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

The total synthesis of (-)-wikstromol, a bioactive alpha-hydroxylated lactone lignan, from natural malic acid using a consecutive alkylation strategy is presented. First, alkylation of a malic acid ester provided the monobenzyl derivative, which was then converted to an alpha-substituted dioxolanone. This derivative was reacted in a second alkylation step to a double benzylated dioxolanone, which was transformed to bis-O-benzyl-protected (-)-wikstromol and subsequently to the natural product. Only six steps were required to produce wikstromol in 30% overall yield. A second approach from malic acid, the double alkylation of dienolates from 5-oxo-1,3-dioxolan-4-yl acetic acid derivatives, was not successful. No reaction conditions were found to afford the dienolates. Instead, rapid fragmentation of the dioxolanones to fumaric acid derivatives and pivalaldehyde occurred even at -105 degrees C, and aldol reaction products with good stereoselectivity were formed. The relative configuration of the major isomer was determined by X-ray structure analysis. By comparison of NMR data it is shown that a previous assignment of the configuration of one of the described aldol products was incorrect.