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Diastereoselective synthesis of 2,4,5 trisubstituted piperidines: application in natural product synthesis

Sadler, Matthew James (2011)
Ph.D. thesis, University of Birmingham.

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Abstract

This thesis describes the diastereoselective synthesis of 2,4,5-trisubstituted piperidines using carbonyl-ene and Prins cyclisations and their application in natural product synthesis. Following on from previous work in the group, we investigated how a preinstalled substituent in the 2-position can help to control the sense of induction at the two newly forming stereocentres.

We utilised the Prins reaction in the formal synthesis of pseudodistomin F, a marine alkaloid that posses a 2,4,5-tribsubstituted piperidine core. An initial first generation synthesis focused on the construction of a cyclisation precursor containing a crotyl-ene component, however, cyclisation with anhydrous hydrogen chloride at -78 °C resulted in side product formation, presumably resulting from the relative instability of the secondary carbocation. Changing the ene component to a prenyl group resulted in successful cyclisation to yield the trans, cis-2,4,5-trisubstituted piperidine, with diastereomeric ratios of up to 200:1. An improved second generation synthesis completed the formal synthesis of pseudodistomin F on a multi-gram scale. Progress towards the total synthesis of pseudodistomin F by a third generation synthesis was undertaken.

An investigation into how varying the electronics of the Prins reaction would alter the diastereoselectivity was conducted with a range of para-substituted cinnamyl substrates. The results indicated that selectivity in favour of the trans diastereomer was favoured as the electron withdrawing power of the substituent increased.

Type of Work:Ph.D. thesis.
Supervisor(s):Snaith, J. S.
School/Faculty:Colleges (2008 onwards) > College of Engineering & Physical Sciences
Department:School of Chemistry
Subjects:QD Chemistry
Institution:University of Birmingham
ID Code:2901
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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