapability of solvent and support, steric effects of the matrix with decreased accessibility of the active sides for the substrate, and deactivation of the active centers.

Although, high activity and better control of stereoselectivity are generally easier to achieve with homogeneous systems, they create major problems in terms of product purification and separation of expensive metal catalyst that leads to toxic wastes. These problems are particularly important when dealing with large scale-synthesis for environmental and economic concerns.

To reach high activity of catalyst and minimize obstacles many immobilization techniques have been used:

Covalent binding is the most frequently used strategy. It is carried out with polymeric organic matrix or inorganic matrices, both by copolymerization of functionalized ligand with suitable monomer or by grafting functionalized ligands with reactive groups on surface of the support.

The systematic use of immobilization of organofunctional groups in silica has increased in the past four decades, because this support offers pronounced advantages over other organic/inorganic supports:

Immobilization on silica results in great variety of silylating agents.

Attachment is easier on silica surface than on organic polymeric supports.

It is the first commercially available high specific surface area substrate with constant composition, enabling easy analysis and interpretation of results.

Silica gel has no swelling.

Great resistance to organic solvents.

Very high thermal resistance.

However irreversible binding of metal ions and lack of selectivity are the main disadvantages of silica bound ligands in their repeated cyclic use.

The modification of silica gel using organic functional groups has been a subject of considerable interest, and it can be made by silanization which involves the covalent binding of a silane reagent molecule, either a chlorosilane or an alkyloxysilane (Figure 3.1), to the surface through a siloxane bond. ecologically advantageous. Large interfacial area makes metal easily available even for highly hydrophobic substrates, and metal losses can be reduced by convenient selection of hydrophilic supports and water-soluble ligands. However SAPC is strongly dependent on the water content of the solid support [START_REF] Arhancet | [END_REF] .

Three types of water content effects have been reported: first at very low water content catalytic complex is strongly absorbed to the surface, what caused with lack of mobility and make it very stable, so low catalytic activity is observed. Secondly, at intermediate water contents activity reaches maximum, usually SAPC is efficient over a very restricted hydration range. Thirdly at high water loading the SAPC loose both activity and stability, leaching of catalyst is observed.

It has been proven that SAPC can perform a broad spectrum of reactions such as hydroformylation [START_REF] Arhancet | [END_REF] , hydrogenation 81d , and oxidation 81e for the synthesis of the fine chemicals or pharmaceuticals. Although rhodium complexes are the most extensively used in SAPC few examples with Pd complexes are described in allylic substitution of allyl acetates 82 or in alkoxycarbonylation of alkenes 83 . To our knowledge, no example of Suzuki-Miyaura cross-coupling reaction using SAPC methodology is already described in literature.

Organization of Chapter 3

In this chapter we will focus on three topics. Firstly Supported aqueous phase catalysts (SAPC) based on D-glucosamine will be presented and its use in Suzuki Myaura cross-coupling reaction. In the next subchapter synthesis of ligands containing poly (ethylene glycol) moiety for biphasic catalysis will be presented. Finally catalysts immobilized by covalent binding on silica matrix will be discussed. [START_REF] Arhancet | [END_REF] (a) J. P. Arhancet, M. E. Davis, S. S. Merola, B. E. Hanson, Nature 1989, 339, 454-455 (a) Schneider, F. Quignard, A. Choplin, D. Sinou, New J. Chem., 1996, 20, 545-547, (b) In a second study 25b , it has been demonstrated that a medium conversion is obtained when water is used as solvent, whereas when a mixture of toluene / ethanol / water (3/2/2), where ethanol plays the role of transfer agent, is used as solvent excellent yields have been obtained, with TON up to 97000. Unfortunately, no recoverable has been possible. In this context, we decided to immobilized the Pd-complex obtained from the same D-glucosamine-based phosphine and Pd(OAc) 2 in aqueous layer of the SAPC system in order to recycle the catalyst. According to author this procedure allows to obtain in a reproducible way, a solid with a water content close to 3%. Similarly like in above case to ensure a fast diffusion of the liquid into the porous system and thus a good dispersion of the catalytic active species, the silica was evacuated at 150 o C in vacuum pump prior to impregnation and the final solid was dried under vacuum (25 o C) for 16 hours.

Results and discussion

Supported Aqueous Phase Catalyst (SAPC) for

Synthesis of ligand

Suzuki Miyaura cross coupling

Suzuki Miyaura cross coupling reaction [START_REF] Miyaura | For selected reviews see[END_REF] is probably one of the most studied

[Pd]-catalyzed reactions. Its catalytic system provides simple and practical method for creating C-C and C-N bonds under sustainable conditions with excellent yields.

The cross-coupling reaction of organoboron compounds involving oxidative addition of organic halides or other electrophiles to a Pd(0) complex, transmetalation between Pd-X and R', and reductive elimination of R-R' to regenerate the "Pd (0) L2". and as a result formation of complex and transfer of an activated organic group from boron to palladium (paths B,C). Last step reductive elimination is common for all path and involves creation of product R-R' and regeneration of Pd(0) complex. [START_REF] Miyaura | For selected reviews see[END_REF] For selected reviews see: (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457-2483, (b) Volume 219 devoted to "Cross-Coupling Reactions A Practical Guide" from Top. Curr. Chem., 2002, (c) V. Farina, Adv. Synth. Catal., 2004, 346, 1553-1582, (d) Catal., 2006, 348, 609-679, (e) C. Torborg, M. Beller, Adv. Synth. Catal., 2009, 351, 3027-3043. as reported before and changing SiO 2 by Pd SAPC (1 molar% of Pd loading), after the first run, the Pd SAPC was filtered, washed with toluene and dried under vacuum at room temperature for 16 hours, before to be used in a second run without any addition of Pd(OAc) 2 (Table 1. 1, entries 2, 3). The yield of the coupling product of 4-bromonitrobenzene and phenylboronic acid decreased from 74% to 15%. This drop in performance was explained by the leaching of the metal when the catalyst was filtered and washed with toluene.

(OH) 2 B O Pd R' R OH B OH OH R' X - Path C R-Pd-X R-Pd-R' R -Pd-OR" R-R' R-X R"O - R" R'B (
We then studied the influence of the solvent on the coupling reaction between 4-bromonitrobenzene and phenylboronic acid using 1 molar% Pd(OAc) 2 and L6 as the catalyst, at 60 o C. We noticed that the highest conversions were obtained using toluene and ethanol in ratio 7.5 / 1 (Table 3. 2, entries 5, 6) or toluene and ethanol in ratio 10 / 1 (Table 3.2, entry 4) as the solvent. The use of toluene alone resulted in poor conversions (Table 3 Other tested factor was influence of base. When reaction was carried out in toluene as solvent better results were obtained with potassium phosphate (Table 3.2, entry 1), however using ratio toluene / ethanol (7.5/1) almost full conversion was obtained with sodium carbonate (Table 3.2, entry 6) while in the same conditions K 3 PO 4 gave only 63% of conversion (Table 3.2, entry 5).

Recyclability of catalyst (L/Pd SAPC) was also estimated by repeatedly carrying out

Suzuki coupling reactions at 80°C in toluene / ethanol (7.5 / 1) with model reaction using up to 99%. The reactions were carried out in the same conditions as described above with 1% molar of Pd.

The yields in biaryl coupling of aryl bromides bearing electron withdrawing group with phenylboronic acid were good between 88% and 99% (Table 3.3, entries 1, 5 and 6), except in the case of 4-vinylbromobenzene where the yield was 65% with a conversion of 76% (Table 3.3,entry 7). In the case of coupling of aryl bromides bearing electron donating group with phenylboronic acid, the conversions were over 90% (Table 3 Biaryl coupling of 4-bromonitrobenzene with 4 arylboronic acids was also studied (Table 3.3, entries 1-4). 4-Bromonitrobenzene reacted efficiently with phenylboronic-, 3-acetylphenylboronic-or 4-tolylboronic acid to give with good yields the corresponding biaryl compounds (Table 3.3, entries 1-3). The sterically hindered 2,6-dimethylphenylboronic acid reacted also affording the coupling product in 45% yield (Table 3.3, entry 4).

Finally, when 2-bromonaphthalene in homogeneous conditions gave very low conversion (20%) of coupling product with phenylboronic acid with the same Pd loading in a mixture of Toluene/Ethanol/Water as solvent 25b the same cross-coupling reaction performed under SAPC conditions gave the biaryl compound with a conversion of 85% (Table 3 .3, entry 11). And the condensation of the heterocyclic 2-bromopyridine with phenylboronic acid occurred with a total conversion and a isolated chemical yield of 75% (Table 3.3, entry 12). However starting from 12 it was impossible for us to continue. We try to hydrolyze imino function using hydrochloric acid to obtain amine hydrochloride (Scheme 3.3). 88 H. Myszka, D. Bednarczyk, M. Najder, W. Kaca, Carbohydrate Research, 2003, 338, 133-141. 89 P. A. Wender, J. L. Baryza, Org. Lett., 2005, 7, 1177-1180. Unfortunately every time we had problems with isolation of product. Explanation can be to big solubility in solvents use for hydrolysis, as already mentioned 90 .

PEG-supported ligands

Ligands containing 1-polyethylene arm

Preparation of ligand based on D-glucosamine containing four PEG arms was impossible for us and one for reasons could be spherical effect. We decided to prepare ligand containing only one PEG arm. In our group was already prepared that kind of ligand containing PEG arm in anomeric position (Figure 3.8) 90 . That ligand was used in asymmetric allylation type Tsuji-Trost. With different kinds of nucleophiles compound 14 catalyzed reactions with yield up to 98%, unfortunately with not very high enantiomeric excesses. Explanation could be effect of ether function which creates with palladium less sable complexes than ester function. It was known before that in order to obtain high enantiomeric excess it is necessary to have an ester group at the anomeric center in a -position 24a .

O AcO

AcO

Collect that information we decide to prepare hydrosoluble ligand containing one PEG arm in primary carbon in carbohydrate skeleton and with ester function on anomeric carbon in -position (Figure 3.8).

For establish protocol for synthesis new ligand we decide to use different reagents for protecting primary alcohol.

Using trityl protecting group.

Our first choice was to use trityl chloride (Scheme 3.

+ R = TBDPS R' = Ac (not observed) R' = H (traces) R' = Cbz (89%) R = TBDPS R' = Ac (not observed) R' = H (traces) R' = COCF 3 (75%) R' = Ac R' = H R' = COCF 3 R' = Cbz + R = TBDPS R' = Ac (main)
Scheme 3.5 Effect of sillyl protecting group for D-glucosamine derivatives.

Last tested group was les electronwithdrawing Cbz, reaction proceeded with sillylation of C-1, C-6 positions with 71% of yield (Scheme 3.5).

In order to prepare -anomer we decide to use D-glucosamine derivative with nitrogen group protected with sterically demanding p-anisylbenzylidene function, which is known in literature that during acetylation direct substituent in position 88 . Base on NMR and MS analysis we observed as a main compound product in which reaction occurred in primary hydroxyl group, but also with hydroxyl group of anomeric carbon in carbohydrate skeleton. Also during reaction nitrogen protecting group was removed, what was probably caused by forming hydrochloric acid.

Using tosyl protecting group.

Other method to protect selectively six position is by introducing in carbohydrate skeleton tosyl function. There is not many examples in literature where tosyl function was introduced into carbohydrate skeleton with free hydroxyl group in anomeric position. In mostly cases N-acetyl-D-glucosamine was used as starting material 95 , but there is also one example of use N-allyloxycarbonyl-D-glucosamine 95a , and carboxybenzyl protecting group 96 . However in all of those cases product of the reaction in mixture of anomers. Tosyl group was also introduced into carbohydrate using tosylation and in situ acylation 97,98 .

Chapter 3

When N-acetylglucosamine is used as starting material similarly like in previous cases mixture of anomers was obtained, but when sterically demanded group p-anisyl was used 98 only product of reaction was -anomer.

It was impossible for us to repeat reaction using harsh conditions described by Morel 98

Introducing azido function

Our first choice to replace tosyl function was to prepare azido derivative, with can be easily attached to PEG using reaction of "click chemistry". Substitution with sodium azide in DMF give compound 19 in 77% of yield. (Scheme 3.8) 99 . Hydrolysis with hydrochloric acid in warm acetone allow to obtain compound 20 with 95% of yield and washing it with sodium bicarbonate gave carbohydrate 21 containing amino and azido functions with 71% of yield. It was also possible to obtain 21 directly from 19 without isolation of 20 with 54% of yield, however purification 21 is much more easier when organic residue from protecting p-anisyl group is removed during washing insoluble solid 20 with organic solvents. This avoids a long and tedious purification by column chromatography as in the case of direct deprotection of 21 from 19. Starting from compound 21 using reaction of "click chemistry" we prepared derivative with polyethylene glycol arm placed in C-6 position. Reaction took part in THF with using catalytic amount of copper iodide and after one hour product was obtained quantitatively (Scheme 3.9).

It is known that salts of Cu(I) can catalyze Huisgen 1,3-dipolar cycloaddition 100 , however, the iodide and bromide Cu salts require either the presence of amine base or higher temperatures. In our case no addition of base was required, probably amino function present substrate structure played role of base in reaction.

Unfortunately it was impossible for us to couple PEG derivative 21 with 2-diphenylophosphino benzoic acid, no conversion of starting material was observed. We tried to explain failure of reaction by similarity of triazol ring with coupling reagents, however there are examples of creation of amido bonds when in structure of starting material is present triazol ring 101 . However to our knowledge no example of coupling reaction using EDC, HOBt when starting material containing both triazol ring and phosphorus function is present in literature.

Chapter 3

Other way to prepare ligand L7 is to prepare first amide compound 24 and after "click" it with PEG containing propargyl function but also in this case coupling was unsuccessful in our hands (Scheme 3.9). Using mixture EDC, HOBt as coupling reagents, five different signals from phosphorus atoms were observed on spectrum ( = 30.1 to 35.8 ppm), changing reagents for DCC, DMAP, we obtained complex mixture, using 31 case the main product of reaction was compound with shift characteristic for aza-ylide ( = 34.9 ppm), which after column chromatography decomposed to its oxide ( = 37 ppm). We decide to prepare analogous compound containing instead of amido bond imino function. In this case reaction also did not occurred (Scheme 3.10). Other possible way was first to prepare imino derivative 26 and after make reaction of cycloaddition. Condensation of 21 with pyridine aldehyde proceed quantitatively. In future we plan to prepare ligand L9 and test it in catalytic reactions of allylic alkylation in water.

O OAc

AcO

Introducing alkynyl function

Other way to graft ligands on hydrosoluble matrix by using azide-alkyne Huisgen cycloaddition is by introducing alkynyl function in carbohydrate skeleton.

In literature there is not report mentioned transformation of tosyl carbohydrate into alkynyl compound. However we decided to try replace good leaving group: tosyl with alkynyl chain using standard conditions. Two different bases were tested, in both cases using one equivalent of base for one tosyl function caused appearing small amount of compound in Thin Layer Chromatography confirmed presence of compound in NMR spectra, however increasing time of reaction or increasing amount of base to three equivalents caused with degradation of carbohydrate starting material. We expected that cause of this could be not very stable protection function of nitrogen atom, surprisingly using acetyl as very stable protecting group did not lead to increasing conversion of product. Similarly like in case of p-anisylen protecting group using one equivalent of base give small conversion of product, using three equivalents of base causes with degradation of starting material. We think the reasons for failure is in the nature of the sugar. Because of small amounts products were not isolated.

Silica immobilized ligands

This subchapter deals with a stepwise synthesis of two unsymmetrical silica supported D-glucosamine based phosphorus containing ligands. We decided to prepare two types of ligands. Ligands L11 connected with silica by anomeric position, with two different kind of linkers with phosphorus function: amido linker for ligand L11a and imino linker for ligand L11b (Figure 3.11).

Project was made in collaboration with Doctor Chloe Thieuleux and Doctor Reine Sayah from LCOMS team of University Lyon 1, who provided mesoporous silica materials (SBA-15) and carried out analysis of supported products.

Silica materials

Among provided materials containing azido function were silica SBA-15 with free hydroxyl groups on surface (Figure 3 Materials were analyzed using IR technique (Figure 3.13). In both spectra there are signals with high intensity in area from 500 to 1400 cm -1 corresponding to stretching and deformation vibrations of Si-O-Si groups, and also sharp signal around 2150 cm -1 corresponding to azido function.

Comparing spectra of both of them we observed disappearance of broad signal in area from 3000 to 3800 cm -1 and sharp signal around 1630 cm -1 which are assigned, respectively, to the stretching and deformation vibrations of adsorbed water molecules103 . In Table 3. Similarly like in case of surface area in case of pore volume decreasing of size is observed caused by hindered effect of TMS groups.

N 3 C-H O-H b) a) O-H Si-O-Si

Synthesis of carbohydrate with alkynyl function in -anomeric position

Starting from N-acetyl-D-glucosamine 3 using procedure described by Brimble et al. 104 glucosylation with propargyl bromide was made and followed it acetylation of free hydroxyl functions ( Scheme 3.13).

Carbohydrate 27 was obtained after crystallization as exclusively -anomer in 28% of yield while authors claimed that only product of reaction was -anomer. High coupling constant To deprotect acetyl from amino function procedure described by Lafont 56 was used and compound 29 was obtained with 65% of yield after two steps ( Scheme 3.13). In next step coupling with 2-diphenylophosphino acid was performed using EDC and HOBt as coupling reagents (Scheme 3.15). Bhaumik, Green Chem., 2011, 13, 586-590; (d) Despite of that solvents were distillated and degassed before use and reactions were carried out under argon atmosphere it was impossible for us to avoid oxidation process, even when surface of silica was protected, probably because of the high affinity of the trivalent phosphorus to oxygen from silica material.

Immobilization

Imino type ligand

In previous study made by our team different types of complexation were investigated for carbohydrate based imino type ligands in homogeneous catalysis (Chapter 1, Figure 1.14 and Scheme 1.7). Also in this case we decide to prepare two type of complexes where palladium with phosphorus will be in ratio 1 / 1 (complex 31) and when palladium with phosphorus will be in ratio 1 / 2 (complex 32) ( Scheme 3.16).

Phosphine oxide of L11b

In order to remove oxygen from phosphorus atom reduction of oxide of ligand L11b was made using trichlorosilane as reducing agent in phenylsilane as solvent (Scheme 3.18). Unfortunately product was reduced only partially ( = -17.7), and in spectra were present also other compounds (Figure 3.19). It was impossible for us to obtain ligand L11b without oxidation of phosphorus atom.

Complex L-Pd (2 / 1)

It was shown before that the best results in catalysis were obtained when one palladium was complexed with two phosphorus atoms (Chapter 1, Figure 1.14 and Scheme 1.7). For this reason we decided to prepare palladium complex and after graft it into structure of silica matrix in order to obtain complex 32. Direct grafting on silica matrix and after complexation does not guarantee that two phosphorus atoms will be connected with one palladium atom. Compound 33 was prepared using reaction of "click chemistry" between 29 and 3-azidopropyltriethoxysilane107 with 74% of yield after purification, followed that condensation with 2-(diphenylphosphno)benzaldehyde yielded compound 33 (Scheme 3.19).

Next step complexation with allylpalladium chloride dimer was difficult for us to carry out.

Each time when reaction was made small traces of oxidation occurred (Figure 3.20).

Conclusions

An important task of today's chemistry is to design new products prepared from renewable starting materials and produced using green processes. This chapter we can find many reactions that follow these concepts.

Using Supported Aqueous Phase Catalyst system D-glucosamine based catalyst was prepared and immobilized on silica matrix without the use of tedious protecting and deprotecting steps that allows time-, money-and atom-economies. First time SAPC system was applied to Suzuki coupling reactions. Its efficiency was demonstrated in catalytic reactions with various of substrates, moreover catalyst can be easily isolated and reused four times without loss of activity. And to compare with the coupling reaction perform from the same Pd complex in a mixture of Toluene/Ethanol/Water as solvent, we observed in some cases a positive effect of silica support.

Attempt to obtain D-glucosamine ligand containing 4-polyethylene arms was made and in order to protect selectively primary hydroxide function in D-glucosamine skeleton different reagents were tested. Works on preparation ligands containing polyethylene glycol arm catalysts are ongoing.

Immobilization of unsymmetrical silica supported D-glucosamine based phosphorus containing ligands. on the silica surface was studied. For this purpose reaction of "click chemistry" known from its high efficiency, simple procedure, absence of side products and mild reaction conditions was used.

Unfortunately, because of the high oxygen affinity of the trivalent phosphorus it was impossible to succeed in the synthesis of amido and imino types ligands supported in silica matrix.

Experimental part

Solvents were purified and dried by standard methods. The reagents were purchased from commercial suppliers and used without further purification. All manipulations involving palladium catalyst were performed under usual inert atmosphere techniques in Schlenk tube. Conversion was determinated by GC using Shimadzu GC-14B apparatus with flame ionization detector (FID) and integrator Shimadzu C-R6A. the capillary column Quadrex OV1 (30cm x 0.25mm) was used and helium as a carried gas. The temperature of detector and the cell of injector was 250 o C. The inject volume was 1 μL.

Experiments dealing with SAPC system.

Synthesis of 2-Deoxy-2-{ [4-(diphenylphosphino)benzoyl]amino}-D-glucopyranose L6 25a In Schlenk tube 4-diphenlylophosphino benzoic acid (500.0 mg, 1.63 mmol, 0.5 equiv), EDC (375.5 mg, 1.96 mmol, 0.6 equiv), and HOBt (264.6 mg, 1.96 mmol, 0.6 equiv), were dissolved in degassed DMF (13 mL). In second Schlenk tube D-glucosamine (704.2 mg, 3.27 mmol, 1.0 equiv), and NaHCO 3 (658.8 mg, 7.84 mmol, 2.4 equiv), were stirred in water (6.5 mL) in 0 o C during 1 hour, and after this time transferred using canula to the first Schlenk. Solutions were stirred 20 hours in room temperature. Solvents were evaporated on vacuum pump and crude was purified using flash chromatography under argon atmosphere using chloroform : ethanol 3 : 1 as eluent. 3.11 (dd, 1H, J=5.1, J=9.8Hz, H-6), 3.23 (m, 1H, H-6), 3.64 (ddd, 1H, J=3.2, J=6.3, J=11.1Hz, H-2), 3.83 (ddd, 1H, J=1.5, J=5.1, J=10.8Hz, H-5), 4.67 (d, 1H, J=6.3Hz, H-1), 4.89 (dd, 1H, J=5.1, J=10.8Hz, H-4), 4.99 (dd, 1H, J=3.2, J=5.1Hz, H-3), 6.52 (d, 0.8H, J=4.5Hz), 6.62 (d, 0.2H, J=6.3Hz), 7.29 (m, 9H), 7.43 (m, 6H), 7.68 (d, 0.8H, J=8.2Hz), 7.74 (d, 0.2H, J=8.4Hz).

Synthesis of 2-acetamido-1,3,4-tri-O-acetyl-2-deoxy-6-O-trityl-D-glucopyronose 16 113 The trityl compound (2.5 g, 5.4 mmol) was acetylated with acetic anhydride (10 mL, 0.1 mol) and dry pyridine (20 mL) overnight. It was poured into ice-water, and extracted with chloroform, and solution washed with water dried (Na 2 SO 4 ) and evaporated. The residue was freed from pyridine by addition and evaporation of toluene and passed through a column of silica gel. The product was eluted with chloroform and crystallized from hot carbon tetrachloride. After 4 days first part of compound 16 was filtrated.

Yield 58%

Colorless oil R f = 0.22 (dichloromethane : methanol 20:1)

1 H NMR (CDCl 3 ): (ppm) = 1.02 (s, 9H, tert-butyl), 1.08 (s, 9H, tert-butyl), 1.96 (bs, 2H, NH 2 ), 2.73 (dd, 1H, J=7.6, J=9.4Hz, H-2), 3.04 (ddd, 1H, J=1.0, J=5.1, J=9.8Hz, H-5), 3.24 (dd, 1H, J=9.4, J=9.4Hz, H-3), 3.68 (m, 3H, H-4, H-6, H-6'), 4.32 (d, 1H, J=7.6Hz, H-1), 7.45 (m, 20H, 4 x H arom ). IR: (thin film, cm -1 ) = 2975, 2929, 2889, 1744, 1599, 1444, 1366, 1322, 1295, 1232, 1216, 1167, 1146, 1099, 1068, 1026, 985, 948, 922, 899, 884, 846, 790, 766, 724, 681. , 2974, 2927, 2883, 2323, 2109, 1980, 1745, 1638, 1585, 1560, 1480, 1435, 1365, 1223, 1163, 1099, 1069, 1028, 956, 784, 746, 696, 695,

Green chemistry constitutes a good theoretical framework for pollution prevention in the development of chemical products and processes. The 12 guiding principles offered by this framework are useful as fundamental approaches motivating and inspiring chemists and chemical engineers to design chemical products and processes that reduce or eliminate the use and generation of hazardous substances.

This work involved the synthesis and the application of the new ligands derived from D-glucosamine compound easy available from biomass. Compounds were designed especially for two kind of catalysis, homogeneous catalysis and heterogeneous catalysis.

Among ligands for homogeneous catalysis were compounds based on 1,2--glucodiamine which is structural analogous of 1,2-cyclohexadiamine. Various ligands and catalysts were prepared to perform a series of metal-catalyzed or organocatalyzed reactions such as allylic alkylation, hydrogenation and Michael addition.

Heterogeneous SAPC system was prepared without the use of tedious protecting and deprotecting steps that allows time-, money-and atom-economies. Its efficiency was demonstrated in catalytic reactions with various substrates, moreover catalyst can be easily isolated and reused four times without loss of activity.

Also attempts for preparing heterogeneous catalysts easily that could be easy separated after catalytic reactions by simple filtration were made. Unfortunately, because of the high oxygen affinity of the trivalent phosphorus, synthesis of ligands was not successful.

Taking care of environment and consider economic reasons use of water poly(ethylene) glycol can be good support for ligands and seems to be very interesting object because they are known to be inexpensive, thermally stable, and nontoxic. For this reason synthesis of poly(ethylene) glycol containing ligand was made and work are ongoing. Mo liwy okaza si tak e recykling katalizatora SAPC. Reakcje przeprowadzone zosta y z dwoma ró nymi ilo ciami katalizatora i w obydwu przypadkach okaza o si mo liwe jego atwe odzyskanie i u ycie w czterech kolejnych cyklach katalitycznych bez znacz cego spadku konwersji w przypadku (Wykres 1). Niestety, podobnie jak w przypadku liganda L11a, podczas prób czenia liganda z matryc nieorganiczn nast powa o utlenienie funkcji fosforowej.

Wst p

Cz eksperymentalna

Cz eksperymentalna (Rozdzia y 2. 5-2.8, 3.4-3.6) pracy doktorskiej zawiera wyniki przeprowadzonych bada eksperymentalnych zwi zanych z opracowaniem procedur syntetycznych wykorzystanych do syntezy i oczyszczania nowych zwi zków i kompleksów, a tak e substratów i produktów reakcji katalitycznych. W tej cz ci zosta y równie przedstawione szczegó owe dane z przeprowadzanych analiz z zastosowaniem metod analitycznych t.j. 1 H NMR, 13 C NMR, 31 P NMR, GC, HPLC, IR, ESI MS.

Podsumowanie i wnioski

Opracowana zosta a synteza trans-1,2-glukozodiamiy, której struktura zbli ona jest do struktury trans-1,2-cyklohexodiaminy, jednego z powszechnie u ywanych elementów konstrukcyjnych w syntezach chiralnych ligandów.

Otrzymane zosta y ligandy amidowe i iminowe o strukturze zbli onej do struktury "liganda Trosta", Ligand amidowy przetestowany zosta w reakcjach substytucji allilowej z u yciem dwóch ró nych substratów.

Annex C

Supplementary work

FacultéInstitut

  Abbreviations

1 Figure 1 . 1

 111 Figure 1.1 Structures of D-glucosamine hydrochloride and chitin.

Figure 1 . 2 1

 121 Figure 1.2 Monophosphines based D-glucosamine derived by Zapf.

Lig2Figure 1 . 3

 13 Scheme 1.2 Hydroformylation.

Figure 1 . 4

 14 Figure 1.4 Phosphites ligands Lig3a,b, and aminophosphine ligand L4.

Figure 1 . 8

 18 Figure 1.8 Diimino and diamino ligands Lig8.

Figure 1 . 9

 19 Figure 1.9 Carbohydrate-based bis(oxazoline) ligands Lig9.

  (a) M.Irmak, A. Groschner, M. M. K. Boysen, Chem. Commun., 2007, 177-179, (b) T. Minuth, M. Irmak, A. Groschner, T. Lehnert, M. M. K. Boysen, Eur. J.Org. Chem., 2009, 997-1008, (c) T. Minuth, M. M. K.

Figure 1 .Figure 1 .

 11 Figure 1.11 Phosphite D-glucosamine oxazoline type ligands Lig11-15a-g.

Figure 1 . 13

 113 Figure 1.13 Examples of olefins used for hydrogenation and results of catalysis.

Figure 1 .

 1 Figure 1.14 Phosphino-amido ligands L28-L30 for allylic alkylation reactions.

Figure 1 .

 1 Figure 1.15 Phosphino-imino Lig20 and phosphino-amino Lig21 type ligands.

Figure 1 .

 1 Figure 1.16 Ligands L22 prepared by Ruffo.

Figure 1 . 18

 118 Figure 1.18 Bisoxazoline ligand prepared by Boysen.

Figure 1 . 19

 119 Figure 1.19 Bispyridine ligands Lig26.

Figure 1 . 20

 120 Figure 1.20 Tridentate ligands prepared by Ruffo.

Figure 1 .

 1 Figure 1.22 D-glucosamine based organocatalysts L44.

Figure 1 . 23

 123 Figure 1.23 Organocatalysts Lig31a-f.

(Figure 1 . 25

 125 Figure 1.25 Various carbohydrate-derived catalysts screened for aldol reaction. D-glucosamine hydrochloride and catalysts Lig33a-e were tested in the enantioselective aldol reaction of ketones with different isatins derivatives.

Figure 1 .

 1 Figure 1.26 Glucosaminylurea-based organocatalysts.

  prepared series of ketones, readily available from N-acetyl-Dglucosamine Lig35a-f (Figure 1.27) and in 2012 Schöberl and Jäger 47 enlarged library of those compounds for new Lig35g, Lig36,37 organocatalysts.

Figure 1 . 27

 127 Figure 1.27 Organocatalysts Lig35-37.

Figure 1 . 28

 128 Figure 1.28 Results of asymmetric olefin epoxydation by organocatalysts L35-37.

Figure 1 . 30 14 Scheme 1 . 15

 13014115 Figure 1.30 Ligands with polystyrene resin prepared by Ruffo.

Figure 1 . 31

 131 Figure 1.31 Urea organocatalysts.

Figure 2 . 1

 21 Figure 2.1 Structures of 1,2--glucodiamine and 1,2-cyclohexanediamine This is based on the assumption that that (1R,2R)-cyclohexanediamine has a structural analogy with the 1,2--glucodiamine frame, because in both cases neighboring amino functions are in trans-diequatorial position of a six-member ring (Figure 2.1).

Figure 2 . 2

 22 Figure 2.2 Examples of ligands prepared by Ruffo and by our team.

Scheme 2 . 1

 21 Scheme 2.1 Synthesis of 2-acetamido-3,4,6-tri-O-acetyl-1-azido-2-deoxy--D-glucopyronose.

This synthesis was described by Cunha 52 Scheme 2 . 2

 5222 Scheme 2.2 Mechanism of nucleophilic substitution leading to the formation of 3.

Figure 2 .

 2 Figure 2.3 a)"Trost modular ligand", b) general "Trost ligand" system

  P NMR, IR, ESI-MS (See experimental part). Spectra analysis allows to confirm the ligands structure and to check his purity. The sugar identity was confirmed by the typical pattern of glucosamine (Figure 2.4, protons H-1 to H-6').

Figure 2 .

 2 Figure 2.4 1 H NMR from 1.6 to 8.0 ppm of ligand L1.

Figure 2 . 5

 25 Figure 2.5 COSY 1 H-1 H from 3.0 to 8.0 ppm for diamido ligand L1 COSY 1 H-1 H from 3.0 to 8.0 ppm for diamido ligand L1, and zoom in area of amido bonds 6.0 ppm to 8.0 ppm.

Figure 2 . 6 Figure 2 . 7

 2627 Figure 2.6 COSY 1 H-1 H from 3.0 to 10.0 ppm for diimino ligand L2, and zoom in area of imine bonds 8.3 ppm to 9.5 ppm.

Figure 2 .

 2 Figure 2.8 1 H NMR from 3.0 to 5.6 ppm and 8.4 to 9.2 for ligand L2. a) after purification of reaction mixture b) after 18 hours.

10

 10 Scheme 2.10 Mechanism of allylic alkylation.

Figure 2 . 9

 29 Figure 2.9 BINAP/diamine-Ru II catalyst developed by Noyori.

2 Scheme 2 . 11

 2211 Scheme 2.11 Preparation of ligand for hydrogenation. Formation of nitrogen-Ru bond was confirmed by shift of protons of starting material on 1 H NMR spectra (Figure 2.10).

Figure 2 .

 2 Figure 2.10 1 H NMR spectra from 2.0 to 5.20 ppm for: a) compound 2, b) complex 10.

Figure 2 .

 2 Figure 2.11 ESI-MS spectra for complex 10.

12

 12 Scheme 2.12 Catalytic cycle of hydrogenation of ketones with BINAP/diamine-Ru II /strong base combined system.

Scheme 2 . 13

 213 Scheme 2.13 Preparation of thiourea organocatalysts..

Figure 2 .(Figure 2 .

 22 Figure 2.13 1 1 H NMR from 3.0 to 6.1 ppm of ligands: a) L3, b) L4, c) L5.

Figure 2 . 15

 215 Figure 2.15 Proposed hydrogen-bonding activation models used in the computational study of the Michael addition of nitronate anion to chalcone.

Scheme 2 . 14

 214 Scheme 2.14 Ligands obtained for homogeneous catalysis.

Synthesis of 3

 3 ,4,6-tri-O-acetyl--1,2-D-diamineglucopyranose 2 A mixture of azide compound 8 (0.46 g, 1.5 mmol) in degassed ethyl acetate (30 mL) was hydrogenated at room temperature under 2.5 atm pressure for 3 hours in the presence of Pt 2 O (0.045 g, 0.20 mmol). The catalyst was removed by filtration through celite and washed with ethyl acetate. Solution was evaporated under reduced pressure producing

  mL). After 30 minutes solution was filtrated and solid was washed by methanol anhydride. Mixture was cooled to 0 o C and acetic anhydride (2 mL, 20.9 mmol) was added drop wise. Solution was stirred overnight in room temperature. Solution was filtrated and wash with methanol : diethyl ether 1 : 3. Solid was recrystallized from mixture water : ethanol and dry on vacuum pump. . 209-211 o C lit.72 203-205 o C After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by crystallization from ether diethyl.

13 C 3 (

 133 NMR (CDCl 3 ): (ppm) = 20.9 (COCH 3 ), 21.0 (COCH 3 ), 21.3 (COCH 3 ), 23.COCH 3 ), 53.7 (C-2), 61.5 (C-6), 67.4 (C-4), 70.4 (C-3), 71.2 (C-5), 94.0 (C-1), 169.5 (COCH 3 ), 170.7 (COCH 3 ), 170.9 (COCH 3 ), 171.7 (COCH 3 ), according to the literature 52 . Synthesis of 2-acetamido-3,4,6-tri-O-acetyl-1-azido-2-deoxy--D-glucopyronose 5 After being stirred, a solution of 2-acetamido-3,4,6-tri-O-acetyl-1-chloro-2-deoxy--Dglucopyranse (2.23 g, 6.0 mmol) and sodium azide (0.39 g, 6.0 mmol) in dry DMF (15 mL) was heated under argon atmosphere at 75 -80 o C for 4 hours. To the mixture, icewas added and then extracted with ethyl acetate (4 x 15 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradnient from pure cyclohexane to cyclohexane : ethyl acetate 1 : 2.

6 A

 6 tri-O-acetyl-1-amino-2-deoxy--D-glucopyronose mixture of azide compound (1.0 g, 2.6 mmol) in degassed methanol (30 mL) was hydrogenated at room temperature under 2.5 atm pressure for 15 hours in the presence of Pd/C 10% (0.30 g). The catalyst was removed by filtration through celite and washed with ethanol. Solution was evaporated under reduced pressure producing a white solid.

B 3 , 4 , 6 - 8 ( 2 ,

 34682 tri-O-acetyl-1-azido-2-[(tert-butoxycarbonyl)amino]-2-deoxy--D-glucopyronose 66 g, 6.2 mmol) was dissolved in dichloromethane (6.5 mL) and trifluoroacetic acid (2.6 mL) was added. Mixture was stirred overnight in room temperature. After that time solution was diluted with dichloromethane and washed with NaHCO 3sat , dried (Na 2 SO 4 ) and evaporated. Filtration through pad of silica gave 1.80 g (88%) of pure 7.

  mL) and acetic anhydride (11.1 mL) After overnight solvents were removed under vacuum pressure and solid coevaporated three times with toluene. Chromatography on silica using dichloromethane : methanol 20 : 1 gave 4.57 g of pure 8. 0.81 (dichloromethane : methanol 20 : 1) m.p. 163-164 o C [ ] D 20 = -18.91 (c = 1.01, chloroform)

  155.2 (NHC=O), 169.7 (COCH 3 ), 170.8 (COCH 3 ), 170.9 (COCH 3 ).IR: (thin film, cm -1 ) = 3400 ( NH ), 2115 ( N3 ), 1744 ( C=O ), 1684, 1527 ( NH ),

  tri-O-acetyl-1,2-diamino-1,2-deoxy--D-glucopyronose 2 (100 mg, 0.33 mmol), 2-diphenylphosphinobenzoic acid (202 mg, 0.66 mmol), EDC (122 mg, 0.79 mmol), and HOBt (97 mg, 0.79 mmol) were dissolved in a mixture of dichloromethane (2 mL) and THF (4 mL) in a Schlenk tube under argon. After being stirred for 5 h at room temperature, the solvents were evaporated. The residue was washed with 5% NaOH (10 mL), and 0.5 M HCl (5 mL). Product was purified with column chromatography using cyclohexane :

  Figure 2.16 1 H NMR spectra of racemic aimethyl (1-methyl-2-butenyl)propanedioate, b) with addition of europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate], c) zoom in area of methyl group and visible differentiation of signals from enantiomers.

  (ppm) = 1.83 (s, 3H, CH 3 ), 1.87 (s, 3H, CH 3 ), 1.94 (s, 3H, CH 3 ), 2.06 (m, 1H, NH), 2.73 (m, 2H, H-1, H-3), 3.19 (m, 1H, NH), 3.51 (ddd, 1H, J=2.1, J=3.

  (CDCl 3 ): (ppm) = 2.61 (s, 3H, CH 3 ),7.42-7.60 (m, 3H, H arom ), 7.93t R = 13.63 min, (S) t R = 15.52 min. 1 H NMR (CDCl 3 ): (ppm) = 1.42(d, 3H, J=6.4Hz, CH 3 ),1.80 (s, 1H, OH), 4.82 (q, 1H, J=6.4Hz), 7.25 (m, 5H, H arom ).

  Synthesis of Thiourea, N-[3,5-bis(trifluoromethyl)phenyl]-N'-{3,4,6-tri-O-acetyl-2-[(tert- butoxycarbonyl)amino]-2-deoxy--D-glucopyronose} L3 A mixture of azide compound 8 (0.300 g, 0.69 mmol) in degassed ethyl acetate(10 mL) was hydrogenated at room temperature under 2.5 atm pressure for 2 hours in the presence of PtO 2 (0.016 g, 0.069 mmol). The catalyst was removed by filtration through celite and washed with ethyl acetate. Solution was evaporated under reduced pressure. Obtained white solid was placed in argoned Schlenk tube, dissolved in dry dichloromethane, and then thiocyiano compound was added. Mixture was stirred overnight in room temperature. TLC show full conversion of starting material, solvent was evaporated, compound was crystallized from mixture of solvents dichloromethane : pentane in low temperature to gave 0.445 g of pure L3.

Figure 3 . 1

 31 Figure 3.1 Silane molecules used in silanization.

Figure 3 . 2

 32 Figure 3.2 Product of silization

Figure 3 . 4

 34 Figure 3.4 Polyhydroxylated ligand prepared by our team.

Synthesis of 2 -Scheme 3 . 1 Figure 3 . 5

 23135 Scheme 3.1 Synthesis of hydrophilic ligand for grafting in SAPC system

Figure 3 . 6

 36 Figure 3.6 Catalytic cycle of cross-coupling.

3. 2 . 1 Scheme 3 . 2

 2132 Scheme 3.2 Esterification with polyethylene anhydride.

3

 3 Scheme 3.3 Attempts for deprotecting amino function.

14 Figure 3 . 8

 1438 Figure 3.8 Ligands containing 1-polyethylene arm.

  4). Starting from 2-acetamido-2deoxy-6-D-glucopyranose 3 we obtained 2-acetamido-2-deoxy-6-O-trityl-D-glucopyranose 15 using protocol described by Sharama et al. 91 with yield 70%. Acetylation in pyridine overnight gave mixture of and anomers with ratio: 85:15 and with yield 71%. Crystallization was prepared as described by Anderson and Percival 92 . Unfortunately from mixture we obtained only -anomer 16 , in opposite to describe by authors postulated -anomer.

Scheme 3 . 4

 34 Scheme 3.4 Attempts for employed of trityl group as protection for primary hydroxyl function.

6

 6 Effect of protection D-glucosamine derivative with sillyl group .Standard conditions for preparation of sillyl eters were tested with tert-butyl diphenyl, -2-[p-methoxybenzyldiene(amino)]-D-glucopyranose 11 it was impossible for us to protect selectively six position in carbohydrate ring (Scheme 3.6)94 .

Figure 3

 3 Figure 3.9 COSY 1 H-1 H (DMSO-d 6 ) from 2.3 to 4.6 ppm for compound 17

Scheme 3 . 7

 37 Scheme 3.7 Preparation of carbohydrate containing azido function in 6-pozition

Scheme 3 . 8

 38 Scheme 3.8 Preparation of azido carbohydrate 21

Scheme 3 . 9

 39 Scheme 3.9 Preparation of Ligand L7 containing PEG function Probably reaction of phosphorus atom with azido group occurring in first place to give aza-ylide, and presence complex reaction mixture can be explained by interactions of situated in orto position carboxylic function. Products of reaction had not been examined 102 . To avoid interaction of phosphorus with azido function, 2-diphenylophosphino benzoic acid was protected with sulfur, unfortunately also in this

Scheme 3 . 11

 311 Scheme 3.10Because it was possible for us to prepare before imino function containing phosphorus group and triazol ring(Subchapter 3.3.3.4,Scheme 3.19) we have suspected that maybe cause of not working of reaction was presence of water in polyethylene arm. Unfortunately even liofilisation of starting material before reaction did not leaded reaction to work.

  Scheme 3.12

Figure 3 . 11

 311 Figure 3.11 Structure of ligands supported on silica.

  Figure 3.12 Silica materials.

Figure 3 .

 3 Figure 3.13 IR spectra from 700 to 3800 cm -1 of azido functionalized silica a) SBA-15, b) passivated SBA-15.

Figure 3 .Figure 3 .

 33 Figure 3.14 BET analysis for a) SBA-15: BET Surface Area (1226.7584 m 2 /g), b) passivated SBA-15: BET Surface Area (583 m 2 /g),

Table 3 . 4

 34 4 are featured values of pores determined from isotherms of adsorption and desorption of nitrogen. Values of pore size for SBA-15 and passivated SBA-15 determined from isotherms of adsorption and desorption of nitrogen.

of H- 1 ( 29 Scheme 3 . 13

 129313 Scheme 3.13 Synthesis of carbohydrate 28 containing alkynyl function in -anomeric position.

of silica with carbohydrate via anomeric position 3 . 3 . 3 . 1 14 1 (

 3331141 Scheme 3.14 Preparation of ligand L11a

Figure 3 .

 3 Figure 3.16 DRIFT IR spectra from 700 to 3800 cm -1 of a) compound 28, b) silica containing azido function c) product 29.

Scheme 3 . 15

 315 Scheme 3.15 Coupling reaction

Figure 3 .

 3 Figure 3.17 MAS 31 P NMR from -100 to 150 ppm for reaction of 29 with 2-diphenylophosphino benzoic acid, a) without protection of surface b) with protected surface

16

 16 Scheme 3.16 Imino type ligand with two different types of complexation.

Scheme 3 . 17

 317 Scheme 3.17 Condensation reaction.

Figure 3 .

 3 Figure 3.18 MAS 31 P NMR spectra from -40 to 100 ppm for grafted ligand L11b.

  Scheme 3.18 Reduction of 32.

Figure 3 .

 3 Figure 3.19 MAS 31 P NMR spectra from -100 to 100 ppm after reduction of phosphine oxide of ligand L11b.

19

 19 Scheme 3.19 Synthesis of palladium complex 32.

Figure 3 .

 3 Figure 3.20 31 P NMR spectra from 10 to 40 ppm after reaction of complexation.,

Figure 3 .

 3 Figure 3.21 a) Drift IR spectra from 800 to 2200 cm -1 of complex after grafting of complex 31, b) MAS 31 P NMR spectra from -40 to 100 ppm after grafting of complex 31.

12 In

 12 Schlenk flask with argon balloon was dissolve (0.30 g, 1.0 mmol) 2-desoxy-2-[pmethoxybenzyldiene(amino)]-D-glucopyranose 10 in 10 mL of dry pyridine. Mixture was cooled to 0 o C and anhydride (3.43 g, 10.15 mmol) dissolved in 10 mL pyridine was added.After 1 h ice bath was removed and solution was stirred in room temperature overnight.Mixture was evaporated, and chromatographed on silica gel column using gradient from dichloromethane : methanol 40 : 1 to dichloromethane : methanol 20 : 1.

Synthesis of 2 -

 2 acetamido-2-deoxy-6-O-trityl-D-glucopyranose 15112 A solution of 2-acetamido-2-deoxy-6-O-trityl-D-glucopyranose (2.0 g, 9.0 mmol) and chlorotriphenylmethane (2.52 g, 9.0 mmol) in dry pyridine was stirred at room temperature for 5 days. The reaction mixture was heated at 80 o C for 1 h, cooled, and poured into icewater. After 30 min, chloroform was added and solutions were extracted, dried (Na 2 SO 4 ), and evaporated. The residue was freed from pyridine by addition and evaporation of toluene, and chromatographed on a silica gel column. Chloroform eluted the fast moving triphenylmethanol and the product was eluted with methanol-chloroform 1:9.

13 C

 13 NMR (DMSO-d 6 ): (ppm) = 19.4 (C-(CH 3 ) 3 ), 19.5 (C-(CH 3 ) 3 ), 27.1 (C-(CH 3 ) 3 ), 27.5 (C-(CH 3 ) 3 ), 59.9 (C-2), 63.9 (C-6), 70.12, 76.9, 77.61, 99.5 (C-1), 114.7 (s, 1H), 128.0 (2 x C arom ), 128.1 (2 x C arom ), 128.3 (2 x C arom ), 128.3 (2 x C arom ), 130.2 (C arom ), 130.3 (C arom ), 130.3 (C arom ), 130.3 (C arom ), 133.6 (C arom -Si), 133.7 (C arom -Si), 133.7 (C arom -Si), 133.8 (C arom -Si), 135.7 (2 x C arom ), 135.7 (2 x C arom ), 136.0 (4 x C arom ). Synthesis of 1,3,4-tri-O-acetyl-2-deoxy-2-(p-methoxybenzylideneamino)-6-O-tosyl--Dglucopyronose 18 98 Carbohydrate compound 11 (4.00 g, 13.4 mmol) was suspended in pyridine (30 mL) and cooled to 0 o C. Under vigorous stirring tosyl chloride (2.56 g, 13.4 mmol) dissolved in 10 mL of pyridine was added dropwise. Mixture was stirred in -5 o C overnight. After this time mixture was cooled to 0 o C and acetic anhydride was added, mixture was left to warm to room temperature and stirred 2 h. 2Mixture was poured into ice water, and precipitate filtered off to give 1.74 g of 18.

99 A

 99 arom c), 128.1 (2 x C arom f), 128.2 (C arom a), 129.8 (2 x C arom g), 130.2 (2 x C arom b), 132.4 (C arom e), 144.9 (C arom h), 162.3 (C arom d), 157.0 (N=CH), 168.6 (COCH 3 ), 169.5 (2 x COCH 3 ). Synthesis of 1,3,4-tri-O-acetyl-6-azido-2,6-dideoxy-2-(p-methoxybenzylideneamino)--Dglucopyronose 19 mixture of tosyl compound 18 (1.74 g, 3.10 mmol), sodium azide (0.20 g, 3.10 mmol), and N,N-dimethylformamide (15 mL) was heated at 80-90 o C under stirring for 4 h. The reaction mixture was evaporated and the residue was extracted with chloroform (200 mL).The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give syrup, which was recrystallized from ethanol to give 1.08 g of 19.

4 (

 4 COCH 3 ), 169.3 (COCH 3 ), 169.7 (COCH 3 ), according to the literature99 .Synthesis of1,3,4-tri-O-acetyl-2-amino-6-azido-2,6-dideoxy--D-glucopyronose 21 Compound 20 (0.69 g, 1.88 mmol) was suspended in 5 mL of dichloromethane, and saturated solution of NaHCO 3 (5 mL) was added, mixture stirred for one hour till starting material was completely dissolved. Mixture was transferred to separatory funnel, organic phase separated, and water phase washed two times with dichloromethane. Organic phases were collected, dried over Na 2 SO 4 and solvent were evaporated. Colorless oil was flirted through pad of silica to gave 0.439 g of white solid. 0.16 (dichloromethane : methanol 20:1) m.p. 79-80 o C [ ] D 20 = 22,8 (c = 1.01 chloroform)

4 (

 4 COCH 3 ), 169.6 (COCH 3 ), 169.8 (COCH 3 ), 170.5 (C=CH-"triazole ring").

ESI

  full ms calcd. for C 24 H 43 N 4 O 11 Si (M + H + ): 591.2698, found 591.2692.Synthesis of 3,4,6-tri-O-acetyl-2-deoxy-2-{[2-(diphenylophosphino)benzoyl]imino}--Dglucopyronose,1-[(1H-1,2,3-triazol-4-yl]methyl)-1-(3-propyltriethoxysilane)] 34In a Schlenk tube under argon atmosphere, triazole compound 33 (0.728 g, 1.23 mmol), and 2-diphenylphosphinobenzoic aldehyde (0.322 g, 1.11 mmol), were stirring with MgSO 4 in dry, degassed toluene in 60 o C. After being stirred for 5 hours in 60 o C, solution was filtered under argon, MgSO 4 washed with deglazed toluene and the solvents were evaporated, mixture was dried on vacuum pump (m = 0.969g).

1 (

 1 Kolejnym z celów pracy by o przygotowanie katalizatorów tak e dla katalizy heterogenicznej. Pomimo, e w literaturze opisanych jest wiele przyk adów u ycia ligandów bazuj cych na wykorzystaniu D-glukozaminy w katalizie homogennej, ich produktywno wymaga jednak dalszego usprawnienia w celu osi gni cia np. wysokiej liczby cykli katalitycznych (ang turnover number-TON). Oczekiwano, e zadanie takie mog oby by zrealizowane poprzez heterogenizacj katalizatorów otrzymanych przeze mnie wcze niej dla potrzeb procesów prowadzonych w rodowisku homogennym. Rozdzia Cz literaturowa Celem przegl du literaturowego stanowi cego Rodzia 1 dysertacji by o przedstawienie aktualnego stanu wiedzy dotycz cej zwi zków na bazie D-glukozaminy dla katalizy homogennej i heterogennej. Opisane zosta y tylko te pochodne D-glukozaminy, które zawiera y w swej strukturze pier cie piranozowy natomiast acykliczne i heterocykliczne pochodne D-glukozoaminy zosta y pomini te. Przedstawione zosta y wszystkie przyk ady u ycia tego typu ligandów (Rozdzia y 1.1-1.2, 1.5-1.6), organokatalizatorów (Rozdzia 1.3) i reagentów (Rozdzia 1.4), oraz omówione zosta y najlepsze wyniki w reakcjach katalitycznych z poszczególnymi pochodnymi, opisane w literaturze do kwietnia 2012. Ligandy homogeniczne podzielone zosta y w zale no ci od typu grupy donorowej na homodonorowe (Rozdzia 1.1) i heterodonorowe (Rozdzia 1.2) i uszeregowane w pierwszej kolejno ci w zale no ci od atomu donora (P, N, S, O), a nast pnie od funkcjonalizacji liganda. Ligandy heterogeniczne podzielone zosta y w zale no ci od sposobu u ycia na ligandy dla katalizy dwufazowej (Rozdzia 1.5) i ligandy zwi zane na matrycy organicznej przedstawiona zosta a synteza 1,2-glukozodiaminy z N-acetyloglukozaminy. Zwi zek zsynteztowany zosta w pi ciu etapach z sumaryczn wydajno ci ko cow 33% (Schemat 1). u yty zosta nast pnie jako materia startowy do syntezy ligandów i katalizatorów przedstawionych w rodziale 2. Ligandy typu "Trosta" dla substytucji alkilowej (Rozdzia 2.2) W tej cz ci pracy opisana zosta a synteza dwóch nowych ligandów wywodz cych si ze struktury 1,2--glukozodiaminy t.j. liganda amidowego L1 i liganda iminowego L2 (Rysunek 2) o strukturze zbli onej do struktury tzw. "liganda Trosta" Ligand amidowy L1 u yty zosta w kompleksie z palladem jako katalizator w reakcji substytucji alkilowej z dwoma ró nymi substratami (Tabela 1). Najlepsze wydajno i nadmiary enancjomeryczne otrzymane zosta y kiedy jako substrat u yty zosta octan 1,3-difenyloallilu. Wyniki te by y nieco lepsze w porównaniu z wynikami otrzymanymi z ligandem Trosta, jednak e wci nie w pe ni satysfakcjonuj ce bowiem wiele innych ligandów wywiedzionych z w glowodanów katalizuje tak reakcj z wysokimi wydajno ciami i nadmiarami enancjomerycznymi (patrz Rozdzia 1Aplikacja liganda iminowego w reakcji substytucji alkilowej okaza a si by niemo liwa ze wzgl du na jego nisk stabilno i szybk degradacj do monoiminy w rodowisku reakcji (Schemat 2).

4 )( 4 WRozdzia 3 1 )

 4431 Nadmiar enancjomeryczny 75% osi gni ty zosta y jedynie w przypadku kiedy jako katalizator u yty zosta kompleks Noyori'ego zawieraj cy zawieraj cy chiraln 1,2difenyloetylenodiamin . Niestety, zupe nym niepowodzeniem zako czy y si próby zastosowania kompleksu 10 do tej reakcji. W adnym z badanych przypadków produkt uwodornienia nie zosta zaobserwowany.Organokatalizatory dla addycji Michaela (Rozdzia 2.Nast pnie opisana zosta a synteza trzech zwi zków L3-L5 zawieraj cych ugrupowanie tiomocznikowe do czone do pier cienia w glowodanowego w oczekiwanie na uzyskanie korzystnych w a ciwo ci takich zwi zków jako organokatalizatorów nast pnej cz ci pracy, która realizowana by a we wspó pracy z Profesor Florence Popowycz i mgr Marciem Baronem z laboratorium CASYEN na Uniwersytecie Claude Bernard Lyon 1, którzy przeprowadzili testy katalityczne z wykorzystaniem zwi zków L3-L5 jako organokatalizatorów w reakcji addycji nitrometanu do chalkonu. Reakcja w obecno ci nieorganicznej zasady (K 2 CO 3 ) przebiega a z prawie pe n konwersj 96%. W przypadku u ycia chiralnej zasady organicznej (chinina) obserwowana by a indukcja asymetryczna na poziomie 50-55% ale osi gni te konwersje by y bardzo niskie. Podj te próby zastosowania chiralnych zwi zków L1-L3 zasady zako czy y si niestety niepowodzeniem. W warunkach ustalonych dla chininy zwi zki L3-L5 nie da y wy szych konwersji ni 0.1%. Annex B Ligandy dla katalizy heterogennej Kataliztory typu SAPC dla reakcji Suzuki-Miyaura (Rozdzia 3.Dla potrzeb tej fazy projektu na drodze jednoetapowej syntezy wychodz cej z D-glukozaminy otrzymany zosta najpierw ligand zawieraj cy dodatkow funkcj fosfinow , który nast pnie zosta zaimpregnowany w cienkim filmie wody na powierzchni elu krzemionkowego z wykorzystaniem wi za niekowalencyjnych (Schemat 3). Tak przygotowany katalizator, tzw. Supported Aqueous Phase Catalyst (SAPC), u yty zosta nast pnie w reakcjach sprz gania Suzuki-Miyaura z wykorzystaniem aktywowanych i dezaktywowanych bromków arylowych oraz ró nych kwasów boronowych. Podczas takiego procesu katalizy substraty i produkty pozostaj w fazie organicznej za reakcja zachodzi na powierzchni pomi dzy fazami wodn i organiczn (Schemat 3). Pocz tkowo przeprowadzone zosta y eksperymenty bez u ycia katalizatora i w takich warunkach reakcja nie by a obserwowana. Kiedy el krzemionkowy zaimpregnowany by jedynie octanem palladu (bez liganda), konwersja substratów wynios a 75% w pierwszym cyklu i 15% w drugim cyklu. Najwyra niej kataliza mia a tym razem miejsce ale katalizator nie by zwi zany z pod o em i nast powa o jego szybkie wyp ukiwanie do fazy organicznej. Zastosowanie przygotowanego katalizatora SAPC z wykorzystaniem liganda L6 przynios o natomiast bardzo dobre rezultaty. Tym razem ró ne bromki arylowe i kwasy boronowe ulega y konwersji do oczekiwanych produktów biarylowych z wydajno ciami dochodz cymi do 99% (Tabela 4).

Wykres 1 6 ( 5 W

 165 Wykres 1 Recykling katalizatora SAPC w reakcji sprz gania p-bromonitrobenzenu i kwasu fenyloboronowego

  Ten projekt by wykonywany we wspó pracy z Dr Chloe Thieuleux i Dr Reine Sayah z Laboratorium LCOMS z Uniwersytetu Claude Bernard Lyon 1. Dostarczy y one mezoporowate materia y SBA-15, oraz przeprowadzi y analizy produktów metodami IR DRIFT, BET oraz MAS 31 P NMR. Podj te w nast pnej kolejno ci próby otrzymania heterogenizowanego liganda L11a niestety nie okaza y si owocne. Przy próbach zwi zania liganda z matryc SBA-15 obserwowano utlenienie atomy fosforu i to nawet wtedy gdy wolne grupy hydroksylowe u ytego SBA-15 zabezpieczone by y grupami trimetylosililowymi. Równie w przypadku liganda L11b podj te próby przygotowania dwóch kompleksów z palladem (Rysunek 7) nie zako czy y si powodzeniem..

Kompleks 1 , 2 -

 12 glukozodiaminy z rutenem i BINAP-em wykorzystany zosta w reakcji uwodornienia acetofenonu Przeprowadzona zosta a synteza trzech ligandów glukozaminowych zawieraj cych ugrupowania tiomocznnikowe. Ligandy te wykorzystane zosta y nast pnie w reakcjach addycji Michaela nitrometanu do chalkonu. Bez u ycia mudnych procesów protekcji i deprotekcji grup funkcyjnych, zwykle niezb dnych przy syntezie ligandów na bazie w glowodanów, otrzymany zosta z glukozaminy na drodze jednoetapowej syntezy nowy ligand fosfinowy dla katalizowanych palladem reakcji sprz gania Suzuki-Miyaury. Ligand ten zosta nast pnie sheterogenizowany na elu krzemionkowym za pomoc oddzia ywa niekowalencyjnych (Supported Aqueous Phase Catalyst-SAPC) Uzyskany SAPC wykorzystany zosta w reakcjach sprz gania Suzuki-Miyaura aktywowanych i dezaktywaowanych bromoaryli z ró nymi kwasami boronowymi. Odpowiednie biaryle otrzymane zosta y z wydajno ciami dochodz cymi do 99% a katalizator mo e by z atwo ci oddzielony od mieszaniny reakcyjnej i u yty czterokrotnie bez znacz cego spadku aktywno ci wyniki otrzymane z u yciem systemu SAPC by y lepsze ni wyniki katalizy przeprowadzone z tym samym ligandem w warunkach homogenicznych. Przebadane zosta y ró ne warunki selektywnego zabezpieczania pierwszorz dowej grupy hydroksylowej w cz steczce D-glukozaminy Podj te zosta y próby przygotowania liganda zawieraj cego ugrupowanie polietylenoglikolowe w celu jego u ycia w reakcjach substytucji alkilowej w wodzie Próby przygotowania kompleksów zawieraj cych funkcj fosfinow w jednostce glukozaminy osadzonych na mezoporowatym silika elu za pomoc reakcji cykloaddycji Huisgena zako czone zosta y niepowodzeniem ze wzgl du na trudne do opanowania procesy utleniania funkcji fosfinowej.

  It is better to prevent waste than to treat or clean up waste after it is formed.

	et al. s	et alia-and others singlet
	Et	SAPC	ethyl Supported Aqueous Phase Catalyst
	g	sat.	gram(s) saturated
	GC SBA-15	gas chromatography Santa Barbara-15
	HOBt SLPC	1-hydroxybenzotriazol Supported Liquid Phase Catalyst
	HPLC t	High-Performance Liquid Chromatography triplet
	HSQC TBDMS	heteronuclear single quantum coherence spectroscopy tert-butyldimethylsilyl
	Hz	TBDPS	hertz t-Butyldimethylsilyl
	i-Bu t-Bu	iso-butyl tert-butyl
	i-Pr Temp. BINOL IR TES Bn L, Lig TFA BOC m THF bs m-meta TIPS Bu Bz Calcd. COD Conv. COSY c-Pr Cy d DAIPEN DCC DCM dd ddd dddd DIPEA DMAP DMF DMSO-d 6 DPEN DPPBA dq dqd dt EDC ee equiv er ESI rt R f rac. R q Ps Pr ppm Piv Ph PEG p-para OTf o C o-ortho Nu Np NMR n-Bu MS MPSO 2 mol MPSO L mmol mL Xyl min t r mg Tr Mes TON Me Tol m/z TMS M TLC 1. Prevention: iso-propyl temperature infrared triethylsilyl 2,2-dihydroxy-1,1-binaphthyl 1,1 -binaphthalene ligand trifluoroacetic acid benzyl multiplet tetrahydrfuran t-butoxycarbonyl position of an aryl ring Triisopropylsilyl broad singlet room temperature electrospray ionization Retention Factor enantiomeric ratio racemate equivalent general alkyl or aryl substituents enantiomeric excess quartet 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide polystyrene support doublet of triplets propyl doublet of quartets of dublets parts per million doublet of quintets pivaloyl diphenylophosphino benzoic acid phenyl Diphenylethylenediamine poly(ethylene glycol) Dimethyl sulfoxide deuterated position of an aryl ring N,N-dimethylformamide trifluoromethanesulfonate (triflate) 4-dimethylaminopyridine degrees Celsius Diisopropylethylamine position of an aryl ring doublet of doublet of doublet of doublets nucleophile doublet of doublet of doublets naphthyl doublet of doublets nuclear magnetic resonance dichloromethane n-butyl dicyclohexylcarbodiimide mass spectrometry frequency 1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine methyl phenyl sulfone micromol(s) doublet methyl phenyl sulfoxide microliter(s) cyclohexyl millimole(s) chemical shift in NMR spectroscopy cyclo-propyl milliliter(s) 3,5-dimethylbenzoyl gradient-selected Correlation Spectroscopy minutes retention time converison milligram(s) trityl cyclooctadiene mesityl, -C 6 H 2 (CH 3 ) 3 Trunover number calculated methyl 4-methylbenzoyl benzoil mass per charge trimethylsilyl butyl general transition metal Thin Layer Chromatography

Table 1 . 1

 11 12a,b . Asymmetric allylic alkylation.Ligands Lig5c,d,e were also were investigated in the copper catalysed Me 2 Zn and Et 2 Zn conjugate additions to linear enones (Table1.1) 12c . Asymmetric conjugate addition reaction.

	Ts	NH	N H	Ts			O	N Ts	H
	O	O	O	O				O
								H
							(3R, 6S)
					Lig5a 99% 97%ee	Lig5c 99% 98%ee
					Lig5b 99% 97%ee	Lig5d 99% 98%ee
		O Scheme 1.4 R R'	CuOTf 2 Zn(R") 2	R	R"	O	R'
	ligand	R		R'	R''		yield(%)	ee(%)
	Lig5c	C5H11		Me	Me			70	95(R)
		C6H13		Me	Et			95	93(R)
		i-Pr		Me	Et			79	93(R)
		Me		Et	Et			65	67(S)

Table 1 . 2

 12

	Lig6a	SbF 4	-	Ph	H	95
		SbF 4	-	Ph	Me	95
	Lig6b	BF 4	-	Ph	Me	98
		BF 4	-	4-F(C 6 H 5 )	Me	98

[Rh]

-catalysed asymmetric hydrogenation of alanine derivatives.

Table

Table 1 .

 1

	alkene	+	N 2	COOR	[Cu]	R1	COOR	+	R1	COOR
	ligand		alkene	R	Yield trans/cis ee trans (%) ee cis (%)
	Lig9b		OC 6 H 4 4-Me	Et t-Bt	72 63	65 : 35 73 : 27	77 76	80 68
			Ph		Et t-Bt	60 44	70 : 30 68 : 32	82 74	82 64
	Lig9c				Et	86	63 : 37	84	94
	Lig9f				Et	90	79 : 21	93	82
	Lig9h				Et	90	64 : 36	62	49

3 Copper (I) catalysed cyclopropanation of olefins with ethyl or tert-butyl diazoacetates.

Table 1 .

 1

				[Cu]	OH
			R-CHO		R	NO 2
	Ligand	R	Yield (%)	ee (%)	R		Yield (%)	ee (%)
	Lig9b	Ph	85	94	2,5-(MeO) 2 -C 6 H 4	88	92
		4-Cl-C 6 H 4	92	92	2,5-(MeO) 2 -C 6 H 4	84	99
		4-Me-C 6 H 4	82	91	2-Np		95	90
		2-NO 2 -C 6 H 4	88	91	2-MeO-C 6 H 4	82	90

4 Enantioselective Henry reaction of aldehydes catalysed by complex of ligand Lig9b with copper. N O O

PivO PivO Ph 2 P PivO Ph 2 PO O

Table 1 . 5

 15 Allylic substitution with different nucleophiles.

	Ligand	R	R	NuH	Yield(%)	ee(%)
	Lig10b COOEt Ph	Benzylamine	78	94 (R)
	Lig10d				72	95 (R)
	Lig11a				60	94 (R)
	Lig16d	OAc		CH 2 (COOEt) 2	94	88 (S)
				CH 2 (COOBn) 2	90	88 (S)
			Me CH 2 (COOEt) 2	58	93 (S)

Table 1 . 6

 16 Asymmetric intramolecular Heck reaction.

	2

Table 1 . 7

 17 .7). Addition of diethylzinc to acyclic enones

			O		CuOTf 2	O
			R	Ph	Zn(Et) 2	R	Ph
	ligand	R	Yield (%) ee (%) ligand	R		Yield (%)	ee (%)
	Lig17a	Ph	81	78(S)	Lig17a	4-Me-C 6 H 4	60	73(S)
		4-Cl-C 6 H 4	52	74(S)		4-MeO-C 6 H 4	43	73(S)

Table 1 .

 1 6)Reactivity of ligands Lig18,20 was studied in reaction of Suzuki-Myaura coupling with different kind of boronic acids and different halides. Results are collected in Table1.9.

	Chapter 1

containing carbohydrate molecule as bulky substituent in anomeric carbon (93% of yield and 88% ee) ( Scheme 1.7).

Among ligands Lig19-21 two the best efficient were tested with other nucleophiles. In both cases high yields (up to 96%) and enantioselectivities (up to 97% ee) were observed (Table

1

.8)

. 8 Allylic substitution with different nucleophiles

[Pd] Suzuki Myaura cross-coupling.

Table 1 .

 1

9 Suzuki-Miyaura cross-coupling reactions catalysed by ligands L16e, L29-L35.

Yield (%) ee (%) (R) Lig23a

		H	99	97
		4-OMe	95	89
	L ig23d	H	92	94
		3-OMe	74	99
		2-F	84	94
	L ig23d	2-Cl	94	98
	L ig23e	H	98	94

Table 1 .10 Enantioselective

 1 addition of phenylacetylene to various aldehydes.

	Excellent results generated ligands containing -configuration on anomeric center, with
	sterically demanding sulfonamides, yields up to 99% and enantioselectivities up to 99%
	were obtained (Table 1.10).
	Ligands Lig23 were also tested in phenylacetylene addition to different aldehydes.
			O		[Ti]	Ph		OH
	Ph	+	R	H	Zn(Et) 2	Ar	+	R
						OH
		Ligand	R		Yield (%)	ee (%) (R)		68:69
		Lig23a	H		73	66		95 : 1
		Lig23e	H		74	53		98 : 2
		Lig23g	H		82	90		99 : 1
			2-OMe		92	94		72 : 28
			2-F		68	92		85 : 15

Table 1 .11 Enantioselective

 1 addition of phenylacetylene to various aldehydesIn test made with benzaldehyde as model substrate ligand Lig23g showed the biggest efficiency. This ligand was chosen for reaction with several aromatic aldehydes and enantiomeric excesses up to 94% were obtained (Table1.11).

	In 2008 Cheng et al. 29 used D-glucosamine as a natural ligand, in the N-arylation of
	imidazole with aryl and heteroaryl halides using CuI as a catalyst (Table 1.12).
					[Cu]
	N	NH	+	Ar-X	D-glucosamine	N	N	Ar
	Aryl halide Ar-X	Yield (%)	Aryl halide Ar-X			Yield (%)
	Bromobenzene	84	2-Bromothiophene		82
	2-Bromonaphtalene	86	3-Bromothiophene		83
	1-Bromo-3,5-bis(trifluoromethyl)benzene	91	N-(2-bromo-4-methylphenyl)-2,2,2-trifluoroacetamide	90
	4-Bromofluorobenzene	90	2-Chloropyrimidine		95

Table 1 .

 1 12 N-arylation of imidazole catalysed by D-glucosamine.

Aryl halide Ar-X Yield (%) Aryl halide Ar-X Yield (%) 4

				[Cu]
	Ar-X	+	NH 3	D-glucosamine	Ar NH 2
	-Iodobenzoic acid		96	3-Iodobenzophenone	95
	4-Iodoanisole		90	2-Bromonitrobenzene	83
	4-Bromonitrobenzene		98	1-Iodonaphtalene	95
	4-Iodonitrobenzene		98	4-Iodobenzophenone	85

Table 1 .13 Synthesis

 1 of primary aryl amines catalysed by D-glucosamine.

	29 D. Cheng, F. Gan, W. Qian, W. Bao, Green Chem., 2008, 171-173.
	30 K. G. Thakur, D. Ganapathy, G. Sekar, Chem. Commun., 2011, 5076-5078.

1.2.2 Tridentate ligands 1.2.2.1 P/N/S ligands

	The tridentate phosphine imine thioglycoside ligand Lig24a derived from D-glucosamine
	(Scheme 1.8) 31 was found to be a highly efficient catalyst precursor for [Pd]-catalysed
	asymmetric alkylation of 1,3-diphenylpropenylacetate with dimethyl malonate.
	PivO			a R = o-PPh 2		OAc	[Pd] / Lig	MeOOC	COOMe
	PivO	O	SH t-Bu	b R = p-OMe	Ph	Ph	1 / 2	Ph	Ph
	PivO	N		PPh 2				(S) Lig24a 80%, 88%ee
								Lig24b 54%, 34%ee
	Lig24

Scheme 1.8 D-glucosamine based thioether ligands Lig24 and their use in allylic allylation reaction

	S-enantiomer was obtained with rather good yield 80% and enantiomeric excess 88%.
	Similar bidentate N/S ligand Lig24b without phosphine function was prepared and tested
	in the same reaction, with bad results (Scheme 1.8).

%) ee(%)

	Lig25b	Ph	Ph	Ph	69	99
		Ph	4-MeOC 6 H 4	Ph	38	90
		Ph	Ph	TMS	21	90
		4-MeOC 6 H 4	Ph	Ph	33	80
		4-i-PrC 6 H 4	Ph	Ph	57	75
		4-ClC 6 H 4	Ph	Ph	46	74

Table 1 .14 Enantioselective alkynylation of imines with Lig25b. 1.2.2.3 N/N/O ligands

 1

	Ruffo et al. 33 prepared tridentate bis(pyridine-2-carboxamides) containing D-glucosamine
	moiety (Figure 1.19) and applied them in [Mo]-catalysed allylic alkylation by using both
	methyl (E)-3-phenyl-2-propenyl and methyl rac-1-phenyl-2-propenyl carbonates and
	dimethyl malonate as nucleophile under microwave irradiation (Table 1.15).

Table 1 .15 Asymmetric Allylic Alkylation reaction

 1

		[Mo]	MeOOC	COOMe	MeOOC	COOMe
	Substrate			+
			Ph	*	Ph
	Ligand	Substrate		Yield (%) (Conv.)	Regioselectivity (38/39)	ee (%)
	Lig26a Ph Lig26b	COOMe	90 (42)	49 : 1 12 : 1	99 (R) 87 (R)
	Lig26a	COOMe		90	8 : 1	96
	Ph

Ligand Conv. (%) Selectivity (MPSO/MPSO 2 ) ee (%) (S) Lig27a 99

  .16).

			Me S Ph	[V]	Me S Ph OH +	+	HO Me Ph S OH 2+
					(S)-MPSO	MPSO 2
			95/5	42
	Lig27b	99	97/3	60

Ligand Conv. (%) Selectivity (MPSO/MPSO 2 ) ee (%) (S) Lig27c 99

			90/10	26
	Lig27g	99	85/15	45

Table 1 .16 Vanadium-catalysed oxidation of thioanisole.

 1

	All tested ligands give excellent conversions. Ligand Lig27b was the best choice from all
	examined. Very good selectivity and enantioselectivity (60% ee) was obtained.
	In 2006 other Schiff base carbohydrate ligand Lig28 was described and used by Muzart et
	al. in [Ru] 35 -and [Cr]-catalysed 36 asymmetric epoxydation of olefins. In all cases results
	achieved with [Ru] were better comparing to yields obtained with [Cr] complex, and

Table 1 .17 Epoxydation of styrenes with complexes Lig28-[Ru], and Lig28-[Cr].

 1

1.2.3 Tetradentate ligands 1.2.3.1 N/N/O/O ligands "Salen" type tetradentate ligands Lig29 (Figure 1.21) were prepared and in combination with Yttrium or Manganese were used as catalysts.

	O					H	O
				O				O
	O				OBn	H	O	OBn
		N		N			N	N
	R	OH	H	O	R		OH	H	O
	t-Bu		t-Bu
	Lig29	a R = t-Bu
			b R = H

t-Bu t-Bu Lig29c Figure 1.21 Tetradentate ligands prepared by Ruffo.

										Chapter 1
	Ligand Lig29a was tested with Yttrium in trans-acylation between enolesters and chiral
	secondary alcohols (Scheme 1.9) 37 .
		H	O	+	MeCO 2	[Y]	MeCO 2	*	+	O
							Lig29a (69%) 61%ee
				Scheme 1.9 Transacylation catalysed by ligand Lig29a.
	Kinetic resolution of 1-(1-naphthyl)ethanol using 2-propenyl acetate as the acyl transfer
	agent was examined. Product was obtained in enantiomeric excess of 61% with 69% of
	conversion of starting material.
	Activity of ligands Lig29a,b was studied in asymmetric epoxydation of styrene and
	cis--methylstyrene (Table 1.18) 38 .
				R	[Mn]	*	R O *	+		*	O *	R
						cis			trans
	Ligand			Alkene		R	Conv. (%)		Selectivity (cis/trans)	ee (%)
	Lig29a			Styrene		H	99		-	50(S)
	Lig29b			Styrene		H	99		-	54(S)
	Lig29a	cis--Methylstyrene	Me	99		95/5	86(1S,2R)
	Lig29b	cis--Methylstyrene	Me	99		96/4	86(1S,2R)
	Lig29d	cis--Methylstyrene	Me	99		80/20	80(1S,2R)

Table 1 .18 Epoxydation of styrenes with Ligands Lig29

 1

Yield (%) anti:syn ee(%) anti

	Lig30f	CH 2	2-Nitro	97	97 : 3	96
		CH 2	2-Bromo	85	97 : 3	97
		CH 2	2-Methoxy	86	97 : 3	99
		O	2-Nitro	96	94 : 6	97
		S	2-Nitro	89	98 : 2	97
	Lig30h	CH 2	4-Chloro	99	97 : 3	98
		CH 2	4-Cyano	99	97 : 3	96
		CH 2	2-Nitro	96	98 : 2	99
		CH 2	4-Fluoro	99	96 : 4	98

Table 1 .19 Aldol

 1 reaction of cyclic ketones with substituted benzaldehydes in the presence of Lig30.

	Catalysts Lig30e-g were tested in Asymmetric Michael addition in solvent free
	conditions 40d .
	O				R
		+	NO 2	O	NO 2
			R
	L	R	Yield (%)	dr (syn/anti)	er (syn)
	Lig30f	2-NO 2	96	90 : 10	76 : 24
		3-NO 2	94	93 : 7	84 : 16
		2-Br	98	86 : 14	77 : 23
		4-Br	92	98 : 2	78 : 22
	Lig30g	H	91	95 : 5	-

Table 1 .20 The addition of acetylacetone to b-nitrostyrenes catalysed by ligands Lig30.

 1

24 Urea organocatalysts. Urea Lig32a was tried in enantioselective Mannich reactions giving rather low selectivity.

		N	R2	(i) TMSCN Lig	H	N	R2
		R1	H	(ii) (CF 3 CO) 2 O	R1		H CN
	ligand	R1		R2	Yield (%)	ee (%)
	Lig32a	4-MeO-C 6 H 4	allyl7 9	8 2
		4-Br-C 6 H 4	allyl			77	84
		4-tBu-C 6 H 4	allyl			82	84
		1-Np		allyl			78	80
		Ph		allyl			86	95(S)
		6,7-dimethoxyisoquinoline			97	86
		NBoc		TBDMS			NHBoc
		H	+	O
							O	O
							Lig32a 73% 58%ee
		Scheme 1.11 Enantioselective Catalysis of the Mannich Reaction.
	Other ligands were used in Strecker reaction of different imines with trimethylsilyl
	cyanide. Best results were obtained for catalyst Lig32b containing in anomeric -position
	the urea moiety and the Schiff base linked to the 2-amino function, which lead to product
	with excellent enantioselectivity 95% ee. (Table 1.21). Remaining catalyst proceed to
	product with poor results.

Table 1 .21 Hydrocyanation

 1 of Imines (Strecker Reaction).

R' Ketone Yield (%) ee (%) (S) Lig33d

		H	Bn	acetone	95	60
		Cl	H	acetone	95	72
		Br	H	acetone	82	75
		H	H	acetone	99	67
		H	H	cyclohexanone	99	63
	D-glucosamine	H	H	acetone	90	10

Table 1 .22 Organocatalytic

 1 enantioselective aldol reaction addition of different ketones to various isatins.

Table 1

 1

	.23)
	NO 2	+		Me(O)C	C(O)Me NO 2
	R	O	O
				R
	Ligand	R	Yield (%)	ee (%)
	Lig34f	H	27	55
	Lig34b	H	93	83
		Me	71	82
		Cl	84	84
		CF 3	78	85

Table 1 .23 The addition of acetylacetone to b-nitrostyrenes catalysed by ligands Lig34.

 1

Table 1 .

 1 24 Alkynylation of aldehydes.

						Ligand	R	R'	Yield (%)	ee (%)
		Pr	Ph	80	95	Lig39k CyclohexylH O (CH 2 ) 2	90	98
	Lig38l Cyclohexyl Ph	94	99		Cyclohexyl Ph(CH 2 ) 2	89	95
	Lig39k	i-Pr	Ph	70	97		t-Bu	Ph(CH 2 ) 2	77	99

48

(a) D. P. G. Emmerson, R. Villard, C. Mugnaini, A. Batsanov, J. A. K. Howard, W. P. Hems, R. P. Tooze, B. G.

Davis, Org. Biomol. Chem., 2003, 3826-3838, (b)

D. P. G. Emmerson, W. P. Hems, B. G.

Davis, Org. Lett., 2006, 8, 207-210.

Ar 2 P NMeEt 2 Lig43 Ar = BF 4 -

					OAc	NuH		Nu
	Ph	O	O		Ph	Ph	[Pd]	Ph	*	Ph
		O	O	Run	solvent		NuH	Yield(%) ee(%)
		O	N	1 1	MeCN THF		CH 2 (COOMe) 2 CH 2 (COOMe) 2	95 97		92(S) 89(S)
				2	THF		CH 2 (COOMe) 2	90		89(S)
				1	MeCN/H 2 O	CH 2 (COMe) 2	85		83(S)
			+	1	MeCN/H 2 O CH 3 CH(COMe) 2	51		80(R)
				1	MeCN/H 2 O		Benzylamine	80		84(R)
				2	MeCN/H 2 O		Benzylamine	/		77(S)

Table 1 .

 1

25

Water soluble ligand D-glucosamine-oxazoline type and its use in Allylic substitution with different nucleophiles.

Table 2 .

 2 1, entry 3).

	Entry Compound	Shift (ppm)	Coupling constant (Hz)
	1	4 *	= 4.62	J=4.3Hz
	2	4 *	= 4.52	J=5.6Hz
	3	5	= 6.18	J=3.7Hz
	4	3	= 4.74	J=9.3Hz
	5	6	= 4.13	J=9.2Hz
	6	7	= 4.86	J=9.3Hz
	7	8	= 4.52	J=9.0Hz
	8	2	= 3.98	J=8.8Hz

Table 2 .

 2

1 Chemical shift and coupling constant of H-1 for each carbohydrate in synthesis of 1,2--glucodiamine 2 ( * starting material 4 is mixture of anomers in ratio 4 : 4 87:13).

  Synthesis of "Trost type" carbohydrate based ligand.Different conditions were tested. It was impossible to increase temperature because degradation of carbohydrate was ongoing, also changing time of reaction leaded to creation of many phosphorus byproducts present on 31 P NMR. Other coupling reagents were also

				OAc
	OAc	COOH	O	O
	AcO AcO	O NH 2 NH 2	PPh 2 EDC, HOBt, THF, DCM,	AcO AcO O	NH	N H	PPh 2 PPh 2
			rt, 16 h,
	2		22%	L1
		Scheme 2.7

2 with 2-(diphenylphosphino)benzoic acid in mixture dichloromethane and tetrahydrofurane 1 : 1 using HOBt and EDC as coupling reagents ligand L1 was prepared and isolated using flash chromatography in only 22% of yield (Scheme 2.7). tested. Using DCC / DMAP in catalytic amount in dichloromethane no product was observed, however the same reagents used by Ruffo in big excess and THF as solvent leaded to creation of desired product with 73% of yield (Scheme 2.5).

O PPh 2 PPh 2

		OAc	[Pd( 3 -C 3 H 5 )Cl] 2 ligand 4%	MeOOC	COOMe
	R	R	dimethyl malonate	R	R			N H
	Entry 1	Ligand Trost ligand	62	R Solvent Ph THF	Base NaH	Yield (%) 24	ee 12 (%)	O	NH
	2	L1		Ph	THF	NaH	39	42
	3	Trost ligand	62	Me DCM Cs 2 CO 3	98	92
	4	L1		Me DCM Cs 2 CO 3	0	0
	5	L1		Me	THF	NaH	0	0

1,3-dimethyl-2-propene, and a standard nucleophile, dimethyl malonate, were chosen. (Table 2.2).

Trost ligandTable 2 . 2

 22 Shortlists and compare of results of allylic alkylation with "Trost ligand"(entry 1, 3) and ligand L1

	(entry 2, 4, 5).

Table 2

 2

		O		[Ru]		OH
				isopropanol,		*			Ph	Ph
				base, H 2			DPEN:	H 2	N	NH 2
	Entry Amine	Base	Pressure (atm)	Cat. (%)	Time (h)	Conv. (%)	Yield (%)	ee (%)
	1	DPEN 63b	KOH	4	0.2	3	100	>99	87
	2	2	KOH	4	0.2	72	0	0		-
	3	DPEN 63d	t-BuOK	45	0.4 x10 -4	48	100	100	80
	4	DPEN	t-BuOK	20	0.2	72	60	40		75
	5	2	t-BuOK	10	0.2	48	0	0		-
	6	2	t-BuOK	20	0.2	72	0	0		-

.3, entry 2)

.

Table 2 . 3

 23 Shortlist and compare of results of hydrogenation of acetophenone with "Noyori ligand" (entry 1, 3, 4) and ligand L4 (entry2, 5, 6).

Another base (potassium tert-butoxide) was used by group of Noyori 63d in a big scale reactions and TON up to 2400000 was achieved. Authors obtain product of hydrogenation with full conversion and 80% of enantiomeric excess (Table

2.3, entry 3

). Because it was imposibe for us to repeat exacly the same conditions, reaction with the DPEN was carried out in our laborathory with preasure decreased from 45 to 20 atmosphers and amount of catalyst increased from 0.4 x 10 -4 to 0.2% molar. (Table

2

.3, entry 4), to give product of reaction with 60% of conversion and comparable enantiomeric excess 75%. The same condition were applied for complex containing 1,2--glucodiamine, unfortunately in this case reaction did not leaded to any conversion of starting material

(Table 2.3, entries 5, 6)

.

Table 2 .

 2

	Entry Ligand	H-1 (ppm)	C-1 (ppm)	H-2 (ppm)	C-2 (ppm)
	1	L3	5.61	85.1	4.40	54.4
	2	L4	5.20	84.3	3.04	61.5
	3	L5	6.01	85.0	5.52	58.6
		4 Chemical shifts of H-1, H-2, C-1, C-2 for Ligands L3-L5.

.4 we can observe how protons H-1, H-2, and carbons C-1, C-2 shifts for the particular compounds.

Table 2 .

 2 5).

	O			MeNO 2		O	NO 2
			catalyst (10%),		*
				toluene
	Entry Catalyst Time	Others Temp.	Conv.	ee	H	O	N
			(h)		( o C)	(%)	(%)	O
	1	K 2 CO 3	5	sonication	25	96	-
	2	quinine	96	-	110	4	50		N
	3	quinine	45	sonication	25	18	55	quinine
	4	L3	36	sonication	25	<0.1	-
	5	L4	36	sonication	25	<0.1	-
	6	L5	36	sonication	25	<0.1	-

Table 2 . 5

 25 Results of Michael addition of nitromethane to chalconeReaction of addition works very well with inorganic base (Table2.5, entry 1), nevertheless conditions to obtain chiral product were investigated. Due to the privileged role in

asymmetric organic synthesis, alkaloid-based compound-quinine was employed in reaction in these Michael reactions as catalyst to give up to 55% enantiomeric excess. The best conditions established for quinine: room temperature and sonification (Table

2

.5, entry 3) were applied for carbohydrate based thiourea organocatalysts. However in any case conversion didn't exceed 0.1%

(Table 2.5, entry 4, 5, 6)

.

  (ppm) = 21.1 (COCH 3 ), 21.2 (2 x COCH 3 ), 57.8 (C-2), 63.0 (C-6), 69.4 (C-4), 73.3 (C-5), 77.0 (C-3), 87.9 (C-1), 170.38 (COCH 3 ), 171.1 (COCH 3 ), 171.2 (COCH 3 ).

	IR: (thin film, cm -1 ) = 3402 ( NH ), 3364 ( NH ), 3262 ( NH ), 2891, 2842, 1736
	( C=O ), 1594 ( NH ), 1421, 1366, 1218, 1174, 1100, 1042, 1006, 957, 912, 881, 837,
	732.
	ESI full ms calcd. for C 12 H 20 N 2 NaO 7 (M + Na + ): 327.1163, found 327.1167.
	Synthesis of 2-acetamido-2-deoxy-6-D-glucopyranose 3 72

13 C NMR (CDCl 3 ):

  52 . 166-167 o C

	Chapter 3
	J=12.5Hz, H-6'), 4.74 (d, 1H, J=9.3Hz, H-1), 5.10 (dd, 1H, J=9.3, J=9.9Hz, H-4),
	5.23 (dd, 1H, J=9.3, J=10.2Hz, H-3), 5.63-5.89 (m, 1H, NH), according to the
	literature 52 .

1 H NMR (CDCl 3 ): (ppm) = 1.98 (s, 3H, CH 3 ), 2.03 (s, 3H, CH 3 ), 2.04 (s, 3H, CH 3 ), 2.10 (s, 3H, CH 3 ),

3.78 (ddd, 1H, J=2.4, J=4.7, J=9.9Hz, H-5), 3.92 (dd, 1H, J=9.3, J=10.2Hz, H-2), 4.16 (dd, 1H, J=2.4, J=12.5Hz, H-6), 4.27 (dd, 1H, J=4.7,

50 H 47 N 2 O 7 P 2

	OAc			Yield 28%
	O		Light yellow solid
	AcO AcO	N	N PPh 2 PPh 2	R f = 0.64 (ethyl acetate : cyclohexane 1 : 1) m.p. 97-98 o C [ ] D 20 = +10.7 (c = 1.03, chloroform)
	L2
	1 H NMR (CDCl 3 ): (ppm) = 1.59 (s, 3H, CH 3 ), 1.94 (s, 3H, CH 3 ), 2.01 (s, 3H,
	CH 3 ), 3.26 (ddd, 1H, J=8.2, J=9.0, J=9.0Hz, H-2), 3.81 (ddd, 1H, J=2.0, J=4.6,
	J=10.2Hz, H-5), 4.07 (dd, 1H, J=2.0, J=12.3Hz, H-6), 4.23 (dd, 1H, J=4.6,
	J=12.3Hz, H-6), 4.80 (d, 1H, J=8.2Hz, H-1), 5.06 (dd, 1H, J=9.6, J=10.2Hz, H-4), 1 H NMR (CDCl 3 ): (ppm) = 1.96 (s, 3H, CH 3 ), 1.98 (s, 3H, CH 3 ), 2.01 (s, 3H, 5.31 (dd, 1H, J=9.0, J=9.6Hz, H-3), 6.81 (m, 2H, H arom ), 7.15 (m, 28H, H arom ), 7.93 CH 3 ), 3.66 (ddd, 1H, J=1.9, J=3.9, J=9.8Hz H-5), 3.96 (dd, 1H, J=1.9, J=12.3Hz H-(m, 2H, H arom ), 8.76 (d, 1H, J=4.9Hz, N=CH), 8.99 (d, 1H, J=5.6Hz, N=CH). 6), 4.20 (dd, 1H, J=3.9, J=12.3Hz H-6), 4.37 (ddd, 1H, J=8.7, J=9.6, J=9.8Hz H-2), 13 C NMR (CDCl 3 ): (ppm) = 20.31 (COCH 3 ), 20.7 (COCH 3 ), 20.8 (COCH 3 ), 62.5 4.94 (dd, 1H, J=9.6, J=9.8Hz H-3), 5.08 (dd, 1H, J=9.6, J=9.8Hz H-4), 5.20 (dd, (C-6), 68.7 (C-4), 73.4 (C-3), 73.7 (C-5), 73.9 (C-2), 95.4 (C-1), 127.7-139.6 (36 x
	C
	(C-2), 62.2 (C-6), 68.2 (C-4), 73.4 (C-5), 73.9 (C-3), 80.9 (C-1), 127.2-135.5 (28 x
	C arom ), 137.3-141.1 (8 x C arom ), 168.8 (CONH), 169.7 (CONH), 170.7 (COCH 3 ),
	171.2 (COCH 3 ), 172.3 (COCH 3 ).
	IR: (thin film, cm -1 ) = 3304 ( NH ), 3051, 2925, 1741 ( C=O ), 1655, 1585, 1525
	( NH ), 1479, 1462, 1433, 1366, 1303, 1228, 1082, 1029, 908, 847, 795, 741.
	ESI full ms calcd. for C 50 H 47 N 2 O 9 P 2 (M + H + ): 881.2783, found 881.2751.
	Synthesis of 3,4,6-tri-O-acetyl-1,2-di-{[2-(diphenylophosphino)benzoyl]imino}--D-
	glucopyronose L2.
	In a Schlenk tube under argon atmosphere, diamino compound 2 (125 mg, 0.41 mmol), and
	2-diphenylphosphinobenzoic aldehyde (802 mg, 0.82 mmol), were stirring with MgSO 4 in
	dry, degassed toluene in 60 o C. After being stirred for overnight, the solvent was

1H, J=8.4, J=9.6Hz, H-1), 6.28

(d, 1H, J=8.7Hz

, H-N2),

6.82-7.30 (m, 26H H arom ), 7.35-7.41 (m, 1H, H arom ), 7.45 (d, 1H, J=8.4Hz, H-N1), 7.75 (dd, 1H, J=3.7, J=6.

5Hz, H arom ). 13 C NMR (CDCl 3 ): (ppm) = 21.1 (COCH 3 ), 21.2 (COCH 3 ), 21.4 (COCH 3 ), 53.9 31 P NMR (CDCl 3 ): (ppm) = -10.17, -6.29. evaporated, mixture dissolved in dichloromethane and filtrated through celite. Product was purified with flash column chromatography using cyclohexane : ethyl acetate : NEt 3 80 : 10 : 1 as eluent. arom ), 161.5 (N=CH), 163.7 (N=CH), 170.7 (COCH 3 ), 169.8 (2 x COCH 3 ).

31 P NMR (CDCl 3 ): (ppm) = -15.3, -14.9.

IR: (thin film, cm -1 ) =

3051, 2923, 2866, 2280, 2160, 1980, 1746 ( C=O ), 1636, 1584, 1478, 1461, 1433, 1364, 1224, 1068, 1027, 903, 743.

ESI full ms calcd. for C (M + H + ): 849.2853, found 849.2813.

56 H 52 C l1 N 2 O 7 P 2 Ru

	2, J=9.9Hz, H-5), 3.67 (t, 1H, J=8.3Hz, NH), 3.88 (dd, 1H, J=1.5,
	J=12.5Hz, H-6), 4.07 (dd, 1H, J=3.6, J=12.4Hz, H-6), 4.68 (dd, 1H, J=9.4,
	J=9.4Hz), 4.76 (dd, 1H, J=9.4, J=9.4Hz), 6.05 (d, 1H, J=8.7Hz, H arom ), 6.19 (d, 1H,
	J=8.6Hz, H arom ), 6.41 (m, 6H, H arom ), 6.59 (m, 2H, H arom ), 7.42 (m, 18H), 8.05 (t,
	1H, J=8.4Hz, H arom ), 8.22 (t, 1H, J=8.2Hz, H arom )
	ESI full ms calcd. for C (M + H + ): 1063.1989, found
	1063.1891.

28 H 30 F 6 N 3 O 7

	Synthesis of Thiourea, N-[3,5-bis(trifluoromethyl)phenyl]-N'-[3,4,6-tri-O-acetyl-2-amino-Synthesis of 3,4,6-tri-O-acetyl-1,2-di-{N,N'-dithiourea, N,N'-[3,5-
	benzyl -2-deoxy--D-glucopyronose] L4 bis(trifluoromethyl)phenyl]}--D-glucopyronose. L5
	Thiourea compound L3 (0.28 g, 0.42 mmol) was dissolved in dichloromethane (5 mL) and Diamino compound 2 (0.10 g, 0.33 mmol) was dissolved in dichloromethane (3 mL) and
	trifluoroacetic acid (0.25 mL) was added. Mixture was stirred overnight in room solution of 3,5-Di(trifluoromethyl)phenyl isothiocyianate (0.178 g, 0.66 mmol) in
	temperature. After that time solution was diluted with dichloromethane and washed with dichloromethane (1 mL) was added. Mixture was stirred overnight in room temperature.
	NaHCO 3 , dried (Na 2 SO 4 ) and evaporated. Solid was dissolved in methanol anhydride (4 Solution was concentrated. Compound was purified by column chromatography using
	mL), and benzaldehyde was added. Mixture was stirred overnight in room temperature. Cyclohexane : Ethyl acetate 2 : 1 as eluent. 0.085 g.
	TLC show full conversion of starting material. Acetic acid (2.5 mL) and sodium CF 3 Yield 30%
	cyanoborohydride (0.197 g, 3.1 mmol) were added. Reaction was monitored by TLC. After OAc CF 3 White solid
	1 hour reaction was quenched with water and extracted with dichloromethane. Organic phase was wash with NaHCO 3 sat and brine, dried using Na 2 SO 4 , evaporated. Compound O AcO N H S R f = 0.45 (cyclohexane ethyl : acetate 2 : 1) N H m.p. 174 o C
	was purified by column chromatography using Cyclohexane : Ethyl acetate 1 : 1 as eluent. CF 3 H N Yield 44 % NH AcO S CF 3 [ ] D 20 = +78.2 (c = 1.00, chloroform)
	O NH OAc AcO AcO L5	N H S	CF 3 N H	CF 3	White solid R f = 0.32 (dichloromethane : methanol 20 : 1) [ ] D 20 = +80.4 (c = 0.95, chloroform) CHAPTER 3
	L4
	(ddd, 1H, J=9.7, J=9.7, J=9.9Hz, H-2), 5.41 (dd, 1H, J=9.4, J=9.9Hz, H-3), 6.01 (d,
	1 H NMR (CDCl 3 ): (ppm) = 2.08 (s, 6H, 2 x CH 3 ), 2.13 (s, 3H, CH 3 ), 3.04 (ddd, 1H, J=9.7Hz, H-1), 7.70 (s, 2H, 2 x H arom ), 8.12 (s, 2H, 2 x H arom ), 8.19 (s, 2H, 2 x
	1H, J=9.8, J=9.8, J=9.8Hz, H-2), 3.79 (ddd, 1H, J=1.6, J=5.8, J=8.5Hz, H-5), 3.86 H arom ).
	89 (s, 3H, CH 3 ), 2.05 (s, 3H, (d, 2H, J=2.1Hz, CH 2 ), 4.09 (dd, 1H, J=1.6, J=12.3Hz, H-6), 4.36 (dd, 1H, J=5.8, 13 C NMR (CD 3 OD): (ppm) = 20.6 (COCH 3 ), 20.8 (2 x COCH 3 ), 58.6 (C-2), 63.3
	CH 3 ), 2.10 (s, 3H, CH 3 ), 3.85 (ddd, 1H, J=2.0, J=6.2, J=9.9Hz, H-5), 4.00 (dd, 1H, J=12.3Hz, H-6), 5.04 (dd, 1H, J=8.5, J=9.8Hz, H-4), 5.20 (bd , 1H, J=8.2Hz, H-1), (C-6), 70.1 (C-4), 74.7 (C-3), 74.8 (C-5), 85.0 (C-1), 118.9 (2 x C arom ), 122.8 (2 x
	J=9.9, J=12.3Hz, H-6), 4.14 (dd, 1H, J=2.0, J=12.3Hz, H-6), 4.40 (ddd, 1H, J=7.5, 5.32 (dd, 1H, J=9.8Hz, J=9.8Hz, H-3), 7.02 (s, 1H, NH), 7.23-7.37 (m, 5H, H arom ), CF 3 ), 124.7 (4 x C arom ), 126.4 (2 x CF 3 ), 132.1-133.6 (dq, 4C, J=3.8, J=33.5, 4 x
	J=9.3, J=9.3Hz, H-2), 5.06-5.26 (m, 3H, H-3, H-4, NH), 5.61 (bdd, 1H, J=6.5, 7.60 (s, 1H, H arom ), 7.90 (s, 2H, H arom ). C arom -CF 3 ), 142.4 (2 x N-C arom ), 171.4(COCH 3 ), 172.2 (COCH 3 ), 172.5 (COCH 3 ),
	J=7.5Hz, H-1), 7.63 (bs, 1H, H arom ), 7.93 (bs, 2H, H arom ), 8.00 (bd, 1H, J=7.5Hz, 13 C NMR (CDCl 3 ): (ppm) = 20.6 (COCH 3 ), 20.7 (COCH 3 ), 20.8 (COCH 3 ), 51.2 184.0 (C=S), 184.3 (C=S).
	NH), 8.64 (bs, 1H, NH). (C arom ), 121.1 (CF 3 ), 123.4 (C arom ), 123.5 (C arom ), 124.7 (q, 2C, J=33.7Hz, 2 x CF 3 ), 13 C NMR (CDCl 3 ): (ppm) = 20.5 (COCH 3 ), 20.6 (COCH 3 ), 20.7 (COCH 3 ), 28.0 (CH 2 ), 61.5 (C-2), 62.2 (C-6), 68.8 (C-4), 73.7 (C-3), 74.5 (C-5), 84.3 (C-1), 118.6 ESI full ms calcd. for C 30 H 27 F 12 N 4 O 7 S 2 (M + H + ):847.1124, found 847.1054.
	(C(CH 3 ) 3 ), 54.4 (C-2), 62.2 (C-6), 68.2 (C-4), 72.8 (C-3), 74.2 (C-5), 81.4 (C 127.8 (C arom ), 128.3 (2 x C arom ), 128.8 (2 x C arom ), 131.8 (m, 2 x C arom -CF 3 ), 138.5
	(CH 3 ) 3 ), 85.1 (C-1),119.3 (C arom ), 121.1 (CF 3 ), 124.7 (CF 3 ), 124.8 (C arom ), 124.9 (CH 2 -C arom ), 139.3 (N-C arom ), 169.7(COCH 3 ), 171.0 (COCH 3 ), 171.3 (COCH 3 ),
	(C arom ), 131.3-132.7 (q, 2C, J=33.3Hz, 2 x C arom -CF 3 ), 139.3 (N-C arom ), 157.0 182.6 (C=S).
	(NHC=O), 169.4(COCH 3 ), 170.8 (COCH 3 ), 171.5 (COCH 3 ), 182.9 (C=S).

1 H NMR (CDCl 3 ): (ppm) =

1.35 (s, 9H tert-butyl)

, 1.ESI full ms calcd. for C 26 H 32 N 3 O 9 S (M + H + ):676.1758, found 676.1744. ESI full ms calcd. for C S (M + H + ): 666.1718, found 666.1703.

1 H NMR (CD 3 OD): (ppm) = 2.07 (s, 3H, CH 3 ), 2.08 (s, 3H, CH 3 ), 2.10 (s, 3H, CH 3 ),

3.98 (ddd, 1H, J=2.2, J=4.7, J=10.1Hz, H-5), 4.17 (dd, 1H, J=2.2, J=12.4Hz, H-6), 4.38 (dd, 1H, J=4.7, J=12.4Hz, H-6), 5.14 (dd, 1H, J=9.4, J=10.1, H-4), 5.22

Ligands for heterogeneous catalysis Introduction 3 Ligands for heterogeneous catalysis.

  .2, entries 1-3).

	B(OH) 2	+	NO 2	1 mol% Cat. [Pd(OAc) 2 / L6 (1 / 2)] 500 mg of SiO 2	NO 2
		Br			base (3.0 equiv),
	0.55mmol	0.5mmol			solvent (0.05M), 60 o C
	Entry	Solvent		Base	Time	Conv. (%)
	1	Toluene		K 3 PO 4	4h	8
	2	Toluene		Na 2 CO 3	4 h	4
	3	Toluene		Na 2 CO 3	4days	38
	4	Toluene / Ethanol (10/1)	Na 2 CO 3	18 h	68
	5	Toluene / Ethanol (7.5/1)	K 3 PO 4	18 h	63
	6	Toluene / Ethanol (7.5/1)	Na 2 CO 3	18 h	96

Table 3 .2 Optimalisation

 3

of conditions for solvent and base.

Table 3 . 3

 33 Suzuki-Miyaura cross-coupling of various aryl bromides and arylboronic acids. a Determined by GC. b Isolated chemical yield after column chromatography. c Deterimined by 1 H NMR and 13 C NMR.

d

Not determined.

  Y.He, C. Cai, Chem. Commun., 2011, 47, 12319-12321, (e) E. Alza, S. Sayalero, P. Kasaplar, D. Almas, M. A. Pericàs Chem.Eur. J., 2011, 17, 11585-11595.

Experiments dealing with synthesis of poly(ethylene) based ligands.

  The mixture was stirred for 2 h and then the precipitated product was filtered off and washed with cold water, followed by mixture of EtOH : Et 2 O 1 : 1.

	presented. 1-Phenylnaphthalene	1-Phenylpyridine
	(Table 3.3, Entry 11)	(Table 3.3, Entry 12)
	Analysis of products were made using conditions:
		100°C (0 min)	10°C / min N	250°C (20min)
		GC t R = 12.83 min.	GC t R = 6.90 min.
	4-Nitrobiphenhyl (Table 3.3, Entry 1) 108
		NO 2	Yellow solid
	GC t R = 7.57 min. 1 H NMR (CDCl 3 ): (ppm) = 7.42-7.54 (m, 3H), 7.60-7.66 3.5 Synthesis of 2-deoxy-2-[p-methoxybenzyldiene(amino)]-D-glucopyranose 11 88
	(m, 2H), 7.71-778 (m, 2H), 8.28-8.32 (m, 2H). p-Anisylaldehyde (3.5 mL, 28.8 mmol) was added, in a round bottom flask to a solution of
	D-glucosamine hydrochloride (5 g, 23.0 mmol) in 1M NaOH (24 mL). After short time
	4'-Methyl-4-nitro-biphenyl (Table 3.3, Entry 3) 108 NO 2 Yellow solid GC t R = 8.88 min. 1 H NMR (CDCl 3 ): (ppm) = 2.32 (s, 3H), 7.20 (d, 2H, OH Yield 75% crystallization began. O White solid
	O H	OH	J=7.9Hz), 7.42 (d, 2H, J=7.9Hz), 7.60 (d, 1H, J=8.9Hz), m.p. 159-161 o C , lit. 165-166 o C
	O H	N	8.16 (d, 1H, J=8.9Hz)
		11
	4-Phenyl-acetophenone (Table 3.3, Entry 1) 109 OMe
		White solid 1 H NMR (C 5 D 5 N): (ppm) = 3.70 (s, 3H, CH 3 O), 3.88 (dd, 1H, J=7.8, J=9.0Hz, GC t R = 7.48 min. H-2), 4.24 (ddd, 1H, J=2.5, J=5.6, J=9.2Hz, H-5), 4.45 (dd, 1H, J=9.2, J=9.2Hz, H-1 H NMR (CDCl 3 ): (ppm) = 2.64 (s, 3H), 7.34 -7.55 4), 4.54 (m, 1H, H-6), 4.61 (dd, 1H, J=9.0, J=9.2Hz, H-3), 4.73 (dd, 1H, J=11.8,
	O	(m, 3H), 7.63 (d, 2H, J=7.3Hz), 7.69 (d, 2H, J=8.2Hz), J=2.5Hz, H-6), 5.82 (dd, 1H, J=4.7, J=7.3Hz, H-1), 6.66 (s, 1H, O-H), 7.03 (d, 2H,
		8.04 (d, 2H, J=8.2Hz) J=8.8Hz, H arom ), 7.63 (s, 1H, O-H), 7.94 (d, 2H, J=8.8Hz, H arom ), 8.74 (s, 1H, O-H),
		8.78 (s, 1H, O-H), 8.96 (d, 1H, J=5.
	Analysis of products were made using conditions:
				10°C / min
		60°C (0 min)	250°C (20min)
				3,
		H-4 ) 4.32 (dd, 0.75H, J=8.8, J=9.8Hz, H-4 ) 4.41 (dd, 1H, J=5.6, J=11.6Hz, H-
		6' ) 4.56 (dd, 0.75H, J=2.5, J=11.6Hz, H-6 ) 4.76-4.87 (m, 1.5H, H-3 /H-5 ) 5.12
		(ddd, 0.75H, J=3.4, J=8.5, J=11.8Hz, H-2 ) 5.59 (d, 0.25H, J=8.4Hz, H-1 ) 6.09

  ), 128.2 (C arom ), 130.1 (2 x C arom ), 162.2 (C arom -OCH 3 ), 164.2 (N=CH), 168.6 (COCH 3 ), 169.4 (COCH 3 ), 169.7 (COCH 3 ), according to the literature 99 .

	Synthesis	of	1,3,4-tri-O-acetyl-2-amino-6-azido-2,6-dideoxy--D-glucopyronose
	hydrochloride 20 99
	To a warm solution of 19 (0.89 g, 1.986 mmol) in acetone (3 mL) was added dropwise 6M
	aqueous hydrochloric acid (0.331 mL, 1.986 mmol) under vigorous agitation. After few
	minutes precipitate was observed. The product was collected by filtration and washed with
	ether to give 0.69 g of 20.
	N 3		Yield 95%
	O	Yellow solid
	AcO	OAc	m.p. 152-161 o C (decomp.) , lit. 147-154 o C (decomp.)
	AcO	NH 2 .HCl	[ ] D 20 = +41.1 (c = 0.50 methanol),
	20		lit. 99 , [ ] D	20 = +43 (c = 0.50, methanol)
	CH 3 ), 3.34-3.59 (m, 3H, H-2, H-6, H-6'), 3.92-4.02 (m, 1H, H-5), 4.88 (dd, 1H,
	J=9.5, J=9.5Hz, H-4), 5.35 (dd, 1H, J=9.7, J=9.7Hz, H-3), 5.95 (d, 1H, J=8.6Hz, H-
	1), 8.94 (s, 3H, NH 3 Cl), according to the literature 99 .
	1 H NMR (CDCl 3 ): (ppm) = 1.88 (s, 3H, CH 3 ), 2.02 (s, 3H, CH 3 ), 2.05 (s, 3H,
	CH 3 ), 3.37 (dd, 1H, J=5.3Hz, J=13.3Hz, H-6), 3.41-3,49 (m, 2H, H-2, H-6'), 3.85
	(s, 3H, OCH 3 ), 3.94 (ddd, 1H, J=2.7Hz, J=5.3Hz, J=9.9Hz, H-5), 5.11 (dd, 1H,
	J=9.7, J=9.9Hz, H-4), 5.43 (dd, 1H, J=9.7, J=9.7Hz, H-3), 5.95 (d, 1H, J=8.4Hz, H-
	1), 6.92 (d, 2H, J=8.7Hz, H arom ), 7.67 (d, 2H, J=8.7Hz, H arom ), 8.15 (s, 1H, N=CH),
	according to the literature 99 .

13 C NMR (CDCl 3 ): (ppm) = 20.4 (COCH 3 ), 20.6 (2 x COCH 3 ), 50.6 (C-6), 55.3 (OCH 3 ), 69.1 (C-4), 72.7 (C-2), 73.06 (C-3), 73.6 (C-5), 92.9 (C-1), 113.9 (2 x C arom 1 H NMR (DMSO-d 6 ): (ppm) = 1.98 (s, 3H, CH 3 ), 2.02 (s, 3H, CH 3 ), 2.16 (s, 3H,

  CH 3 ) 3 ), 20.2 (COCH 3 ), 20.6 (COCH 3 ), 20.7 (COCH 3 ), 24.1 (CH 2 CH 2 Si), 52.4 (CH 2 CH 2 CH 2 Si), 58.4

	1 H NMR (CDCl 3 ):	(ppm) = 0.46 (m, 2H, CH 2 Si), 1.13 (t, 9H, J=7.0Hz,
	Si(OCH 2 CH 3 ) 3 ), 1.59 (s, 3H, CH 3 ), 1.82 (m, 2H, CH 2 CH 2 Si), 1.93 (s, 3H, CH 3 ),
	2.01 (s, 3H, CH 3 ), 3.27 (dd, 1H, J=8.0Hz, J=9.6Hz, H-2), 3.72 (q, 6H, J=7.0Hz
	Si(OCH 2 CH 3 ) 3 ), 3.77-3.79 (m, 1H, H-5), 3.98-4.16 (m, 3H, CH 2 CH 2 CH 2 Si, H-6),
	4.25 (dd, 1H, J=4.8Hz, J=12.3Hz, H-6'), 4.63 (d, 1H, J=6.6Hz, H-1), 4.71 (s, 2H,
	CH 2 ), 4.98 (dd, 1H, J=9.6, Hz, J=9.6Hz, H-4), 5.21 (dd, 1H, J=9.6Hz, J=9.6Hz, H-
	3), 6.88 (dd, 1H, J=4.8Hz, J=6.6Hz, H arom ), 7.04-7.59 (m, 14H, H arom ), 7.85 (bs, 1H,
	NCH), 8.90 (d, 1H, J=3.8Hz, C=CH).
	(Si(OCH 2 CH 3 ) 3 ), 62.1 (C-6), 63.3 (OCH 2 ), 68.4 (C-4), 71.8 (C-5), 73.1 (C-3), 73.1
	(C-2), 100.6 (C-1), 122.6 (C=CH-"triazole ring"), 125.1-144.5 (18 x C arom ), 166.5
	(NCH), 169.6 (COCH 3 ), 169.7 (COCH 3 ), 169.8 (COCH 3 ), 170.6 (C=CH-"triazole
	ring").

13 C NMR (CDCl 3 ): (ppm) = 7.4 (CH 2 Si), 18.2 (Si(OCH 2 31 P NMR (CDCl 3 ): (ppm) = -15.17

IR: (thin film, cm -1 ) = 3054

43 H 56 N 4 O 11 PSi

  (M + H + ): 863.3447, found 863.3420.

678.

ESI full ms calcd. for C

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CHAPTER 2

Ligands for homogeneous catalysis Chapter 3 Ionic binding is useful for anionic or cationic catalysts. Various supports with ion exchange capabilities can be used (standard organic and inorganic exchange resins, inorganic materials with polarized groups, zeolites).

Adsorption is easy to perform very often even without need to previously functionalize of the ligand, however applicability is restricted due to possible competition with solvents or substrates.

Physisorption or entrapment for big sizes of metal complexes and strict control of porosity of support is required. Catalyst is building up in well defined cages of porous support or polymer build up network around a preformed catalyst.

Supported aqueous phase catalysts (SAPC) can be seen as special case of adsorption where a water soluble catalysts dissolve in water is adsorbed on a hydrophilic support forming a thin film on the inert surface of the support.

Supported liquid phase catalyst (SLPC) is similar system to SAPC where water film is replaced by a solvent of low vapor pressure Biphasic catalysts. Aqueous (Phase Transfer Catalyst) or non aqueous catalysts containing two immiscible liquids without any additional additive.

The search for better performing and more reliable systems is ongoing, this situation favors the advanced state of immobilization techniques and commercial availability of sufficient number of potential supports and carriers, both organic and inorganic. In this chapter we will focus on three of the systems: SAPC, biphasic catalysis and covalent binding.

Covalent binding. Ligands supported on silica matrix

In the last several years, many efforts have been devoted to the use of mesoporous materials as a support for immobilization [START_REF] Review | Some selected application of silica matrix supported catalysts[END_REF] . Also the large surface areas of mesoporous materials make these materials very attractive as support for homogeneous ligands. In this study silica was used as the support material. Silica matrix is an nanostructurated mesoporous material composed of siloxane groups (Si-O-Si) with silanol groups (Si-OH) distributed on the surface. [START_REF] Review | Some selected application of silica matrix supported catalysts[END_REF] Review: C. E. Song, S. Lee, Chem. Rev., 2002, 102, 3495-3524 Some selected application of silica matrix supported catalysts: (a) R. Sayah, E. Framery, V. Dufaud Green Chem., 2009, 11, 1694-1702, (b) Chapter 3

Biphasic catalysis. Ligands supported with poly(ethylene glycol).

The linear polymer of ethylene oxide: poly(ethylene glycol) (PEG) is inexpensive, nonvolatile, nontoxic, and is becoming attractive reaction media in organic synthesis. PEG has been also used as soluble polymer support. It can be dissolved in various organic solvents specially protic like water or alcohols. Moreover, PEG-supported catalysts have exhibited high catalytic activity and can be recovered conveniently.

The advantages of soluble polymers such as poly(ethylene glycol) (PEG) and its mono methyl ether (MPEG) have been explored as supports for catalyst immobilization and have led to a steadily increasing number of applications [START_REF] Review | Some selected application of poly(ethylene glycol)-supported catalysts[END_REF] .

Supported Aqueous Phase Catalyst (SAPC) [START_REF] Cornils | Supported aqueous-phase catalysis as the alternative method from Multiphase Homogeneous Catalysis[END_REF] is an elegant method of immobilization, where the hydrophilic catalyst system is placed in thin water phase in the surface of hydrophilic carrier while substrates and products stay in organic phase while catalytic reaction taking place efficiently at the aqueous-organic interface (Figure 3.3). SAPC system is promising due to its high capacity in the conversion, the selectivity and also the easy recovery of the catalyst from the organic phase, and thus is economically and Synlett., 2007, 14, 2280-2282, (c) S. H. Hong, R. H. Grubbs, Organic Lett., 2007, 9, 1955-1957, (d)

Chapter 3

Because of its excellent performance, economic and environmental concerns, numerous efforts have been devoted to the development of Suzuki-Miyaura reaction under benign conditions. Among them, the use of water as solvent is one possibility, however many substrates is not suitable with hydrophilic environment. For this reason, the immobilization of the catalyst could be good solution. And in the case of the Pd catalysts derived from mono-or diphosphine ligand, for the Suzuki-Miyaura reaction, numerous examples on organic 85 or inorganic ,86 supports have been used

Before to evaluate our SAPC system, blank experiments were made (Table 3 Similarly to explain the role of our ligand in the SAPC, a catalyst (Pd SAPC) was prepared by impregnating a dried silica with a solution of Pd(OAc) 2 in a mixture of ethanol and water (ratio 2/1), following by concentration and drying under vacuum at room temperature for 16 hours.

Indeed, it is well known that ligand-free Pd(OAc) 2 is able to catalyze the coupling reaction of aryl iodides and activated or deactivated aryl bromides 84b,e,87 . Using the same conditions 85 For selected examples see: (a) Y. Uozumi, H. Danjo, T. Hayashi, J. Org. Chem., 1999, 64, 3384-3384, (b) K. Inada, N. Miyaura, Tetrahedron, 2000, 56, 8661-8664, (c) A. Datta, F. Ebert, H. Plenio, Organometallics, 2003, 22, 4685-4691, (d) K. Glego a, E. Framery, K. M. Pietrusiewicz, D. Sinou, Adv. Synth. Catal., 2006, 348, 1728-1733. 86 For selected examples see:(a) E. Paetzold, I. Jovel, G. Oehme, J. Mol. Catal. A: Chem., 2004, 214, 241-247 (b) R. Sayah, K. Glegola, E. Framery, V. Dufaud, Adv. Synth. Catal., 2007, 349, 373-381, (c) N. J. S. Costa, P. K. Kiyohara, A. L. Monteiro, Y. Coppel, K. Philippot, L. M. Rossi, J. Catal., 2010, 276, 382-389, (d) W. Chen, P. Li, L. Wang, Tetrahedron, 2011, 67, 318-325. 87 Examples: (a) D. Badone, M. Baroni, R. Cardamone, A. Ielmini, U. Guzzi, J. Org. Chem., 1997, 62, 7170-7173 (b) N. A. Bumagin, V. V. Bykov, Tetrahedron, 1997, 53, 14437-14450, (c) J. C. Bussolari, D. C.

Chapter 3

two different amounts of molar Pd loading 1% and 0.1% respectively. After the first run of the reaction, the Pd SAPC was filtered, washed with toluene and dried under vacuum at room temperature for 16 hours, and then recharged with the same substrates, base and solvents for the next run, without any addition of catalyst.

Under the same conditions and with the Pd loading of 1% molar of, the conversions of products remained the same (99-91%) during three runs, and decreased slightly in the fourth (85%), before to decrease in the fifth and sixth run to 40 and 20%, respectively

We also tried to reduce the Pd loading to 0.1% molar, nevertheless application of smaller amounts of catalyst led to poorer results. The conversion of the two first run (93 and 86%) were almost similar to the two first runs with a Pd load ten times higher. But from the third cycle, the conversions decreased drastically from 88% to 44%, 32% and 18% (due to bad decantation and lost of supported silica catalyst). Having these results in hand, we then investigated the scope and limitations of the method.

As shown in temperature, and then using canula, was transferred to silica. After stirring for 2 hours at room temperature, solvents were evacuated under vacuum and the solid was dried under vacuum for 16 hours at room temperature, and then kept under Argon atmosphere prior to be used

General procedure for the Suzuki-Miyaura reaction with 1% molar of Pd catalyst Case of 1.0% molar of Pd: Na 2 CO 3 (156.0 mg, 1.5 mmol), aryl bromide (0.5 mmol) and arylboronic acid (0.55 mmol) were placed in the Schlenk tube containing the SAPC prepared as described above. After to add ethanol (1 mL) and toluene (7.5 mL), the mixture was stirred at 80°C for 24 hours. After cooling down and filtration, silica support was washed with dichloromethane (3 x 8 mL). The combined organic phases were concentrated and filtrated through thin pad of silica before to be analyzed in GC.

Purification of the crude product by flash chromatography on silica gel gave the coupling product.

Recycling cross-coupling reaction of 4-bromonitrobenzene with phenylboronic acid

In the case of 1% molar of Pd catalyst: for the first run, the same experimental condition than described above was used. After decantation and filtration, the SAPC was washed with toluene (5 mL), and was dried under vacuum for 16 hours. After, a mixture of 4-bromonitrobenzene (0.5 mmol), phenylboronic acid (0.55 mmol) and Na 2 CO 3 (156.0 mg, 1.5 mmol) were added to the solid. After that the new cycle was performed following the general procedure for the Suzuki-Miyaura reaction. In the case of 0.1% molar of Pd catalyst: the same protocol as described above was used increasing per ten the amount of base, 4-bromonitrobenzene, phenylboronic acid and solvents.

For different substrates two conditions were used during GC analysis. Below retention time for compounds use in catalytic reactions and characteristics for isolated biaryls are Chapter 3

3-Acetyl-4 -nitrobiphenyl (

Experiments dealing with silica grafted ligands.

General procedure for grafting compounds in silica matrix

Compound for grafting was dissolved in toluene (distillated over CaH IR: (thin film, cm -1 ) = 3267, 3090, 1738, h, 1566, 1432, 1367, 1308, 1202, 1217, 1161, 1113, 1079, 1031, 1015, 974, 942, 928, 902, 699. Propargyl compound 27 (1.22 g, 3.16 mmol) and N,N-dimethyl-4-aminopyridine (0.10 g, 0.95 mmol) was dissolved in THF (65 mL). Di-tert-butyl dicarbonate (1.38 g, 6. mmol) was added, and the mixture was heated to reflux overnight. After the solution was cooled (COCH 3 ), 169.9 (COCH 3 ), 170.9 (COCH 3 ), 171.1 (COCH 3 ).

IR: (thin film, cm -1 ) = 3319, 1739, 1679, 1537, 1365, 1332, 1298, 1219, 1161, 1115, 1087, 1066, 1042, 1016, 962, IR: (thin film, cm -1 ) = 3268, 3090, 1739, 1655, 1566, 1431, 1367, 1231, 1218, 1161, 1112, 1079, 1031, 1014, 975, 942, 928, 902, IR: (thin film, cm -1 ) = 2974, 2927, 2885, 2358, 2093, 1443, 1390, 1365, 1344, 1276, 1242, 1166, 1100, 1074, 945, 831, 774, 703, 687, 681.

IKATALIZY ASYMETRYCZNEJ

Abstract in English

Several ligands derived from D-glucosamine, designed for different catalytic reactions have been synthesized. The ligands for homogeneous catalysis based on 1,2--glucodiamine were prepared, and used in reactions of allylic alkylation, hydrogenation and Michael addition. Supported Aqueous Phase Catalyst (SAPC) system was prepared from D-glucosamine and use with very good results in Suzuki Miyaura cross coupling reactions. Catalyst was also recycled. Attempt to prepare ligands grafted on SBA-silica matrix were made as well as ligands containing poly(ethylene) glycol moiety.

Keywords:

D-glucosamine, "Green chemistry", allylic alkylation, hydrogenation, organocatalysis, PEG, Silica supported catalysts, SAPC, homogeneous catalysis, heterogeneous catalysis. La D-glucosamine a utilisee pour la preparation de catalysateur type de SPAC (Supported Aqueous Phase Catalyst). Ce catalysateur hétérogène été utilisé avec de très bons résultats dans les réactions de couplage croisé de Suzuki Miyaura. Le catalyseur a également été recyclé. Des essais de préparation de ligands greffés sur une matrice de silice de type SBA-15 ont été réalisés ainsi que des ligands à base de poly (éthylène) glycol.

Résumé en Français

Mots-clés:

D-glucosamine, "chimie verte", alkylation allylique, hydrogénation, organocatalyse, PEG, les catalyseurs supporte sur silice, SAPC, catalyse homogène, catalyse hétérogène.