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

J Org Chem. 2001 Apr 6;66(7):2343-9. doi: 10.1021/jo001547z.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Antineoplastic Agents, Phytogenic / chemical synthesis*
  • Crystallography, X-Ray
  • Furans / chemical synthesis*
  • Lignans / chemical synthesis*
  • Magnetic Resonance Spectroscopy
  • Malates / chemistry*
  • Molecular Structure
  • Stereoisomerism

Substances

  • Antineoplastic Agents, Phytogenic
  • Furans
  • Lignans
  • Malates
  • nortrachelogenin
  • malic acid