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Title: Studies towards the total synthesis of the spongistatins
Author: Hodgson, A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2001
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The spongistatins are a novel class of recently isolated marine macrolides exhibiting potent activity against a series of cancer cell lines, through inhibition of microtubule assembly. Progress towards the total synthesis of the spongistatins is described. In particular, the stereocontrolled syntheses of two fragments A and B are described, which employs boron-mediated aldol reactions and allylations. (Fig. 2890A) Fragment A incorporates the AB-spiroacetal ring system of the spongistatins and was derived from acetone and two chiral aldehydes, C and D. Selective deprotection of E occurred with concomitant spiroacetalisation. Oxidation of the C9 alcohol followed by methyl addition to the resulting ketone and subsequent C9-hydroxyl protection led to A. (Fig. 2890B) Aldehydes C and D were obtained by a protection/oxidation sequence performed on the homoallylic alcohols F and G, which were obtained via Brown asymmetric allylation reactions (Fig. 2890C) Fragment B contains the chlorodiene sidechain of spongistatin 1 and a glucopyranose model F-ring system. Horner-Wadsworth-Emmons methodology was employed to synthesise chlorodiene aldehyde H via ester I (Fig. 2890D) Methyl ketone J was formed via enol ether addition to the trichloroacetimidate of benzyl protected D-glucose K, followed by equilibration to the desired anomer. 1,5-Stereoinduction in the boron-mediated aldol coupling of J with aldehyde H was explored using (+)- and (-)-Ipc2BC1 and (cC6H5)2BC1. Protection of the C47 hydroxyl of aldol product L followed by methylenation completed fragment B (Fig. 2890E).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available