Methodology studies on the synthesis of chiral, non-racemic aza-quaternary centres

Doctoral Thesis


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University of Cape Town

The synthesis of chiral, non-racemic aza-quaternary centres is one of the biggest challenges in current organic synthesis. Many natural products contain them and as a privileged biological motif they are of interest to medicinal chemistry. The structural complexities of these functionalities invites the development of new methodologies for their synthesis. The experimental part of the thesis appears in two Chapters. Chapter Two describes studies aimed at the enantioselective synthesis of chiral, non-racemic aza-quaternary centres via reagent -based approaches. In the first part studies are directed towards developing ephedrine -derived stoichiometric chiral aminating reagents in enantioselective nitrogen transfer, while in the second part of the Chapter the emphasis shifts to using an organocatalysis approach involving an ephedrine -hydrazide organocatalyst in conjunction with enantioselective amination methodology using an azodicarboxylate. Chapter Three shifts to a substrate -controlled approach based on using chiral malonate -imidazolidinones as a template for amination. Using KHMDS as base it has been shown that the enolate of α -substituted chiral malonate-imidazolidinones can be azidated with trisyl azide in excellent diastereoselectivity in yields > 92 % and dr ≥ 97:3 by chiral HPLC. The products were subsequently transformed to α,α-disubstituted α-serine derivatives by a series of chemoselective steps: reduction of azide with Zn / AcOH, removal of the chiral auxiliary with LiSEt followed by reduction of the resultant thioester with lithium-tri-tert-butoxyaluminium hydride in up to 75 % yield over 4 steps. The methodology opens up the way towards establishing a general methodology for synthesizing quaternized amino acids with a broad range of R groups, both natural and unnatural in type.

Includes bibliographical references