Millet, Julien (2006) Approaches towards a stereoselective Nicholas reaction. (PhD thesis), Kingston University, .
Abstract
This programme of work has focused on developing ways of inducing stereoselectivity into the Nicholas reaction towards the synthesis of natural products. The first chapter of the thesis reviews the developments of the Nicholas reaction since its discovery in 1972 as well as other applications of cobalt clusters. The following chapter describes chirality and various approaches towards asymmetric synthesis. Chapter 3 details our investigations as well as the results that we achieved in the two areas we explored. The first part of the project attempted to determine which oxazolidinone derivative would provide optimum levels of selectivity in 1, 4-conjugate addition reactions, and then investigate such derivatives in the Nicholas reaction. It was found that oxazolidinones bearing a phenyl group at the C4 position induced much higher levels of stereo selectivity than those with benzyl or methyl groups at the C4 position. Although 4-phenyl-2-oxazolidinone provided optimum levels of diastereoselectivity in the asymmetric conjugate addition reaction of pentenyl organometallic reagents, it less efficient when applied sequencially in an intermolecular Nicholas reaction. In contrast, 4-methyl-2-oxazolidinone provided poor selectivity in an conjugate addition reaction; however it was the auxiliary of choice for the corresponding Nicholas reaction carried out upon optically active prop argyl alcohols derived from citronellal. These were prepared from two different approaches. In the first approach, racemic alcohols were prepared via a Grignard reaction, then oxidised to the corresponding ketone before being reduced to the optically pure alcohol via a stereoselective reduction using alpine borane. In the second approach, optically active prop argyl alcohols were prepared via zinc catalysed asymmetric alkynylation reactions. After complexation of these prop argyl alcohols to cobalt octacarbonyl, the addition of a Lewis acid led to the intramolecular Nicholas cyclisation reaction providing tri-substituted six membered rings in 55% yield. The results show that the reactions carried out on opposite diastereoisomers or racemic mixture provided the same mixture of diastereoisomers of the cyclised products. The final chapter describes all the experimental procedures that were carried out as well as the characterisation of every compound presented in this document.
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