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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.

The stereoselective synthesis of a carboxylic acid ester corresponding to the C1–C16 fragment of bryostatin, with 4-methoxybenzyl (PMB) protection for the 7-hydroxyl group, is reported. The key steps included a Horner-Wadsworth-Emmons reaction between (5R)-3-[(E)-2-tri-isopropylsilyloxyethylidene]-6-(4-methoxybenzyloxy)-5-triethylsilyloxyhexanal and dimethyl (4S,6R,8S)-10-hydroxy-6,8-di-O-isopropylidene-4-(4-methoxybenzyloxy)-3,3-dimethyl-2-oxodecan-1-yl phosphonate, that gave the corresponding (E)-alkene, followed by selective cleavage of the triethylsilyl ether and cyclisation to give the required 2,6-cis-disubstituted 4-[(Z)-tri-isopropylsilyloxyethylide]tetrahydropyran. Oxidation of the primary alcohol gave the corresponding carboxylic acid that was converted into the required allyl ester.

2-Hydroxytetrahydropyrans corresponding to the C16–C27 fragment of bryostatins which have been difluorinated at C20 (bryostatin numbering) have been synthesised. The fluorine substituents were introduced by difluoroallylation. An (E)-selective Wittig reaction using a stabilised ylide provided the required methoxycarbonylmethylene substituent with excellent stereoselectivity.

A variety of aromatic and aliphatic aldehydes are difluoroallylated by the title difluoroalkene (I) leading to fluorinated methylenealkanols (III) in good to excellent yields.

Difluoroallylation of aldehydes mediated by indium powder has been carried out using 2-bromomethyl-1,1-difluorodec-1-ene leading to 2,2-difluoro-3-methylenealkanols in useful yields. The reaction has been applied to a range of aldehydes including both aromatic and aliphatic aldehydes.