The cembrane diterpenes are a large class of 14-membered-ring-containing natural products, many of which show potentially valuable biologically activity. For example, many representative members of the class (lobohedleolide, crassin acetate, asperdiol, 13,14-bis-epijeunicin, sinularin, dihydrosinularin, and sarcophytol B) show considerable anticancer activity both in vitro and in vivo. In spite of this biological activity, relatively little synthetic work has been carried out in the field, probably because few methods exists for preparing large-ring carbocycles. We have devised new synthetic methods for preparing large-ring cycloalkenes, large-ring 1,2-diols, and large-ring ketones. These methods, which involve treatment of a diketone (aldehyde) or keto ester with titanium metal, appear uniquely suited for cembranoid synthesis. We therefore propose to use our methods for the synthesis of several naturally occurring cembranoids of increasing complexity - sarcophytols A and B, cembranolide, lobophytolide, and sinularin. By so doing, we hope to make these natural products and their analogs more readily available for study and testing. In addition, we hope to extend our knowledge of reaction selectivity in these large-ring compounds.
