Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist

Jeremy J. Roach, Yusuke Sasano, Cullen L. Schmid, Saheem Zaidi, Vsevolod Katritch, Raymond C. Stevens, Laura M. Bohn, Ryan A. Shenvi

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Salvinorin A (SalA) is a plant metabolite that agonizes the human kappa-opioid receptor (κ-OR) with high affinity and high selectivity over mu- and delta-opioid receptors. Its therapeutic potential has stimulated extensive semisynthetic studies and total synthesis campaigns. However, structural modification of SalA has been complicated by its instability, and efficient total synthesis has been frustrated by its dense, complex architecture. Treatment of strategic bonds in SalA as dynamic and dependent on structural perturbation enabled the identification of an efficient retrosynthetic pathway. Here we show that deletion of C20 simultaneously stabilizes the SalA skeleton, simplifies its synthesis, and retains its high affinity and selectivity for the κ-OR. The resulting 10-step synthesis now opens the SalA scaffold to deep-seated property modification. Finally, we describe a workflow to identify structural changes that retain molecular complexity, but reduce synthetic complexity - two related, but independent ways of looking at complexity.

Original languageEnglish
Pages (from-to)1329-1336
Number of pages8
JournalACS Central Science
Volume3
Issue number12
DOIs
Publication statusPublished - 2017 Dec 27

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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