Studies in asymmetric synthesis
I the asymmetric alpha-alkylation of N,N-dimethylhydrazones
II the synthesis of 1,3-amino alcohols via the aldol-Tishchenko reaction

Foley, Vera Marie

Studies in asymmetric synthesis I the asymmetric alpha-alkylation of N,N-dimethylhydrazones II the synthesis of 1,3-amino alcohols via the aldol-Tishchenko reaction

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Date

2016

Authors

Foley, Vera Marie

Publisher

University College Cork

Abstract

Part I A large number of optically active drugs and natural products contain α- functionalised ketones or simple derivatives thereof. Furthermore, chiral α- alkylated ketones are useful synthons and have found widespread use in total synthesis. The asymmetric alkylation of ketones represents one of the most powerful and longstanding procedures in organic chemistry. Surprisingly, however, only one effective methodology is available, and this involves the use of chiral auxiliaries. Part I of this research details a novel approach to chiral α-alkylated ketones employing simple non-chiral dimethylhydrazones and effecting their asymmetric alkylation using a range of chiral diamine ligands. While chiral ligands for asymmetric synthesis are not short in abundance, there are a number of structural classes renowned for their broad applicability. Among these, the chiral diamine sparteine has proven itself to be an effective competitor. While enantioselectivities to date are modest (64% ee), this methodology represents the first example of an asymmetric alkylation of non chiral azaenolates. Part II The 1,3-amino alcohol moiety is present in many molecules of pharmaceutical and biological interest with examples found consistently throughout the literature both as chiral ligands and key synthetic intermediates for biologically active natural products. 1,3-Amino alcohols are predominantly synthesised via indirect routes involving various permutations of stepwise construction with asymmetric induction. Part II of this research details a novel approach to the synthesis of this moiety utilising t-butanesulfinimines in an aldol-Tishchenko reaction. Two and even three chiral centres can be installed simultaneously in one synthetic step, affording anti-1,3-amino alcohols in good diastereo-and enantioselectivity. To the best of our knowledge, no strategy involving Tishchenko-hydride reduction of a C=N group instead of a C=O has previously been reported.

Keywords

Novel methodology for the alkylation of ketones , Asymmetric synthesis , One pot aldol-Tishchenko reaction for the synthesis of 1,3-amino alcohol derivatives

Citation

Foley, V. M. 2016. Studies in asymmetric synthesis I the asymmetric alpha-alkylation of N,N-dimethylhydrazones II the synthesis of 1,3-amino alcohols via the aldol-Tishchenko reaction. PhD Thesis, University College Cork.