Version 2 Version 2 19.08.17, 10:27 Version 1 17.08.17, 07:38 preprint preprint Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission. revised on 18.08.2017 and posted on 19.08.2017 Jeremy Roach , Yusuke Sasano , Cullen Schmid , Saheem Zaidi , Vsevolod Katritch , Raymond Stevens , Laura Bohn Ryan Shenvi by

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