Milbemycin synthesis: asymmetric synthesis of spiroketals from methyl α-D-glucopyranoside

Abstract

The 6-chloro-4,6-dideoxygalactoside 8 was prepared by selective dichlorination of methyl α-D-glucopyranoside 6 followed by hydrogenolysis, and was converted into the epoxyalkyldithioacetal 10 by treatment with propane- 1,3-dithiol, protection, and formation of the epoxide. With nucleophiles, the epoxyalkyldithioacetal underwent opening of the epoxide, whereas with strongly basic reagents abstraction of the dithiane proton at C-2 followed by elimination gave the epoxy hydroxy ketone dithioacetal 34. This chemistry was used to prepare a series of anti-1,3-diols 36, 38 and 40 and should be useful for natural-product synthesis. Using the vinyllithium reagent derived from iodide 57, the diol 60 corresponding to the C(11)–C(21) fragment of milbemycin E 1 was prepared, and this was taken through to the spiroketal 64 as a model for a proposed synthesis of the C(11)–C(25) fragment of a milbemycin. The anti-diols 36 and 40 were taken through to the spiroketals 74 and 69, respectively, so providing an asymmetric synthesis of fully functionalised milbemycin spiroketals.