This thesis deals with the development and application of new synthetic methodology in organic chemistry. The first part describes the development of a new protocol for the synthesis of 3-pyrrolines by means of a microwave-assisted ring-expansion reaction of 2-vinylaziridines. In addition, this methodology is implemented as a key-step in a formal total synthesis of the antibiotic (-)-anisomycin. In the second part, a new methodology for the synthesis of arylglycines from Weinreb amides is described. In this procedure, a Grignard reagent is added to the iminium ion formed from the Weinreb amide upon treatment with a base. When a chiral amide is used, the nucleophilic addition proceeds with high diastereoselectivity. Finally, an easy and straightforward synthesis of α-amino amides via a base-mediated rearrangement of modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenylation or alkynylation of this intermediate affords the corresponding α-amino amides in excellent yields. Furthermore, a more generalized protocol for the α-arylation of Weinreb amides lacking an α-amino moiety is also discussed. / QC 20100719

First chapter of the thesis describes the desymmetrization of the bis-dimethyl amide 1 derived from tartaric acid with vinyl Grignard reagents and subsequent reduction of the resultant -keto amides 2a-c to the -hydroxy amides 3a-c. Application of the -hydroxy amides 3a-c in the total synthesis of bio-active natural products such as gabosines, crassalactone C and anamarine is described in the subsequent sections. In section A of the first chapter, application of the -hydroxy amides 3a-b to the total synthesis of gabosine A 4, gabosine F 5 and gabosine H 6 was described. Key strategy in the synthesis was the use of ring closing metathesis (RCM) reaction. Incidentally, the total synthesis of gabosine H 6 was not only accomplished for the first time but the synthesis also ascertained the absolute stereochemistry of the natural product. During the course of the synthesis of gabosine A 4, an unprecedented formation of a unique 14-membered macrocycle 7 was observed. Incisive studies were conducted to elucidate the reaction sequence for the formation of the macrocyle 7. It was found that the formation of the macrocycle 7 was through a tandem cross-metathesis/intramolecular hetero Diels-Alder reaction. Section B of chapter 1 delineated the utility of the -hydroxy amide 3a in the total synthesis of (–)-crassalactone C 8a. Crassalactone C 8a is a cinnamoyl derivative of styryllactone natural product goniofufurone and was found to possess marginal in vitro cytotoxic activity. Pivotal strategies in the synthesis include the use of bis-cinnamoyl ester 10a in the ring closing metathesis reaction which also evades the selective cinnamoylation of the benzylic hydroxy group. Section C of Chapter 1 deals with the total synthesis of (+)-anamarine 11. While the - hydroxy amide 3a was employed to synthesize an important intermediate 12 enroute to the synthesis of anamarine, to mitigate the number of steps in the synthesis, the -hydroxy amide 13 was employed for the synthesis of (+)-anamarine 11. Key reactions in the total synthesis include the use of 1,3-dithiane as a surrogate for the methyl group, Brown’s allylation and ring closing metathesis. In second chapter of the thesis, formal total synthesis of iriomoteolide 3a 16 is presented. Iriomoteolide 3a 16 is a unique 15-membered marine macrolide isolated by Tusda’s group from the Amphidinium strain HYA024, with impressive in vitro cytotoxic activity against human lymphoma cell line DG-75 (IC50 0.08 g/mL) and Raji cells (IC50 0.05 g/mL). Salient features of the synthesis include the synthesis of the chiral aldehyde 19 from the oxazolidinone 17 and the use of -keto phosphonate 20 derived from D-(–)-tartaric acid in the Horner-Wadsworth-Emmons olefination reaction to construct the C1-C10 fragment 23 of iriomoteolide 3a 16. Synthesis of the C10-C18 fragment 29 was accomplished from the butyrolactone 24 using Keck allylation and olefin cross metathesis reactions as key steps. Ring closing metathesis of the ester 30, followed by selective deprotection of the primary TBS group afforded the key intermediate 31, the transformation of which to iriomoteolide 3a 16 is known in literature.

Dans ce travail, il est montré que les alkyl/vinyl/aryl lithiens et magnésiens réagissentavec les acides C-1(F/OMe) naphtoïques en l'absence de catalyseur métallique. Cette nouvelleréaction de substitution nucléophile aromatique permet potentiellement de préparer n’importequel biaryle tout en s'affranchissant des étapes de protection et de déprotection de la fonctionacide (CO2H). Les alkyllithiens linéaires et ramifiés réagissent avec la même efficacité que lesalkylmagnésiens même à basse température (–78 °C). Le déplacement d'un fluor ou d'unméthoxy s'effectue avec la même facilité. L'absence d'ortho-lithiation est confirmée par lepiégeage du milieu réactionnel en fin de réaction par l'iodométhane (après addition de n-BuLi,s-BuLi et t-BuLi). Le bromure de vinylmagnésium requiert un chauffage au reflux du THF.La méthode étudiée permet de préparer extrêmement facilement des 1- et 2-phénylnaphtalènes, 1,1’-binaphtalènes et 2,2’-binaphtalènes. Dans les exemples où lesaryllithiens donnent des rendements moyens-faibles en produits de couplage, les réactifs deGrignard sont beaucoup plus efficaces. Le o-tolyllithium, le bromure de o-tolylmagnésium, lebromure de (4-méthoxyphényl)magnésium, le bromure de (2,5-diméthylphényl)magnésium etle bromure de benzo[d][1,3]dioxol-5-ylmagnésium déplacent facilement le groupefluoro/méthoxy en ortho du groupe CO2M pour donner les produits de substitutioncorrespondants alors que la réaction du bromure de (2,6-diméthoxyphényl)magnésium estmoins efficace sans doute en raison de l'encombrement stérique causé par les deux groupesortho-méthoxy. L'acide 1-(2-méthoxyphényl)-2-naphtoïque est un produit particulièrementintéressant. La déprotection du groupe méthoxy suivie d'une cyclisation est réalisée par BBr3pour donner la 6H-naphtho[2,1-c]chromén-6-one qui est isolée avec un rendement de 97 %.Cette lactone est utile pour la préparation de composés atropoisomères optiquement actifsaprès ouverture énantiosélective du cycle lactone selon la technique mise au point parBringmann. / Alkyl as well as aryl substitution can be readily accomplished in generally excellentyields via a nucleophilic mode by displacement of an ortho-fluoro or methoxy group inunprotected naphthoic acids with lithium and Grignard reagents in the absence of a metalcatalyst.Alkyllithium reagents typically gave good-to-excellent yields, whether primary,secondary, or tertiary at –78 °C. Displacement of a fluoro or a methoxy group occurs withequal efficacy. The absence of ortho-lithiation was confirmed by quenching the reactionproduct with MeI after addition of n-BuLi, s-BuLi and t-BuLi. Alkyl Grignard reagentsEtMgBr and n-BuMgBr proved to be very reactive at –78 °C while vinyl magnesium bromiderequired refluxing in THF.The method provides excellent latitude with respect to the synthesis of 1- and 2-phenylnaphthalenes, 1,1’-binaphthalenes, and 2,2’-binaphthalenes. In those instances wherethe aryllithium reagents gave poor yields of coupling products, the corresponding Grignardreagents proved to be much more effective. o-Tolyllithium, o-tolylmagnesium bromide, (4-methoxyphenyl)magnesium bromide, (2,5-dimethylphenyl)magnesium bromide andbenzo[d][1,3]dioxol-5-ylmagnesium bromide smoothly displaced the fluoro/methoxy grouportho to the CO2M group to give the corresponding substitution products while reaction of(2,6-dimethoxyphenyl)magnesium bromide proceeded with less efficiency presumably due tosteric effects imparted by the two ortho-methoxy groups. Particularly useful is 1-(2-methoxyphenyl)-2-naphthoic acid which allows for further elaboration after the coupling isperformed. Deprotection of the methoxy group followed by cyclization was realized withBBr3 to afford 6H-naphtho[2,1-c]chromen-6-one which was isolated in 97% yield. Thislactone is the starting building block for the preparation of optically active atropisomers byenantioselective ring opening.