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10-step Synthesis of 20-nor-Salvinorin A by Dynamic Strategic Bond Analysis

preprint
revised on 18.08.2017 and posted on 19.08.2017 by Jeremy Roach, Yusuke Sasano, Cullen Schmid, Saheem Zaidi, Vsevolod Katritch, Raymond Stevens, Laura Bohn, Ryan Shenvi
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 semi-synthetic 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.

History

Topic

  • Organic Synthesis and Reactions
  • Natural Products

Email Address of Submitting Author

rshenvi@scripps.edu

Institution

The Scripps Research Institute

Country

USA

ORCID For Submitting Author

0000-0001-8353-6449

Declaration of Conflict of Interest

A patent has been filed

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