Abstract
Construction of hexahydrobenzofuran moiety with both the correct stereochemistry and the C3-C4 double bond is the most important and challenging aspect in the total syntheses of the antiparasitic avermectins and the milbemycins, because this structure, prone to undergo C2-epimerization, double bond-migration, and dehydration, is essential for their biological activity. Successful total syntheses reported thus far have adopted secure strategies introducing the crucial 3, 4-double bond at the final stages after constructing the whole macrolactone structure but they are still less than satisfactory in terms of stereo-and regio-control. We have succeeded for the first time in the straightforward synthesis of the genuine seco-acid possessing the 3, 4-double bond via an oxetane acetal intermediate and have demonstrated that its macrolactonization to milbemycin α1, can be executed without the serious isomerization.
