Enantiospecific synthesis of the spiroacetal moieties of avermectins A1b, B1b, A1a, B1a, A2b, B2b, A2a, and B2a and milbemycins α7 and α8

Abstract

Three differently substituted unsaturated spiroacetals, two of which form part of the structure of avermectins A_1b, B_1b, A_1a, and B_1a, have been prepared by reaction of the appropriately substituted and chiral lithium acetylide with dibenzyl protected (4S,6S)-4-hydroxy-6-hydroxymethyltetrahydropyran-2-one followed by partial hydrogenation and acid-catalysed cyclisation. The preparation of the chiral hydroxyacetylene derivatives is described. Hydration of the double bond via the chlorohydrin followed by tributyltin hydride reduction led to formation of the spiroacetal moiety found in avermectins A_2b, B_2b, A_2a, and B_2a. Epoxidation of one of the unsaturated spiroacetals and subsequent treatment with perchloric acid afforded a diaxial spiroacetal diol from the major epoxide. A protocol for the selective acylation of the diol has been developed which involves selective deprotection of the corresponding dimethyl t-butylsilylated diol under acid-catalysed conditions followed by acylation with the appropriate chiral acid chloride. Desilylation then gave the spiroacetal moiety found in milbemycins α₇ and α₈. The acyl chloride has been prepared by alkylation of a chiral oxazolidone with subsequent hydrolytic removal of the chiral auxiliary and reaction with oxalyl chloride.