Enantioselective Synthesis of the Antiinflammatory Agent (−)-Acanthoic Acid

Taotao Ling,† Chinmay Chowdhury,† Bryan A. Kramer,† Binh G. Vong,† Michael A. Palladino,‡ and Emmanuel A. Theodorakis*†
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, and Nereus Pharmaceuticals, Inc., 9393 Towne Centre Drive, Suite 210, San Diego, California 92121
J. Org. Chem., 2001, 66 (26), pp 8843–8853
DOI: 10.1021/jo0159035
Publication Date (Web): November 22, 2001
Copyright © 2001 American Chemical Society
†

 University of California, San Diego.

,
‡

 Nereus Pharmaceuticals, Inc.

,
*

 Corresponding author. Phone:  858-822-0456. Fax:  858-822-0386.

, email:  etheodor@ucsd.edu

Abstract

Abstract Image

An enantioselective synthesis of the potent antiinflammatory agent (−)-acanthoic acid (1) is described. The successful strategy departs from (−)-Wieland−Miescher ketone (10), which is readily available in both enantiomeric forms and constitutes the starting point toward a fully functionalized AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4 center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C ring of 1 was accomplished via a Diels−Alder reaction between sulfur-containing diene 43 and methacrolein (36), which after desulfurization and further functionalization yielded synthetic acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product and represents a fully stereocontrolled entry into an underexplored class of biologically active diterpenes.

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History

  • Published In Issue December 28, 2001
  • Received July 9, 2001

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