A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion

Felix Kopp, Christopher F. Stratton, Lakshmi B. Akella, Derek S. Tan

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product-based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have developed a concise, modular approach to the diversity-oriented synthesis of macrolactones and macrolactams involving oxidative cleavage of a bridging double bond in polycyclic enol ethers and enamines. These substrates are assembled in only four or five synthetic steps and undergo ring expansion to afford highly functionalized macrocycles bearing handles for further diversification. In contrast to macrocyclization reactions of corresponding seco acids, the ring expansion reactions are efficient and insensitive to ring size and stereochemistry, overcoming key limitations of conventional approaches to systematic macrocycle synthesis. Cheminformatic analysis indicates that these macrocycles access regions of chemical space that overlap with natural products, distinct from currently targeted synthetic drugs.

Original languageEnglish (US)
Pages (from-to)358-365
Number of pages8
JournalNature Chemical Biology
Volume8
Issue number4
DOIs
StatePublished - Apr 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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