Enantioselective synthesis of (-)-wikstromol using a new approach via malic acid

The total synthesis of(-)-wikstromol, a bioactive a-hydroxylated lactone li gnan, from natural malic acid using a consecutive alkylation strategy is pr esented. First, alkylation of a malic acid ester provided the monobenzyl de rivative, which was then converted to an cr-substituted dioxolanone. This d erivative was reacted in a second alkylation step to a double benzylated di oxolanone, which was transformed to bis-O-benzyl-protected (-)-wikstromol a nd subsequently to the natural product. Only six steps were required to pro duce wikstromol in 30% overall yield. A second approach from malic acid, th e double alkylation of dienolates from 5-oxo-1,3-dioxolan-4-yl acetic acid derivatives, was not successful. No reaction conditions were found to affor d the dienolates. Instead, rapid fragmentation of the dioxolanones to fumar ic acid derivatives and pivalaldehyde occurred even at -105 degreesC, and a ldol reaction products with good stereoselectivity were formed. The relativ e configuration of the major isomer was determined by X-ray structure analy sis. By comparison of NMR data it is shown that a previous assignment of th e configuration of one of the described aldol products was incorrect.