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Title: Studies towards the synthesis of the spongistatins and remote asymmetric induction in aldol reactions
Author: Gibson, K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1998
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Abstract:
Spongistatin 1/ altohyrtin A (1) is a member of a family of naturally occurring marine derived macrolide natural products. These natural products possess potent cytotoxicity. All the spongistatins possess a highly complex 42-membered macrolide ring comprised of two spiroacetal systems, a hemi-acetal ring and a tetrahydropyran ring. The thesis describes the asymmetric synthesis of 108, a C16-C28 fragment incorporating the CD spiroacetal rings (scheme A). The first part of the synthesis of aldehyde 154 and ketone 158. The key steps are chelationcontrolled additions of nucleophiles to aldehyde 134, the kinetic resolution of alcohol 118 using the Sharpless asymmetric epoxidation, and a palladium catalysed Wacker oxidation (scheme B). (Fig. 9034) The second part of the dissertation describes the synthesis of spiroacetals 108 and 110 by the cyclisation of dihydropyranone 192. Aldehyde 154 was coupled to ketone 158 via a boron mediated aldol reaction. Oxidation and mild acid catalysed cyclisation afforded dihydropyranone 192, which could be cyclised to spiroacetals 108 and 110 (scheme C). The final part of the thesis describes the remarkable facial selectivity of ketone 158 in boron mediated aldol reactions. Additions of boron enolate 296 to simple achiral aldehydes proceeds with >90% diastereoselectivity in favour of the 1,5-anti diastereomer 294, the reaction is operating with an unprecedented degree of remote 1,5-asymmetric induction. These aldol products can be elaborated by stereoselective reduction to form 1,3,5 polyoxygenated arrays 320-322 and 333. This methodology has great potential application for the synthesis of 1,3-polyol natural products (scheme D). The origins of the 1,5-remote asymmetric induction were investigated by the application of molecular modelling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.599398  DOI: Not available
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