Enantiopure α-alkyl-substituted aldehydes are widely recognised as important building blocks in synthesis. Despite this, methods to prepare such substrates are limited. Strategically, asymmetric intermolecular S_N2 α-alkylation represents a highly straightforward transformation, but still remains an elusive feat. This thesis describes efforts to address this challenge, with attempted access to enantioenriched α-alkyl aldehydes by way of C-alkylation of chiral, non-racemic, hindered aldenamines using simple alkyl halides. Enamines derived from four types of auxiliary (a tropane, an oxazolidine, a pyrrolidine and a homotropane) have been prepared, and their alkylation profile examined. While the desired levels of asymmetric induction were not attained, use of the tropane and homotropane auxiliaries, which differ only by a single methylene group, interestingly, gave complimentary diastereocontrol during alkylation with EtI. The observed stereoselectivity is supported by density functional studies performed for ethylation of both enamines. Additionally, in the course of preparing the homotropane a highly efficient asymmetric synthesis of a homotropinone bearing gem-α-substitution has been developed.

This thesis is divided into four separate parts with amino alcohols as the common feature. The first part of the thesis describes the development of an efficient three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters are formed in high yields and excellent diastereoselectivities. An asymmetric version was also developed by employing chiral α-methylbenzyl imines as dipolarophiles yielding enantiomerically pure syn-α-hydroxy-β-amino esters. This methodology was also applied on a short asymmetric synthesis of the paclitaxel side-chain as well as in an asymmetric synthetic approach towards the proteasome inhibitor omuralide. Furthermore, the use of chiral Rh(II) carboxylates furnishes the syn-α-hydroxy-β-amino esters in moderate enantioselectivity (er up to 82:18), which indicates that the reaction proceeds via a metal-associated carbonyl ylide. The second part describes the development of a 1,3-dipolar cycloaddition reaction of azomethine ylides to aldehydes for the synthesis of α-amino-β-hydroxy esters. Different methods for the generation of the ylides, including Vedejs’ oxazole methology and an Ag(I)/phosphine-catalyzed approach have been evaluated. The best results were obtained with the Ag(I)/phosphine approach, which yielded the desired α-amino-β-hydroxy ester in 68% yield and 3.4:1 syn:anti-selectivity. The last two parts deals with the total synthesis of the amino alcohol-containing natural products D-erythro-sphingosine and (−)-stemoamide. The key transformation in the sphingosine synthesis is a cross-metathesis reaction for the assembly of the polar head group and the aliphatic chain. In the stemoamide synthesis, the key feature is an iodoboration/Negishi/RCM-sequence for the construction of the β,γ-unsaturated azepine core of stemoamide followed by a stereoselective bromolactonization/1,4-reduction strategy for the installation of the requisite C8-C9 trans-stereochemistry. / QC 20100820

Les 1,3-oxazolidinethione-2-thiones (OZT), fonctions thionocarbamates cycliques, ancrées sur des charpentes saccharidiques font l'objet de notre étude. Les travaux menés ont été axés vers l'emploi des OZT chirales en synthèse asymétrique. Dans ce but, nous avons développé une méthodologie de synthèse d'OZT spiraniques sur charpentes saccharidiques ainsi qu'une méthode de N-vinylation des OZT, en poursuivant les connaissances acquises au sein du laboratoire. La chiralité inhérente aux sucres, couplée à la réactivité toute particulière des OZT obtenues, nous a permis d'explorer la réactivité d'auxiliaires chiraux originaux et hautement réactifs : des N-vinyl-1,3-oxazolidine-2-thiones. A la fois sur des molécules chirales simples et sur des charpentes saccharidiques, les OZT N-vinylées ont été testées en transfert de chiralité par hétérocycloaddition de Diels-Alder à demande inverse.