TOTAL SYNTHESIS OF COMBRETASTATIN-D

The 15-membered caffrane ring of the natural product group of combreta statins D is synthesized in high yield with suitably functionalized sa turated seco acids. The key step is a Mitsunobu-type macrolactonizatio n. A common synthon is used for the construction of both combretastati ns. The synthesis of combretastatin D-2 is completed by the use of Sam muelson's dehydroxylation protocol, The asymmetric epoxide of combreta statin D-1 is constructed in two separate operations: one asymmetric c enter is fixed at an early stage of the synthetic route by Sharpless A D of a trans-styrene derivative, inducing the intramolecular formation of the asymmetric epoxide at the final stages. The synthesis of the t itle compounds is accomplished in high overall yields (37% for D-1 and 41% for D-2, 9 steps in both cases). X-ray crystallographic analysis of the (S)-(+) acetylmandelic ester of (-)-combretastatin D-1 verified its revised structure.