Magister Scientiae - MSc (Pharmacy Administration and Policy Regulation) / The aim of this study is to provide more information in terms of the cost-effectiveness of selecting an enantiopure formulation over a racemic mixture in the context of promoting rational use of medicines. This was done by comparing costs and efficacy of escitalopram versus citalopram and esomeprazole versus omeprazole since they are the most commonly used medicines with both racemate and enantiopure products registered.

Les propriétés biologiques intéressantes des biaryles à chiralité axiale ainsi que le défi lié à la construction de la liaison Csp2-Csp2 du motif biarylique ont suscité un vif intérêt des chimistes organiciens de synthèse. Les biaryles à chiralité axiale sont des structures privilégiées en chimie médicinale ainsi qu’en catalyse asymétrique. L’objectif de notre recherche était le contrôle de la chiralité axiale de la (-)-stéganacine en utilisant deux approches atropo-sélectives distinctes: couplage croisé de Suzuki-Miyaura (en présence de métaux de transition), couplage ARYNE (sans métaux de transition). Le couplage croisé de Suzuki-Miyauraatropo-diastéréosélectif a été réalisé en utilisant des β-hydroxysulfoxydes énantiopurs comme auxiliaires de chiralité. Le biaryle diastéréopur issu de ce couplage croisé a été transformé en un intermédiaire rapporté dans la littérature sans épimerisation de la chiralité axiale. La seconde approche était le couplage ARYNE atropo-diastéréosélectif, et fut testée dans un premier temps avec le p-tolylsulfoxyde énantiopur. Cependant nous avions rencontré un problème de manque de réactivité de l’arylsulfoxyde lithié. En revanche la chiralité axiale de la (-)-stéganacine a été contrôlée en utilisant des oxazolines comme auxiliaires de chiralité. / The interesting biological properties of axially chiral biaryls and the challenge of Csp2-Csp2 bond formation ofthe biaryl motif have aroused keen interest among synthetic organic chemists. The axially chiral biaryls areprivileged structures in medicinal chemistry and in asymmetric catalysis. The goal of our research is based onthe control of the axial chirality of (-)-steganacin using two differents atropo-selective approaches: Suzuki-Miyaura cross-coupling (in presence of transition metals), and ARYNE coupling (without any transitionmetals). The atropo-diastereoselective Suzuki-Miyaura cross-coupling was carried out using enantiopure β-hydroxysulfoxydes as chiral auxiliary. The resulting diastereopure biaryl was converted into an intermediatereported in the literature without any epimerization of axial chirality. The second approach was the atropodiastereoselectiveARYNE coupling which was tested for the first time with the enantiopure p-tolylsulfoxyde.However, we encountered a problem due to lack of reactivity of lithiated arylsulfoxide. Finally, the axialchirality of (-)-steganacin was controlled using oxazolines as chiral auxiliary.

The objective of this research was to development new methodologies for the asymmetric syntheses of amine and natural products from enantiopure sulfinimines (N-sulfinyl imines). In this context, new methods was devised for the asymmetric synthesis of 2,5-cis and trans-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates, prepared by an intramolecular metal carbenoid N-H insertion from a sulfinimine derived delta-amino-alpha-diazo- beta-ketophosphonate. Horner-Wadsworth-Emmos reaction of the 3-oxo pyrrolidine 2-phosphonates and aldehydes provided pyrrolidine enones. Hydrogenation (Pd/H2) of the pyrrolidine enones gave cis-2,5-disubstituted pyrrolidines. Luche reduction the pyrrolidine enones followed by a TFA-NaBH3CN mediated hydroxy directed reduction provided the 2,5-trans products. (+)-Preussin, a potent antiviral and antitumor agent was prepared in 9 steps in 28% overall yield from the sulfinimine. An acid catalyzed intramolecular Mannich cyclization of a sulfinimine-derived N-sulfinyl syn-alpha-methyl-beta-amino ketones was employed for the asymmetric synthesis of 2,3,5,6-tetrasubstituted piperidinones. The beta-amino ketones were prepare by treatment of prochiral lithium Weinreb amide enolates with enantiopure (E)-N-(4-(benzyloxy)butylidene)-2,4,6-triisopropylbenzenesulfinamide. This new methodology was highlighted in the first asymmetric synthesis of the poison frog alkaloid (-)-indolizidine 221T. By manipulation of water concentration in tetrahydrofuran, syn- and anti-2,3-diamino esters were prepared by treatment of the lithium enolate of N-(diphenylmethylene) glycine ethyl ester with sulfinimines. Anhydrous THF afforded enantiopure syn-2,3-diamino esters with a syn/anti selectivity of better than 25:1. In a THF-H2O the anti-2,3-diamino esters were formed. The mechanism involves the generation of H2O-LDA species in the formation of enolate which inhibited the retro-Mannich fragmentation in the diamino ester species. (SR,2S,3R)-(-)-Ethyl-2-(N,N-dibenzylamino)-3-N-(p-toluenesulfinyl)amino-pent-4-enoate was employed in an improved total synthesis of the anti-tumor antibiotic (-)-agelastatin A. A series of N-sulfinyl aza-Morita-Baylis-Hillman products were prepared by addition of vinylaluminum and N-methylmorpholine-N-oxide reagents to enantiopure N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines from the least hindered direction via a non-chelation control mechanism. Hydrogenation of the these acrylates with a rhodium(I) catalyst afforded anti-alpha-substituted-beta-amino esters with a anti/syn selectivity of better than 17:1. This new methodology is useful for the asymmetric synthesis of anti-alpha-alkyl-beta-amino esters, which are valuable chiral building blocks for the preparation of biologically active nitrogen-containing natural products. / Chemistry

Section I of the thesis deals with the enantiospecific total synthesis of phomopsolide B. Phomopsolide B was isolated from a strain of Phomopsis Oblonga. Enantiospecific total synthesis of phomopsolide B was accomplished in 13 overall yield in 12 linear steps using (S)-lactic acid and L-tartaric acid as chiral pool precursors. Present approach involves the efficient use of -keto phosphonate derived from commercially available (S)-ethyl lactate. Horner-Wadsworth-Emmons reaction and Still-Gennari olefination were employed as key reactions in the synthesis (scheme 1). Scheme 1: Total synthesis of phomopsolide B. [This work has been published: Prasad, K. R.; Gutala, P. Tetrahedron 2012, 68, 7489-7493.] Section II of the thesis describes the total synthesis of macrosphelides A and E which are isolated from a culture broth of Microsphaeropsis sp. FO-5050 and from the strain Periconia byssoides. Total synthesis of macrosphelides A and E was accomplished in 19 overall yield from commercially available (S)-ethyl lactate. Horner-Wadsworth-Emmons reaction and Yamaguchi lactonization were employed as key reactions for the total synthesis of macrosphelides A and E (scheme 2). Scheme 2: Total synthesis of macrosphelides A and E. [This work has been published: Prasad, K. R.; Gutala, P. Tetrahedron 2011, 67, 4514-4520.] Section III of the thesis deals with total synthesis and determination of absolute configuration of synargentolide B 1. Synargentolide B 1 is a 5,6-dihydro--pyrone containing natural product and was isolated from Syncolostemon Argenteus by Rivett et al. in 1998 (fig 1). The relative stereochemistry at C-6, C-6′ positions in synargentolide B 1 was assigned to be R, S respectively based on the positive cotton effect in the CD spectrum. Threo stereochemistry was proposed for the C1′-C2′ diol unit in synargentolide B 1 based on the NMR studies. The stereochemistry at C-5 could not be assigned, hence the structure of synargentolide B 1 was tentatively proposed as 6R-[5,6S-(diacetyloxy)-1,2-(dihydroxy)-3Eheptenyl]-5,6-dihydro-2H-pyran-2-one (fig. 1). Figure 1: Putative structure of synargentolide B 1. Based on the tentative stereochemistry at the C-6, C-6′ positions proposed by Rivett et al. and taking into consideration the threo relationship for the C-1′-C-2′ diol unit, it is anticipated that the structure of synargentolide B 1 could be one of the four possible diastereomers 1a-1d (fig 2). Figure 2: Possible diastereomers of synargentolide B (1a-d). Incidentally, one of the diastereomers 6R-[5R,6S-(diacetyloxy)-1S,2R-(dihydroxy)- 3E-heptenyl]-5,6-dihydro-2H-pyran-2-one 1d was a reported natural product isolated in 1990 from Hyptis oblangifolia by Pereda-Miranda, R. et al. along with its corresponding diacetylated product 2 (fig 3). Fig. 3: Natural products isolated from Hyptis oblangifolia by Pereda-Miranda, R. et al. Total synthesis and determination of absolute configuration of synargentolide B 1 were accomplished by synthesizing four possible diastereomers of the natural product (1a-1d) and by comparison of the spectral data of all synthesized diastereomers with that of reported for the natural product. Wittig-Horner reaction of -keto phosphonate derived from (S)-lactic acid and ring closing metathesis reaction were employed as key reactions in the total synthesis of synargentolide B 1 (scheme 3 and 4). Scheme 3: Total synthesis of possible diastereomers of synargentolide B (1a, 1b). Scheme 4: Total synthesis of possible diastereomers of synargentolide B (1c, 1d). [This work has been published: Prasad, K. R.; Gutala, P. J. Org. Chem. (in press)]. It was found that spectral data of 1a, 1b, 1c were not in agreement with that reported for synargentolide B 1. However spectral data of 1d was in complete agreement with the data reported for synargentolide B 1. Spectral data of 1d was also in complete agreement with the data reported for the natural product isolated by Pereda-Miranda, R. et al. Since the absolute stereochemistry of tetraacetate 2 is identical to the absolute stereochemistry of 1d, we wanted to confirm the integrity of the diol 1d by synthesizing the corresponding acetate 2 which was also a natural product isolated by Pereda-Miranda et al. 1H NMR data of the synthesized tetraacetate 2 was in agreement with that reported for the isolated tetraacetate, while discrepancies were observed in the 13C NMR spectral data. To clear the uncertainty, X-ray crystal structure analysis of the tetraacetate 2 was performed. It was comprehensively proved that the structure of synthesized tetraacetate 2 was indeed same as the putative structure proposed for the isolated tetraacetate by Pereda-Miranda et al. The crystal structure analysis also confirmed the absolute stereochemistry of the tetraacetate 2 and 1d (synargentolide B 1). (For structural formula pl refer the abstract pdf file)