Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments



Mears, Paul R, Hoekman, Steven, Rye, Claire E, Bailey, Fiona P, Byrne, Dominic P, Eyers, Patrick A ORCID: 0000-0002-9220-2966 and Thomas, Eric J
(2019) Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments. ORGANIC & BIOMOLECULAR CHEMISTRY, 17 (6). pp. 1487-1505.

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Abstract

Bryostatins with modified C17-C27 fragments have not been widely studied. The synthesis of 20,20-difluorinated analogues was therefore investigated. Such substitution would inhibit dehydration involving the C19-hydroxyl group and stabilise the ring-closed hemiacetal tautomers. Following preliminary studies, allyldifluorination was used to prepare difluorinated alkenols. Oxidation followed by stereoselective Wittig reactions of the resulting α,α-difluorinated ketones gave (E)-α,β-unsaturated esters that were taken through to complete syntheses of 2-hydroxytetrahydropyrans corresponding to C17-C27 fragments of 20,20-difluorinated bryostatin. These compounds showed modest binding to protein kinase Cα isozyme. Attempts were also undertaken to synthesise macrocyclic 20,20-difluorinated analogues. During preliminary studies, allyldifluorination was carried out using a 2-alkyl-3-bromo-1,1-difluoropropene.

Item Type: Article
Uncontrolled Keywords: Protein Kinase C, Molecular Conformation, Models, Molecular, Bryostatins, Halogenation, Chemistry Techniques, Synthetic
Depositing User: Symplectic Admin
Date Deposited: 28 Jan 2020 09:10
Last Modified: 19 Jan 2023 00:08
DOI: 10.1039/c8ob03152e
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3072150