Asymmetric Total Synthesis of Dendrobatid Alkaloids:  Preparation of Indolizidine 251F and Its 3-Desmethyl Analogue Using an Intramolecular Schmidt Reaction Strategy

Aaron Wrobleski, Kiran Sahasrabudhe, and Jeffrey Aubé*
Contribution from the Department of Medicinal Chemistry, University of Kansas, Room 4070, Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582
J. Am. Chem. Soc., 2004, 126 (17), pp 5475–5481
DOI: 10.1021/ja0320018
Publication Date (Web): April 9, 2004
Copyright © 2004 American Chemical Society
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, jaube@ku.edu

Abstract

Abstract Image

Total syntheses of alkaloid 251F (1), a natural product detected from the skin extracts of the dendrobatid frog species Minyobates bombetes, and its racemic 3-desmethyl derivative (2) are reported. A Diels−Alder reaction initiated both syntheses and established four consecutive stereogenic centers. Important to the synthesis of 2 was a first-generation ozonolysis/olefination/aldol strategy to convert a [2.2.1] bicyclic acid to the [3.3.0]bicyclooctane diquinane 4b. Further elaboration to an appropriate keto azide allowed for a key intramolecular Schmidt reaction to deliver the tricyclic core of the target molecule. In a second-generation approach, a tandem ring-opening/ring-closing metathesis reaction effected an overall [2.2.1] → [3.3.0] skeletal rearrangement to deliver diquinane 4a. In similar fashion, 4a was manipulated to an appropriate keto azide, and an intramolecular Schmidt reaction generated the core cyclic architecture of 251F.

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History

  • Published In Issue May 05, 2004
  • Received December 30, 2003

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