 Chapter 3: a review of the carbocyclizations of alkynes catalysed by gold(I) is the main topic of this chapter, an overview of the double activation based methods is also discussed.

 Chapter 4: the first part of our synthetic strategy towards vibsatins A and B is disclosed including the studies upon the 7-exo-dig Au(I)-catalyzed cyclization keystep leading to the bridged bicyclic skeleton of the vibsatins.

 Chapter 5: the subjects of this chapter deal with the three different functionalization pathways undertaken toward the accomplishment of the total synthesis of the vibsatins.

 Chapter 6: the deoxygenation problem, encountered in the course of this work, is discussed through all the attempted tests.

 Chapter 7: a summary of the most relevant methodological works and synthetic approaches is discussed, intended to conclude the document.

 Chapter 8: a list of references  Chapter 9: the experimental part gathering all the technical information and relevant analyses.

Preface

The ever-increasing prevalence of neurodegenerative disorders is an unsolved worldwide problematic for the healthcare system. Nervous system growth factors, i.e., neurotrophins, constitute a promising solution to these disorders; however, the development of these polypeptides is currently limited due to their unfavorable pharmacokinetic profile. In this context, vibsatins A 1 and B 2, two diterpenoids isolated as very minor metabolites in 2014 from a Chinese plant, have attracted our attention as these compounds were found to greatly enhance neurite outgrowth. Moreover, vibsatins reveal a structurally dense architecture featuring an unprecedented bicyclo [4.2.1]nonane framework. Since no total synthesis has been reported to date, it was important to develop a straightforward chemical route to evaluate and optimize the biological properties of the parent structure. In this context, the total synthesis of vibsatin A and vibsatin B constitutes the aim of this thesis work.

The key-step allowing the access to the dense bridged bicyclo [4.2.1]nonane skeleton of the vibsatins relies on a recently reported 7-exo-dig Au(I)-catalyzed cyclization. Notably, an intensive study on the key-step has been realized in order to optimize and scale-up this reaction.

The synthetic work directed towards the vibsatins, was devised exploiting the chiral information induced by the first stereocenter, which was asymmetrically installed at an early stage of the synthesis.

This document is composed of eight chapters:

 Chapter 1: the vibsane family is introduced and the various syntheses realized on parent natural substances are debated.

 Chapter 2: the general characteristics of vibsatin A and vibsatin B are presented along with their proposed biosynthesis and a general overview of the neurotrophic biological activity. An examination of the Conia-ene reaction is the conclusive argument.

Introduction

Vibsane-type diterpenoids are considered to be characteristic of the Viburnum since they have not been found in other higher plants. The genus Viburnum consists of about 150 species of shrubs or small trees that were previously included in the family Adoxaceae. 1 They are distributed in the temperate northern hemisphere, with a few species extending into tropical regions in South America and Southeast Asia, and about 15 species found in Japan. 2 Kawazu, in 1980, was the first to report the isolation of vibsane-type diterpenoids, from

Viburnum odoratissimum var. awabuki. Vibsane's skeleton consists of a fumulane framework with five additional carbons that generate an additional lateral chain at C-11 (Figure 1). 3

Figure 1

Vibsanins, a class of molecules of the vibsanes family, can be categorized into three subtypes depending on their carbon backbone, consisting of respectively: eleven-membered ring compounds, seven-membered ring compounds and the rearranged type, also known as the neovibsanins (Figure 2). Other sub-classes of seven-membered ring vibsanins include:

aldovibsanins, featured by a [5.3.0]-bicyclic fused skeleton between carbons 5 and 10, furanovibsanins, in which the ring fusion is located between carbons 4 and 5, and cyclovibsanins which are composed of a tricyclo[6.3.2.0 0.0 ]tridecane skeleton (Figure 2). 4 Figure 2

Synthetically, vibsanins have started to attract the attention of organic chemists at the beginning of the 21 st century, when the biological activity of these compounds was discovered.

Structural studies and biogenetic pathway

The first vibsane-type diterpenoids that were reported by Kawazu were vibsanins A, B, and F respectively 3, 4 and 5 (Figure 3), which possess an 11-membered ring derived from fumulene, and vibsanins C 6, D 7 and E 8 (Figure 4) characterized by a 7-membered ring.

Notably, the structure of vibsanin E is the only one bearing a [6.3.2.0 0.0 ]-tricyclic framework. 5 Figure 3

Figure 4 In the course of the structural studies on vibsanin B 4, Fukuyama and co-workers discovered that heating 4 at 110°C for one hour provided a mixture of four products in which the sevenmembered vibsanin C 6 was the prevailing compound (86%) along with 5-epi-vibsanin C and two other non-natural epimers. These results led to propose that a plausible biogenetic pathway for the synthesis of seven membered ring vibsanes would involve an oxy-Cope rearrangement (Scheme 1). Thus, the absolute configuration of the 11-membered ring vibsanin B turns out to be completely correlated with that of the 7-membered ring vibsanin C.

At this point, saponification of the enol ester function of 6 followed by an intramolecular aldol condensation reaction afforded the resulting aldehyde 9. Conversion of the alcohol at the C-18 position into the bromophenyl carbamate allowed to perform X-ray crystallographic analysis on 10, which unambiguously established the absolute 5S, 10S, and 11S configurations of vibsanin C 6. This result implies that vibsanin B 4 chiral centers are respectively 7R, 8R, and 11S. 6 Scheme 1

The same group reported the conversion of vibsanin C 6 into vibsanin E 8 through a cationic process, precisely by treating 6 with BF 3 .

OEt 2 (Scheme 2). 7 Coordination of boron complex by the ketone at C4 allows the Michael addition reaction (at C2) of the C14-C15 double bond leading to intermediate 11. At this point, the alcohol function at C18 traps the carbocation previously formed at C15, providing vibsanin E 8

(pathway a).

This reaction could even explain the biogenetic pathway that leads to the synthesis of cyclovibsanins. Hence, once the carbocation at C15 is formed, elimination of a proton from one of the two methyl groups in 11 gives rise to 12. Concomitantly, dehydration produces the exomethylene ketone 13 and then the C-4 carbonyl group is protonated triggering the cyclization that results in the formation of the tricyclic framework present in cyclovibsanins 14 (pathway b).

Scheme 2

A biogenetic pathway for the biosynthesis of furanovibsanins was proposed starting from the same assumption. 8 Biogenetic conversion of vibsanin C 6 to furanovibsanins can be intended by a cationic process (a, Scheme 3) followed by an acetal formation between C4 and C7.

Subsequent intramolecular addition of the alcohol at C-18 position onto the isoprenyl cation 15 affords furanovibsanin F 16. At the same time, another plausible pathway leading to a slightly different product (b, Scheme 3) foresees an Alder-ene transformation providing bicyclic intermediate 17 which will then form an acetal generating the desired furanovibsanin D 18. 9

8 Fukuyama, Y.; Minami, H.; Matsuo, A.; Kitamura, K.; Akizuki, M.; Kubo, M.; Kodama, M. Chem. Pharm. Bull. 2002, 50, 363-371. 9 Kubo M.; Fujii T.; Hioki H.; Tanaka M.; Kawazu Y.; Fukuyama Y. Tetrahedron Lett. 2001, 42, 1081-1083.

Scheme 3

Neovibsanins, which correspond to rearranged type diterpenoids, are, from a biological point of view, the most interesting. Their discovery is relatively more recent since the first neovibsanins extracted were neovibsanin A 19 and neovibsanin B 20 in 1996. 10 It is only in the next decades that the others neovibsanins were discovered. Recently, it was found that neovibsanin A 19 and neovibsanin B 20 are artefacts deriving from treatment of vibsanin 21

in MeOH. Neovibsatins are categorized into three subclasses: ketal neovibsanins, caged neovibsanins and bicyclic neovibsanins (Figure 5).

Figure 5

Their biosynthesis was postulated starting from the same starting point: vibsanin B 4. The first step is assumed to be an acid-catalysed rearrangement of the eleven-membered ring to 10 Fukuyama Y.; Minami H.; Takeuchi K.; Kodama M.; Kawazu K. Tetrahedron Lett. 1996, 37, 6767-6770. give cyclohexene 22 which undergoes acid-catalysed intramolecular conjugate addition of the allylic alcohol to provide intermediate 23. At this stage, two outcomes are possible: pathway a leads to acid-catalysed hemiketal formation 24, providing the tricyclic ketal neovibsanins (Scheme 4). Following pathway b, acid-catalysed dehydration to give 25 followed by nucleophilic addition (path c, Scheme 4) delivers bicyclic neovibsanins. However, if cation 25 is intramolecularly trapped by the alkene of the prenyl side-chain (path d, Scheme 4), the caged neovibsanins are formed 26.

Scheme 4

Biological activity

In 1980, Kawazu reported the first isolation of a piscicidal compound, vibsanin A 3, and a plant growth inhibitor, vibsanin B 4. 11 Later, many vibsane-type diterpenoids were reported, among which, vibsanin C 6, 5-epi-vibsanin C, vibsanol A 12 , and vibsanins K and P 13 exhibited significant and/or moderate cytotoxicity against tumor cells.

More interesting is the activity of neovibsanins. Indeed, it has been established that neovibsanin 21, neovibsanin A 19 and neovibsanin B 20 possess neurotrophic activity, i.e.

these molecules are capable to enhance the action of nerve growth factor (NGF), a protein implicated in life cycle of neurons, in appropriate cell population. 14 More specifically, it has 11 Kawazu K., Agric. Biol. Chem. 1980, 44, 1367-1372. 12 ; Wang C.-H., J. Nat. Prod. 2004, 67, 74-77. (b) Tang W.; Kubo M.; Harada K.; Hioki H.; Fukuyama Y., Bioorg. Med. Chem. Lett. 2009, 19, 882-886. 14 Brinton R.S.; Yamazaki R.S., Pharm. Res. 1998, 15, 386-398. been shown that they promote neurite outgrowth of NGF-mediated PC-12 cells at concentrations ranging from 10 to 40 µM. Among the three compounds, neovibsanin A seems less potent than neovibsanin and neovibsanin B. However, all of them had no effect on morphology of PC12 cells in the absence of NGF. Additionally, other vibsane-type diterpenoids such as 7-membered and 11-membered ring subtypes have not been found to show neurotrophic activity in PC12 cells so far.

However, the neurotrophic activity will be developed and discussed more deeply in chapter 2.2.

Reported total synthesis

Up to date have been reported seven total synthesis of vibsane-type diterpenoids. One of them aimed to the synthesis of the 11-membered ring (+)-vibsanin A 3 along with two total synthesis of 7-membered ring compounds, specifically (±)-vibsanin E 8 and (-)-5-epivibsanin E 27. On the other hand, four total synthesis of rearranged-type vibsanins have been accomplished, respectively: (±)-2-O-methylneovibsanin H 30, (-)-neovibsanin G 31, (-)-14epi-neovibsanin G 32 and (±)-neovibsanin B 20. Besides these seven total synthesis, one formal enantioselective synthesis of (+)-neovibsanin B 20 has been described.

The total synthesis of the 11-membered ring of (+)-vibsanin A 3 is based on a ring closure exploiting a Nozaki-Hiyama-Kishi (N.H.K.) reaction (Scheme 5, A). The total synthesis of both (±)-vibsanin E 8 and (-)-5-epi-vibsanin E 27 relied on a formal [4+3] cycloaddition in order to construct the 7-membered ring followed by a hetero Diels-Alder reaction to complete the skeleton (Scheme 5, B). One total synthesis of racemic (±)-neovibsanin B 20 was pubblished. This report exploited a cationic process for providing access to the framework of (±)-neovibsanin B 20 (Scheme 5, C). Starting from this assumption, an enantioselective formal synthesis of the same molecule was also reported. (-)-Neovibsanin G 31, (-)-14-epineovibsanin G 32 and (±)-2-O-methylneovibsanin H 30 have a common point, their skeletons have been set up starting from the same intermediate (Scheme 5, D). The latter undergoes two diverse rearrangements leading to various backbones depending on the reaction conditions.

Scheme 5

Total synthesis of (±)-vibsanin E and (-)-5-epi-vibsanin E

Vibsanin E 8, 15 attracted attention of various groups around the world because of its synthetically challenging structure featured by five stereocenters installed on the tricyclic backbone. At the beginning, the Williams group reported the synthesis of the vibsanin E core, 4 while the Srikrishna group investigated a ring closing metathesis approach towards the bicyclic core of the molecule. 5 The total synthesis of this natural product along with its epimer, 5-epi-vibsanin E 27, 16 was completed through a collaborative effort between the Davies and Williams groups. Indeed, they exploited the sequential cycloaddition reaction developed by the Davies group and the Williams extensive experience on vibsatin E structure. [START_REF] Davies | Advances in Cycloaddition[END_REF] Retrosynthetically, Davies and Williams envisaged that the two side-chains of 8 and 27 could be installed through a 1,4-addition followed by an α-alkylation on the corresponding enone 33 (Scheme 6), they expected to obtain a trans-configuration between these two stereocenters exploiting chirality transfer throughout the tricyclic structure. The two fused six-membered rings could be formed through a hetero Diels-Alder cyclisation of 34. Noteworthy, the stereochemical outcome of this reaction at the C2 carbon was logically 15 Schwartz B.D.; Denton J.R.; Davies H.M.L.; Williams C.M., Aust. J. Chem. 2009, 62, 980-982. 16 Schwartz B.D.; Denton J.R.; Lian Y.; Davies H.M.L.; Williams C.M., J. Am. Chem. Soc. 2009, 131, 8329-8332. [START_REF] Davies | Advances in Cycloaddition[END_REF] ; Houser, J.H. J. Am. Chem. Soc. 1998, 120, 3326-3331. (c) Reddy, R.P.; Davies, H.M.L. J. Am. Chem. Soc. 2007, 129, 10312-10313. assumed to follow the configuration at C11, which was previously controlled through a

formal asymmetric [4 + 3] cycloaddition.

Scheme 6

The synthesis began with an enantioselective formal [4 + 3] cycloaddition between diene 36 and vinyldiazoacetate 37, catalysed by the chiral rhodium catalyst Rh 2 (R-PTAD) 4 38.

Mechanistically, [Rh]-catalyst inserts into the diazocompound 37 and produces a cyclopropane 39 through a metallacyclobutane. The cyclopropane then rearranges (Cope rearrangement) providing cycloheptadiene 40 in 65% yield and 90% ee (Scheme 7), notably, using this chiral catalyst, the first quaternary stereocenter at C11 was controlled.

Scheme 7

Once the seven-membered ring was obtained, 40 was converted into aldehyde 41 over 5 steps to give the hetero Diels-Alder precursor (Scheme 8). Subsequent treatment of this aldehyde with BF 3 •OEt 2 afforded cycloaddition adduct 42 in 85% yield with the right stereoconfiguration at C2. Reduction of enol ether 42 delivered the third stereocenter at the C3 position, sequential allylic oxidations, then, furnished tricycle 43. With the tricyclic core in hands, stereoselective installation of the C5 and C10 side-chains was achieved. To this aim, Williams group successfully employed the cuprate derived from MOMOCH 2 Li to perform a diastereoselective conjugate addition on the enone 43 (91% yield). TMSCl addition was found to be essential in driving this reaction and quenching out the kinetic enolate.

Subsequent transmetallation of silyl enol ether 44 with MeLi, followed by trapping of the enolate with allyl bromide provided 45 in 74% yield. Heating 45 under microwave for 2 hours at 185°C in toluene (8.5 mM) resulted in a Claisen rearrangement affording a mixture of 41% cis and 11% trans-products (respectively 46 and 47). Although diastereoselectivity was not fully controlled, both epimers were useful; vibsanin E 3 and 5-epi-vibsanin E 27 could be accessed through each of these epimers. Towards 5-epi-vibsanin E 27, cis-epimer 46 was deprotected to restore the primary alcohol, which was oxidised into the corresponding aldehyde. The allylic lateral chain at the C5 position was oxidized under Wacker conditions allowing the final elaboration of the C10 side-chain starting from 48 through an Anders-Gaβner 18 variant of the Wittig reaction. Indeed, treatment of aldehyde 48 with ylide 49 finally provided 5-epi-vibsanin E 27 (Scheme 8).

Scheme 8

To complete the synthesis of vibsanin E 8, the yield of 47 had to be improved. Fortunately, the cis/trans ratio relative to the Claisen rearrangement could be modified: by changing the concentration (0.02M) and the reaction time (5 hours) 34% of the cis-isomer 46 and 26% of the desired trans-isomer 47 were obtained. It was also found that 46 could be epimerised into 47 in 51% yield using K 2 CO 3 in MeOH under microwave irradiation (Scheme 9). This improvement allowed 47 to be obtained in 44% yield from enol 45. After subjecting 47 to the same conditions asfor the synthesis of the 5-epi-vibsanin E 27, the total synthesis of vibsanin E 8 was achieved. From this point, Williams and his group envisaged that the bicyclic core of the molecule could be accessible by exploiting a cationic rearrangement, hypothesized in the Fukuyama biogenesis, in which the intermediate allylic cation is captured by the solvent. An esterification of the aldehyde at the C10 side chain would then provide (±)-2-Omethylneovibsanin H 30.

Scheme 10

Treatment of cyclohexenone 50 with isoprenyl magnesium bromide in the presence of CuI and subsequent oxidation and Baylis-Hillman reaction afforded keto alcohol (±)-51 as a racemic mixture in 24% yield over three steps (Scheme 11). The primary alcohol was protected and it was found that treatment of the latter with LDA and ethyl iodoacetate delivered a mixture of diastereoisomers in which (±)-52 (10R) and (±)-53 (10S) were respectively obtained in 37% and 24% yield. Several two-carbon nucleophiles were explored in an attempt to install the enone functionality on (±)-52, but without success. A two steps approach was thus employed. Treatment of ketone 52 with lithium dithiazide yielded 57% of the corresponding lactone (±)-54, stereo-and chemoselectively. Subsequent deprotection and reaction of the resulting aldehyde with ylide 55 provided enol (±)-56 in 66% yield (2 steps).

Inspired from the biogenetic pathway of neovibsanines, it was discovered that the treatment of the latter enone (±)-56 with sulphuric acid in methanol at room temperature initiated a five steps cascade leading to (±)-57 diastereoselectively. Notably, this reaction consists in:

deprotection of the primary alcohol (58), intramolecular 1,4-addition of the alcohol onto C5 (59), solvolysis via allyl cation that induces ring opening of the lactone ( 60), epimerisation at the C5 position and final esterification. Once the four stereocenters were relatively controlled, conversion of the ester into the corresponding aldehyde allowed the installation of the sidechain starting from (±)-61 and using DMAP and 3,3-dimethylacrylic anhydride in order to complete the synthesis of (±)-2-O-methylneovibsanin H (±)-30. This synthesis was an important milestone in synthetic vibsane chemistry, as it represented the first total synthesis of a vibsane natural product, and lent support to Fukuyama's proposed biosynthesis.

Scheme 11

Total synthesis of (-)-neovibsanin G and (-)-14-epi-neovibsanin G

Neovibsanin G 31 and 14-epi-neovibsanin G 32 are synthetically intriguing targets due to their structurally dense bicyclo [3.3.1]nonane caged ring system. After having realised the total synthesis of (±)-2-O-methylneovibsanin H (±)-30 exploiting the 5-steps-cascade reaction, the William's group imagined a different route for intermediate 56. Indeed, in the absence of a nucleophilic solvent like methanol, the secondary carbocation on the C2 position would be trapped by the olefin located at C14-C15 leading to a tricyclic structure featuring a tertiary carbocation at C15 (Scheme 12). Thus, key intermediate 56 had to be obtained in an enantioenriched form in order to pursue an enantioselective synthesis of the targets.

Scheme 12

In order to control all four stereocenters, the key-point was the asymmetric synthesis of the quaternary center at C11 position, the control of the other stereocenters being expected from chirality transfer. A chiral NHC-Cu catalytic system for conjugate additions recently developed by Mauduit and Alexakis seemed to be suitable for this purpose. 20 Indeed, addition of isoprenyl magnesium bromide to 3-methyl-2-cyclohexenone in the presence of chiral NHC

Scheme 13

Total synthesis of (±)-neovibsanin B

As previously mentioned, among the numerous vibsane-type diterpenoid targets, neovibsanins A and B are the most valuable from a biological point of view, therefore, these ketal-bearing neovibsanins have been the subject of a number of synthetic studies from various groups. The Mehta group has investigated the synthesis of the tricyclic core, 22 while the Williams group has completed the synthesis of 4,5-bis-epi-neovibsanins A and B. 23 The first total synthesis of neovibsanin B 20 was achieved by Imagawa and Nishizawa, 24 in collaboration with Fukuyama, using a biosynthetical-inspired route. Retrosynthetically, the Nishizawa's group started by disconnecting the methyl group in C7 position to give lactone 70 (Scheme 14). They then proposed that the latter lactone would be derived from a biogenetic inspired cascade from cyclohexene 71. The four carbons required for the two fivemembered rings were introduced by 1,2-addition and a Baylis-Hillman reaction on the 22 11, 1253-1255. intermediate 72, which could be formed using an intramolecular Diels-Alder from homogeranic acid 73.

Scheme 14

Homogeranic acid 73 was esterified to give tetraene 74 in 79% yield over two steps. Heating the tetraene in 1,3-dimethylimidazolidin-2-one (DMI) as solvent at 200°C afforded lactone (±)-75 in 56% yield (Scheme 15). Subsequent reduction of the lactone, selective protection of the primary alcohol with 2,4-dimethoxybenzyl chloride (2,4-DMPMCl) and oxidation of the secondary alcohol delivered (±)-76 in 62% over four steps. A Baylis-Hillman reaction allowed to introduce the hydroxymethyl group, which was subsequently protected to give (±)-77 in 83% yield, over two steps. To complete the core of neovibsanin B, lithio ethyl propiolate was stereoselectively added in 87% yield to afford (±)-78, the stereospecificity and efficacy of this process relying on the coordinating effect of the polyoxygenated 2,4dimethoxybenzyl protecting group on the lithiated nucleophile (Figure 6).

Figure 6

Unsaturated ester (±)-78 was partially reduced with Red-Al to give the E-alkene (±)-79 in 89% yield. TBS deprotection induced concomitant furan formation and subsequent lactonisation to give (±)-80 in 87% yield. At this stage, the primary alcohol was transformed into its -TBS derivative. Elaboration of the characteristic ketal ring system (±)-81 was completed by action of Tebbe's reagent and subsequent acid catalysed addition of methanol on the resulting vinyl ether in 75% yield over four steps. Finally, synthesis of neovibsanin B (±)-20 was completed by deprotection of the alcohol, oxidation into aldehyde and trapping of the corresponding potassium enolate by acid chloride. Synthetic (±)-neovibsanin B (±)-20

was found to have a similar degree of activity on neurite outgrowth as natural (+)neovibsanin B.

Scheme 15

Formal enantioselective total synthesis of (+)-neovibsanin B

As neovibsanin B 20 was a biologically active target, an enantioselective synthesis of this compound was of primary interest. In this context, the Fukuyama's group reported the formal enantioselective total synthesis of this natural product in 2010. 25 The target of They envisioned that upper fragment 96 would be obtained from commercially available 4pentynyl acetate 98 through an asymmetric epoxidation that will control the configuration of stereocenters C6 and C7. A Barbier-type allylation procedure on geranyl chloride 99 would deliver the lower fragment 97. In the latter case, they assumed that employing a chiral aldehyde like L-glyceraldehyde would allow to control the configuration of the quaternary center C11.

Scheme 18

The synthesis of the lower fragment 97 began with the construction of the quaternary stereocenter (Scheme 19). This stereocenter was installed by a zinc-mediated Barbier-type allylation in an aqueous medium involving L-glyceraldehyde acetonide 100 and geranyl chloride 99 to generate a 6:1 mixture of diastereomers in favour of the desired isomer 102a.

In this reaction, L-glyceraldehyde 100 was employed as the chiral source, indeed, the 27

Conclusions

The principal characteristics of vibsane-type diterpenoids have been presented in this chapter.

Starting from an introduction of vibsanins and passing through the different classes and subclasses of these natural products, the molecular structures have been elucidated along with the most reliable proposed biogenetic pathways.

Vibsatins A and B: presentation and synthetic analysis

In this chapter, vibsatin A 1 and vibsatin B 2 will be introduced. Their origins, a proposed biogenetic pathway and their biological properties will be discussed. Our retrosynthetical analysis for the realization of their total synthesis will be presented followed by a focus on the key step reaction, identified as a Conia-ene reaction.

Vibsatins A and B

In the last chapter, vibsane-type diterpenoids were disclosed together with a presentation of their different subtypes. Very recently, in 2014, a new subtype of these diterpenoids was reported by He and Zhao: vibsatin A 1 and vibsatin B 2 (Figure 7). These two molecules were isolated in low yields, respectively 2.9 . 10 -5 % for 1 and 7.3 . 10 -5 % for 2, from Viburnum tinus cv. variegatus by extraction with acetone, partition in ethyl acetate and subsequent purifications by flash chromatography. 28 Notably, Viburnum tinus cv. variegatus is a cultivated species of Viburnum tinus. [START_REF] Li | Landscape Architecture Trees of China[END_REF] First phytochemical investigations on this plant resulted only in the isolation of various compounds like iridoids, coumarins, saponins and flavonoids associated with neuroprotective, hepatoprotective, sedative and spasmolytic activities. [START_REF] Yilmaz | [END_REF] No new chemical constituents were reported from this plant until the discovery of vibsatin A and vibsatin B.

Figure 7

The and a new bond between C13 and C2 (Figure 8). The structures and the absolute configurations have been confirmed using X-ray diffraction and vibsatin B 2 proved to be the C3 epimer of vibsatin A 1. Notably, the configurations confirmed to be: 2R, 3S, 5S, 10S, 11S

for vibsatin A 1 and 2R, 3R, 5S, 10S, 11S for vibsatin B 2.

Figure 8

A biogenetic pathway starting from geranylgeraniol 115 (Scheme Neurodegenerative disease (NDD) is a general term for indicating heterogeneous and often sporadic maladies that are characterized by progressive dysfunction of the nervous system, resulting from loss of neural structure and function as well as from brain-death. 31 Alzheimer,

Parkinson and Huntington diseases are notable examples of these disorders. 32 Nowadays, these diseases affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion per year. 33 Efforts to understand their progression point to various molecular and cellular events, like accumulation of misfolded proteins, protofibril formation, dysfunction of the ubiquitin-proteasome system, mitochondrial damage, oxidative stress, and synaptic failure. [START_REF] Bossy-Wetzel | [END_REF] However, the etiologies of these diseases still remain under investigation and, noteworthy, very limited treatment options are currently available.

The neurotrophin family (NTF) forms a class of functionally and structurally related proteins that regulates growth, differentiation and survival of central and peripheral neurons. NTF includes Nerve Growth Factor (NGF), brain-derived neurotrophic factor (BDNF), TrkC but also binds TrkA and TrkB, noteworthy all neurotrophins bind to p75. 35 The imbalance in neurotrophin receptor activity described to occur in neurodegenerative diseases may constitute a promising target for therapy.

Trk-signals are normally required for neuronal maintenance and function, and defects in Trkreceptor tyrosine kinase activation (e.g. reduced receptor expression, impaired cellular transport, agonist deficiency) are associated with early stages of neurodegeneration. This supports the view that Trk-agonism may be therapeutic (Figure 9). N. Engl. J. Med. 1999, 340, 1970-1980. 32 (a) The p75 receptors, which are members of the TNFα receptor superfamily, are implicated in normal developmental pruning and neuronal death. When upregulated and activated in certain tissues, they can cause neurotoxicity associated with neurodegenerative diseases. Notably, the p75 receptors are commonly upregulated in neurodegenerative states. This supports the view that p75-antagonism may be therapeutic.

In summary, the neurotrophin imbalance underlying neurodegenerative diseases can be a disease-modifying therapeutic target. The pathogenic mechanisms of increased p75 expression and/or signaling can be counteracted by p75 antagonism. A decrease in Trk expression and/or signaling can be therapeutically corrected by Trk agonism.

While the rationale for targeting Trk and p75 is robust, clinical validation is mostly absent because it requires the use of disease-modifying drugs acting through these receptors. The use of the neurotrophins themselves as drugs has mostly failed despite significant efforts and growingly sophisticated -yet risky-delivery methods (these molecules must be administered directly into the central nervous system). The poor pharmacological profile of these large proteins, short half-lives, inability to penetrate tissue barriers, undesirable high potency and pleiotropic effects, and the activation of multiple receptors (where p75 activity can negate the benefit of Trk activity) may significantly reduce the therapeutic benefit. Thus, there is an urgent need for drugs without such setbacks.

The development of small molecule drugs that target neurotrophin receptors could overcome these obstacles. Currently, a number of clinical trials are being carried out using neurotrophic factor mimetics. Results from these trials, especially concerning side effects and efficacy, will broaden and enhance neurotrophic factor-based therapy for treating neurodegenerative disorders. 36 In this field, natural products displaying neurotrophic activity hold significant promise as tools for biological studies and as original and privileged structures; presently, several compounds are in clinical trials. However, often, the chemical biology of neurotrophic natural products has not been methodically explored. This could be due to the complexity of pathways that account for neural degeneration and the difficulties related to conducting biological experiments in primary neural cells.

The readily available rat pheochromocytoma (PC-12) cell line offers an attractive and reliable alternative to the primary cell cultures and has been used as a good in vitro model of neuronal differentiation. After stimulation with NGF, PC-12 cells differentiate to extend neurites and develop the characteristics of sympathetic neurons. 37 It has been found that neovibsanin 21, neovibsanin A 19 and neovibsanin B 20 possess neurotrophic properties. Namely, they promote neurite outgrowth of NGF-mediated PC-12 cells at concentrations ranging from 10 to 40 M. [START_REF] Kishimoto | The 126th Annual Meeting of Pharmaceutical Society of Japan[END_REF] As shown in Figure 10, neovibsanin (Figure 10B), neovibsanin A (Figure 10C), and neovibsanin B (Figure 10D) significantly promoted neurite outgrowth from NGF (10 ng/mL)-treated PC-12 cells at 40 M (Figure 10A is the control experiment). Among these three compounds, neovibsanin A seems less potent than neovibsanin and neovibsanin B. However, all of them had no effect on morphology of PC-12 cells in the absence of NGF. Additionally, other vibsane-type diterpenoids such as 7membered and 11-membered ring subtypes have not been found to show neurotrophic activity in PC-12 cells so far. In the course of the investigation concerning Viburnum tinus cv. variegatus, the ability to stimulate the nerve growth factor (NGF) mediated neurite outgrowth on PC-12 cells was examined for all the various resulting isolated fractions. From these studies, it was reported that vibsatin A 1 increased the neuronal differentiation in 72h at a concentration of 10 μM, in the presence of 5 ng/mL of NGF.

Because of this promising biological activity and the challenging structural core of vibsatins A and consequently B, our group cultivated interest for the total synthesis of these two novel diterpenoids in order to provide a better understanding of the mechanism of neurotrophic action as well as to lead to the synthesis of analogues with promising neurotrophic activity.

Synthetic strategy

To this aim, it was developed a retrosynthetic pathway in which, after having asymmetrically configured one stereocenter, all the others would be controlled by chirality induction exploiting the bicyclic shape of the molecule. Accessing the bicyclo [4.2.1]nonane skeleton of vibsatins appeared as the most challenging step of this synthesis. In the last years, gold chemistry demonstrated to be a powerful tool in carbocyclizations. Thus, it has been foreseen to employ a Conia-ene derived 7-exo-dig cyclization catalysed by a gold(I) complex in order to access to 121 starting from enantiomerically enriched silyl enol ether 122 (Scheme 24). An asymmetric Michael addition starting from 2-methylcyclopentanone 123 would provide the 2(R) configuration at C11 required for the precursor 122. This Conia-ene derived reaction was identified as the key-point of the strategy since in one single reaction, the challenging

Conia-ene reaction, a brief overview

The key stage, as specified before, relies on a transformation derived from the renowned Conia-ene reaction. As described by Conia and Le Perchec in their in-depth review in 1975, 39 the original version of this reaction refers to the thermal intramolecular cyclization of enolizable carbonyl compounds 126 with a tethered alkyne or alkene moiety leading to valuable five-or six-membered carbocycles 127 (Scheme 25a). In this reaction, the enol tautomer of the ketone 128 undergoes an Alder-ene type rearrangement delivering the cyclic product. Nevertheless, without extra-stabilization effects that favour the enol form, the available amount of this nucleophilic form is scarce and the use of high temperatures (usually between 250°C and 350°C) is required to trigger the cyclization. For this reason, the tolerance of functional group is restricted and decomposition of the substrate is often produced severely limiting the synthetic utility of the reaction. In the case of carbonyl compounds with a tethered alkyne, a direct consequence regards the isomerization of the newly formed double bond, which, at these temperatures, shifts from exo-position to thermodynamically favoured endo-position 129. This shows that, obviously, conjugation effects influence the transformation. Indeed, the isomerized compound 129 is usually obtained from a thermal Conia-ene reaction, as in the case of oct-7-yn-2-one 130 which, if heated to 260°C, provides a mixture of 131 and 132 in 85:15 ratio (Scheme 25b). 40

Scheme 25

Because of the harsh reaction conditions and the lack of selectivity of the reaction, various modifications have been accomplished during the years. One approach utilised to overcome these problems was the utilization of β-dicarbonyl compounds as substrates. Indeed, carbonyl compounds providing an extra stabilizing group in the β-position offer various advantages:

the presence of an extra electron-withdrawing group is beneficial for the acidity and enolization rate. Moreover, the enol is stabilized by hydrogen-bonding between the OH of the enol and the basic oxygen of the β-functionality. Additionally, these compounds can act as efficient chelate ligands for hard Lewis acids. Upon coordination, the substrates experience an increase in acidity thus facilitating deprotonation and metal enolate formation (Figure 11).

Notably, the introduction of an additional carbonyl function in the β-position of the original carbonyl moiety allowed the development of catalytic conditions; in this topic, a recapitulatory review on catalyzed Conia-ene cyclizations of β-dicarbonyl compounds has been recently published by Enders et al. 41 Figure 11 40 Different catalytic systems have been developed in order to catalyse Conia-ene reactions.

These systems are divided into five different subtypes depending on the activation mode (Scheme 26). 42 a) The first method regards the enolate activation by a metal, however, there are only a few examples of this kind of activation due to the fact that the involved carbocyclization is an endothermic process. Interestingly, the addition onto the triple bond occurs in an antifashion for metals like Na and Li and in a syn-fashion for Ti and Sn (Scheme 26a).

b) Activation of the alkyne moiety, instead, is a more common and more studied type.

Generally, late-transition metals trigger carbocyclization in this way thank to their soft carbophilic Lewis acid character. The addition takes place in an anti-fashion (Scheme 26b).

c) Ene-yne activation is related with transition metals that usually catalyse [2+2+2] cycloadditions such as Co and Ni. In this case, even if products seem to be issued from a simple Conia-ene reaction, the process includes oxidative addition, β-hydride elimination and reductive elimination. For this reason, the addition of the enol onto the alkyne is realized in a syn-fashion (Scheme 26c).

d) Recently, methods for activating the enol and the alkyne moieties have been the subject of various researches. It has been found that some metals possess the ability to catalyse the cyclization of β-dicarbonyl compounds acting on both the enol and the triple bond if combined with external factors (bases, microwaves, etc.) and the addition follows a synaddition pathway. Interestingly, some of these metals are not particularly known for their capability to activate alkynes (Scheme 26d). 43 e) The usage of a hard metal ion able to chelate the enol moiety together with a softer carbophilic Lewis acid capable to activate the triple bond constitutes the fifth method, in which two metals activate two different moieties of the substrate. Notably, this method allows the development of asymmetric version as the hard metal ion easily coordinates chiral phosphines. The attack proceeds through an anti-fashion manner (Scheme 26e).

Scheme 26

To this aim, a few examples of the exploitation of this chemistry in total synthesis are reported below. One elegant total synthesis realized through a key Conia-ene reaction of a malonate moiety, is the total synthesis of (+)-oxazolomycin, published by Hatakeyama in 2011. 44 Starting from homopropargylic alcohol 133 and triflate derivative 134 the amidomalonate 135 was synthesised in five steps (Scheme 27). Indium(III) triflate (In(OTf) 3 )

proved to be able to catalyse the cyclization of 135 into pyrrolidone derivative 136. In this case, the catalyst activates either the triple bond or the enol moiety. A strong base is required and high temperatures are needed. Subsequently, 23 more steps were required to access to (+)-oxazolomycin 137.

Scheme 27

One impressive synthesis of phyllocladane skeleton was reported by Malacria in 1996 exploiting ene-yne activation of a cobalt(I) catalyst to a β-ketoester followed by [2+2+2] and 44 Eto, K.; Yoshino, M.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2011, 13, 5398-5401.

[4+2] cycloaddition reactions (Scheme 28). 45

Scheme 28

In some cases, the developed catalytic conditions are extremely performing, leading to the utilization of about 1 mol% of catalytic charge. In this field, the cyclization of linear or cyclic β-ketoesters 144 to access cyclopentenes 145 catalysed by Au(I), reported by Toste in 2004, is depicted in Scheme 29. 46 Scheme 29 45 Cruciani, P.; Stammler, R.; Aubert C.; Malacria, M. J. Org. Chem. 1996, 61, 2699-2708. 46 Kennedy-Smith, J.J.; Staben, S.T.; Toste, F.D. J. Am. Chem. Soc. 2004, 126, 4526-4527. Although broadly applicable to the diastereoselective formation of a variety of cyclic and bicyclic systems, these methods are limited to the synthesis of quaternary carbon atoms that bear two carbonyl functionalities. Therefore, it has been envisioned to take advantage of the nucleophilicity of silyl enol ethers as 'frozen enol equivalents". However, unlike for enol nucleophiles, an external proton source is required in order to protodemetallate the intermediate vinyl-metal adduct and, thus, to complete the catalytic cycle. Nevertheless, despite some examples in which Pd catalysed 5-exo-dig cyclizations of alkyne-tethered silyl enol ethers have been reported, 47 in most of the reports dealing with the use of silyl enol ethers, a Au(I)-based cationic complex was selected as catalyst. The mechanism of this kind of reactions will be discussed in section 3.2.6. Remarkably, in synthetic chemistry field, employing silyl enol ethers as nucleophiles in Conia-ene carbocyclizations is generally seen as a more elegant solution, although it is necessary to stoichiometrically install the silyl enol ether function.

One example is the synthesis of the [6-6-5-7] tetracyclic core of daphnilongeranin B reported in 2014 by Shao and Li (Scheme 30). 48 Cyclohexenone 146 was transformed into silyl enol ether 147 in two steps. Alkyne activation was exploited by using triphenylphosphino gold(I) bistriflimide complex (PPh 3 AuNTf 2 ) in order to perform a 6-exo-dig cyclization and afford the [6-6] bicyclic compound 148. The [6-6-5-7] tetracyclic core of daphnilongeranin B 149 was synthesized then in 9 steps.

Conclusions

In this chapter, Vibsatin A 1 and vibsatin B 2 were introduced (Figure 12). Their unique bridged [5,7] bicyclic structures were elucidated along with a biosynthesis proposed by He and Zhao. Then, an introduction on neurodegenerative diseases followed by a disclosure of neurotrophins and neurotrophic activity was presented. Thus, the preliminary biological essays on vibsatin A 1 explaining the deriving interest in these molecules were illustrated.

Figure 12

The retrosynthetic pathway elaborated by our group was described along with a focus on the involved key-step reaction type (Scheme 31). The general characteristics of the metal catalysed Conia-ene reaction were reported, highlighting the most important keypoints relative to substrates, mechanisms and activation modes. Selected examples of applications in total synthesis complete the chapter and provide an overview on the practical utilization of these processes.

Carbocyclization of alkynes: gold(I) catalysis and double activation

In this chapter, the gold(I)-catalysed reactions of alkenes with alkynes for the synthesis of carbocycles will be discussed and a special attention will be devoted to silyl enol ethers. At the beginning, the most relevant historical examples of these carbocyclizations will be reviewed giving a brief overview over the activation methods reported in the last century.

Then the emerging technologies will be examined and a particular focus will be paid to the Conia-ene reaction, that will further constitute the key-step of our strategy towards the total synthesis of Vibsatins A and B. In the final part, combination of organo-and metal-catalysis will be examined as a novel area in carbocyclization chemistry.

Pioneeristic works

The first example of guided carbocyclization between a silyl enol ether and a triple bond moiety was reported by Conia and his group in 1985. 49 They were searching a method capable to catalyse thermal Conia-ene cyclizations in order to perform this kind of transformations at lower temperature. 39 It was found that the use of stoichiometric mercury(II) salts was efficient to catalyse the cyclization of easily enolizable alkynyl-βdiketones. 50 They then exploited HgCl 2 in order to perform 5-exo-dig and 6-exo-dig cyclizations of acetylenic carbonyl compounds through their trimethylsilyl enol ether derivatives 150 affording cyclic derivatives 151 (Scheme 32).

Scheme 32

Mechanistically, starting from simple silyl enol ether 152, it was demonstrated that 33). Notably, this reaction was reported on cyclic and acyclic substrates and 5-or 6membered rings were synthesized. The main drawback of this method was, obviously, the 49 stoichiometric utilization of mercury salt. Moreover, cyclization of α'-silyl enol ethers or internal alkynes were ineffective under these conditions.

Scheme 33

The subsequent example of activation of triple bonds toward C-alkylation of a silyl enol ether was described in 1998 by Iwasawa and his group. 51 Their objective was to exploit the tendency of triple bonds to form vinylidene and/or η 2 -complexes with carbonyl adducts of group 6 metals like Cr, Mo or W with general formula M(CO) 5

.

L (where L = THF, Et 3 N, etc.). Hence, it was found that TBS-based acetylenic silyl enol ethers like 156 undergo 5-and 6-endo-dig cyclization to give cyclohexenes 157 in the presence of stoichiometric or catalytic quantities of W(CO) 5

.

THF and a proton source like water or methanol (Scheme 34). Other metals like Cr and Mo were not effective for this kind of transformation. Finally, whereas internal alkynes were found to be inert, in this case α'-silyl enol ethers were shown to be reactive under these conditions.

Scheme 34

After extensive deuteration studies on simple silyl enol ethers like 158, the same group proposed that the reaction proceeds through both a η 2 -complex 159 and a vinylidene complex 160 (Scheme 35). Replacing one equivalent of water by 10 equivalents of D 2 O, a 1:1 mixture of monodeuterated products 161 and 162, deriving from 163 and 164, was obtained. 51 Maeyama, K.; Iwasawa N. J. Am. Chem. Soc. 1998, 120, 1928-1929.

Scheme 35

Yamamoto and his group, in 1999, described a similar reaction using an aluminium complex. 52 One year before, the same group reported an endo-selective Lewis-acid catalysed intramolecular allylsilylation of internal triple bonds and they decided to apply the same methodology to silyl enol ethers. 53 They found that treatment of alkynyl α-trimethylsilyl or alkynyl α'-trimethylsilyl enol ethers such as 165 with a stoichiometric amount of EtAlCl 2 afforded the 6-endo-cyclized products 166 in good to excellent yields (Scheme 36). The importance of this methodology relies on the possibility to react even internal alkynes, although a stoichiometric quantity of Lewis acid is still required.

Scheme 36

This reaction proceeds through a different pathway from those seen before. Indeed, the Lewis acid coordinates onto the triple bond of 167 and a vinyl metallate 168 is formed. Attack from the nucleophilic carbon of the silyl enol ether moiety on the newly formed carbocation provides the carbocycle 169 that, after elimination of TMSCl ( 170) and protodemetallation, affords the 6-endo-dig cyclized ketone 171 (Scheme 37). 52 Imamura, K.I.; Yoshikawa E.; Gevorgyan V.; Yamamoto Y. Tetrahedron Lett. 1999, 40, 4081-4084. 53 Imamura, K.I.; Yoshikawa E.; Gevorgyan V.; Yamamoto Y. J. Am. Chem. Soc. 1998, 120, 5339-5340.

Scheme 37

Gold mediated carbocyclizations of alkynes

The use of gold complexes in homogeneous catalysis is a fascinating story full of unforeseen developments. Although some reports regarding the chlorination of arenes mediated by AuCl or AuCl 3 were already published, it is possible to state the discovery of the potential of this kind of catalysts in the last decade of the 20 th century. The first application of gold in homogeneous catalysis is usually attributed to the report of Teles in 1998 54 in which the author introduce the activity of phosphine-gold cationic complexes. However, preliminary results regarding the activation of triple bonds using gold were reported by Hayashi in 1986. 55 Since then, homogeneous gold catalysis has seen an exponential growth leading to the development of many synthetic transformations of considerable importance for the building of complex molecular systems. Gold-based catalysts have been utilised to activate alkenes, allenes, alkynes, diazocompounds, nitriles etc.. Herein, we will only discuss the transformations regarding alkynes and their derivatives.

General considerations on Gold and its reactivity

Gold, along with silver and copper, is part of the 11 th group in the periodic table and shows the following electronic configuration 4f 14 5d 10 6s 1 . However, gold possesses characteristics that makes it differ from the other late-transition metals, for example the high red-ox potential and the relative inertness toward elementary organometallic reactions (i.e. oxidative insertion, reductive elimination and so on). Although both +1 and +3 oxidation states are catalytically active, Au(I) species have seen a broader utilization making them the most studied forms. Cationic gold(I) complexes, moreover, attracted interest from synthetic chemists all around the world due to their unique reactivity given by a strong Lewis acidity coupled with a great ability to stabilize cationic intermediates. Indeed, the widest application that Au(I) complexes have found is the activation of alkynes toward nucleophilic addition (Figure 13). 54 Teles, J.H.; Brode, S.; Chabanas, M. Angew. Chem. Int. Ed. 1998, 37, 1415-1418. 55 Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405-6406.

Figure 13

Gold(I) complexes selectively activate π-bonds of alkynes in complex molecular settings, this specificity has been related to relativistic effect. Before taking into account the general alkynyl activation methods reported with the usage of gold complexes, some key-points explaining why the behaviour of gold is so different compared to other metals and why gold is alkynophilic should be briefly explained from a theoretical point of view.

The relativistic effect arises from the confluence of quantum mechanics and special relativity.

The term "relativistic effect" refers to any phenomena resulting from the need to consider velocity as significant relative to the speed of light (c), indeed, this is the case of electrons. A primary issue of the special theory of relativity is that mass increases towards infinity as a body's velocity approaches c, which can be mathematically described as

m = m 0 /√[1-(v/c) 2 ]
where v is the velocity of the body, m is its mass and m 0 is its non-relativistic mass. In the case of atoms, the average radial velocity of a 1s electron Vr = Z, where Z is the atomic number and the expression can be calculated as c = 137. In this way, the relative mass of electrons can be weighted. The atomic number of gold is 79, and the resolved equation states m = m 0 / 0.81 that equals to m = 1.22 m 0 . This means that the recalculated relative mass of an electron is 22% heavier than the non-relative. At the same time, it is known that the Bohr radius of orbitals is inversely proportional to the mass of electrons, thus, the orbitals of gold are more contracted. This effect also applies to all other orbitals, not only the 1s 2 , putting the electrons closer to the nucleus and consequently enhancing the ionization potential. 56 The effects of this contraction are various, one of the most pronounced is that 6s orbital results in a greatly strengthened Au-L bonds, where L is a ligand. 57 Moreover, the relativistic contraction is responsible for the superior Lewis acidity of cationic Au(I) complexes compared with other metals of the 11 th group. The contraction makes the valence s and p orbitals correspond to a lower "lowest unoccupied molecular orbital" (LUMO) and therefore a strong Lewis acidity is resulting.

The last key-point that needs to be elucidated is the superior reactivity of Au-alkyne towards nucleophilic addition. Studies on Au + -ethylene and Au + -ethyne bonding indicate a ≈10 kcal 56 Gorin, J.D.; Toste, F.D. Nature 2007, 446, 395-403. 57 Desclaux, J.P.; Pyykko, P. Chem. Phys. Lett. 1976, 39, 300-303. mol -1 greater stabilization for the ethylene complex over the ethyne complex. 58 Since Au(I) apparently does not complex selectively alkynes over other π-systems, the observed reactivity may be due to discrimination by the nucleophile in selecting between Au(I)-activated electrophiles. In chemical synthesis, gold(I) complexes have been utilised to majorly perform four classes of transformation:

Synthesis

1. hydroarylation and hydroheteroarylation of alkynes, 2. reactions implying propargylic carboxylates, 3. addition of heteronucleophiles to alkynes, 4. and the most important, reactions involving alkenes with alkynes

Hydroarylation and hydroheteroarylation of alkynes

The direct auration of electron-rich arenes and heteroarenes by gold(I) and gold(III) is a wellknown process, but the resulting aryl-gold complexes are apparently not involved in subsequent C-C bond forming reactions with alkynes. 60 Indeed, aryl-gold(I) complexes only react with alkynes combined to a palladium(0) catalyst, or a palladium(II) precatalyst. 61 In the presence of triple bonds, electrophilic metal catalysts form, upon coordination to an alkyne, electrophilic complexes that undergo electrophilic aromatic substitution reactions with arenes. Gold(I) and gold(III)-complexes generally promote reactions according to this pathway. In the case of intermolecular hydroarylation, Sommer and Reetz demonstrated that terminal or internal aryl-substituted alkynes 175 provide 1,1-disubstituted alkenes 176 when treated with AuCl 3 and AgSbF 6 (Scheme 38a). It was additionally found that terminal electron poor alkynes 177 undergo hydroarylation affording 1,2-disubstituted alkenes 178 in the presence of Au(I)-complexes, although internal electron-poor alkynes revealed to be unreactive (Scheme 38b). 62 Usually, in this kind of reaction, gold catalysis provides better yields and milder reaction conditions compared to other metals. Finally, it is possible to control the regioselectivity of the formed double bond but not the substituting position of the arene counterpart.

Scheme 38

A wider applicability is attributed to intramolecular hydroarylations, as the problems of selectivity of the nucleophilic arylic position can be avoided by various methods. In this area, N-propargyl-N-sulfonylaniline 179 undergoes intramolecular hydroarylation in the presence of 5% of [JohnPhosAu(MeCN)]SbF 6 (181) affording dihydroquinoline derivative 180 (Scheme 39). 63

Scheme 39

In this reaction, the mechanism has been elucidated and, starting from anisole derivative 182, it foresees the nucleophilic attack of an aromatic carbon onto the Au(I)-alkyne adduct to form the cyclopropyl carbene 183 (Scheme 40). The latter subsequently rearranges and, after protodeauration, bicyclic compound derived from a 6-endo-dig cyclization 184 is provided.

Scheme 40 Generally, cyclizations which follow the 5-exo and 6-endo pathway are common, 6-exo transformations, instead, are less frequent. An interesting example of 6-exo-dig cyclization consists in the use of Au(I) catalysis for hydroarylation of o-propargylbiphenyls to afford phenanthrenes (Scheme 41). 64 Indeed, diphenyl derivatives like 185 cyclize in the presence of a catalytic quantity of (C 6 F 5 ) 3 PAuNTf 2 and a half equivalent of bistriflimide (HNTf 2 ) to give phenanthrene 186.

Scheme 41

Pyrroles and indoles, as well, undergo Au(I)-catalysed hydroarylation with alkynes. An interesting example is the recently reported synthesis of dihydroindoloazepinones from indole-3-carboxamides (Scheme 42). 65 N-propargylindoles 187 undergo 6-endo-dig cyclization in the presence of SPhosAuNTf 2 to provide spiro-intermediates 188, which instead of passing through a cyclopropyl carbene, rearrange to form azepinone derivatives 189.

Scheme 42

The synthesis of medium size rings is usually challenging. In this field, the synthesis of 8membered rings through a

Scheme 45

In 2005, Toste and his group reported the cyclopropanation of propargylic esters in the presence of gold(I). 70 Various propargylic esters 207 were transformed into the corresponding carbene 208, which directly undergoes cyclopropanation onto the alkene 209 to afford the cyclopropane (±)-210 (Scheme 46). In the same paper, employing chiral phosphines, an asymmetric version of this reaction was also proposed. 68 1,5-Enynes bearing propargylic acetates undergo this transformation through ester function first. 73 1,6-, 1,7-and 1,8-enynes such as (±)-218 behave similarly to afford analogous products, allowing the synthesis of 6-, 7-and 8-membered ring (±)-219 (Scheme 49). 74 Scheme 49

1,6-Enynes such as (±)-220, instead, proceed through an "alkene first" pathway and deliver the exocyclic enol ether (±)-221 (Scheme 50). 75 Scheme 50

In the case of 1,4-enynes bearing propargylic carboxylates (±)-222 (Scheme 51), the delivered products are simple cyclopentenones (±)-223 as a pericyclic transformation on the intermediate 224 takes place instead of the cyclopropanation step. 76 Scheme 51

Addition of heteronucleophiles to alkynes

As previously mentionned, the first example of gold-complex catalysed addition of a nucleophile into an alkyne was reported by Teles in 1998, aiming to the addition of alcohols

Scheme 52

Despite its efficiency, this method suffered from various drawbacks like the use of stoichiometric quantities of protic acids. Over the years, significant improvements have been accomplished: one good witness of this evolution was reported by Nolan and his group in 2009. 77 They employed N-heterocyclic carbenes (NHC) as ligands for gold(I) in order to accomplish the hydration of terminal or internal alkynes 229 in acid free conditions with a catalyst loading lowered down to 10 ppm (Scheme 53). The main drawback consists in the lack of regioselectivity, leading to a mixture of two compounds 230 and 231.

Scheme 53

The activity of gold complexes has been widely employed for intra-and intermolecular

Scheme 54

These transformations also take place in the case of propargylic epoxides (by ring opening) 79 or propargylic ketones and in both cases a furane is generally delivered.

Scheme 57

The intramolecular version possesses a wider applicability as it permits to synthesize 5 and 6membered nitrogen-containing heterocyclic rings. In this area, an efficient method for the synthesis of pyrroles was reported by Akai in 2009. 85 General amino-3-alkyn-2-ols 247 (Scheme 58) undergo 5-endo-dig cyclization followed by dehydration providing the pyrrole derivatives 248. Good results were obtained using PPh 3 AuOTf and also with PPh 3 AuNTf 2 .

Scheme 58

The electronic properties of the alkyne substituents play a crucial role in the control of regioselectivity. Indeed, electron-donating substituents tend to favor 6-endo-dig cyclization 84 pathway, whereas electron-withdrawing substituents favour the 5-exo-dig cyclization. An example of the electronic effects on the regioselectivity was reported by Catalan in 2013 aiming the cyclization of o-alkynylbenzyl carbamates. 86 It was found that modifying the alkynyl substituent of 249 inverted the regiochemistry of the cyclization (Scheme 59). 250 arised from a 5-exo-dig cyclization in the presence of an electron donor substituent on the alkyne. On the contrary, as the substituent possesses an electron withdrawal character, product 251 generated through a 6-endo-dig cyclization was delivered. However, steric factors must still be taken into account when predicting the regiochemical outcome of such kind of cyclization as these factors provide an explanation on the selectivities reached in the two extreme cases. Hence, anisole-substituted alkyne provides only 3:1 ratio in favour of the 6-endo-dig cyclized product, whereas the formation of the 5-exo-dig derived product is sterically favoured and the ratio turns to > 30:1.

R 1 5-exo -dig 250 6-endo -dig 251 4-MeOC 6 H 4 1 3 3-CF 3 C 6 H 4 >30 1

Scheme 59

Cyclic alkynylureas are also suitable substrates for intramolecular hydroamination catalysed by gold(I). Whereas acyclic ureas follow a O-alkylation pathway, cyclic ureas selectively react following N-alkylation mode. An elegant example was reported by Cuenca and his group in 2009. In this paper, 3-substituted 1-(o-alkynylphenyl)ureas 252 (Scheme 60) was reacted with various gold(I) complex. 87 Generally, if gold(I)-based catalysts are used, ureas bearing an internal alkyne follow the 5-endo-dig pathway in which nitrogen N1 behave as the nucleophile and indolic derivative 253 is afforded. The regiochemistry can be inverted by tuning the employed gold(I) complex. Hence, it was found that NHC-based catalyst IPrAuSbF 6 favoured the N3-attack of the urea onto terminal alkynes leading to a 6-exo-dig cyclization. Under these conditions, quinazoline derivative 254 is delivered. 86

Scheme 60

Noteworthy, other nucleophiles are able to insert onto triple bonds in the presence of Au(I) or Au(III), this is the case of thiols, thioethers or boronates, but these topics will not be described in this manuscript.

Reactions of alkene with alkynes

Cycloisomerization of [1,n]-enynes is probably one of the most studied reaction of the first decade of the 21 th century. This transformation showed to be extremely powerful for the elaboration of complex molecular architectures from simple starting materials. The first examples of electrophilic activation of enynes were reported using Pd(II) and Pt(II) 88 and only several years later, in the mid 2000's, the potential of Au(I) catalysed cycloisomerization of enynes was discovered. 89 From a mechanistic point of view, a particular focus has been undoubtedly put on the cycloisomerizations of 1,6-enynes. Generally, gold(I) complexes are assumed to form a η 2alkyne-complex on the triple bond like 255 (Scheme 61). The Au(I)-alkyne complex then reacts with the double bond through a 5-exo-dig or a 6-endo-dig pathway to form the corresponding carbene 256 or 257. If internal or external nucleophiles are not present in the reaction mixture, the latter carbenes rearrange in different ways affording various complex molecular architectures. These systems exhibit a high delocalization degree, which means that their structures are intermediates between cyclopropyl gold(I) carbenes and gold(I)stabilized carbocations (Figure 15). On the other hand, the carbene deriving from the 6-endo-dig cyclization 257 can provide the bicyclic structure 262 through a 42 In most cases, these rearrangements are stereospecific and the original configuration of the alkene is retained. On the contrary, 1,6-enynes bearing an electron-donating group on the alkene such as 268 usually afford Z-1,3-dienes 267 (Scheme 62b). 92 Enynes featuring an internal alkynes 269 prefer a double cleavage pathway leading to 1,3-dienes 266 (Scheme 62c). 42,43 62d). 42,43 The formation of the 6-membered ring 271 is favoured with respect to the formation of single cleavage product 272, but it is usually possible to invert the selectivity toward one of the two products by modifying steric and electronic character of the catalyst. However, the tendency of tosyl amines to deliver 6-membered rather than 5-membered rings is underlined in the cyclization of 273 (Scheme 62e). 93 The product (±)-274, resulting of a Scheme 62

1,5-Enynes react through endocyclic rather than exocyclic pathways. This behaviour is easily explainable considering the deriving carbenes (Figure 16). the reaction of silyl enol ethers catalysed by Au(III). 98 Toste in 2006 developed the synthesis of 5-and 6-membered rings exploiting the nucleophilic character of silyl enol ether in the presence of gold(I) complexes. 99 bicyclic products 288 and 289 (Scheme 65). The mechanism involves the addition of the silyl enol ether onto the η 2 -complex 290 formed between the Au(I) catalyst and the alkyne moiety.

Subsequent protonolysis of the resulting vinyl-gold(I) species 291 delivers the product, for this reason an external proton source like MeOH is of mandatory use. However, competitive reactions between the proton source and the electrophilic cationic Au(I) species with the highly nucleophilic silyl enol ether must be avoided. In this field, the nature of the counterion in the gold complex proved to be the key-factor.

Scheme 65

This reaction proved to be really powerful. Hence, silyl enol ethers coming from amides, aldehydes or ketones were reacted onto terminal or internal alkynes. 100 Linear, cyclic, conjugated and benzylic silyl enol ethers were found to be suitable substrates (Figure 17). 101

In the case of carbocycles, it was demonstrated that the relationship between the silyl enol ether and the alkynylic side-chain can be 1,2-for the synthesis of spirocyclic products, enol ethers (±)-292 undergo 5-exo-dig cyclization affording bicyclic compounds (±)-293 (Scheme 66) . Notably, electron-rich aromatic substituents on the triple bond influence the mechanism of the reaction. As an example, in the case of anisole substituted alkyne the 6endo-dig resulting bicycle (±)-294 is obtained.

Scheme 66

In 2011 Barriault et al. reported the 6-endo-dig cyclization of alkynyl silyl enol ethers. 104 In order to switch from a 5-exo-dig selectivity to a thermodynamically unfavoured 6-endo-dig process, the steric and electronic nature of the Au(I) catalyst was tuned by the use of sterically demanding phosphine 295 (Scheme 67). To this extent, cyclopentanone-derived silyl enol ethers (±)-296 were easily converted to a mixture of fused bicycles (±)-297 and (±)-298, compound (±)-297 deriving from a 6-endo-dig pathway was always found as the major product.

Scheme 67

The synthesis of medium size carbocycles like 7-and 8-membered rings is renowned to be more challenging than the elaboration of smaller rings. Indeed, in numerous total synthesis, a ring expansion strategy starting from cyclohexanone derivative is used in order to access such scaffolds. In 2006, the group of Sawamura developed a class of bulky semihollow phosphines 105 299 to 301 (Figure 18). In association with gold(I), these phosphines allow the 104 unprecedent gold catalysed cyclization of large substrates through 7-exo-dig 106 and 8-exo-dig processes. 107

Figure 18

It was proposed that the cavity of the phosphine forces the nucleophilic center of the silyl enol ether to be closer to the gold-activated alkyne, rendering ring-closing feasible. Cyclic and acyclic silyl enol ethers (±)-303 and (±)-304 (Scheme 68) underwent 7-exo-dig cyclization to afford monocyclic product (±)-305 or bicyclic product (±)-306. Silicon-based phosphines 299 and 300 both proved to be effective for this transformation, however, 300 afforded slightly better results. The scope remains however restricted to terminal alkynes.

Scheme 68

With regard to silicon-based phosphine, carbon-based phosphines 301 and 302 demonstrated a higher activity toward 8-exo-dig cyclization of silyl enol ethers (±)-307 and (±)-308 (Scheme 69 the scope is limited to terminal alkynes and yields are lower if compared to the reaction leading to 7-membered cycles.

Scheme 69

Conclusive overview

The general characteristics of gold(I)-catalysed activation of alkynes have been discussed: after a brief historical review, the reasons why gold possesses its astonishing behaviour have been elucidated. The four major transformations: hydroarylation and hydroheteroarylation of alkynes, reactions of propargylic carboxylates, addition of heteronucleophiles to alkynes, and the most important, reactions of alkenes with alkynes have clearly widened the chemical toolbox of synthetic chemists. Remarkable is the difference in the reactivity of the various substrates. Hence, for the purpose of the synthesis of vibsatins, it is important to note that alkyne-tethered indoles undergo 7-exo-dig and 8-endo-dig cyclization by simple employment of classic Au(I)-catalysts. On the contrary, for most other substrates, cyclization leading to medium size rings (7, 8), are very difficult or even impossible to accomplish. To date, this transformation shows several restrictions since it remains limited to silyl enol ethers and a special commercially unavailable phosphine is of mandatory use.

Finally, enyne cycloisomerizations have significantly expanded the synthesizable scaffold array opening new possibilities in the synthesis of complex molecular architectures.

Noteworthy, from its discovery, the field of gold catalysis has emerged as one of the top subjects in organic chemistry. If the activity in gold catalysis had followed a normal "life cycle", a slow decay would have been expected in the numbers of publications after about a decade. After 20 years from the publishing of the pioneeristic paper of Teles, is the opposite situation that is observed, meaning that the interest is not decreasing but rather continues to grow.

Dual activation catalysis for the cyclization of alkynes

In the second part of the 20 th century, the main evolution that concerned organic chemistry has undoubtedly been the area of transition metal catalysis. This field led to four Nobel prices and enabled discoveries that practically changed the every-day life all over the world. At the same time, organocatalysis has been part of the chemical research since the founding of organic chemistry. However, this is only in the end of the 20 th century that the number of articles dealing with organocatalysis significantly increased. Despite the demonstrated power and wide applicability, these two fields still present drawbacks and limitations. One way of broadening their spectra of application is the use of multicatalysis strategy. Together, they can display different activation modes, allowing for new reactivity generally not accessible with a single catalyst. Here both fields can profit from one another and jointly strengthen their capacity. Generally, it is possible to rationalise the concomitant use of two catalytic sites in three different types of strategies: cooperative dual catalysis (Figure 19a), bifunctional catalysis (Figure 19b) and double activation catalysis (Figure 19c).

Figure 19

In cooperative dual catalysis, the two separate catalysts activate two different reactive species: one lowers the LUMO energy of the electrophile and the other raises the HOMO energy of the nucleophile. Bifunctional catalysis is accomplished by a single catalyst in which two catalytic moieties are joined together. In double activation catalysis, instead, two catalysts activate either the electrophile or the nucleophile.

Multiple catalysts are employed one-pot in one, separated, coupled or sequential catalytic cycles (Figure 20). However, in this thesis only cooperative systems will be discussed. These systems are made of a single catalytic cycle in which both substrates are activated by the two catalysts.

Figure 20

Usually, the organic catalyst is a primary or secondary amine which activates a carbonyl group in five different manners. 108 The first activation mode foresees the formation of a nucleophilic enamine which reacts with an electrophile to afford an α-functionalized carbonyl compound (Scheme 70a). Exploitation of the electrophilic character of an iminium ion by a nucleophile represents the second method (Scheme 70b). A β-functionalized carbonyl compound is delivered. In the SOMO activation, the reactive species are electrophilic radical cations deriving from enamine oxidation (Scheme 70c

Scheme 70

On the other hand, metals activate various functional groups following different pathways.

The major activation modes observed for metals in combination with aminocatalysts are depicted in Scheme 71. For our purpose, only umpolung activation of alkynes through Lewis acid activation will be considered (Scheme 71b).109 Scheme 71

Kirsch, Dixon and Michelet

Before discussing the various alkyne activation methods through dual cooperative activation, it must be noted that numerous publications have been reported recently aiming the activation of alkynes. In this document, only seminal reports and latest important achievements in this field will be treated introducing the concept of carbocyclization of alkynes through dual activation.

In 2008 Dixon and co-workers reported the development of a tandem reaction aiming to the synthesis of cyclopentenes featured with an exocyclic ketone 311 starting from an α,βunsaturated ketone 312 and a homopropargylic malonate 313 (Scheme 72). 110,111 Scheme 72

Pyrrolidine was elected as the organic catalyst and copper(II) triflate (Cu(OTf) 2 ) as the metallic counterpart. Various linear and cyclic ketones were suitable substrates for this reaction, nevertheless, only one example of internal alkyne was reported. Mechanistically, the pyrrolidine reacts with the ketone function of 314 and forms the iminium ion 315 (Scheme substituted aldehydes is usually longer in terms of time, [(Ph 3 PAu) 3 O]BF 4 proved to be more resistant to decomposition and thus more appropriate.

Scheme 74

Evolution of the development of a dual activation catalysis system is observed in a series of papers published by the group of Michelet regarding the concomitant use of a copper catalyst with a primary amine. In 2011, the cyclization of α-substituted ε-alkynylaldehydes 322 into homoallylic exocyclic products (±)-323 was reported (Scheme 75). 113

Scheme 75

After extensive studies, the best conditions were identified. Along with the use of cyclohexyl amine (CyNH 2 ), copper(I) catalyst was generated in situ by reduction of copper(II) triflate (Cu(OTf) 2 ) by PPh 3 . The same year, the group turned the reaction asymmetric by using chiral phosphines and reaching enantiomeric excess up to 94%. 114 One year after, it was found that indium(III) chloride (InCl 3 ) was also capable to catalyse this transformation. 115 In this report, a model explaining the enantioselectivities was also proposed (Scheme 76). 113

Scheme 76

Conditions A (InCl 3 ) afforded either good yields of (±)-327 and low enantiomeric excess or low yields and high enantioselectivities. Conditions B (Cu(OTf) 2 ), on the other hand, delivered yields of (±)-327 up to 88% along with moderate to good enantiomeric excess (up to 90%). In this latter case, it is possible to rationalise such results by focusing on the chairlike transition states (TS) 328 and 329 (Scheme 77). Hence, the bulky ligand imposes a quadrant like steric environment around the triple bond. Pseudo axial γ-substituents (Y) are responsible for the promotion of one or the other TS and, for steric reasons, transition state 328 is favoured.

Scheme 77

Very recently Dixon and co-workers developed a desymmetrizing cycloisomerization of alkyne-linked cyclohexanones. 116 Ketones (±)-330 undergo 6-exo-dig cyclization affording asymmetric bicycles 331 in the presence of silver bistriflimide (AgNTf 2 ), chiral pyrrolidine 332 and the cinchonidine-derived aminophosphine 333 (Scheme 78). Notably, a catalytic quantity of an acidic additive 2,4-dinitrophenol is also required in order to enhance the catalytic turnover.

Scheme 78

An explanation for the asymmetric selective alkenylation at the α-position was researched by performing DFT computations on the competing transition states of this transformation (Figure 21). The aminophosphine-silver complex is likely to be rapidly formed by coordination of the quinuclidine nitrogen, the phosphorous atom and the amide nitrogen to the silver center. Concomitantly, it was demonstrated that pyrrolidines bearing bulky groups as substituents preferentially form s-cis enamines. 117 The matching effect of the chiralities between these two moieties provides a single α-alkenylation product enantiomerically enriched.

Conclusive remarks

The aim of this part was to introduce the concept of dual activation catalysis through selected relevant examples. Double-activation carbocyclizations involving a carbonyl moiety and a triple bond are still a merging field in organic chemistry, indeed, nowadays only systems leading to 5-and 6-membered rings have been developed. With respect to the use of silyl enol ethers, these systems offer the possibility to avoid the stoichiometric installation of the nucleophilic site. In section 3.2.6, the utilization of a bulky phosphine as an essential requirement for the execution of 7-exo-dig or 8-exo-dig carbocyclizations is described.

However, for this purpose, and most specifically for the purpose of vibsatins syntheses, the development of a double activation system which would allow access to medium size rings like 7-or 8-membered carbocycles it would be of great interest. Compared to the amount of developed methodologies exploiting transition metal catalysis, dual activation cooperative catalysis is still a partially unexplored area of organic chemistry that offers great potential for improvement, while respecting sustainability concepts, i.e. greener and cheaper conditions.

Scheme 79

At the beginning, the synthetic approach leading to the substrates 122 engaged in the studies of the key-step reaction will be introduced. A practical explanation on the Au(I)-catalysed methodology will be the subsequent topic followed by the synthesis of the employed phosphine.

An important optimization process upon the best conditions utilised in the key-step reaction was realized and explained. To this aim, various model substrates related to the molecules originally reacted in the Sawamura's report were synthesized in order to reproduce the transformation and to evaluate its feasibility. The analysis of the essays leading to the optimization of the cyclization on the precursor 122 will be discussed. The chapter will then be closed by the investigation of various cyclization reactions exploiting double activation catalysis.

Synthesis of the precursor 122

In order to control the quaternary stereocenter at C11, it was decided to take inspiration from the works of d'Angelo and Desmaële. 118 The synthesis of enantiomerically enriched 2,2- Michael addition involving the enaminic tautomer 338 and the α,β-unsaturated carbonyl compound 340. In this manner, the enantioenriched ketone 334 is finally delivered after an acid hydrolysis.

Scheme 80

The substrate suitable for the cationic gold(I) catalysed cyclization was synthesized in a eight steps sequence starting from 30 grams (0.3 mol) of 2-methylcyclopentanone 123 (Scheme 81). p-Toluene sulfonic acid (10 mol%) catalysed condensation of (S)-(-)-phenylethylamine onto 123 afforded the corresponding imine 341 in 83% yield. 119 The latter was purified by direct distillation from the reaction mixture and, due to its sensitivity to water and moisture, it was immediately reacted with methyl acrylate. After an acidic hydrolysis of the resulting adduct, enantioenriched ketoester 342 was provided in 93% yield and 91% e.e.. Noteworthy, the reaction time was about three days and hydroquinone was added in order to avoid the radical polymerization of the acrylate.

A classical chemistry based sequence, inspired from a previous work reported by Miesch and her group, was next employed for the functionalization of the newly obtained ketoester 342. 120 Firstly, the ketone function was protected as a ketal 343 and the ester was reduced to alcohol 344 employing lithium aluminium hydride (LiAlH 4 ) in 51% yield over two steps.

Notably, if the ketal is directly engaged in the reduction step without purification, the global yield increases to 80%. The primary alcohol was then transformed into its tosylate derivative 345 in quantitative yield and the newly formed functional group was displaced by lithiumacetylide delivering terminal alkyne 346 in 82% yield. The six step sequence resulted in 50% overall yield and 32 grams (0.15 mol) of acetonide 346 were obtained starting from 30 grams (0.3 mol) of 2-methylcyclopentanone.

Scheme 81

The ketone 347 was regenerated under acidic conditions making the installation of the silyl enol ether functionality to be the last step (Scheme 82). In the purpose of studying the 7-exodig cyclization reaction, two different silyl groups were introduced. Noteworthy, the TBSbased silyl enol ether 348 and the bulkier TIPS-derivative 349 were both synthesized in excellent yields.

Au(I)-catalysed 7-exo-dig cyclization

In 2010, Sawamura and his group reported the 7-exo-dig cyclization of alkyne-tethered silyl enol ethers. 106 As explained in section 3.2.6, a gold(I) complex formed using a noncommercial bulky phosphine catalyses the cyclization of alkyne-tethered silyl enol ethers providing 7-membered ring compounds (Scheme 83). Notably, among various different phosphines developed by Sawamura, 300 was individuated to be the most active for the setup of 7-exo-dig cyclizations. Temperatures and reaction times were tuned for each substrate.

Scheme 83

Technically, those transformations were reported under strict oxygen-and water-free conditions by using a glove-box and, moreover, on a very small 0.1 mmol scale (≈ 20 mg), which is not acceptable in the context of a total synthesis project. Based on these considerations, an adaptation of this methodology to glove-box free conditions was our primary objective. Also, the second objective was represented by the scale up of the process until reaching the possibility to engage about 10 grams of substrate.

As reported by Sawamura, TBS-based silyl enol ether (±)-350 underwent 7-exo-dig cyclization to provide racemic bicyclic ketone (±)-351 in quantitative yield at room temperature in five minutes (Scheme 84). tBuOH was employed as a proton source and molecular sieve was added in order to trap the putative remaining traces of water. MeOH or tBuOH were indicated as totally interchangeable, the choice of using tBuOH was probably due to easier purification and storage practical protocols.

Scheme 84

Notably, in the same report, the cyclization of a TIPS-derived silyl enol ether required stronger conditions. Indeed, silyl enol ether (±)-350 underwent cyclization affording bicyclic ketone (±)-351 in five minutes in quantitative yields (Scheme 85). In this case, the temperature was set to 80°C instead of room temperature, demonstrating that bulkier TIPSbased substrates were less reactive compared to TBS-based ones.

Scheme 85

Synthesis of the model substrates and phosphine 300

In order to optimize the cyclization process without using glove-box techniques, it was decided to start the investigations on the model substrate (±)-350 along with two other similar racemic silyl enol ethers (±)-354 and (±)-355 (Scheme 86). These three silyl enol ethers were first synthesized in three steps starting from 5-pentyn- The synthesis of the phosphine 300 was realized as reported by Sawamura, in three steps starting from 30 grams of bromophenol derivative 360 (Scheme 87). 105 The latter was quantitatively transformed into its anisole derivative 361, then a one-pot process made of three distinct steps leaded to silane 362. 361 (3 eq.) was exchanged with tert-butyllithium and the resulting anion was reacted with one equivalent of SiCl 4 . Lithium acetylide was then added to the resulting adduct in order to provide alkyne-tethered silane 362 in 70% yield.

Phosphine 300 was finally obtained in 75% yield by reaction of intermediate 362 with n-butyllithium and PCl 3 . The overall yield was calculated to be 53% starting from 5.5 grams of SiCl 4 .

Scheme 87

Cyclization studies

With the substrates and the phosphine in hands, we started to examine the 7-exo-dig cyclization reaction. It is important to notice that the side reaction of this process regarded the electrophilic cleavage of the silyl enol ether which regenerated the original ketone. Oxygen and moisture-free conditions were described as mandatory when performing these transformations. Consequently, in order to run these reactions on a simple vacuum line, special Schlenk tubes were tailor-made and employed (see experimental part for a picture).

The catalyst was synthesized in-situ for each tested substrate. In this aim, (Me 2 S)AuCl was stirred in DCM with a slight excess of phosphine 300 (1.01 equivalents) and, after 30 minutes, the volatiles were evaporated in order to afford intermediate (300)AuCl and to eliminate the remaining Me 2 S (Scheme 88). Solubilisation with DCM and addition of 1.5 equivalent of AgNTf 2 led to the precipitation of AgCl and to the concomitant generation the active species [(300)Au]NTf 2 over 10 minutes. Filtering the suspension under inert atmosphere through a pad of Celite (R) directly into the reaction vessel delivered the active catalyst.

Scheme 88

Our studies started by investigating the cyclization on 0.3 mmol (≈50 mg) of silyl enol ethers (±)-303 derived from β-ketoesters in the presence of 5 mol% catalyst and one equivalent of tBuOH in dichloromethane at room temperature, the concentration of the substrate resulted to be 0.02 mol/L (Scheme 89). The first attempts employing the TBS-based substrates (±)-350 resulted mostly in the cleavage of the silyl enol ether affording ketone (±)-359 (Table 1, entry 1). Moreover, TBS-based substrates proved to be very sensitive to environmental-induced differences in the preparation of the catalyst and the reaction was hardly reproducible leading to a maximum 12% of isolated yield in desired product (Table 1, entries 2 and 3). TBDPSderived silyl enol ether (±)-355 exhibited a greater resistance toward electrophilic cleavage but at the same time a slight reluctance to react as well, however, from this essay the isolated yield raised to 31% (Table 1, entry 4). Triisopropylsilyl enol ether based substrate (±)-354 displayed to be the most inert, since after three hours, only 38% of the starting product was consumed (Table 1, entry 5). However, following the guidelines mentioned in the original Sawamura's paper, TIPS-derived substrate was refluxed in DCE providing total conversion of the departing product, but the amount of cleavage was still prevailing (Table 1, entry 6).

On the other hand, refluxing the TIPS-based silyl enol ether (±)-354 in DCM for five minutes provided a 82:18 ratio and bicyclic ketone (±)-306 was isolated in 68% yield. Notably, in order to investigate the mandatory utilization of the phosphine 300 in the execution of 7-exodig cyclization reactions, a phosphine classically used in Au(I) catalysis such as JohnPhos 181 was utilized instead of 300. 121 Under these conditions, the same TIPS-based silyl enol ether (±)-354 underwent cyclization at room temperature displaying a low conversion of 10% but interestingly without formation of the side product (±)-359 ( Comparing the results of Table 1 and Table 2, it is possible to notice the higher reactivity towards both cleavage and cyclization of the ketone-derived silyl enol ethers (R = Me) compared to ketoesters-derived silyl enol ethers (R = COOMe). This is especially well displayed for TIPS-silyl enol ether derivatives: 349 reacted properly and quantitatively at room temperature, whereas raising the temperature only promoted the cleavage of the silyl group. On the other hand, a temperature of 40°C was mandatory for the cyclization of (±)-

354.

Once the best conditions for the synthesis of the key-intermediate 121 determined, scale up was realized until the transformation could be performed on more than 8 g (25 mmol) of TIPS-based substrate 349 (Scheme 91).

Scheme 91

To this aim, the purification step plays a special role in this reaction. The quench was done by a simple filtration on a silica pad in order to remove the catalyst, but the total removal of the phosphine from the product revealed to be a difficult task. Phosphine 300, indeed, showed the tendency to partially co-eluate with the bicyclic ketone 121. Purification by column chromatography usually afforded ketone 121 along with traces (2-3%) of the phosphine.

During the scale-up phase, this problem was overcome by precipitation and subsequent filtration of the phosphine employing EtOH. In this way, the following column chromatography purification afforded pure product and, moreover, the solid phosphine was recovered. The recycled phosphine, usually around 60% of the original engaged quantity, exhibited the same reactivity of the freshly synthesised one.

Double activation catalysis

In parallel to the synthesis of the vibsatins, it was investigated an alternative route in order to get access to the bicyclo[4.2.1]nonane scaffold. As explained in the last Section, the key step of our synthesis of the vibsatins relied on a 7-exo-dig cyclization catalysed by gold(I). Three major drawbacks are associated with this reaction: the stoichiometric utilization of a silyl source for the synthesis of the silyl enol ether substrate, the strong oxygen-and moisture-free conditions and the utilization of the non-commercial bulky phosphine. Starting from these assumptions, we aimed to overcome these drawbacks by the use of double activation catalysis. In Section 3.3, the general characteristics of double activation catalysis were previously discussed. In our case, the substitution of a preformed silyl enol ether by an in situ formed enamine and the usage of commercially available cheaper metal catalysts based on Ag or Cu will be discussed.

Concept and substrates syntheses

Our original idea regarded the execution of cyclization reactions by using a secondary amine coupled to a metal catalyst. To this aim, pyrrolidine was elected as the secondary amine and different silver and copper catalysts were tested. The foreseen mechanism would be divided into three steps. In the first step, enamine 363 would be in-situ synthesised starting from the starting ketone 364 (Scheme 92). The metal catalyst would then complex the triple bond moiety and allow the cyclization of the enamine affording iminium compounds 365 or 366 depending upon the exo-or endo-pathway followed. Hydrolysis of the iminium ion and protodemetallation would then provide the bicyclic ketones 367 or 368.

Scheme 92

We started our investigations on six different substrates depicted in Figure 22. Ketoester (±)-359 and ketone 347 were already available and their achievement was previously detailed in Section 4.3 and 4.1.

Figure 22

Ketoester (±)-369 was easily synthesized as reported in the literature starting from cyclopentanone-2-carboxylate and propargyl bromide 372 (Scheme 93). 122 A mild base such as K 2 CO 3 in acetone was used and compound (±)-369 was obtained in 73%.

Scheme 93

Internal alkyne 370 was obtained starting from formerly synthesized terminal alkyne 347 by exploitation of classic Sonogashira protocols (Scheme 94). The use of phenyl iodide together with a catalytic quantity of palladium tetrakis (Pd(PPh 3 ) 4 ) and copper iodide in a mild base like NEt 3 as solvent, readily provided arylation of the triple bond affording 370 in 92% yield.

Scheme 94

The ester (±)-371 was instead synthesized in three steps starting from cyclopentanone 373 (Scheme 95). The latter was reacted with 1,1-dimethylhydrazide affording hydrazone 374 quantitatively. Alkylation using 5-iodopent-1-yne and acidic cleavage of the hydrazone afforded alkyne tethered ketone (±)-375 in 60% yield. 123 Installation of the methylester on the alkyne moiety was tested, at the beginning, by the use of a strong base (LDA) and ClCO but surprisingly failed. 124 Palladium mediated solvocarbonylation, on the other hand, afforded the desired terminal ketoester (±)-371 in 62% yield. 125 Scheme 95

Cyclizations essays

Once the substrates synthesized, we then started to investigate the cyclization reactions. We started our essays with ketoester (±)-369 exploiting the conditions reported by Dixon and his group (Scheme 96). 109126 Various temperatures were tested but cyclized product (±)-376 was never observed. On the other hand, switching from methanol to ethanol and heating to reflux, delivered product (±)-377 deriving from the ethanol addition onto the ketone and ring opening.

Scheme 96

Increasing the catalytic charge to sub-stoichiometric quantities, however, permitted to obtain Lett. 2015Lett. , 17, 1946Lett. -1949. 126 . 126 For the discussion upon the Dixon's reported dual activation cyclizations, see Section 3.

Scheme 97

Various conditions were then explored in order to contrast the formation of the dimeric product (dilution, degased solvent, lower temperatures) but it mostly resulted in the same unfavourable ratio. Various metal catalysts were then tested in order to avoid the Glaser-Hay coupling, including: AgNTf 2 , AgSbF 6 , 109 PPh 3 AuSbF 6 , 112 In(OTf) 3 , 41 Fe(OTf) 3 128 and the best result to date was obtained using AgOTf. Indeed, heating at 70°C in toluene (±)-369 in the presence of one equivalent of pyrrolidine and a catalytic quantity of AgOTf, delivered bicyclic product (±)-376 in 30% yield (Scheme 98).

Scheme 98

A very similar cyclization using the same silver complex was reported by Chegondi and his group in late 2015 (Scheme 99). 129 For instance, internal alkyne (±)-379 underwent 6-endodig cyclization affording bicyclooctene (±)-380 in 91% yield. Notably, the only presence of AgOTf was capable to catalyse the formation of the nucleophilic enol concomitantly to the activation of the triple bond moiety. This report raised doubts about the real necessity to use pyrrolidine in the studied reactions, however, only internal alkynes were suitable in this process.

Scheme 99

We then turned our attention to suitable substrates for 7-exo-or 8-endo-dig cyclizations.

From first essays, it was demonstrated that simple ketone 347 and ketoester (±)-359 reacted with stoichiometric amount of pyrrolidine and substoichiometric quantity of Cu(OTf) 2 to give surprisingly condensed tricycles 381 and (±)-382 in respectively 55% and 40% yield (Scheme 100).

Scheme 100

At the beginning, it appeared that yields follow the amount of utilised Cu(OTf) 2 , but lowering or enhancing the percentage of copper catalyst resulted in lower yields. The same results

were observed concerning of pyrrolidine: the utilization of two equivalents or half equivalent of pyrrolidine lowered the yields. Other metals were also tested but only Cu(OTf) 2 provided the formation of this type of tricyclic products. However, on the other hand, aryl-tethered alkyne 370 showed no reactivity in the same conditions and the starting product was recovered (Scheme 101).

Scheme 101

The concomitant application of 20 mol% of copper(II) triflate and one molar equivalent of pyrrolidine to (±)-371, delivered the spiro-ketone (±)-383 in 31% yield instead of a condensed tricycle (Scheme 102). In this case, the 6-endo-dig cyclization pathway was preferred.

Scheme 102

Conclusions

In the course of the synthesis of vibsatins, the bicyclic ketone key-intermediate 121 was synthesized (Scheme 103). The configuration at C11 was controlled by using a reported method exploiting an asymmetric Michael reaction and, starting from 30 grams of 2methylcyclopentanone 123, the cyclization precursor 349 was obtained in 53% yield over eight steps with an enantiomeric excess of 91%.

Scheme 103

A In parallel to these studies, an investigation upon alternative medium size ring cyclizations exploiting dual activation was engaged in order to overcome the drawbacks relative to this gold(I) developed methodology. The stoichiometrically installed silyl enol ether moiety was replaced by the in-situ preparation of an enamine using pyrrolidine and AgOTf or Cu(OTf) 2 complexes were used instead of a gold(I)-based catalyst. At the present time, we were not able to reach the synthesis of 7-or 8-membered ring under these conditions. However, from preliminary studies some interesting results were observed, for instance, the reaction of

Towards the total syntheses of Vibsatins A and B

The main topic of this chapter will be the functionalization of the bicyclic skeleton 121. The requisite transformations for the synthesis of the vibsatin A and B are depicted in Scheme 105. C4 carbon would be oxidized and the double bond between C3 and C18 would be dihydroxylated. Two stereoselective alkylation reactions would be executed at C5 and C10

and the deoxygenation at C1 would be done at the best stage of the synthesis.

Scheme 105

At the beginning of this project, the deoxygenation of the ketone at C1 was assumed to be of easy realization through classical reported methodologies. Unfortunately, this transformation, which appeared to be a highly challenging step of the synthesis, will be discussed in the next chapter. Remarkably, various deoxygenation essays on early intermediate ketone 121 failed.

For this reason, three different functionalization sequences of the bicyclic backbone have been realized to overcome this problem. To this aim, deoxigenative tests were conducted on almost all the intermediates presented in this unit.

This chapter is divided into three sections, each one devoted to a particular strategy. At the beginning, the direct functionalization of ketone 121 leading to vibsatin B, C3 epimer of vibsatin A, will be presented. A strategy based on a transthioketalization will then follow and the chapter will be closed by a discussion upon the C1-alcohol series which represents the up to date ongoing synthesis. These two last approaches would lead to a vibsatin A derived C3 epimer.

N.B. In some cases, the configuration of the newly formed stereocenters is anticipated in the schemes, but the confirmation of such geometries will be immediately discussed.

Direct functionalization strategy

Direct functionalization of the unprotected bicyclic ketone 121 was initially envisaged. It was decided to perform an allylic oxidation at C4 followed by a dihydroxylation of the C3-C18 In 1983, Kishi and co-workers reported an empirical rule for the stereochemical outcome of the dihydroxylation reactions of allylic alcohols. 133 It was demonstrated, on a series of enantioenriched linear allylic alcohols, that the relative stereochemistry between the preexisting hydroxyl or alkoxyl group and the adjacent newly introduced hydroxyl group of the major diastereomer in all cases was anti. One example is depicted in Scheme 107, olefin 389 is dihydroxylated in the presence of OsO 4 and NMO affording mainly diastereomer 390 (390/391, d.r. 79:21), which presents an anti-relationship between the newly formed stereocenter and the adjacent pre-existing one.

Scheme 107

However, this anti-relationship is only an empirical rule. Hence, very often, the observed diastereoselectivities were modest and at the same time, for instance, exceptions were found.

On cyclic substrates the situation appeared relatively more complex. Arseniyadis in 2007, investigated dihydroxylative reactions starting from an exocyclic allylic alcohol in the course of the synthesis of iridal's core structure. 134 Condensed bicycle (±)-392 underwent osmylation providing the cis-triol (±)-393 as single diastereomer (Scheme 108).

Scheme 108

On the other hand, in the Hatakeyama's synthesis of the (-)-cinatrin C 1 , it was found that, on a This mixture was directly engaged in the dihydroxylation reaction. This transformation was performed using catalytic potassium osmate (20 mol%) together with NMO and pyridine and resulted to be highly stereoselective since only 3(S)-triol 414 was isolated in 84%. 138 The primary alcohol of triol 414 was protected as a TIPS-derivative 415 in 98% yield and the 138 By NMR analysis on the crude, it was observed also the dihydroxylation product deriving from the minor diastereomer produced in the allylic oxidation step but during the purification stage it was not recovered. OEt 2 5 delivered complex mixtures of products.

Scheme 115

It has not been possible to prove the C4 configuration of the major diastereomer 413 deriving from allylic oxidation through NOESY analysis. However, submitting the mixture of 413 and its epimer 417 to aqueous HCl (3M in THF) for 30 minutes at room temperature, yielded a mixture of three components in which the prevailing form was the tricyclic hemiketalic product 385 presented in Section 5.1 (Scheme 116). On the basis of these results, it was possible to attribute the origin of the hemiketal 385 to alcohol 413, thus, the configuration at C4 of the predominant diastereomer after allylic oxidation was assumed to be 4(R).

C1 alcohol series: ongoing synthesis

This last part of Chapter 5 will describe the ongoing synthesis that should hopefully lead to the total synthesis of the vibsatin A. To this aim, ketone 121 was reduced to alcohol 418 in quantitative yields and it was then decided to protect the hydroxyl function in two different forms: benzyl ether 419 and TBS ether 420. These products were respectively obtained in 96% and 95% yields (Scheme 117). Both compounds readily underwent allylic oxidation promoted by SeO 2 and subsequent Dess-Martin oxidation, affording α,β-unsaturated ketones 421 in 74% yield and 422 in 63% yield, respectively for benzyl and TBS series. Noteworthy, it was decided to oxidize the C4-alcohol to ketone in order to investigate about the driving factor of the stereoselection during the subsequent dihydroxylative osmylation.

Scheme 117

Thus, TBS ether 422 was treated with potassium osmate in the aforementioned conditions stereoselectively delivering the vibsatin A type diol 423. This result finally validates our hypothesis regarding the shape-induction of the substrate toward functionalization of the double bond (Scheme 118).

Compound 424 was then obtained in quantitative yield after acetonide protection of the diol 423. Noteworthy, TBAF mediated deprotection of the TBS-group immediately produced another hemiketalic product 425 confirming the (R)-configuration of the alcohol at the bridge position (C1). Based on this observation, another evidence arised upon the steric hindrance on the Re-face of the ketone of compound 121.

Scheme 118

Benzyl ether 421 followed a similar synthetic route: stereoselective dihydroxylation provided diol 426 in 90% yield and protection of the latter with dimethoxypropane afforded compound 427 in 95% yield (Scheme 119). The introduction of a phenylselenyl group at C10 and subsequent selenoxide elimination through H 2 O 2 in the presence of pyridine, produced the desired α,β-unsaturation in 68% yield over two steps furnishing the substrate 428 suitable for 1,4-addition.

Scheme 119

Once more, in this series, the C3 configuration of 426 was elucidated by NOESY analysis.

This time, NOE effect between C3-OH and C13 was observed (Figure 28 and Figure 29). exploiting a catalytic quantity of palladium were performed. Shibasaki's, Larock's and Tsuji conditions were employed but only starting material was recovered in cases. 146 Scheme 120

The configuration at C10 of 430 was disclosed by NOESY analysis. A weak NOE interaction was detected between one of the two diastereotopic protons at C18 and the C10 proton (Figure 30 and Figure 31) At the present time, the 1,4-addition step is currently under investigation. Initial attempts of insertion of a MOMOCH 2 -group employing the methodology previously described by Williams in the total synthesis of vibsanin E (8, Chapter 1) proved to be unsuccessful. 16 In this method, the -CH 2 OMOM group was insalled by reaction of an in-situ made cuprate starting from nBu 3 SnCH 2 OMOM precedently synthesized in two steps as reported in the literature (Scheme 121). 147 Initially, two equivalents of stannane were transmetallated with nBuLi and reacted with a single equivalent of copper iodide in the presence of TMEDA and TMSCl to form the Gilman type cuprate (Scheme 121, conditions a), however the latter demonstrated to be ineffective in the alkylation at C10 position of 428 and failed to deliver compound 431. A modified procedure was then utilized. This time, a more reactive Lipshutztype cuprate was used. Practically, four equivalents of cyanocuprate were reacted with 428 in previously described conditions, but this approach only afforded the total recovery of the starting material (Scheme 121, conditions b). 147 Danheiser, R.L.; Romines, K.R.; Koyama, H.; Gee, S.K.; Johnson, C.R.; Medich, J.R. Org. Synth. 1993, 71, 133-137.

Scheme 121

Considering the bulkiness of (MOMCH 2 ) 2 CuCN . LiCN reagent or of MOMOCH 2 -cuprate, a test reaction was next conducted in order to investigate the reactivity of cyanocuprates for alkylation of the C10 position. To this aim, four equivalents of methyl cyanocuprate were reacted with 428 and, surprisingly, smoothly delivered the desired ketone 432 in 50% yield as a single diastereomer (Scheme 122).

Scheme 122

Moreover, the configuration of the newly formed C10 stereocenter of 432 was confirmed to be 10(S), i.e. the same configuration as the vibsatins. This assumption was verified through NOESY analysis, which are depicted in Figure 33. A strong NOE correlation between the C10-hydrogen and one proton at C12 was found, validating the 10(S) configuration of the newly formed stereocenter (Figure 32).

Figure 32

Figure 33 Regarding the low reactivity of alkylcyanocuprates, the insertion of a cyanide group was foreseen as a good alternative to the -CH 2 OMOM group. Indeed, based on the work on pyrrocidines described by Kobayashi, α,β-unsaturated ketone 428 was treated with 1.1 eq.

Et 2 AlCN (1M sol. in toluene). 148 Noteworthy, this reaction was performed on a very small scale (0.1 mmol) and two products were obtained after purification. Surprisingly, the major fraction resulted to be 433 and from preliminary NMR analysis it appeared that the minor fraction should contain the desired compound 434 (Scheme 123).

Scheme 123

433 was subjected to NOESY experiment, two NOE interactions were found between the C10 and the C12 proton and also between the C10 and the C13 (Figure 34 and35). Once again, this analysis confirmed the 10(S) configuration of the C10 center relative to the vibsatin structures.

148 Tanaka, R.; Ohishi, K.; Takanashi, N.; Nagano, T.; Suizu, H.; Suzuki, T.; Kobayashi, S. Org. Lett. 2012, 14, 4886-4889.

Figure 34

Figure 35 136 | P a g e C h a p t e r 5 : T o w a r d s t h e t o t a l s y n t h e s i s

Conclusion and perspectives

The up to date functionalizations of the bicyclic framework of ketone 121 were presented in this chapter. The first strategy was undertaken starting from unprotected ketone 121 at C1 leading to 3(R) vibsatin B type intermediates 435 (Scheme 124a). An inverted stereochemical outcome leading to vibsatin A type 3(S) configuration such as 436 was observed when C1 ketal and C1 benzyl or silyl ether substrates were used. These synthetic routes were presented respectively in the second and third part of the chapter (Scheme 124b). Noteworthy, common transformations between the various strategies regarded the allylic oxidation using selenium oxide followed by a dihydroxylation step employing potassium osmate and the Dess-Martin oxidation at C4 providing a carbonyl group. Moreover, the stereochemistry of the dihydroxylation reactions demonstrated to be dependent on the substituent present at C1, whereas the C4 configuration appeared to be irrelevant.

Scheme 124

The conjugate addition at C10 of the α,β-unsaturated ketone 428 is still under investigation (Scheme 125). Notably, among the various methods, the insertion of a cyanide group already provided promising results but, at the moment, it was only performed on a small scale and further optimization of the reaction is required in order to afford C10 alkylation product 434 in larger scales. Once the alkylation at C10 validated, our attention will be turned to the alkylation at the C5 position in order to complete the installation of all the five stereocenters of the vibsatin skeleton such as in 437.

Scheme 125

Noteworthy, most of the synthesized compounds underwent various deoxygenative tests presented in the next chapter.

Deoxygenation

Once the bicyclic scaffold was set-up, the removal of the oxygen at the C1 carbon was of

Scheme 126

In this chapter, the various employed techniques will be briefly introduced followed by the analysis of all the trials performed on the different substrates. The chapter is divided in four parts, depending on the type of chemistry employed. Wolff-Kishner based reactions will be the topic of the first part and Mozingo type reductions will be explained in the second subchapter along with a brief introduction upon Clemmensen based deoxygenation.

Discussion upon hydride displacement transformations will be gathered in the fourth part and Barton-McCombie reductions will also be discussed. Finally, a ring opening metathesis approach will close then the chapter.

Wolff-Kishner type reductions

The Wolff-Kishner reduction reaction is one of the oldest chemical transformation discovered, originally reported in 1911 by Nikolai Kishner and Ludwigg Wolff. The primary reported harsh procedures involved the addition of the preformed hydrazone or semicarbazone to hot potassium hydroxide. 149 Over the years, various modification have been accomplished aiming to the execution of the transformation under milder conditions. The most famous is the Huang-Minlon modification, which employs hydrazine hydrate and a base 149 (a) Kishner, N.J. Russ. Phys. Chem. Soc. 1911, 43, 582-595. (b) Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 86-108. in a one-pot tandem sequence in high boiling point solvents. 150 This methodology foresees the formation of the hydrazone around 120°C, subsequent addition of the base and final distillation of the excess of hydrazine and water at 160°C. The expulsion of nitrogen gas is then afforded at temperatures over 190°C. One recent example is represented by the synthesis of sec-cedrenol 438 reported by Pettus in 2011 in which ketone 439 undergoes deoxygenation affording 440 in 52% (Scheme 127). 151 Notably, the hydrazone formation was performed at 120°C over 48 hours, the temperature was then raised to 185°C for 6 hours in order to eliminate the hydrazine excess and finally the expulsion of the nitrogen molecule was realized at 215°C over 6 hours.

Scheme 127

Moreover, during the same year, Kassiou and his group demonstrated the successful applicability of the procedure on hemiacetalic centers during their synthesis of homocubanes. 152 Intramolecular hemiacetal 442 and its open form 441 underwent deoxygenation in quantitative yields affording alcohol 443 (Scheme 128).

Scheme 128

Metallic sodium was also used as a base in protic solvents.

Scheme 129

In our case, the first attempt exploiting this chemistry was performed on ketone 121 using metallic sodium and hydrazine (1M sol. in THF) in ethylene glycol (Scheme 130). 154 The expected product 446 would have been relatively volatile and, due to the high temperatures required in this transformation, this reaction was performed in a sealed tube in order to avoid the possible loss of the product. The use of high boiling point polar solvents resulted in problematic work-up stages. However, in this case, only starting product was recovered.

Scheme 130

Our attention then turned to three different less volatile substrates illustrated in Figure 36.

Various conditions were investigated and triols 388 and 397 both provided a complex mixture of degradation products. Hemiacetal 385, on the other hand, demonstrated to be inert toward hydrazine in the presence of various bases also at temperatures above 200°C and the starting material was systematically recovered. 155 relatively popular and is still employed in various synthetic reports. For instance, it was used in the total synthesis of (+)-cyperolone by Kirsch in 2012. 157 Ketone 447 was reacted with p-TsNHNH 2 affording hydrazone 448 in 92% yield, further reduction of the latter by DIBAL-H then delivered the deoxygenated cyclohexane 449 in 77% yield (Scheme 131).

Scheme 131

The Caglioti modification was employed for our deoxygenation essays. The first test was conducted using ketone 121 by treatment with tosyl-hydrazide in MeOH affording hydrazone 450 in 85% yield (Scheme 132).

Scheme 132

The resulting tosyl hydrazone was reacted with an array of reducing agents, including: The condensation of the tosyl hydrazide was tested onto various carbonyl compounds, which are depicted in Figure 37. Notably, the substrates were heated in MeOH in the presence of tosyl hydrazine and, when 385 and 388 were reacted, catalytic PTSA. However, in all cases the departing product was recovered.

Mozingo type reductions and sulphur chemistry

As previously explained in section 5.2, the thioacetalization strategy at an advanced stage of the synthesis failed. Nevertheless, the installation and subsequent desulfurization of a thioacetal remain methodologies that are still exploited in much reported synthesis and represent a classical method for the deoxygenation of carbonyl compounds. 163,164 It was interesting to test the possibility to synthesize and reduce some dithianes and thus reducing the C1 ketonic carbon to methylene. To this aim, our objective was to test the feasibility of the process, not the chemoselectivity. Ketone 121 was reacted with ethanedithiol and with phenylthiol affording compounds 451 and 452 respectively in 68% and 81% yield (Scheme 133). The conditions employed for the syntheses of these dithianes foresee the stoichiometric utilization of TiCl 4 and a large excess of NEt 3 . Triethylamine was utilized in order to prevent the shift of the double bond from the exo-to the endo-position. 165 Notably, other Lewis acid were tested: both BF 3 .

OEt 2 and SnCl 4 caused the addition of the thiol onto the double bond affording 453. Org. Chem. 1965, 30, 1316-1317. 165 The utilization of Lewis acids usually catalyse the shift of the double bond from an exo-position toward an endo position. See Section 6.6 for an accurate explanation.

Scheme 133

The presence of the exo-double bond was taken into account when executing these reactions and, as formerly said, an eventual hydrogenation of the unsaturation was irrelevant. The synthesised dithianes were subsequently engaged in desulfurization tests: 451 and 452 were treated with Raney-Ni or with NaBH 4 /NiCl 2 in various conditions (Scheme 134). Compound 446 was never observed and the various reactions mostly resulted in the recovery of the starting products or in the hydrogenation of the double bond.

Scheme 134

The possibility to synthesize and then reduce a thiocarbonyl group was then explored.

Lawesson's reagent is renowned to be a powerful reagent for thionation of oxygen containing functional groups. Indeed, Lawesson's reagent demonstrated to be more effective on hindered substrate and to necessitate shorter reaction times compared to P 4 S 10 . 166 Otherwise, it is not selective for oxygenated groups and usually the order of reactivity is: alcohol > amides > ketones > esters. 167

Clemmensen reaction

The Clemmensen reaction is one of the oldest deoxygenative transformation published. 168 The originally reported conditions employ zinc amalgam and gaseous hydrochloric acid.

Various modifications aiming to avoid the use of mercury and to execute this reduction in organic solvents were reported over the years. The exact mechanism of the reaction has not been fully elucidated although it is known that alcohols are not intermediates. 169 It was decided to test the reactivity of our compounds in the acidic conditions related to the reaction.

Because of the aforementioned acidity, only a small array of three compounds represented in Figure 38 were thought as suitable substrates. Two different sets of conditions corresponding to different degrees of reactivity were tested. We started examining the behaviour of Zn powder and TMSCl in a mixture of iPrOH and DCM then we switched to harsher aqueous hydrochloric acid and Zn powder refluxed in ethanol. 170 In all cases the starting material was recovered.

Figure 38

Hydride displacement

Once the difficulty of deoxygenating the C1 carbon in the form of sp 2 carbon stated, the latter was reduced to sp 3 carbon and various attempts to eliminate the resulting alcohol were conducted. The transformation of an alcohol function to a leaving group followed by a nucleophilic substitution by an hydride is a common method for the deoxygenation of alcohols. 171 To this aim, the precedently synthesised alcohol 418 was transformed into its mesyl derivative 455 (Scheme 136). This compound demonstrated to be unstable towards usual operative conditions and the crude mixture was obtained by simple evaporation of the solvent from the reaction flask using a flush of argon followed by vacuum. The solvent was added and the hydride displacement tests were accomplished. 168 Clemmensen, E. Chemische Berichte 1913, 46, 1837-1843. 169 Saji, T.; Hoshino, K.; Ishii, Y.; Goto, M. J. Am. Chem. Soc. 1991, 113, 450-456. 170 For Zn/TMSCl see: (a)

Scheme 136

In order to get access to alkene 446, various hydride sources were examined, including:

LiAlH 4 , DIBAL-H, NiCl 2 /NaBH 4 and LiEt 3 BH. In most cases, the attack of the reducing agent occurred on the sulphur atom and the corresponding alcohol 418 was regenerated.

However, in order to investigate about the possibility to invert the configuration at C1, a

Finkelstein reaction was also tested on the mesylate 455 in order to get access to iodo derivative 456. Refluxing 455 over 16 h in acetone resulted only in the recovery of the starting alcohol 418 (Scheme 137). 172 Scheme 137

Barton-McCombie reaction

In 1975, British chemists Derek Barton and Stuart McCombie, developed a new radical method for the deoxygenation of alcohols. 173 The method states the transformation of the alcohol into a thiocarbonyl-derivative and subsequent deoxygenation by the using a radical source such as nBu 3 SnH and a radical initiator, for example AIBN (Scheme 138).

Scheme 138

Although various modifications aiming to avoid the utilization of tin derivatives were described, this method is still one of the most powerful and reliable. 174 Nowadays it is still utilised in a variety of the total synthesis reports in which an alcohol must be reduced. For instance, Sarpong and his group applied this approach in the course of the synthesis of the hetidine and atisine skeletons. 175

Scheme 139

Another example of this method regards the total synthesis of (±)-cafestol reported by Hong and co-workers. 176 Notewothy, in this case, the deoxygenation was run in the presence of an exo-unsaturation. Indeed, alcohol 460 was transformed into xanthate 461 and radical deoxygenation was accomplished providing alkene 462 in 75% yield (Scheme 140). This example was particularly relevant because of the similarity between substrate 460 and the bicyclic alcohol 418.

Scheme 140

Various thiono-derivatives are capable to undergo radical deoxygenation, two of the most utilised are the methyl xanthate and the imidazol-1-ylthiocarbonyl (Figure 39). 177

Figure 39

A imidazol- Therefore, it was decided to test our substrates under these conditions. We started our investigations by the synthesis of the thiono-derivative from alcohol 418 (Scheme 142).

Various conditions were tested but the utilization of NaH, CS 2 and MeI on this substrate demonstrated to mainly deliver degradation products. Otherwise, the synthesis of the imidazolyl derivative was accomplished affording 466 in 85% yield by using thiocarbonyldiimidazole ((imid) 2 CS) and DMAP.

Scheme 142

Unfortunately, the application of nBu 3 SnH/AIBN to derivative 466 in refluxing THF leaded to the rapid degradation of the substrate independently from the amount of stannane employed. Thus, this result drove us to investigate the reactivity of thiono-derivatives derived from other alcoholic substrates. To this aim, derivatization to thiono-compounds was tested onto the three alcohols represented in Figure 40 in various conditions, however, xanthate or a thiono-derivatives were never obtained.179

Figure 40

It was observed that these substrates underwent various side reactions. When reacted with CS 2 and MeI in the presence of NaH in refluxing THF, bisprotected triol 402 did not show any reactivity and the starting material is recovered (Scheme 143). Alternatively, when toluene was used as solvent, instead of affording 467, elimination of the tertiary alcohol occurred and silyl enol ether 468 was retrieved.

Scheme 143

Compound 403 was also submitted to similar conditions. In this case, refluxing 403 in THF afforded a TBS-group shift from C4 alcohol to C1 alcohol leading to structure 469 (Scheme 144).

Scheme 144 However, the treatment of the three above mentioned compounds with thiocarbonyldiimidazole resulted in the recovery of the starting material.

Ring Opening Metathesis strategy

Once the difficulties related to the reduction of the C1 oxygen established, another synthetic scheme was devised to circumvent this problem. Our hypothesis regarded the steric hindrance induced by the bicycle itself as one of the plausible explanation for the inertness of the C1oxygen towards reduction conditions. Thus, starting from 121, it was envisaged to open the 7-membered ring through ring opening metathesis and run a deoxygenation reaction on 470 to get access to cyclopentane derivative 471 (Scheme 145). Ring closing metathesis would then deliver bicyclic compound 472.

Scheme 145

Starting from ketone 121 (Scheme 146), the C3-C18 exo-double bond was shifted into C3-C4 endo position by stoichiometric BF 3 . OEt 2 affording 454 in 93% yield. The ketone function was reduced to alcohol 473 and allylic oxidation performed on the latter compound delivered a mixture of primary allylic alcohol and α,β-unsaturated aldehyde. 180 Luche reduction executed directly on the crude mixture allowed to obtain diol 474 in 84% yield.

Scheme 146

With substrates 454, 473 and 474 in hands, we then turned our attention to the search for most suitable catalyst for ring opening metathesis with ethylene. The choice was based on the reported works of Martin and Aubé in which Hoveyda-Grubbs 2 nd generation catalyst (H-G II) was employed for the opening of a strained ring in the presence of gaseous ethylene. 181 Under these conditions, bicyclic compound 475 underwent ring opening metathesis, affording tetrahydrofuran derivative 476 in 78% yield (Scheme 147).

Scheme 147

Various substrates were next submitted to these reaction conditions (Scheme 148). Notably, ketone 454 reacted poorly with ethylene both at 25°C or 110°C (Table 3, entries 1 and 4). 180 The configuration of the C1 center was not proved but it was assumed to possess a similar stereochemistry as alcohol 418 showed in Section 5.3. 181 (a) Ghosh, P.; Judd, W.R.; Ribelin, T.; Aubé, J. Org. Lett. 2009, 11, 4140-4142. (b) Benjamin, N.M.; Martin, S. Org. Lett. 2011, 13, 450-453. Diol 474 mostly exhibited the same reactivity (Table 3, entries 2 and5). On the other hand, alcohol 473 demonstrated to be slightly more reactive, delivering the corresponding cyclopentanol 477 in 28% yield (Table 3, entry 3). Additionally, microwave irradiation proved to be ineffective in enhancing the yields of this transformation (Table 3 When this alternative strategy was planned, we were conscious of the substantial extension of the synthetic scheme it may involve, however, it was mandatory to find a method capable to overcome the deoxygenation problem. Opening the bicyclic scaffold would undoubtedly permit to enhance the reactivity at C1 center toward various deoxygenation techniques, however, the modest yields obtained in these preliminary essays did not allow to pursue the investigations following this route.

Conclusion

In this chapter all the various deoxygenation essays have been reviewed in a bibliographic point of view and the main results have been presented. In the Wolff-Kishner related reactions, among the various substrates engaged, deoxygenation was never achieved. Only tosyl hydrazone 450 was isolated and subsequent reduction regenerated the starting alcohol or the intermediate hydrazone (Scheme 149).

General Conclusion

Neurodegenerative disorders still represents an unsolved worldwide problematic for the healthcare system. Nervous system growth factors, i.e., neurotrophins, constitute a promising solution to these disorders. To this aim, natural products displaying neurotrophic activity such as some vibsane-type diterpenoids hold significant potential as tools for biological studies.

Vibsatin A 1 and vibsatin B 2, two vibsane derivatives isolated as very minor metabolites in 2014, attracted our attention as these compounds were found to greatly enhance neurite outgrowth (Figure 1). Moreover, vibsatins reveal a structurally dense architecture featuring an unprecedented bicyclo [4.2.1]nonane framework.

If various synthetic studies were accomplished towards the elaboration of vibsane-type natural substances, no total synthesis of vibsatins A 1 and B 2 were reported to date (Figure 41). Therefore, it was important to develop a straightforward chemical route to evaluate and optimize the biological properties of these natural products. In this context, the total synthesis of vibsatin A and vibsatin B constitutes the aim of this thesis work.

Figure 41

The key-step of the synthesis was identified as the cyclization reaction. Thus, the retrosynthetic pathway elaborated by our group was mainly divided in two parts. The access to the bridged bicyclo [4.2.1]

Scheme 156

The second approach was based on the installation of a ketal at C1 in order to perform a transthioketalization and subsequent desulphurization reaction at a further stage (Scheme 157). This synthetic line provided an inverted stereochemical outcome at the dihydroxylation step leading to vibsatin A type, 3(S) configuration. A wide array of catalysts were tested in order to perform a transthioketalization reaction on compound 416, previously synthesized in 41% yield over 5 steps starting from ketone 121. However, the desired C1 thioketal was never obtained.

Scheme 157

In the third strategy, the ongoing one, it was decided to reduce the C1 oxygen to alcohol and to protect it as an ether (Scheme 158). Following roughly the same synthetic route, as previously described, a vibsatin A derived, 3(S) compounds 423 and 426 were afforded, demonstrating that the stereochemistry of the dihydroxylation reactions only depended on the substituents present at C1 and proving the irrelevance of the C4 configuration at this stage.

The synthesis was next pursued through simple chemical transformations until the α,βunsaturated compound 428 was reached.

Scheme 158

At the present time, the conjugate addition at C10 of the α,β-unsaturated ketone 428 is under investigation and, after preliminary studies, the insertion of a cyanide group exploiting Et 2 AlCN appeared to be the most effective method, affording compound 434. Further optimization of this reaction is required in order to afford C10 alkylation on larger scales, interestingly, the configuration at C10 resulted to be 10(S), i.e. in accordance with vibsatin A and B. With four stereocenters controlled out of five, our attention will next be turned to the alkylation at the C5 position in order to achieve the set-up of the last stereocenter of the vibsatin skeleton such as in 437 (Scheme 159).

Scheme 159

All the intermediates synthesized in these last three strategies underwent deoxygenation essays. Clemmensen, Wolff-Kishner, Barton-McCombie, hydride displacement and sulphur chemistry based methodologies were employed, however, the removal of the C1 oxygen was, to date, never obtained.

In the period ahead, our work will aim to pursue the ongoing strategy. Achieving the installation of all the five stereocenters of the vibsatins will be the first objective and, starting from this point, our efforts will be directed toward finding a better stage for performing a successful deoxygenation at C1 (Scheme 160).

Scheme 160

Otherwise, one alternative approach would consist in the possibility to shift the carbonyl from C1 to C13 by synthesizing silyl enol ether 482 (Scheme 161). The cyclized product 483

bearing a carbonyl at C13 should exhibit a different reactivity allowing the deoxygenation to occur.

Scheme 161

In parallel to the studies on gold(I) catalysed cyclization, an investigation upon alternative Whenever "deactivated silica gel" is mentioned, the corresponding flash chromatography was performed using solvents containing 3% of triethylamine.

Physical data and spectroscopic measurements

NMR Spectra were recorded on Bruker Avance 300 MHz, 400 MHz or 600 MHz spectrometers. 1 H NMR spectra were recorded using an internal deuterium lock at ambient temperature.

Internals references of δ H 7.26 and 3.35 were used respectively for CDCl 3 and methanol-d 4

(MeOD). . Data are represented as follows: chemical shift (in ppm), multiplicity (s = single, d = doublet, t = triplet, q = quartet and br. = broad), integration, coupling constant (J), expressed in Hz, attribution. 13

Organometallic titration

The procedure of S.C. Watson and J.F. Eastham was used. 182 The solution of organolithium or organomagnesium compound to be titrated was slowly added at 0 °Cto a solution of benzylalcohol (500 μL, 4.83 mmol, 1.0 equiv) in dry diethyl ether or THF containing a small amount of 2,2-biquinoline or 1,10-phenanthroline. The addition was stopped when the colourless solution became red.

Nomenclature

IUPAC nomenclature was used for all the compounds.

Synthesis of bicyclic ketone 121

Methyl (R)-3-(1-methyl-2-oxocyclopentyl)propanoate 342

Step 1

In a round-bottomed flask equipped with a Dean-Stark apparatus were placed 2methylcyclopentanone, (7.42 g, 75.7 mmol), (S)-1-phenylethylamine (9.17 g, 75.7 mmol) and p-toluenesulfonic acid (14.5 mg, cat.) in toluene (50 mL). The reaction mixture was heated at reflux for 16 h then concentrated under reduced pressure. The residue was distilled (b.p.

110°C, 2 mBar) to give the intermediary imine 341 as a greenish oil (1.1 diastereomeric mixture, 12.23 g, 83%). IR (film): ν˜ = 1673 cm -1 (C=N).

Step 2

To the imine 341 (12.23 g, 60.8 [α] D 20 = + 1.2 (c 1.0, CHCl 3 ). [α] D 20 : -4.12 (c 1.0, CHCl 3 ). [α] D 20 : +56,71 (c 1.0, CHCl 3 ).

(S)-tert-butyldimethyl((5-methyl-5-(pent-4-yn-1-yl)cyclopent-1-en-1-yl)oxy)silane 348

In a round-bottom flask containing ketone 347 (645 mg, 3.93 mmol, 1 equiv.) dissolved in DCM (170 mL) at 0°C, were successively added 2,6-lutidine (1.37 mL, 11.8 mmol, 3 equiv.) and TBSOTf (1.08 mL, 4.72 mmol, 1.2 equiv.). The ice bath was removed and the mixture was stirred overnight. DCM was removed under reduced pressure and the oily residue was purified by flash chromatography over silica gel (cyclohexane/AcOEt, 98:2 to 90:10) to afford pure 348 (10.5 g, quantitative yield).

[α] D 20 = -2.20 (c 1.0, CHCl 3 ). General procedure for Au I mediated 7-exo-dig cyclization In a dry aluminum foil wrapped vial, were placed (Me 2 S)AuCl (0.05 equiv.) and 300 (>0.05 equiv.) dissolved in DCM (≈0.01 M) and the mixture was stirred in the dark for at least 30 min. The solvent was removed under successively an argon flow and vacuum.

The vial was refilled with DCM and AgNTf 2 (≈0.075 equiv.) was subsequently added, the resulting suspension was stirred for 10 min.

Concomitantly, A 2-neck-schlenk containing dry MS4Å was fitted with a glass filter system equipped of a glass or young® tap. The filter was covered with dry celite® (see figure below) and the whole system was carefully flame-dried and flushed with argon (x3 vacuum-argon cycles) then wrapped in an aluminum foil.

The solution was transferred via cannula onto the filtration system and the filter was washed several times with DCM. One equivalent of t-BuOH was added in the reaction vessel and dry DCM was added until the concentration of the catalyst reached 0.003M.

The substrate 349 (8 g, 25 mmol, 1 eq.) was solubilized in dry DCM (0.6M) and the resulting solution was added dropwise to the reaction vessel. After 10 min, the resulting solution was filtered on a pad of silica gel and the solvent was removed under reduced pressure. Precipitation and filtration of the phosphine in EtOH followed by purification over silica gel (pentane/Et 2 O, 100:0 to 95:5) afforded the bicyclic ketone 121 (3.9 g, 95% yield).

[α] D 20 = +122.4 (c 1.0, CHC). 3075, 2961, 2927, 1737, 1636, 1451, 1374, 1309, 1167, 1075, 895, 892

Synthesis of ketone 416

(1S,6S)- 1-methyl-5-methylenespiro[bicyclo[4.2.1]nonane-9,2'- [1,3]dioxolane] 411

To a solution of 121 (200 mg, 1.22 mmol, 1equiv.), ethylene glycol (905 mg, 14.6 mmol, 12 equiv.) and (MeO) 3 CH (388 mg, 3.66 mmol, 3 equiv.) in dry dichloromethane (12 mL) was added camphorsulfonic acid (51 mg, 0.220 mmol, 0.18 equiv.) and the solution was stirred for 4 days at room temperature. A saturated NaHCO 3 solution was added and the aqueous layer was extracted with DCM (x3). The organic layers were washed with water, dried over MgSO 4 , concentrated under reduced pressure and the residue was purified by flash chromatography over silica gel (pentane/Et 2 O, 100:0 to 95:5) to afford 411 as a colorless oil (188 mg, 74% yield). 13.8, 10.8, 10.7, 2.5 Hz, 1H, Ha-13), 1.70-1.48 (m, 7H, H-5, H-10, H-12, Hb-13), 0.93 (s, 3H, H-20) ppm. 13 C-NMR (100MHz, CDCl 3 ) δ = 151.6 (C, C-3) Methyl (1R,4R,6S)- 1-methyl-5-methylenespiro[bicyclo[4.2.1]nonane-9,2'- [1,3]dioxolan]-4-ol

and 417

In a round-bottomed flask was placed 411 (500 mg, 2.4 mmol, 1 equiv.) in DCM (12 mL).

selenium dioxide (40 mg, 0.36 mmol, 0.15 equiv.), TBHP (5.5M in decane, 0.48 mL, 2.66 mmol, 1.15 equiv.) and dry acetic acid (21 µL, 0.36 mmol, 0.9 equiv.) were successively added and the mixture was stirred for 3 h. Saturated NaHCO 3 (10 mL) was added, the aqueous layer was extracted with DCM (x3) and the organic layers were dried over MgSO 4 and filtered. Removal of the solvent under reduced pressure provided a brown oil.

Purification by flash chromatography over silica gel (pentane/Et 2 O, 80:20 to 50:50) afforded 413 and 417 (d.r. : 83 : 17, 480 mg, 79% yield) as an inseparable mixture (white solid). 2.8, 6.7, 11.1, 14.0 Hz, 1H, Ha-13), 1.93 (ddd, J = 15.3, 12.4, 3.6 Hz, 1H, Ha-5), 1.82-1.69 (m, 3H, Hb-5, Hb-13, Ha-10), 1.69-1.49 (m, 2H, H-12), 1.25 (ddd, J = 14.9, 5. Major isomer 388 1 H-NMR (400MHz, CDCl 3 ) δ = 3.87 (d, J = 12 Hz, 1H, Ha-18), 3.76 (s, 1H, OH), 3.64 (d, J = 9.6 Hz, 1H, H-4), 3.44 (d, J = 11.6 Hz, 1H, Hb-18), 3.01 (broad s, 2H, OH), 2.63 (dd, J = 9.9, 6.0 Hz, 1H, H-2), 2.10-1.95 (m, 1H, Ha-13), 1.90-1.78 (m, 1H, Ha-12), 1.75-1.61 (m, 4H, Ha-5, Ha-10, Hb-12, Hb-13), 1.59-1.48 (m, 2H, Hb-5, Hb-10), 1.08 (s, 3H, H-20) ppm. H-5, H-10, H-12, Hb-13), 1.10 (s, 3H, H-20), 0.90 (s, 9H, Si-C(CH 3 ) 3 ), 0.09 (s, 6H, Si(CH 3 ) 2 ) ppm. 3.79 (dd, J = 9.4, 1.3 Hz, 1H, H-4), 3.57 (s, 2H, H-18), 2.89 (s, 1H, C3-OH), 2.61 (dd, J = 10.3, 5.6 Hz, 1H, H-2), 1.57-2.00 (m, 7H, Ha-10, H-5, H-12, H-13), 1.41 (ddd, J = 12.8, 8.6, 2.6 Hz, 1H, Hb-10), 1.06 (s, 3H, H-20) 1.74 (m, 2H, Hb-5, Ha-13), 1.66-1.60 (m, 1H, Hb-13), 1.59 (s, 3H, O-C-CH 3 ), 1.50-1.58 (m, 1H, Ha-12), 1.34-1.46 (m, 1H, Hb-12), 1.39 (s, 3H, O-C-CH 3 ), 1.14-1.07 (m, 1H, H-10), 1.03 (s, 3H, H-20), 0.89 (s, 9H, Si-C(CH 3 ) 3 ), 0.06 (s, 3H, Si(CH 3 ) 2 ), 0.04 (s, 3H, Si(CH 3 ) 2 ) ppm. Hz, 1H, Ha-13), 1.79 (ddd, J = 12.5, 13.2, 4.0 Hz, 1H, Ha-10), 1.69-1.51 (m, 4H, H-5, Ha-12, Hb-13), 1.47-1.38 (m, 1H, Hb-12), 1.36-1.29 (m, 1H, Hb-10), 1.07 (s, 3H, H-20) ppm. 11.0, 5.3 Hz, 1H, H-4), 3.53 (d, J = 7.6 Hz, 1H, H-1), 3.22 (ddd, J = 10.2, 7.6, 1.7 Hz, 1H, H-2), 2.17-2.06 (m, 1H, Ha-5), 2.01 (td, J = 14.1, 2.2 Hz, 1H, Hb-5), 1.95-1.73 (m, 2H, H-13), 1.70-1.60 (m, 1H, Ha-10), 1.58-1.49 (m, 1H, Ha-12), 1.49-1.39 (m, 1H, Hb-10), 1.26-1.17 (m, 1H, Hb-12), 1.08 (s, 3H, H-20) ppm. 2',6-trimethylspiro[bicyclo[4.2.1]nonane-2,4'- [1,3]dioxolan]-

3-one 427

A solution of 426 (2.14 g, 7.07 mmol, 1 equiv.), 2,2-DMP (152 mL) and PPTS (670 mg, 2.7 mmol, 0.3 equiv.) in DCM (112 mL) was stirred for 24 h. A saturated solution of NaHCO 3 (150 mL) was added, the aqueous layer was extracted with DCM (x3) and the organic layers were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. Flash chromatography over silica gel (pentane/Et 2 O, 9:1 to 7:3) afforded 427 (2.31 g, quantitative yield). = 11.6, 5.6, 4.2 Hz, 1H, Hb-5), 2.27 (dddd, J = 15.4, 10.4, 7.6, 2.6 Hz, 1H, Ha-13), 1.85-1.72 (m, 2H, Ha-10, Hb-13), 1.65 (ddd, J = 14.0, 10.4, 3.8 Hz, 1H, Ha-12), 1.56-1.47 (m, 1H, Hb-12), 1.44-1.39 (m, 1H, Hb-10), 1.37 (s, 3H, O-C-CH 3 ), 1.30 (s, 3H, O-C-CH 3 ), 1.06 (s, 3H, H-20) ppm. ,2,7-trimethyl-3a,4,5,6,7,8hexahydro-4,7-methanocycloocta[d][1,3]dioxol-8-yl acetate 430 C h a p t e r 9 : E x p e r i m e n t a l P a r t P a g e | 219

To a solution of 427 (240 mg, 0.69 mmol, 1 eq.) in THF (4 mL) cooled at -78°C was added LDA (1 mL, 1.03 mmol, 1.5 eq.) and the mixture was stirred for 10 min. TMSCl (0.26 mL, 2.07 mmol, 3 eq.) was added and the temperature was raised to r.

  Shen Y.-H.; Prakash C.V.S.; Wang L.-T.; Chien C.-T.; Hung M.-C., J. Nat. Prod. 2002, 65, 1052-1055. 13 (a) Shen Y.-C.; Lin C.-L.; Chien S.-C.; Khalil A.T.; Ko C.-L.

  (a) Davies, H.M.L. In Advances in Cycloaddition; Harmata, M., Ed.; JAI Press: Greenwich, CT, 1998; Vol. 5, 119-164. (b) Davies, H.M.L.; Stafford, D.G.; Doan, B.D.

Scheme 9 1. 4 . 2

 942 Scheme 9

  Scheme 16Vinyl iodide 86 was selectively synthesised in two steps and 98% yield by a Negishi iodomethylation 26 of 4-pentyn-1-ol followed by a protection step (Scheme 15). Vinyl iodide was subjected to a palladium catalysed carbonylation-imidation with (R)-4-phenyl-2oxazolidinone to provide 87 in 68% yield. Having introduced an asymmetric inductive group, the vinyl cuprate selectively attacked the Si-face of the olefin providing 88 in 85% yield diastereoselectively(90% d.e.). In this manner, the crucial quaternary center was controlled as 11S. At this stage, the imide was converted into the corresponding aldehyde 83 by oxazolidinone removal, esterification and a reduction/oxidation sequence. Then, the

Finally, oxidation of

  Scheme 20The upper and lower fragments were coupled by treatment of alkenyl iodide 97 with tBuLi and addition of two equivalents of aldehyde 96 (Scheme 21). The coupling adducts 112a and 112b, relative to isomers 8S and 8R respectively, were recovered in 52% yield, for 112a, and 10% for 112b. Since the newly formed stereogenic center in major isomer 112a possessed the opposite configuration to the synthetic target, esterification of 112a under Mitsunobu conditions was explored. Although 3,3-dimethylacrylic acid was a weak acid, the Mitsunobu reaction of 112a proceeded smoothly providing desired ester 113 with configurational inversion in 72% yield. On the other hand, the minor isomer 112b was converted into 113 in 52% yield by using a mixture of 3,3-dimethylacryloyl chloride and pyridine. Deprotection of 113 followed by oxidation of the resulting primary alcohol furnished compound 95 in 76% yield. From this aldehyde, it was possible to explore Nozaki-Hiyama-Kishi type reaction: indeed, treatment of dilute solution of 95 (0.005 M) with CrCl 2 and catalytic NiCl 2 led to the formation of the 11-membered ring and provided the cyclized product 114 as a single isomer in 82% yield. At this stage, the diastereomer derived from the minor enantiomer of the upper fragment 96 was separated by flash chromatography, allowing the isolation of diastereomerically pure 114. As expected, the allylic rearrangement of 114 into 3 was achieved by Mitsunobu reaction using p-nitrobenzoic acid and chemoselective methanolysis of the resulting diester. (+)-Vibsanin A 3 was finally obtained in 73% yield.

neurotrophin 4 / 5 (

 45 NT-4/5) and neurotrophin-3 (NT-3). NTF acts through two distinct receptors: a high-affinity and selective receptor tyrosine kinase called Trk and a low affinity receptor called p75. NGF binds TrkA, BDNF and NT-4 bind TrkB, whereas NT-3 prefers

31 ( a )

 a Thompson, L.M. Nature 2008, 452, 707-708. (b) Palop, J.J.; Chin, J.; Mucke, L. Nature 2006, 443, 768-773; (c) Martin, J.B.

Figure 9

 9 Figure 9

Figure 10

 10 Figure 10

  Scheme 24

  Starting from methyl acetoacetate 138, the precursor of the cyclization (±)-139 was synthesized in 5 steps. Treating this compound with dicarbonylcyclopentadienyl cobalt(I) (CpCo(CO) 2 ) under UV irradiation at 80°C afforded the cyclized intermediate (±)-140. The subsequent change of solvent, temperature and addition of bis(trimethylsilyl)ethyne (BTMSE), triggered a [2+2+2] cycloaddition that formed benzocyclobutane (±)-141. Electrophilic ring opening of (±)-141 into (±)-142 took place by raising the temperature to 175°C and the newly formed compound underwent a [4+2] Diels-Alder rearrangement providing the tetracyclic diterpene backbone (±)-143, typical of phyllocladane.

Scheme 31 C h a p t e r 2 :

 312 Scheme 31

  mercury(II) forms a Z-vinylmercurial intermediate 153 through a rearrangement of a transient α-mercury ketone 154. Hydrolysis of the intermediate delivers the homoallylic ketone 155 (Scheme

6 -

 6 using gold catalysts: a broad overview Despite the fact that simple gold salts such as NaAuCl 4 or AuCl are active enough to catalyze numerous transformations, linear two-coordinate 14-electrons gold(I) complexes bearing phosphines or N-heterocyclic carbenes as ligands have found more wide-ranging applications. The active species are often generated in situ by chloride abstraction from[LAuCl] upon treatment with a silver salt bearing a weakly coordinating anion. Complexes[LAuY] only exist as neutral species when Y -is a coordinating anion (halides, carboxylates, sulfonates, and triflimides). The corresponding complexes with less coordinating anions, such as SbF most cases not stable. In this document it is implied that all the catalysts written as [LAuY] (PPh 3 AuSbF 6 for example) are synthesized mixing phosphine gold(I)chloride (PPh 3 AuCl) and the silver salt (AgSbF 6 ) unless when specified. Although[AuL] + species are often suggested in mechanistic proposals, structural proof for their existence as stable, isolable species is still lacking. The properties of gold(I) complexes can be easily tuned sterically or electronically depending on the ligand, consequently modulating their reactivity towards the activation of alkynes, alkenes, and allenes. Thus, complexes containing more donating N-heterocyclic carbenes 172 are less electrophilic than those bearing phosphine ligands 173 (Figure14). Complexes with less donating phosphite ligands 174 and related species are the most electrophilic catalysts.59

Figure 14 58

 14 Figure 14

Figure 15 The

 15 Figure 15The mechanism of these transformations has been extensively studied via DFT. Kinetically 5exo-dig cyclization is frequently favoured, but the discrimination between 5-exo-dig or 6endo-dig pathway is usually related to the substituents on the two unsaturations. Indeed, according to DFT, once the cyclopropyl carbene 256 derived from a 5-exo-dig cyclization is formed, it can undergo three different rearrangements. The first foresees the cleavage of a single bond of the cyclopropane concomitantly with the 1,3-migration of the terminal carbon of the alkene into the carbenic carbon. After the elimination of the catalyst, a β-diene 258 is formed (Scheme 61, pathway c). An alternative endo-type single cleavage rearrangement provides the 6-membered ring diene 259 (Scheme 61, pathway b). The last transformation that carbene 256 can undergo, only occurs when the terminal position of the original double bond is not fully substituted (R 4 =H). In this rearrangement, a formal migration of the terminal carbon of the original double bond onto the carbenic carbon followed by a cleavage of the exacetylenic σ-bond provides the gold(I)-carbene 260. A 1,2-hydride shift on the latter affords then the β-diene 261 (Scheme 61, pathway a).90

  A 4-exo-dig cyclization would lead to the bicyclic carbene 280. Such structure would suffer from strong ring strain due to the cyclobutane ring, thus, 5-endo-dig derived carbene 281 is favoured. 9595 Nevado, C.; Cárdenas, D.J.; Echavarren, A.M. Chem. -Eur. J. 2003, 9, 2627-2635.

Figure 16 Alkyl

 16 Figure 16Alkyl-and aryl-substituted 1,5-enynes 282 (Scheme 63) undergo cycloisomerization to give bicycle[3.1.0]hexane derivatives 283.96

  Scheme 73 Kirsch and his group reported in 2008 the first dual activation reaction in which Au(I) catalysis was used together with organocatalysis. 112 ε-Alkynyl aldehydes and α-methyl εalkynyl aldehydes 319 (Scheme 74) undergo 5-exo-dig cyclization in the presence of a secondary amine and a gold catalyst. α-Substituted aldehydes (R 1 = Me) afford exocyclic alkenes (±)-320, otherwise, α,β-unsaturated compounds 321 are delivered. Both [(Ph 3 PAu) 3 O]BF 4 and PPh 3 AuSbF 6 are suitable catalysts, but as the cyclization of α-

Figure 21 117

 21 Figure 21

C h a p t e r 3 : 99 4.

 399 C a r b o c y c l i z a t i o n o f a l k y n e s P a g e | Synthesis of the bicyclic key intermediate In this chapter, the investigations upon the Au(I)-catalyzed 7-exo-dig cyclization leading to the bicyclic key intermediate 121 of vibsatins will be presented (Scheme 79). The first purpose, in order to get access to the bicyclo[4.2.1]nonane skeleton of the key-intermediate 121, was the synthesis of the precursor 122, which will start from 2-methylcyclopentanone 123.

  disubstituted cyclic ketones 334 was developed employing (S)-or (R)-phenylethylamines 335 (Scheme 80). This procedure was composed of two successive reactions: first, the condensation of the chiral amine 335 onto the ketone 336 to afford imine 337 and the 118 (a) Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. J. Am. Chem. Soc. 1985, 107, 273-274. (b) D'Angelo, J.; Desmaële, D. Tetrahedron lett. 1990, 31, 879-882. (c) D'Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459-505.

  3.1 127 (a) Balaraman, K.; Kesavan, V. Synthesis 2010, 20, 3461-3466. (b) Eglinton, G.; Galbraith, A.R. Chem. Ind. (London) 1956, 737 (c) Hay, A.S. J.Org. Chem. 1960, 25, 1275-1276. (b) Hay, A.S. J. Org. Chem. 1962, 27, 320-320.

  study upon the 7-exo-dig cyclization was first engaged on a model substrate. This study demonstrated the superior reactivity outcome of the TIPS-based silyl enol ether (±)-354. The various trials of this study suggest that the two competitive reactions (7-exo-dig cyclization and the electrophilic cleavage) possess different kinetic profiles and tuning the operative conditions results in the promotion of one of the two processes. Notably, the utilization of a JohnPhos based catalyst resulted only in the formation of the bicyclic ketone and, even if the conversion was low, it represents an interesting departing point for a study aiming to the substitution of the bulky ligand 300 with commercially available phosphines. Once the best conditions tuned, the desired key-intermediate 121 was obtained in 92% yield and the subsequent scale up allowed to run this 7-exo-dig gold(I)-catalysed cyclization on up to 8 grams of substrate in glove-box free conditions.

  Scheme 109In order to obtain accurate structural informations on compounds 385/386 and 387/388, crystals suitable for X-ray diffraction analysis were obtained from mixtures of cyclohexane and Et 2 O. Moreover, upon the four structures, only crystals from the hemiketalic forms were obtained and analysed. In Figure23is shown the X-ray diffraction analysis representation of compound 385. From this figure, it is clearly evidenced that the faces of the double bond differ in accessibility. The Si-face is expected to be less hindered and consequently preferred in the case of dihydroxylation reaction.

Figure 23 This

 23 Figure 23This hypothesis was in good agreement with the reaction involving 385, 386 and potassium osmate to produce triols 387 and 388. The hemiketalic form 387 crystallized and its X-ray diffraction structure is shown in Figure24. Moreover, the configuration at the C3 resulted to be directly related to vibsatin B, meaning a cis-relationship between C3 and C4 alcohols.

Figure 27

 27 Figure 27

Figure 28 Figure 29

 2829 Figure 28

Figure 30 146

 30 Figure 30

Figure 31

 31 Figure 31

  mandatory importance. In this context, first deoxygenation tests were conducted on bicyclic ketone 121 depicted in Scheme 126. Despite the various powerful chemical techniques employed in this aim, the deoxygenation at C1 appeared to be a critical step. For this reason, the numerous intermediates synthesised in Chapter 5, bearing an alcohol or a ketone function at C1, were engaged. Notably, in the literature, examples of successful deoxygenation reactions applied on bridged bicyclic-[n.m.1] molecules are scarce but further investigation are currently in progress.

Figure 36 In 1963 ,

 361963 Figure 36In 1963, Caglioti and his group developed a two-step process for the deoxygenation of ketones or aldehydes derived from the classical Wolff-Kishner procedure.156 This represents one of the mildest methodology as it allows to execute the deoxygenation of carbonyl compounds at lower temperatures. On the other hand, this modification foresees the isolation of the intermediate hydrazone. Indeed, in the first step, a tosyl hydrazone is generated and subsequent reduction of the latter completes the deoxygenation. This method became

LiAlH 4 ,

 4 158 DIBAL-H, 159 NaBH 3CN, 160 NaBH 3 CN/ZnCl 2 , 161 catecholborane/NaOAc 162 and CeCl 3 /LiEt 3 BH. When hydrides like NaBH 3 CN were used, the departing product was systematically recovered, otherwise LiAlH 4 and DIBAL-H induced the cleavage of the hydrazone and provided the starting ketone 121.

Figure 37

 37 Figure 37

163

  References relative to Raney-Ni: (a)Paquette, L.A. ; Ham, W.H. J. Am. Chem. Soc. 1987, 109, 3025-3036. (b) Meng, X-L.; Liu, T.; Sun, Z-W.; Wang, J-C.; Peng, F-Z.; Shao, Z-H. Org.Lett. 2014, 16, 3044-3047 (c) Pal, S.K.; Gupta, P.D.; Mukherjee, D. Tetrahedron 2002, 58, 1765-1771. (d) Padwa, A.; Brodney, M.A.; Dimitroff, M.; Liu, B.; Wu, T. J.Org. Chem. 2001, 66, 3119-3128. 164 References relative to NiCl 2 /NaBH 4 : (a) Clark, J.; Grantham, R.K.; Lydiate, J. J.Chem. Soc. 1968, 1122- 1124. (b) Paul, R.; Buisson, P.; Joseph, N. Ind. Eng. Chem. 1952, 44, 1006-1010. (c) Truce, W.E.; Perry, F.M. J.

  Scheme 153The enantioenriched precursor 122 was first synthesized in 53% yield over eight steps and with 91% enantiomeric excess (Scheme 154). The configuration at C11 was controlled by exploiting an asymmetric Michael reaction starting from 30 grams of 2methylcyclopentanone 123. A study upon the 7-exo-dig cyclization was first engaged on a model substrate employing phosphine 300. This study demonstrated the superior reactivity outcome of the TIPS-based silyl enol ether (±)-354. The numerous trials peformed in the course of this study, suggested that the two competitive reactions (7-exo-dig cyclization and electrophilic cleavage) possess different kinetic profiles and tuning the operative conditions results in the promotion of one out of the two processes. Once the best conditions defined, the desired bicyclo[4.2.1]nonane vibsatin's derived skeleton 121 was obtained in 95% yield from 349 and the subsequent scale up allowed to run this 7-exo-dig gold(I)-catalysed cyclization on 8 grams of substrate.

  Scheme 162

1 H

 1 -NMR (400MHz, CDCl 3 ) δ = 7.62 (d, J = 8.0 Hz, 2H, H-ar), 7.32 (d, J = 8.0 Hz, 2H, Har), 3.98 (t, J = 6.4 Hz, 2H, C-4), 3.89-3.77 (m, 4H, O-CH 2 -CH 2 ), 2.42 (s, 3H, Ar-CH 3 ), 1.83-1.45 (m, 7H, H-2, H-5, Ha-12, H-13),1.45-1.35 (m, 1H, Hb-12), 1.30(m, 2H, H-10), 0.87 (s, 3H, H-20) ppm.

  ),25.3 (CH 3 , C-20), 24.2 (CH 2 , C-5), 19.3 (CH 2 , C-4), 18.2 (C, Si-C), -4.6 (CH 3 , Si-CH 3 ), -4.9 (CH 3 , Si-CH 3 ) ppm.

  1 H-NMR (400MHz, CDCl 3 ) δ = 4.79 (s, 1H, H-18), 4.74 (s, 1H, H-18), 3.15 (dd, J = 9.7, 3.0 Hz, 1H, H-2), (dd, J = 15.6, 6.9 Hz, 1H, Ha-4), 2.26 (dtd, J = 13.4, 10.1, 5.0 Hz, 1H, Ha-5), 2.15-2.05 (m, 1H, Hb-4), 2.01 (ddd, J = 12.9, 8.8, 3.7 Hz, Ha-12), 1.89-1.62 (m, 4H, Hb-12, Hb-5, H-13),1.58 (dt, J = 13.7, 4.4 Hz, 1H, 10),1.42 (ddd, J = 11.9, 12.6, 4.4 Hz, 1H, 10),1.09 (s, 3H, 20) ppm.

  [α] D 20 = +12.69 (c 1.0, CHCl 3

  ): ν = 3496, 3070, 2928, 1631, 1155, 1046 cm -1 . HRMS (ESI): m/z calcd for C 13 H 20 O 3 Na + : [M+Na] + : 247.2892; found: 247.2896. (4R,5S)-1-methyl-5-(((triisopropylsilyl)oxy)methyl)spiro[bicyclo[4.2.1]nonane-9,2'-[1,3]dioxolane]-4,5-diol 415 In a round-bottomed flask were placed 414 (150 mg, 0.58 mmol, 1 equiv.) and 2,6-lutidine (135 µL, 1.16 mmol, 2 equiv.) dissolved in DCM (5 mL) at 0°C. TIPSOTf (156 µL, 0.58 mmol, 1 equiv.) was added dropwise and the mixture was stirred overnight. Water (5 mL) was added, the aqueous layer was extracted with DCM (x3), the organic layers were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. The oily residue was purified by flash chromatography over silica gel (pentane/Et 2 O, 90:10 to 70:30) affording 415 (235 mg, quantitative yield)

1 H

 1 -NMR (400MHz, CDCl 3 ) ) δ = 4.03-3.88 (m, 6H, O-CH 2 , Ha-18, C-4-OH), 3.72-3.64 (m, 2H, H-4, Hb-18), 2.86 (s, 1H, C-3-OH), 2.37 (dd, J = 10.2, 2.2 Hz, 1H, H-2), 2.25 (dddd, J =

  NMR (100MHz, CDCl 3 ) δ = 119.4 (C, C-1),75.2 (CH, C-4),74.3 (C, C-3), 68.3 (CH 2 , C-18), 66.5 (CH 2 , O-CH 2 ), 63.9 (CH 2 , O-CH 2 ), 48.9 (CH, C-2), 46.7 (C, C-11), 33.5 ): m/z calcd for C 22 H 42 O 5 SiNa + : [M+Na] + : 437.2702 ; found: 437.2685. C h a p t e r 9 : E x p e r i m e n t a l P a r t P a g e | 195 (5S)-5-hydroxy-1-methyl-5-(((triisopropylsilyl)oxy)methyl)spiro[bicyclo[4.2.1]nonane-9,2'-[1,3]dioxolan]-4-one 416 To a stirred solution of Dess-Martin Periodinane (327 mg, 0.77 mmol, 1.5 equiv.) and NaHCO 3 (136 mg, 1.54 mmol, 3 equiv.) in DCM (10 mL) was added a solution of 415 (213 mg, 0.51 mmol, 1 equiv.) in DCM (3 mL) and the mixture was stirred for 18 h. A saturated solution of Na 2 S 2 O 3 (15 mL) was added, the aqueous layer was extracted with DCM (x3) and the organic layers were washed with brine, dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. Purification by flash chromatography over silica gel (pentane/Et 2 O, 9:1 to 7:3) afforded ketone 416 (203 mg, quantitative yield).

1 H

 1 -NMR (400MHz, CDCl 3 ) δ = 4.59(d, J = 9.8 Hz, 1H, Ha-18), 4.06 (s, 1H, C-3-OH), 4.05-3.87 (m, 4H, O-CH 2 ), 3.63 (d, J = 9.8 Hz, 1H, Hb-18), 2.99 (ddd, J = 12.1, 9.5, 7.6 Hz, 1H, Ha-5), 2.51 (ddd, J = 12.1, 6.8, 5.0 Hz, 1H, Hb-5), 2.15 (d, J = 8.1 Hz, 1H, H-2), 1.92(dddd, J = 14.0, 10.0, 3.5, 1.4 Hz, 1H, Ha-13),1.83 (ddd, J = 13.7, 7.6, 5.0 Hz, 1H, Ha-10),1.74 (ddd, J = 13.7, 9.6, 6.8 Hz, 1H, Hb-13),1.65-1.56 (m, 2H, Hb-10, Ha-12),1.38 (ddd, J = 13.9, 10.0, 7.6 Hz, 1H, Hb-12), 1.09-1.01 (m, 21H, Si-CH-(CH 3 ) 2 ),0.98 (s, 3H, H-20) ppm.

  13 C-NMR (100MHz, CDCl 3 ) δ = 212.1(C, C-4), 118.6 (C, C-1), 80.0(C, C-3), 69.0 (CH 2 , C-18), 66.2 (CH 2 , O-CH 2 ), 64.1 (CH 2 , O-CH 2 ), 49.3 (CH, C-2), 45.4 (C, C-11), 37.8 (CH 2 , C-10), 36.0 (CH 2 , C-5), 35.1 (CH 2 , C-12), 23.8 (CH 3 , C-20), 21.3 (CH 2 , C-13), 18.06 (6CH 3 , Si-CH-(CH 3 ) 2 ), 12.1 (3CH 2 , Si-CH) ppm. (1R,4R,5R,6S)-4,5-dihydroxy-5-(hydroxymethyl)-1-methylbicyclo[4.2.1]nonan-9-one 387 and 388 To a stirred solution of 385 and 386 (300 mg, 1.67 mmol, 1 equiv.) in t-BuOH/water (3:1, 17 mL), NMO (1.17 g, 10 mmol, 6 equiv.), pyridine (134 μL, 1.67 mmol, 1 equiv.) and potassium osmate dihydrate (184 mg, 0.50 mmol, 0.3 equiv.) were successively added. After 4h stirring at room temperature, a 20% (m/m) aqueous solution of NaHSO 3 (20 mL) was added and the mixture was stirred for an additional hour. Sodium chloride was added (2 g) and the mixture was extracted with AcOEt (x5). The organic layers were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. Purification by flash chromatography over silica gel (AcOEt/MeOH, 10:0 to 80:20) afforded 388 and 387 as an unseparable mixture (310 mg, 87% yield). HRMS (ESI): m/z calcd for C 11 H 18 O 4 Na + : [M+Na] + : 237.1103 ; found: 237.1097.

  Some of the are not distinguishable from the signals of 388. This renders uncomplete the assignement of the13 C-NMR signals of 387. CDCl 3 ) δ = 4.88 (s, 1H, C3-OH), 4.16(d, J = 7.2 Hz, 1H, H-4),3.76 (dd, 2H, J = 22.3, 12.6 Hz, 2H, H-18), 2.26 (dd, 1H, J = 10.5, 5.4 Hz, C-2), 1.05 (s, 3H, C-C h a p t e r 9 : E x p e r i m e n t a l P a r t P a g e | 199 20) ppm. The other proton signals are overlapped with the signals of the major diastereoisomer 13 C-NMR (100MHz, CDCl 3 ) δ = 115.3 nonan-9-one 397 and 398To a stirred solution of 388 (420 Mg, 1.96 mmol, 1 equiv.) and 2,6-lutidine (420 mg, 456 µL, 3.92 mmol, 2 equiv.) in dichloromethane (18 mL) at -78°C, was added TBSOTf (517 mg, 450 µL, 1.96 mmol, 1 equiv.) over 30 min and the mixture was stirred at -78°C for 90 min.The reaction was quenched with a saturated solution of NaHCO 3(25 mL), the aqueous layer was extracted with dichloromethane (x3). The organic layers were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. Purification by flash chromatography over silica gel (pentane/Et 2 O, 100:0 to 90:10) afforded 397 as a light yellow oil (480 mg, 75% yield) along with 398 (50 mg, 6% yield).

397 1 H

 1 -NMR (400MHz, CDCl 3 ) δ = 3.79 (d, J = 10.2 Hz, 1H, Ha-18), 3.70 (ddd, J = 9.7, 8.4, 3.3 Hz, 1H, H-4), 3.59 (d, J = 10.2 Hz, 1H, Hb-18), 3.15 (s, 1H, C3-OH), 2.83 (d, J = 8.4 Hz, 1H, C4-OH), 2.56 (dd, J = 10.4, 5.8 Hz, 1H, H-2), 2.01-1.91(m, 1H, Ha-13), 1.84-1.52 (m, 7H,

2 (

 2 ), 49.9 (CH, C-2),48.7 (C, C-11), 36.8 (CH 2 , C-12), 35.5 (CH 2 , C-10), 30.3 (CH 2 , C-5), 26.0 (3CH 3 , Si-C(CH 3 ) 3 ), 22.2 (CH 3 , C-20), 19.2 (CH 2 , C-13), 18.4 (C, Si-C(CH 3 ) 3 ), -5.CH 3 , Si-CH 3 ), -5.4 (CH 3 , Si-CH 3 ) ppm.

1 H

 1 -NMR (400MHz, CDCl 3 ) δ =

0 ( 8 (

 08 3 , C18-O-Si-C(CH 3 ) 3 ), 25.9 (3CH 3 , C4-O-Si-C(CH 3 ) 3 ), 22.7 (CH 3 , C-20), 20.CH 2 , C-13), 18.4 (C, C18-O-Si-C), 18.2 (C, C4-O-Si-C), -4.2 (CH 3 , C-4-O-Si-CH 3 ), -4.CH 3 , C4-O-Si-CH 3 ), -5.2 (CH 3 , C18-O-Si-CH 3 ), -5.4 (CH 3 , C18-O-Si-CH 3 ) ppm. HRMS (ESI): m/z calcd for C 23 H 46 O 4 Si 2 Na + : [M+Na] + : 465.2835; found: 465.2829. C h a p t e r 9 : E x p e r i m e n t a l P a r t P a g e | 201(3aR,4R,7R,9aR)-3a-(((tert-butyldimethylsilyl)oxy)methyl)-2,2,7-trimethyloctahydro-4,7methanocycloocta[d][1,3]dioxol-10-ol 401 Monoprotected diol 397 (180 mg, 0.55 mmol, 1 eq.) was solubilized in DCM (9 mL), 2,2dimethoxymethane (9 mL) and PPTS (34 mg, 0.137 mmol, 0.25 eq.) were added and the mixture was stirred for 16 hours. Solvent was then evaporated under reduced pressure and Et 2 O (25 mL) was added to the residue. The mixture was cooled to 0°C and LiAlH 4 (31 mg, 0.82 mmol, 1.5 eq.) was portionwise inserted. After 30 minutes the reaction was quenched by sequential addition of H 2 O (30 μL), 2M aqueous NaOH(30 μL) and again water(90 μL).White aluminium salts were filtered over a celite pad and the filtrate was reduced under reduced pressure. Purification on silica gel (Pentane/Et 2 O 80:20) afforded 401 in 91 % yield (185 mg).

1 H

 1 -NMR (400MHz, CDCl 3 ) δ = 4.06(d, J = 4.8 Hz, 1H, H-4), 3.71 (t, J = 8.6 Hz, 1H, H-1), 3.66 (dd, J = 12.7, 11.2 Hz, 2H, H-18), 3.50 (d, J = 9.0 Hz, 1H, C-1-OH), 2.68 (ddd, J = 10.0, 8.6, 2.0 Hz, 1H, H-2), 2.11-2.04 (m, 1H, Ha-5), 1.99 (td, J = 14.3, 1.9 Hz, 1H, Ha-10); 1.85-

  of NaH (226 mg, 5.64 mmol, 1.5 equiv.) andTBAI (182 mg, 0.56 mmol, 0.15 equiv.) in THF (4 mL) was added dropwise a solution of 418 (624 mg, 3.76 mmol, 1 equiv.) in THF (4 mL). BnBr (535 µL, 771 mg, 4.51 mmol, 1.2 equiv.) was then added and the mixture was stirred for 18 h at room temperature. A saturated solution of NaHCO 3 was added, the aqueous layer was extracted with Et 2 O (x3), the organic layers were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. Purification by flash chromatography over silica gel (pentane/Et 2 O, 100:0 to 90:10) afforded 419 (920 mg, quantitative yield).

1 H

 1 -NMR (400MHz, CDCl 3 ) δ = 7.31-7.39 (m, 4H, H-ar), 7.24-7.30 (m, 1H, H-ar), 4.70 (d, J = 11.9 Hz, 1H, O-CHaHb-Ar), 4.65 (d, J = 2.3 Hz, 2H, H-18), 4.40 (d, J = 11.9 Hz, 1H, O-CHaHb-Ar), 3.52 (d, J = 7.7, 1H, H-1), 3.17 (ddd, J = 10.2, 7.7, 2.0 Hz, 1H, H-2), 2.70-2.60(m, 1H, Ha-4), 2.46 (dd, J = 15.1, 5.6 Hz, 1H, Hb-4), 2.08 (dddd, J = 11.9, 13.5, 10.2, 3.1

9 (

 9 13 C-NMR (100MHz, CDCl 3 ) δ = 154.3(C, C-3), 139.5(C, C-ar), 128.3 (2CH, C-ar), 127.5 (2CH, C-ar), 127.3 (CH, C-ar), 110.3 (CH 2 , C-18), 88.2 (CH, C-1), 71.6 (CH 2 , O-CH 2 -Ar), 47.0 (CH, C-2), 44.6 (C, C-11), 37.9 (CH 2 , C-10), 36.2 (CH 2 , C-4), 34.2 (CH 2 , C-12), 29.CH 2 , C-13), 29.0 (CH 3 , C-20), 23.9 (CH 2 , C-5). HRMS (ESI): m/z calcd for C 18 H 24 ONa + : [M+Na] + : 279.1719 found: 279.1721. C h a p t e r 9 : E x p e r i m e n t a l P a r t P a g e | 215 (1S,6R,9R)-9-(benzyloxy)-6-methyl-2-methylenebicyclo[4.2.1]nonan-3-one 421 To a stirred solution of alkene 419 (850 mg, 3.32 mmol, 1 equiv.) in DCM (12 mL) were successively added TBHP (5.5M in decane, 0.69 mL, 1.15 mmol, 1.15 equiv.), dry acetic acid (29 µL, 0.5 mmol, 0.15 equiv.) and selenium dioxide (55 mg, 0.50 mmol, 0.15 equiv.). The mixture was stirred for 1 h and a saturated solution of NaHCO 3 (15 mL) was added. The aqueous layer was extracted with DCM (x3). The organic layers were dried over MgSO 4 , filtered, and removal of the solvent under reduced pressure provided desired allylic alcohol 419b as a mixture of two epimers at C-4 (ratio 73:27) that was directly engaged in the next reaction. HRMS (ESI): m/z calcd for C 18 H 24 O 2 Na + : [M+Na] + : 295.1669 found: 295.1667. Major Diastereoisomer 1 H-NMR (400MHz, CDCl 3 ) δ = 7.30-7.35 (m, 4H, H-ar), 7.30-7.35 (m, 1H, H-ar), 5.11 (d, J = 1.7 Hz, 1H, Ha-18), 5.0 (d, J = 1.7 Hz, 1H, Hb-18), 4.74 (d, J = 11.5 Hz, 1H, O-CHaHb-Ar), 4.64 (d, J = 10.7 Hz, 1H, C4-OH), 4.47 (d, J = 11.5 Hz, 1H, O-CHaHb-Ar), 4.32 (dd, J =

  NMR (400MHz, CDCl 3 ) δ = 7.29-7.38 (m, 5H, H-ar), 5.13 (t, J = 1.9 Hz, 1H, Ha-18), 4.89 (t, J = 1.9 Hz, 1H, Hb-18), 4.64 (d, J = 11.9 Hz, 1H, O-CHaHb-Ar), 4.52-4.49 (m, 1H, H-4), 4.37 (d, J = 11.9 Hz, 1H, O-CHaHb-Ar), 3.50(d, J = 7.8 Hz, 1H, H-1), 3.28 (ddd, J = (1R,2S,6R,9R)-9-(benzyloxy)-2',

1 H

 1 -NMR (400MHz, CDCl 3 ) δ = 7.36-7.26 (m, 3H, H-ar), 7.25-7.21 (m, 2H, H-ar), 4.63 (d, J = 8.8 Hz, 1H, Ha-18), 4.58 (d, J = 11.8 Hz, 1H, O-CHa-Ar), 4.56 (d, J = 11.8 Hz, 1H, O-CHb-Ar), 3.72 (d, J = 8.1 Hz, 1H, H-1), 3.71 (d, J = 8.8 Hz, 1H, Hb-18), 2.79-2.70 (m, 2H, Ha-5, H-2), 2.51 (ddd, J

  ): m/z calcd for C 21 H 28 O 4 Na + : [M+Na] + : 367.1885 found: in progress (3aS,4R,7S,8R,10R)-10-(benzyloxy)-3a-(hydroxymethyl)-2

1 H

 1 -NMR (400MHz, CDCl 3 ) δ = 7.43-7.28 (m, 5H, H-ar), 5.66 (d, J = 1.4 Hz, 1H, H-10), 4.86 (d, J = 11.7 Hz, 1H, O-CHaHb-Ar), 4.78 (d, J = 1.7 Hz, 1H, H-5), 4.54 (d, J = 11.7 Hz, 1H, O-CHaHb-Ar), 4.19 (t, J = 10.8 Hz, 1H, Ha-18), 3.75 (d, J = 7.0 Hz, 1H, H-1), 4.19 (d, J = 11.7 Hz, 1H, Hb-18), 2.82 (td, J = 7.0, 1.3 Hz, 1H, H-1), 2.14 (br. d, J = 10.8 Hz, 1H, OH), 2.05 (s, 3H, C(O)-CH 3 ), 2.04-1.98 (m, 1H, Ha-12), 1.80-1.70 (m, 2H, H-13), 1.55 (s, 3H, O-C-CH 3 ), 1.45 (s, 3H, O-C-CH 3 ), 1.26-1.34(m, 1H, Hb-12),1.07 (s, 3H, H-20) ppm.

  13 C-NMR (100MHz, CDCl 3 ) δ = 170.2 (C, O-C(O)), 151.1 (C, C-4), 137,7 (C, C-ar), 128.4 (2CH, C-ar), 128.1 (2CH, C-ar), 127.9 (CH, C-ar), 110.4 (C, O-C-CH 3 ), 102.4 (CH 2 , C-5), 88.7 (CH, C-1), 87.4 (C, C-3), 73.6 (CH, C-10), 73.6 (CH 2 , O-CH 2 -Ar), 66.6 (CH 2 , C-

  β-chelated/6-membered ring model 101 could easily explain the selective allylation of the Re-face of the aldehyde. At this point, benzylation of 102ab followed by hydroboration with thexylborane and subsequent oxidative work-up provided diol 103 in 76% yield. The minor diastereoisomer, derived from 102b, was removed at this stage. The primary alcohol was selectively protected and treatment of the secondary alcohol with Martin sulfurane (Ph 2 S[OC(CF 3 ) 2 Ph] 2 ) regenerated the trisubstituted olefin 104 as a single isomer in 85% yield. Selective hydrolysis of the isopropylidene acetal and subsequent cleavage of the benzyl group under Birch conditions afforded triol 105 in 65% yield. Oxidative cleavage of 105 provided aldehyde 106, which was next subjected to Takai olefination to provide enantiomerically pure fragment 97 in 63% yield.

	Scheme

Takao K.I.; Tsunoda K.; Kurisu T.; Sakama A.; Nishimura Y.; Yoshida K.; Tadano K.I. Org. Lett. 2015, 17, 756-759. proposed 19 Upper fragment 96 was prepared starting from 4-pentynyl acetate 98 (Scheme 20). Hydroiodination of the triple bond and deprotection of the alcohol delivered vinyl iodide 107 in 65% yield. Dess-Martin oxidation of alcohol and treatment of the corresponding aldehyde with Ando reagent 108 afforded the Z-unsaturated ester 109 in 71% yield along with 9% of the E-isomer. Reduction of 109 by DIBAL-H provided allylic alcohol 110, and asymmetric epoxidation of 110 was next examined. Although moderate enantioselectivity (70% ee) was observed for the Sharpless asymmetric epoxidation under catalytic conditions, stoichiometric conditions significantly improved the enantioselectivity to deliver epoxide 111 in 80% ee.

nonane scaffold of vibsatins 120. The resulting carbocation is finally quenched by water and the ketone at C4 was restored by ring opening of the oxetane providing vibsatin A 1 or vibsatin B 2. Scheme 23 2.2 Neurotrophins and neurotrophic activity

	23) was proposed. It was
	suggested that geranylgeraniol pyrophosphate cyclizes to afford the humulene-type 11-
	membered skeleton of vibsanins 116. Vibsanin F 5 arises from epoxidation of the olefin
	between C6 and C7 and allylic oxidation at C18 of 116. Another allylic oxidation followed
	by esterification onto C8 of vibsanin F provides vibsanin A 3. Subsequent opening of the
	oxirane ring and oxidation at C4 afford vibsanin B 4. The previously described Oxy-Cope
	rearrangement transforms vibsanin B 4 into vibsanin C 6 and consecutive oxidation of the
	side chain at C15 furnishes vibsanin K 117, which features a peroxide group in its structure.
	Oxidative cleavage of the double bond between C14 and C15 then forms intermediate 118.
	At this point, after reduction at C13, an hemiacetal 119 is generated and protonation of the
	newly formed primary alcohol allows attack from the C2-C3 double bond leading to the
	characteristic bicyclo[4.2.1]As mentioned earlier in section 1.3, in 2010, neovibsanins were found to display important
	neurite outgrowth activity by Fukuyama, suggesting that several vibsane-type diterpenoids
	may be promising candidates for the development of novel therapeutic agents to treat
	neurodegenerative diseases. More recently (in 2014), first biological studies achieved by He
	and Zhao showed that vibsatins A and B also induced significant neurite outgrowth. These
	promising biological results associated with the unique structure of these vibsane family
	diterpenoids have logically attracted our attention.
	Before clarifying these features, an introduction concerning neurodegenerative diseases
	(NDDs), is mandatory. Neurotrophins, a family of related factors involved in neuronal
	development and maintenance, will be also presented, taking into account that NDDs often
	display with neurotrophin imbalance.

2.4 Reaction of propargylic carboxylates

  Propargylic carboxylates such as 201 are interesting scaffolds in organic synthesis as they undergo 5-exo-dig or 6-endo-dig cyclization affording intermediates 202 and 203.

	Intermediate 202 is subjected to 1,2-acyloxy migration affording carbene 204. On the other
	hand, 1,3-acyloxy migration delivers allene 205 from intermediate 203. Notably, allene 205
	and carbene 204 are in equilibrium through another 1,2-acyloxy migrative intermediate 206
	(Scheme 45). 68 Carbene 204, however, was reacted with alkenes, ynamides, carbon
	nucleophiles, imines and sulphides. 69
	8-endo-dig hydroarylative cyclization has never been observed
	prior to 2006. The first example has been reported by Echavarren and his group, who
	developed a method for the synthesis of 7-and 8-membered indole condensed rings
	exploiting Au(III) and Au(I)-complexes. N-propargyl tryptophans or N-propargyl tryptamines
	191, undergo 7-exo-dig cyclization affording 192 if exposed to cationic Au(I)-complex

64 Shu, C.; Li, L.; Chen, C.B.; Shen, H.C.

; Ye, L.W. Chem. Asian J. 2014, 9, 1525-1529.

65

Hashmi, A.S.K.;

Yang, W.; Rominger, F. Adv. Synth. Catal. 2012, 354, 1273-1279.

3.

  water onto a triple bond following the Markovnikov rule. 7 They employed the air stable [AuMe(L)] (L = phosphine, phosphite or arsine) activated in situ by protic acids to form acetals such as 225 or ketones 226 starting from simple alkynes, respectively 227 and 228

	73 (a) Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 8654-8655. (b) Marion, N.;
	de Frémont, P.; Lemière, G.; Stevens, E.D.; Fensterbank, L.; Malacria, M.; Nolan, S.P. Chem. Commun. 2006,
	2048-2050.

74

Moreau, X.; Goddard, J.-P.; Bernard, M.; Lemière, G.; López-Romero, J.M.; Mainetti, E.; Marion, N.; Mouriès, V.; Thorimbert, S.; Fensterbank, L.; Malacria, M. Adv.

Synth. Catal. 2008, 350, 43-48

.

75

Gung, B.W.; Bailey, L.N.; Craft, D.T.; Barnes, C.L.;Kirschbaum, K. Organometallics 2010, 29, 3450-3456.

76

(a) Shi, X.; Gorin, D.J.; Toste, F.D. J. Am.

Chem. Soc. 2005, 127, 5802-5803. (b)

Nieto Faza, O.; Silva López, C.; Álvarez, R.; de Lera, A. J. Am.

Chem. Soc. 2006, 128, 2434-2437.

and (Scheme 52).

  SPhos 190) as ligand in order to carry out this reaction. The resulting complex is active under mild conditions and displays a regioselectivity based on electronic rather than steric factors leading to a higher preference for one of the two isomers.

	80 Carboxylic acids 235 (Scheme 55a), carbonates 236 (Scheme 55b) and carbamates 237 (Scheme 55c) react with alkynes in the presence of Au(I) to give respectively lactones 238, cyclic carbonates 239 A nice example of this chemistry appeared in 2009 from the hands of Corma and Leyva. 84 They exploited the reactivity of a Au(I)-based catalyst made from a low coordinating (trifluoromethane)imidate counteranion (-NTf 2 ) and a dicyclohexyl(2',6'-dimethoxy-[1,1'-and cyclic carbamates 240. Scheme 56 biphenyl]-2-yl)phosphine (

81

Scheme 55

Nowadays, a great number of tandem sequences have been developed starting from these simple nucleophilic addition reactions onto a triple bond. In this report they will not be treated as not directly related to the synthesis of vibsatins A and B.

Amines are capable to add onto a triple bond. The first to discover the hydroamination reactivity of amines was Nozaki in 1987 using Au(III),

82

but, it was much more recently (2003) that Hayashi and Tanaka developed the first Au(I)-catalysed intermolecular amination of alkynes 241 using anilines to form imines 242 and 243 in a 1:1 mixture (Scheme 56).

83

In Scheme 23, for instance, dissymmetric alkyne 244 (Scheme 57) undergoes hydroamination under these conditions affording the two imines 245 and 246 in a 70:30 ratio respectively.

  is favoured with respect to 271, derived from an endo-type cleavage. 1,7-Enynes such as 275 have been much less studied. However, it has been shown that gold(I) complexes catalyse the 6-endo-dig single cleavage rearrangement providing 1,3-dienes 276 (Scheme 62f).43 In 2013, Chung and his group reported the synthesis of bicyclo[3.2.0]hept-6-enes 277 from amides or esters 278 exploiting gold(I) catalysis (Scheme 62g). This reaction can be described as a formal [2+2] intramolecular cycloaddition between the alkene and the alkyne.Notably, in the presence of oxygen tricarbonyl compounds 279 are formed.

	6-endo-dig
	S.; Gu, Z. Angew. Chem. Int. Ed. 2006, 45, 200-203 (g) Lopez-Carrillo, V.; Echavarren, A.M. J. Am. Chem. Soc.
	2010, 132, 9292-9294.

92

Jiménez-Núñez, E.; Claverie, C.K.; Bour, C.; Cárdenas, D.J.;

Echavarren, A.M. Angew. Chem., Int. Ed. 2008, 47, 7892-7895. 93

(a) Harrak, Y.; Simonneau, A.; Malacria, M.; Gandon, V.; Fensterbank, L. Chem. Commun. 2010, 46, 865-867. (b) Fourmy, K.; Mallet-Ladeira, S.; Dechy-Cabaret, O.; Gouygou, M. Organometallics 2013, 32, 1571-1574. (c) Dubarle-Offner, J.; Barbazanges, M.; Augé, M.; Desmarets, C.; Moussa, J.; Axet, M.R.; Ollivier, C.; cyclization 94 Aubert, C.; Fensterbank, L.; Gandon, V.; Malacria, M.; Gontard, G.; Amouri, H. Organometallics 2013, 32, 1665-1673. (d) Zhang, D.-H.; Wei, Y.; Shi, M. Chem. -Eur. J. 2012, 18, 7026-7029. 94 (a) Lee, Y.T.; Kang, Y.K.; Chung, Y.K. J. Org. Chem. 2009, 74, 7922-7934. (b) Patil, D.V.; Park, H.-S.; Koo, J.; Han, J.W.; Shin, S. Chem. Commun. 2014, 50, 12722-12725.

  1,6-and 1,7-alkynyl silyl enol ethers 287 respectively undergo 5-exo-dig and 6-exo-dig cyclization in the presence of PPh 3 AuBF 4 to afford fused-

96

Luzung, M.R.; Markham, J.P.; Toste, F.D. J. Am.

Chem. Soc. 2004, 126, 10858-10859. 97

(a) Shibata, T.; Ueno, Y.; Kanda, K. Synlett 2006, 411-414. (b) Michon, C.; Liu, S.; Hiragushi, S.; Uenishi, J.; Uemura, M. Tetrahedron 2008, 64, 11756-11762. (c) Aziz, J.; Frison, G.; Le Menez, P.; Brion, J.-D.; Hamze, A.; Alami, M. Adv.

Synth. Catal. 2013, 355, 3425-3436

.

98

Dankwardt, J.W. Tetrahedron Lett. 2001, 42, 5809-5812.

99

Staben, S.T.; Kennedy-Smith, J.J.; Huang, D.; Corkey, B.K.; LaLonde, R.L.; Toste, F.D. Angew.

Chem. Int. Ed.. 2006, 45, 5991-5994.

  ). Although disfavoured kinetically, the gold(I) catalysed formation of 8-

	membered rings has appeared as a powerful tool. Phosphine 302 exhibited a major activity
	with cyclic substrates (±)-307 affording bicyclic ketones (±)-309 and phosphine 301 was
	more suitable for linear substrates providing 8-membered ring compounds (±)-310. Again,

106 Ito, H.;Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12, 4380-4383.

107

Iwai, T.; Okochi, H.; Ito, H.; Sawamura, M. Angew. Chem. Int. Ed. 2013, 52, 4239-4242.

Table 1 ,

 1 entry 8).

	Scheme 89

121 Huwyler, N.; Carreira, E.M. Angew. Chem. Int. Ed. 2012, 51, 13066-13069. a

Calculated via NMR.

b

Reaction time 3 h. c JohnPhos utilised instead of 300.

Table 1

 1 Starting

	Scheme 90

from these results, we then decided to turn our attention toward enantiomerically enriched silyl enol ethers derived from ketones 122 (Scheme 90). The TBS-derived substrate 348 was first tested and, also in this case, it resulted in mostly total cleavage of the silyl enol ether function (Table

2

, entry 1). However, moving toward the TIPS-based silyl enol ether 349 provided better results. The first trial, realized in refluxing at 40°C, majorly afforded desilylated product 347 (Table

2

, entry 2).The second test at room temperature surprisingly resulted in the total conversion of the substrate into the bicyclic target molecule 121 and an isolated yield of 80% was reached (Table

2

, entry 3). With this good result in hands, concentration was raised to 0.05 M affording 92% of isolated product (Table

2

, entry 4) and, the last essay, conducted with a concentration of 0.1 M finally afforded the best result in terms of isolated yield (95%) (Table

2

, entry 5).

a Calculated via

Table 2

 2

  alkene. At the beginning, reported copper and palladium catalysed methods for the allylic C h a p t e r 5 : T o w a r d s t h e t o t a l s y n t h e s i s P a g e | 119 oxidation were tested, but they mostly resulted in the decomposition of the substrate.130 Oxidation through the use of a catalytic quantity of selenium oxide (SeO 2 ) in the presence of tert-butyl hydroperoxyde (TBHP) and acetic acid, on the other hand, readily provided allylic oxidation in 77% yield in a diastereomeric ratio of 92:8 (Scheme 106).131 After purification, minor isomer 384 was obtained in 5% yield and the major diastereomer was afforded in 70% yield. This latter compound revealed to be an inseparable mixture of two forms 385 and 386 in a 82:18 ratio due to a hemiketalic equilibrium between the C4 alcohol and the C1 ketone.

	The hemiketalic tricyclic form 385 was favoured and this behaviour demonstrated the spatial
	close proximity between C4 and C1 and, thus, confirmed the configuration of C4. The
	dihydroxylation reaction at the C3-C18 double bond of 385 and 386 was performed
	exploiting a catalytic quantity of potassium osmate dihydrate (K 2 OsO 4	. 2H 2 O) in the presence
	of NMO and pyridine. Scheme 106
	130 (a) Chen, M.S.; Prabagaran, N.; Labenz, N.A.; White, C.M. J. Am. Chem. Soc. 2005, 127, 6970-6971. (b)
	García-Cabeza, A.; Marín-Barrios, R.; Azarken, R.; Moreno-Dorado, F.J.; Ortega, M.J.; Vidal, H.; Gatica, J.M.;
	Massanet, G.

132

The reaction smoothly delivered a mixture of triols 387 and 388 in 87% yield ascribable to the hemiketalic equilibrium. Notably, this equilibrium is totally inversed toward the open form 388

(387/388 = 15:85)

. No C3-epimers were observed (diasteromeric ratio higher than 95:5). M.; Guerra, F.M. Eur. J. Org. Chem. 2013, 8307-8314. (c) García-Cabeza, A.; Marín-Barrios, R.; Moreno-Dorado, F.J., Ortega, M.J.; Massanet, G.M.; Guerra, F.M. Org.

Lett. 2014Lett. , 16, 1598Lett. -1601. 131 . 131

For recent reviews upon allylic oxidation see: (a) Weidmann, V.; Maison, W. Synthesis 2013,

45, 220145, - 2221. (b) Nakamura, A.;. (b) Nakamura, A.; Nakada, M. Synthesis 2013, 45, 1421-1451. 132

Martín Hernando, J.I.; Rico Ferreira, M.d-R.; Candela Lena, J.I.; Birlirakis, N.; Arseniyadis, S. Tetrahedron: Asymmetry 2000,

11, 951-973.

  5-membered ring exocyclic allylic benzyl ether 394, the dihydroxylation reaction afforded a mixture of two diastereomers relative to a 70:30 ratio in favour of the trans related diol 395, which underwent lactonisation to provide the bicyclic structure 396 (Scheme 109).135

133 (a) Cha, J.K.;

Christ, W.J.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3943-3946. (b)

Cha, J.K.; Christ, W.J.; Kishi, Y. Tetrahedron 1984, 40, 2247-2255.

134

Corbu, A.; Gauron, G.; Castro, J.M.; Dakir, M.; Arseniyadis, S. Org.

Lett. 2007, 9, 4745-4748. 135

Urabe, F.; Nagashima, S.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. J.

Org. Chem. 2013, 78, 3847-3857.

  secondary alcohol underwent subsequent Dess-Martin oxidation to afford ketoalcohol 416 in 97% yield. In order to run the transthioketalization of the ketal function of 416, several catalysts were tested in the presence of ethanedithiol in various conditions. Lewis acid catalysts such as InCl 3 , 139 SiO 2 /SOCl 2 , 140 nBu 4 NBr 3

				141 and TiCl 4	142 together with non-acidic
	in-situ prepared (Me 3 AlSCH 2 ) 2	143 failed to catalyse the reaction. On the other hand, treatment
	with I 2	144 and BF 3	.

  However, the application of the Lawesson's reagent to ketone 121 at 110°C in toluene for five hours failed to afford 453 deriving from thionation of the carbonyl function (Scheme 135). On the other hand, compound 454, in which the double bond shifted to a more stable endo-position, was obtained in 65% yield.

	Scheme 135

166 Ozturk, T.;Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210-5278. 167

Ori, M.; Nishio, T. Heterocycles 2000,

52, 111-116.

  Xu, S.; Toyama, T.; Nakamura, J.; Arimoto, H. Tetrahedron Lett. 2010, 51, 4534- 4537. For Zn/HCl see: (b) Kraft, P.; Eichenberger, W. Eur. J.Org. Chem. 2003, 3735-3743.

171

(a) Mortimore, M.; Cockerill, G.S.; Kocienski, P.; Treadgold, R. Tetrahedron

Lett. 1987, 28, 3747-3750. (b)

Hanessian, S.; Murray, P.J.; Sahoo, S.P. Tetrahedron

Lett. 1985, 26, 5623-5626.

  Ketoalcohol 457 was transformed into xanthate 458 by 172 Baughman, T.W.; Sworen, J.C.; Wagener, K.B. Tetrahedron 2004, 60, 10943-10948 173Barton, D.H.R.; McCombie, S.W. J. Chem. Soc., Perkin Trans. 1 1975, 0, 1574-1585. 174 (a) Chatgilialoglu, C. Acc. Chem. Res.1992, 25, 188-194. (b) Postigo, A.; Kopsov, S.; Ferreri, C.; Chatgilialoglu, C. Org. Lett. 2007, 9, 5159-5162. (c) Barton, D.H.R.; Jang, D.O.; Jaszberenyi, J.Cs. Tetrahedron Lett. 1991, 32, 2569-2572. (d) Barton, D.H.R.; Jang, D.O.; Jaszberenyi, J.Cs. Synlett 1991, 6, 435-438. 175 Hamlin, A.M.; Lapointe, D.; Owens, K.; Sarpong, R. J. Org. Chem. 2014, 79, 6783-6800. sequential addition of: NaH, CS 2 and MeI (Scheme 139). Heating 458 in toluene at 95°C for one hour in the presence of nBu 3 SnH and AIBN afforded 65% of deoxygenated compound 459.

  1-ylthiocarbonyl derivative, for instance, was successfully employed in the synthesis of Platencin reported by Yadav and his group. 178 Alcohol 463 was transformed into 176 Zhu, L.; Luo, J.; Hong, R. Org. Lett. 2014, 16, 2162-2165. 177 McCombie, S.W.; Motherwell, W.B.; Tozer, M.J. Organic Reactions (Hoboken, NJ, United States) 2012, 77, 161-591. 178 Yadav, J.S.; Goreti, R.; Pabbaraja, S.; Sridhar, B. Org. Lett. 2013, 15, 3782-3785. thionocarbamate 464 and subsequent application of nBu 3 SnH and AIBN delivered the deoxygenated product 465 (Scheme 141)

	Scheme 141

  , entry 6).

				Scheme 148
	Entry	Substrate	X	R	Solvent	Temperature	Yield
	1	454	=O	H	DCM	25°C	7%
	2	474	OH	OH	DCE	60°C	5%
	3	473	OH	H	toluene	110°C	28%
	4	454	=O	H	toluene	110°C	8%
	5	474	OH	OH	toluene	110°C	9%
	6 a	473	OH	H	toluene	MW, 110°C	6%

a Reaction time: two hours

Table 3

 3

9. Experimental Part 9.1 Usual procedures

	Unless otherwise stated, all commercially available reagents and solvents were used without
	further purification.
	All reactions were carried out in oven or flame-dried glassware under an argon atmosphere
	employing standard techniques in handling air-sensitive materials. For reactions requiring
	anhydrous conditions, dry solvents were freshly distillated prior to use (THF, diethyl ether
	and toluene over sodium/benzophenone system, CH 2 Cl 2 and DMSO over calcium hydride
	and MeOH and EtOH over magnesium turnings).
	Reactions were magnetically stirred and monitored by thin layer chromatography with 0.20
	mm Merck 60F 254 pre-coated silica gel plates. Visualization was accomplished with UV light
	and subsequent treatment with a 10% ethanolic phosphomolybdic acid solution followed by
	heating at 100-110 °C.

Flash chromatography was performed with silica gel 60 (particle size 0.040-0.063 μm) supplied by SDS Carlo Erba. Yield refers to chromatography and spectroscopically pure compounds, unless otherwise noted.

  C-NMR spectra were recorded at 75 MHz, 100 MHz or 125 MHz. Internals references of δ C 77.00 and 49.8 were used respectively for CDCl 3 and methanol-d 4 (MeOD).13 C NMR assignments were confirmed by 2D COSY, HSQC and HMBC spectra.C h a p t e r 9 : E x p e r i m e n t a l P a r t P a g e | 177Mass spectra were recorded on a GC/MS coupling unit with a MSD 5973 spectrometer and a Hewlett-Packard HP-GC 6890 chromatograph. Ionization was obtained either by electronic impact (EI) or chemical ionization with methane (CI, CH 4 ). Mass spectral data are reported as

	m/z.
	High-resolution mass-spectra were obtained on a Thermo-Electron MAT-95 or Q-TOF1
	spectrometer (Waters). Ionization was obtained by electrospray (ES) using Na, K or Li. Mass
	spectral data are reported as m/z.
	Optical rotations were recorded on a Perkin Elmer Model 341 polarimeter at 589 nm and
	reported as follows: [α] D , concentration (c in g/100 mL) and solvent.

  mmol) was added freshly distilled methyl acrylate(5.23 g, 60.8 mmol) and hydroquinone(67 mg, cat.). The mixture was stirred at 50 °C for 3 days and min and the solution was stirred for 3 h at room temperature. A saturated solution of NaHCO 3 (100 mL) was then added. The organic layer was separated and the aqueous layer was extracted with DCM (2x). The organic layers were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. Flash Purification over silica gel (cyclohexane/AcOEt: 50:50) afforded 345 (7.04 g, quantitative yield) as a colourless oil.

	C h a p t e r 9 : E x p e r i m e n t a l P a r t P a g e | 181
	Methyl (R)-3-(6-methyl-1,4-dioxaspiro[4.4]nonan-6-yl)propanoate 343 (R)-3-(6-methyl-1,4-dioxaspiro[4.4]nonan-6-yl)propan-1-ol 344 (R)-2-(6-methyl-1,4-dioxaspiro[4.4]nonan-6-yl)ethyl 4-methylbenzenesulfonate 345
	concentrated under reduced pressure. To the residue was added 20% aqueous acetic acid (18
	mL) and THF (30 mL). After being stirred for 24 h at 20 °C, the mixture was concentrated in
	vacuo and 3M hydrochloric acid (20 mL) was added. The aqueous layer was extracted with
	diethylether (4 × 50 mL) and the organic layers were washed with brine, dried over MgSO 4 In a round-bottomed flask equipped with a Dean-Stark apparatus was placed ketoester 342 Diethyl ether (100 mL) was added to a round-bottom flask containing crude 343 (27.0 g) and To a solution of 344 (4.07 g, 20.35 mmol, 1 equiv.), triethylamine (7.1 mL, 50.9 mmol, 2.5
	and concentrated. Purification over silica gel (cyclohexane/AcOEt, 50:50) afforded (R)-3-(1-(20.0 g, 109 mmol), ethylene glycol (54.2 g, 0.87 mol, 8 equiv.) and p-toluenesulfonic acid the mixture was cooled down to 0°C. The solution was slowly added to a suspension of equiv.) and 4-dimethylaminopyridine (50 mg, 0.41 mmol, 0.02 equiv.) in DCM (40 mL) at
	methyl-2-oxocyclopentyl)propanoate 342 as a colourless oil (9.8 g, ee = 70% from 2-(2.07 g, 10.9 mmol, 0.1 equiv.) in benzene (650 mL). The reaction mixture was reflux for 16 LiAlH 4 (4.14 g, 109 mmol, 1 equiv.) in diethyl ether (250 mL) at 0°C. The mixture was then 0°C was added tosyl chloride (4.08 g, 21.4 mmol, 1.05 equiv.) portionwise. Ice bath was
	methylcyclopentanone). h and a saturated solution of NaHCO 3 (300 mL) was added. The organic layer was separated. allowed to warm up to room temperature. After 30 min the reaction was quenched by removed after 30
	RN: 94089-46-0. The aqueous layer was extracted with Et 2 O (x3). The organic layers were then dried over successive addition of water (5 mL), 2M solution of NaOH (5 mL) and water (15mL). After
	[α] D MgSO 4 , filtered and concentrated under reduced pressure. 343 was obtained as a brown oily stirring for 30 min, a white precipitate appears and the suspension was filtered on celite and 20 = + 36.4 (c 1.0, CHCl 3 ). residue (27.0 g, quantitative yield) and was directly engaged in the next reaction without the solvent was removed under reduced pressure. Flash purification over silica gel
	further purification. (cyclohexane/AcOEt: 70:30 to 40:60) afforded the alcohol 344 as a colorless oil (17.4 g, 80%
	RN: 197163-97-6. yield over two steps).
	[α] D RN: 211235-36-8. 20 : -4.11 (c 1.0, CHCl 3 ). C-11), 37.4 (CH 2 , C-2), 36.1 (CH 2 , C-12), 31.4 (CH 2 , C-10), 29.3 (CH 2 , C-5), 21.4 (CH 3 , C-20), 18.6 (CH 2 , C-13) ppm. 1 H-NMR (400MHz, CDCl 3 ) δ = 3.92-3.80 (m, 4H, O-CH 2 -CH 2 ), 3.66 (s, 3H, OCH 3 ), 2.20-[α] D 20 : -6.81 (c 1.0, CHCl 3 ).
	2.40 (m, 2H, H-5), 1.87-1.77 (m, 2H, H-2), 1.72 (t, J = 8.4 Hz, 2H, H-10), 1.68-1.56 (m, 3H, 1 H-NMR (400MHz, CDCl 3 ) δ = 3.89 (s, 4H, O-CH 2 -CH 2 ), 3.61 (t, J = 6.8 Hz, 2H, H-4), FTIR (neat): ν = 2957, 1731, 1436, 1374, 1199, 1164 cm -1 . H-12, Ha-13), 1.52-1.43 (m, 1H, Hb-13), 0.95 (s, 3H, H-20) ppm. 1.88-1.75 (m, 2H, H-2), 1.67-1.31 (m, 8H, H-5, H-10, H-12, H-13), 0.95 (s, 3H, 20) ppm.
	HRMS (ESI): m/z calcd for C 10 H 16 O 3 Na + : [M+Na] + : 207.0992; found: 207.0993. 13 C-NMR (100MHz, CDCl 3 ) δ = 175.0 (C, C-4), 119.5 (C, C-1), 64.9 (CH 2 , O-CH 2 ), 64.7 13 C-NMR (100MHz, CDCl 3 ) δ = 119.8 (C, C-1), 64.9 (CH 2 , O-CH 2 ), 64.7 (CH 2 , O-CH 2 ),
	(CH 2 , O-CH 2 ), 51.7 (CH 3 , OCH 3 ), 45.4 (C, C-11), 35.6 (CH 2 , C-13), 33.5 (CH 2 , C-2), 30.4 64.1 (CH 2 , C-4), 45.7 (C, C-11), 35.5 (CH 2 , C-12), 33.6 (CH 2 , C-2), 31.0 (CH 2 , C-10), 28.3
	(CH 2 , C-10), 30.2 (CH 2 , C-5), 20.1 (CH 3 , C-20), 18.0 (CH 2 , C-12) ppm. (CH 2 , C-5), 20.2 (CH 3 , C-20), 18.0 (CH 2 , C-13) ppm.
	FTIR (neat): ν = 2950, 2875, 1735, 1435, 1374, 1033 cm -1 . FTIR (neat): ν = 3394, 2947, 2872, 1137, 1052, 948 cm -1 .
	HRMS (ESI): m/z calcd for C 12 H 20 O 4 Na + : [M+Na] + : 223.1310; found: unstable. HRMS (ESI): m/z calcd for C 11 H 20 O 3 Na + : [M+Na] + : 223.1310; found: 223.1307.

1

H-NMR (400MHz, CDCl 3 ) δ = 3.62 (s, 3H, OCH 3 ), 2.

36-2.12 (m, 4H, H-2, H-5), 1.93-1.63 (m, 6H, H-10, H-12, H-13)

, 0.97 (s,

3 H, H-20)

ppm.

13

C-NMR (100MHz, CDCl 3 ) δ = 222.3 (C, C-1), 173.8

(C, C-4)

, 51.6 (CH 3 , OCH 3 ), 47.5

(C, RN: 1215086-63-7.

  , 50 mL) was added dropwise and the temperature was warmed to room temperature over 2 h. A saturated solution of NH 4 Cl (150 mL) was then added and the mixture was extracted with Et 2 O (x4). The organic layers were washed with brine (x2), dried over MgSO 4 , filtered and removal of the solvent under reduced pressure provided 346 as a crude brown oil that was directly engaged in the next step.

	C h a p t e r 9 : E x p e r i m e n t a l P a r t P a g e | 183
	(S)-6-methyl-6-(pent-4-yn-1-yl)-1,4-dioxaspiro[4.4]nonane 346 and (S)-2-methyl-2-(pent-4-
	yn-1-yl)cyclopentan-1-one 347
	To a suspension of lithium acetylide, ethylenediamine complex (7.0 g, 68.2 mmol, 1.5 equiv.)
	in DMSO/THF (2:1, 85 mL) at 0°C, a solution of 345 (16.1 g, 45.5 mmol, 1 equiv.) in
	DMSO/THF (2:1
	13 C-NMR (100MHz, CDCl 3 ) δ = 144.6 (C, C-ar), 133.4 (C, C-ar), 129.8 (2CH, C-ar), 127.9
	(2CH, C-ar), 119.4 (C, C-1), 71.7 (CH 2 , C-4), 64.8 (CH 2, O-CH 2 ), 64.5 (CH 2, O-CH 2 ), 45.4
	(C, C-11), 35.5 (CH 2 , C-12), 33.4 (CH 2 , C-2), 30.8 (CH 2 , C-10), 24.6 (CH 2 , C-5), 21.7 (CH 3 ,
	C-ar-CH 3 ), 20.1 (CH 3 , C-20), 17.9 (CH 2 , C-13) ppm.
	HRMS (ESI): m/z calcd for C 18 H 26 O 5 SNa + : [M+Na] + : 377.1399; found: 377.1392.

  1. Dry Hamilton gas-tight syringes are preferred however plastic syringes can be used if properly dried under vacuum at r.t. before a single and unique usage. When silver complex is added, the solution can turn different colors depending upon the presence and the concentration of Au 0 nanoparticles that comes from the disproportionation of Au I .

	(1S,6S)-1-methyl-5-methylenebicyclo[4.2.1]nonan-9-one 121
	2. When large volumes are required, a dry canula is used for the transfer (dried at 120°C
	at first and then cooled down under vacuum in a big round-bottom flask before
	quench with Ar).
	3. (Me 2 S)AuCl is light sensitive, water sensitive but air stable
	4. AgNTf 2 is particularly light sensitive but air and water stable (but has to be treated as
	water sensitive as well)
	5. Molecular sieves is activated for 16h at 400°C under vacuum then for 20 min under
	vacuum in the reaction vessel prior to the reaction.
	6. Celite® must be stored in the oven at 120°C.
	7. During the preparation of the catalyst, direct sun or artificial light irradiation must be
	avoided.
	8. The presence of this particles depends upon: the age of gold and silver complexes, the
	attention paid to moisture and light in the course of the synthesis and the possible
	presence of triflic acid. Depending on the quality of the catalyst, the precipitate can
	range from white (good) to bright/dark violet for good (efficient) to black/brown
	(much less efficient).
	9. N.B.: the catalyst's intermediate, [L 1 AuCl], is more stable against disproportionation
	compared with (Me 2 S)AuCl.
	Operative method

  ). O-CH 2 ), 2.85-2.80 (dd, J = 10.7, 2.2 Hz, 1H, H-2), 2.57-2.36 (m, 2H, H-4), 2.18 (dddd, J =

  , 118.7 (C, C-1), 110.4 (CH 2 , C-18), 65.94 (CH 2 , O-CH 2 ), 63.72 (CH 2 , O-CH 2 ), 53.2 (CH, C-2), 46.44 (C, C-11), 39.5 (CH 2 , C-10), 34.8 (CH 2 , C-5), 33.9 (CH 2 , C-12), 29.5 (CH 2 , C-13), 23.4 (CH 2 , C-4), 22.7 (CH 3 , C-20) ppm. FTIR (neat): ν = 3067, 2954, 2924, 1629, 1469, 1212, 1150, 1077, 1049, 1038, 1007, 878 cm -1 . HRMS (ESI): m/z calcd for C 13 H 20 O 2 Na + : [M+Na] + : 208.1463; found: unstable.

  t.. Water (4 mL) was added the aqueous phase was extracted with Et 2 O (x3) and thegathered organic layers were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure. To the resulting crude mixturewere added ACN (12 mL) and Pd(OAc) 2 (618mg, 2.76 mmol, 4 eq.) and the mixture was stirred at r.t. for 24 h. Then, the mixture was filtered on Celite® and the solvent was evaporated under reduced pressure. Flash purification over silica gel (pentane/Et 2 O 95:5 to 70:30) afforded 430(29 mg, 10% yield).

Kawazu, K. Agric. Biol. Chem. 1980, 44, 1367-1372.

Fukuyama Y.; Minami H.;Takaoka S.; Kodama M.; Kawazu K.; Nemoto H. Tetrahedron Lett. 1997, 38, 1435-1438.

Fukuyama, Y.; Minami, H.; Kagawa, M.; Kodama, M.;Kawazu, K. J. Nat. Prod. 1999, 62, 337-339.

Esumi T.;Mori Y.;Zhao M.;Toyota M.; Fukuyama Y. Org. Lett. 2010, 12, 888-891.

(a) Ichige T.; Okano Y.; Kanoh N.; Nakata M. J. Org. Chem. 2008, 74, 230-243. (b) Negishi E.; Van Horn D. E.; King A.O.; Okukado N. Synthesis 1979, 501-502.

Conia, J.M.; Le Perchec, P. Synthesis 1975, 1-19

Itoh, Y.; Tsuji, H.; Yamagata, K.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am. Chem.Soc. 2008, 130, 17161-17167.

Fürstner, A.; Davies, P.V. Angew. Chem. Int. Ed. 2007, 46, 3410-3449.

[START_REF] Torres | [END_REF] Cordova, A. Chem. Rev. 2016, 116, 13512-13570.

In CDCl 3 solvent, 1H-NMR analysis confirmed that compound 341 is found as an imine.

Schafer, C.;Miesch, M.; Miesch, L. Org. Biomol. Chem. 2012, 10, 3253-3257.

Jnaneshwara, G.K.; Barhate, N.B.; Sudalai, A.; Deshpande, V.H.; Wakharkar, R.D.; Gajare, A.S.; Shingare, M.S.; Sukumar, R. J.Chem. Soc. Perkin Trans. 1998, 1, 965-968.

(a) Njardarson, J.T., Wood, J.L. Org.Lett. 2001Lett. , 3, 2431Lett. -2434. (b) Murphy, G.K.; Hama, N.; Bedermann, A.; Dong,P.; Schneider, C.M.; McMahon, T.C.; Tao, R.N.; Twenter, B.M.; Spiegel, D.A.; Wood J.L. Org. Lett. 2012, 14, 4544-4547. (c) Njardason, J.T., McDonald, I.M.; Spiegel, D.A.; Inoue, M.; Wood, J.L. Org.Lett. 2001Lett. , 3, 2435Lett. -2438. .

Another substrate underwent such tests: the acetonide of 401 was replaced by -MEM groups, but also in this case it was recovered only the departing product.

Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.

 CDCl 3 ) δ = 4.61 (s, 1H, 4.55 (s, 1H, 4H,

Acknowledgements

I would really like to thanks everybody worked on this project. Je voudrais vraiment remercier tout les personnes qui ont travaillé sur ce soujet.

Scheme 22 Scheme 46

Propargylic esters can react even through their allenic form. Indeed, in 2008, De Brabander reported a cycloetherification of ω-hydroxy propargylic acetates (Scheme 47). 71 Exposing (±)-211 to AuCl delivered the tetrahydropyran derivative (±)-212 throughout the allenic intermediate (±)-213. Notably, this method is limited to internal alkynes.

Scheme 47

In the presence of gold(I), enynes bearing propargylic carboxylates such as 214 can react in two parallel ways (Scheme 17). Depending upon the order of reaction of the different moieties, i.e., the reaction of the ester or the alkene function onto the alkyne. This transformation is well known as the Ohloff-Rautenstraucht rearrangement. 72 when the alkene reacts first the propargylic ester 214 undergoes cyclopropanation giving the intermediate 215, which after 1,2-acyloxy migration delivers the allylic cyclopropane 216 (Scheme 48a). On the contrary, when the ester reacts first the allylic carbene 217 is provided and subsequent cyclopropanation affords 216 (Scheme 48b). Scheme 48 71 De Brabander, J.K.; Liu, B.; Qian, M. Org. Lett. 2008Lett. , 10, 2533Lett. -2536. 72 . 72 (a) Strickler, H.; Davis, J.B.; Ohloff, G. Helv. Chim. Acta 1976, 59, 1328-1332. (b) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950-952.

Figure 24

Ketotriol 388 was then protected employing TBSOTf. The use of a single equivalent of TBSOTf provided a mixture of monoprotected and bisprotected ketone 397 and 398 in respectively 75% and 6% yield (Scheme 110). Four equivalents of TBS-triflate, instead, afforded ketone 399 in 37% yield along with 10% of protected hemiketal 400. Diol 397 was next transformed into an acetonide and subsequent reduction of the ketone function afforded compound 401 stereoselectively in 91% yield (d.r. > 95:5). On the other hand, ketones 398 and 399 were reduced to their corresponding alcohols 402 and 403 in respectively 55% and 42% yield, 399 was stereoselectively reduced but 398 exhibited a diastereomeric ratio of 91:9. The configuration of the newly formed stereocenter at C1 was not proven but the reduction step for these three compounds is likely to follow the same stereochemical outcome undertaken by ketone 418, as formerly explained in section 5.3, relative to a 1(R) configuration, i.e. vibsatin B series.

Scheme 110

Each intermediate synthesised in this Section, represented below in Figure 25, has been tested in various deoxygenative conditions and this will be the subject of the next chapter.

Transthioketalization strategy

In order to pursue the study of the deoxygenation reaction at C1, it was concomitantly then decided to investigate the possibility to exchange an acetal group by a thioacetal scaffold in the presence of ketones or other functional groups. Indeed, kinetically, the acid catalysed transformation of a ketal into a thioketal is faster than the direct conversion of a ketone into a thioketal. This difference allows for the selective synthesis of thioketals in the presence of free carbonyl groups. For instance, mildly acidic kaolinitic clay catalyses the selective transthioketalization of ketal monoprotected pentanedione 404, affording thioketal 405 in 75% yield (Scheme 111). 136

Scheme 111

This transthioketalization strategy was formerly employed in many total synthesis. Wood and his group, for instance, exploited this reaction in the synthesis of the core of phomoidride B. 137 Intermediate (±)-406, synthesized in a 6 steps sequence, was treated with ethanedithiol in the presence of a stoichiometric quantity of BF 3

. OEt 2 affording dithiolane (±)-407 (Scheme 112). Hydrogenation by Raney-Ni (50% weight in water) then delivered intermediate (±)-408 which was converted in the target molecule (±)-409 over two steps.

Scheme 112

This above mentioned application to the synthesis of a complex structure, constituted a reliable basis for our work. A synthetic route based on the transthioketalization was devised including successive installation of a ketal at C1 position, oxidation at C4 and

Scheme 116

The stereochemical outcome of the dihydroxylation reaction at C3 was determined by running NOESY analysis. Due to the overlap of the diastereotopic proton signals resonating in the alkylic spectral zone (1-2 ppm), it was impossible to clearly conclude about the stereochemistry at C3 of triol 414. On the contrary, on ketone 416, a strong NOE interaction was found between the C3 hydroxyl group and the C13 proton confirming the 3(S) configuration at C3 (Figure 26 and Figure 27), namely vibsatin A series. In this synthetic scheme, the installation of a ketalic group at C1 appeared to be responsible for the inversion of the stereochemistry relative to the dihydroxylation step. Together with the results obtained for the unprotected ketone in the precedent section, it is suggested that, on this type of bridged bicyclic structures, the substituent at C1 is at the origin of the facial selectivity, regardless the configuration of the allylic alcohol.

Figure 26

Scheme 149

The feasibility of the Mozingo desulfurization process was next studied. Two different thioketals 451 and 452 were synthesized and desulfurization was tested using NiCl 2 or Raney-Ni (Scheme 150). Both catalysts resulted to be ineffective in delivering 446. However, these essays provided a preliminary idea about the reluctance of the C1 to undergo total reduction to methylene.

Scheme 150

The Clemmensen-based tests conducted on the free carbonyl compounds 121, 385 and 388, provided only the recovery of the starting materials even in harsh conditions (Scheme 151).

The same results were observed when hydride displacement was investigated from alcohol 418.

Scheme 151

It was then demonstrated that thiocarbonyl compounds suitable for Barton-McCombie reaction were hardly synthesizable and only the imidazolyl thiocarbonyl derivative 466 was obtained (Scheme 152). Radical deoxygenation essays on the latter were tested and unfortunately led to the decomposition of the substrate.

Scheme 152

At the moment, we are not able to provide a reliable explanation for the failure of such number of deoxygenation strategies, however, one of the most plausible hypothesis regards the steric hindrance at C1 induced by the bicycle, especially well highlighted by the totally diastereoselective reduction of the ketone at C1. The ROM-based strategy tends to prove the accuracy of the last affirmation even if further investigation on the metathesis step are nonetheless needed.

In order to circumvent this putative problem of steric hindrance, it was next envisioned to pursue the synthesis of vibsatin A and B while protecting the alcohol at C1. Functionalization of the bicyclic skeleton would then be targeted and the deoxygenation would be envisaged at a later stage of the synthesis. Hence, steric and electronic factors may be significantly different once the functions installed at C3, C4, C5, C10 and C18.

Major diastereoisomer 413 1 H-NMR (400MHz, CDCl 3 ) δ = 5.06 (d, J = 1.6 Hz, 1H, Ha-18), 4.89 (d, J = 1.8 Hz, 1H, Hb-18), 4.28 (dd, J = 10.8, 5.3 Hz, 1H, Ha-4), 4.09 (d, J = 10.8 Hz, 1H, OH), 4.01-3.91 (m, 4H, O-CH 2 ), 2.92 (dd, J = 10.7, 2.3 Hz, 1H, H-2), 2.28-2.14 (m, 1H, Ha-13), 2.03-1.86 (m, 2H, Ha-10, Hb-13), 1.86-1.75 (m, 1H, Ha-5), 1.75-1.57 (m, 2H, H-12), 1.53-1.41 (m, 1H, Hb-5), 1.30-1.23 (m, 1H, Hb-10), 0.94 (s, 3H, H-20) ppm. 13 (m, 2H, H-2, Ha-13), 1.87-1.69 (m, 3H, Hb-5, Ha-10, Hb-13), 1.69-1.50 (m, 2H, H-12), 1.29-1.22 (m, 1H, Hb-10), 0.92 (s, 3H, H-20) ppm. 13

Direct functionalization

(2R,4aR,7S,7aS)-4a-methyl-8-methylenehexahydro-2,7-methanocyclopenta [b]pyran-7a(2H)ol 385 and 386

To a stirred solution of 121 (400 mg, 2.44 mmol, 1 equiv.), TBHP (5.5 M in heptane, 0,51 mL, 1.15 equiv.) and dry acetic acid (22 µL, 0.366 mmol, 0.15 equiv.) in DCM (11 mL), was added selenium dioxide (40 mg, 0.366 mmol, 0.15 equiv.). The mixture was stirred for 5 h at room temperature and then quenched with a saturated solution of NaHCO 3 (15 mL) Hemiacetal 400 1 H-NMR (400MHz, CDCl 3 ) δ = 4.02 (d, J = 5.2 Hz, 1H, H-4), 3.98 (d, J = 9.3 Hz, 1H, Ha-18), 3.42 (d, J = 9.3 Hz, 1H, Hb-18), 2.90 (dd, J = 9.3, 1.9 Hz, 1H, H-2), 2.30 (td, J = 13.3, 2. 3 Hz, 1H, Ha-10), 2.16 (dddd, J = 15.0, 14.4, 5.2, 2.7 Hz, 1H, Ha-5), 1.78-1.61 (m, 5H, Hb-5, H-12, H-13), 1.17 (ddd, J = 13.3, 3.8, 3.2 Hz, 1H, Hb-10), 0.95 (s, 3H, H-20), 0.90 (s, 9H, Si-C(CH 3 ) 3 ), 0.89 (s, 9H, Si-C(CH 3 ) 3 ), 0.87 (s, 9H, Si-C(CH 3 ) 3 ), 0.20 (s, 3H, Si(CH 3 ) 2 ), 0.18 (s, 3H, Si(CH 3 ) 2 ), 0.06 (s, 6H, Si(CH 3 ) 2 ), 0.05 (s, 6H, Si(CH 3 ) 2 ) ppm. Ketone 399 (100 mg, 0.18 mmol, 1 eq.) was solubilized in Et 2 O (2 mL), and the mixture was cooled to 0°C. LiAlH 4 (7 mg, 0.18 mmol, 1 eq.) was added and the ice bath was removed.

After 30 minutes the reaction was quenched by sequential addition of H

Si(CH 3 ) 2 ) ppm. (2'R,4S,4a'R,7'R,7a'R)-2,2,4a'-trimethylhexahydrospiro[ [1,3]dioxolane-4,8'- [2,7] NOE interaction between signal at 4.50 ppm (s, 1H, C3-OH) and another at 1. 78-1.88 (m, 2H, H-12, H-13).

Ongoing strategy

In a round bottom flask containing 427 (200 mg, 0.58 mmol, 1 eq.) in THF (14 mL) cooled to -78°C was added LDA (1.34 mL, 0.87 mmol, 1.5 eq.) and the mixture was stirred for 15 min. at -78°C. A solution of PhSeCl (331 mg, 1.73 mmol, 3 eq.) in THF (14 mL) was added, the temperature was raised to r. (1R,2S,5S,6R,9R)-9-(benzyloxy)-2',2 ',5,6-tetramethylspiro[bicyclo[4.2.1]nonane-2,4'- [1,3] tris((tris (3,5-di-tert-butyl-4-methoxyphenyl)silyl)ethynyl)phosphane 300

Miscellaneous reactions

To a suspension of NaH (8.0 g, 200 mmol, 1.5 equiv.) in THF (480 mL) at 0 °C was slowly added a solution of 4-bromo-2,6-di-tert-butylphenol (38 g, 134 mmol, 1 equiv.) in THF (120 mL) and the mixture was stirred for 1 h at room temperature. After cooling to 0 °C, dimethyl sulfate (18.5 g, 147 mmol, 1.1 equiv.) was added and the mixture was refluxed for 16 h.

Water was added at 0 °C followed by hexane at r.t. and the organic layer was washed with water until it became a clear solution. The organic layer was dried over MgSO 4 and concentrated under reduced pressure. Purification by flash chromatography over silica gel (hexane, 100%) delivered the title compound as a white solid in quantitative yield.

RN: 1516-96-7

Spectroscopic data were consistent with those reported in the literature.

To a solution of 361 (46.4 mmol) in THF was added t-BuLi (2.5 M in pentane, 92.8 mmol) at -78 °C. After stirring for 1.5 h at this temperature, the mixture was warmed to room temperature, cooled again to -78 °C and silicium tetrachloride (15.5 mmol) was then added.

The mixture was slowly warmed to room temperature, stirred for 1 day and subsequently transferred via cannula to a solution of lithium acetylide cooled at -78 °C. Spectroscopic data were consistent with those reported in the literature.

Hydrazone 374 (5 mmol, 1 equiv.) was placed in dry THF (5 mL) under argon, nbutyllithium (2.3 M in hexane, 2.4 mL, 5.5 mmol, 1.1 equiv.) was added to the solution at -78 °C. The mixture was stirred at this temperature for 1 h and 5-iodo-1-pentyne (1.45 g, 7.5 mmol, 1.5 equiv.) was added to the solution, which was allowed to stir at room temperature overnight. The reaction mixture was quenched with a saturated NH 4 Cl solution and extracted with diethyl ether. The combined organic layers were washed with brine, dried over magnesium MgSO 4 , filtered and the solvent was removed in vacuo. The residue was diluted in diethyl ether (10 mL), a saturated oxalic acid solution was added and the mixture was stirred at room temperature for 4 h then diluted with water. The aqueous layer was extracted with diethyl ether, the combined organic layers were washed with a saturated NaHCO 3 .55-1.44 (m, 1H, Hb-4), 1.42-1.30 (m, 1H, Hb-6) ppm. A mixture containing (±)-369 (40 mg, 0.22 mmol, 1 eq.), AgOTf (11 mg, 44 μmol, 0.2 eq.) and pyrrolidine (18 μL, 0.22 Methyl 1-oxospiro [4.5]dec-6-ene-6-carboxylate (±)-383

A mixture containing (±)-371 (40 mg, 0.19 mmol, 1 eq.), Cu(OTf) 2 (14 mg, 38 μmol, 0.2 eq.) and pyrrolidine (16 μL, 0.19 (m, 4H, Hb-2, Ha-10, Ha-12, Ha-13), 1.89-1.73 (m, 3H, Hb-10, Hb-12, Hb-13). Methyl 3a,4,7,8-tetrahydro-5H-pentaleno[6a,1-b]furan-5a(6H)-carboxylate (±)-382

A mixture containing (±)-359 (100 mg, 0.51 mmol, 1 eq.), Cu(OTf) 2 (94 mg, 0.25 mol, 0.5 eq.) and pyrrolidine (42 μL, 0.51 (m, 3H, Hb-4, Ha-13, Ha-5), 1.71 (ddt, J = 12.5, 7.2, 2.6 Hz, 1H, Hb-13), 1.64-1.54 (m, 2H, Hb-5, Hb-12), 1.49-1.41 (m, 1H, Hb-10) ppm.