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Issue 6, 2019
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Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments

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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.

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

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Publication details

The article was received on 19 Dec 2018, accepted on 16 Jan 2019 and first published on 16 Jan 2019


Article type: Paper
DOI: 10.1039/C8OB03152E
Citation: Org. Biomol. Chem., 2019,17, 1487-1505

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

    P. R. Mears, S. Hoekman, C. E. Rye, F. P. Bailey, D. P. Byrne, P. A. Eyers and E. J. Thomas, Org. Biomol. Chem., 2019, 17, 1487
    DOI: 10.1039/C8OB03152E

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