Unified Total Syntheses of Benzenoid Cephalotane-Type Norditerpenoids: Cephanolides and Ceforalides

J Am Chem Soc. 2022 Oct 19;144(41):19173-19185. doi: 10.1021/jacs.2c08803. Epub 2022 Oct 5.

Abstract

Detailed herein are our synthetic studies toward the preparation of the C18- and C19-benzenoid cephalotane-type norditerpenoids. Guided by chemical network analysis, the core structure of this natural product family was constructed in a concise manner using an iterative cross-coupling, followed by a formal inverse-electron-demand [4 + 2] cycloaddition. Initial efforts to functionalize an alkene group in the [4 + 2] cycloadduct using a Mukaiyama hydration and a subsequent olefination led to the complete C18-carbon framework. While effective, this approach proved lengthy and prompted the development of a direct alkene difunctionalization that relies on borocupration to advance the cycloadduct to the natural products. Late-stage peripheral C-H functionalization facilitated access to all of the known cephanolides in 6-10 steps as well as five recently isolated ceforalides in 8-13 steps.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkenes
  • Biological Products*
  • Carbon / chemistry
  • Cycloaddition Reaction
  • Diterpenes* / chemistry

Substances

  • Diterpenes
  • Biological Products
  • Alkenes
  • Carbon