The large scale synthesis of the C19 to C32 portion of swinholide A, the total synthesis of dactylolide, and the synthesis of a novel bryostatin analogue

An efficient macrolactonization procedure utilizing a polymer bound carbodiimide was developed. The procedure uses the polymer supported reagent as a replacement for dicyclohexylcarbodiimide and thus considerably simplifies the workup for such reactions. Partitioning between macrolactone and diolide is shown to depend upon the equivalents of reagent used in cases for which lactonization is difficult.; Swinholide A was found as one of the many antifungal isolates obtained from the Okinawan marine sponge of the genus Theonella swinhoei by Carmely and Kashman in 1985. The structural assignment consists of a dimeric, 44-membered macrolide ring with 15 stereocenters, a trisubstituted tetrahydropyran, a disubstituted dihydropyran as well as two isomerizable olefins. Due to the unique challenges posed by this amazing structure, coupled with its impressive cytotoxicity against a number of cancer cells, this molecule beckoned to synthetic chemists worldwide. The chemistry described herein is an account of the gram scale synthesis of the C19 to C32 subunit of swinholide A though methods discovered in our laboratories.; Dactylolide was one of the many cytotoxic metabolites isolated from the Vanuatu sponge Dactylospongia sp. by Riccio and co-workers in 2001. Dactylolide was shown to have cytotoxicity towards a number of cancer cell lines. The major architectural elements of dactylolide consist of a highly unsaturated but moderately functionalized 20-membered macrolactone, a 2,6- cis-disubstituted methylene tetrahydropyran and two trisubstituted olefins. Our interest in dactylolide stemmed from its molecular structure. Recent work in our laboratories has provided an exceptionally facile access to stereodefined 2,6-cis-4-methylene tetrahydropyrans. The chemistry described herein is an account of the total synthesis of dactylolide utilizing chemistry developed in our laboratories. This synthesis is the shortest and highest yielding reported to date.; Noteworthy discoveries stemming from the Wender labs have prompted us to set up a program to synthesize novel bryostatin analogs. The synthesis of an innovative analogue was completed using a powerful, unprecedented pyran annulation reaction developed in our laboratories.