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20-nor-SalA_chemrxiv copy.pdf (1.88 MB)
10-step Synthesis of 20-nor-Salvinorin A by Dynamic Strategic Bond Analysis
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revised on 18.08.2017 and posted on 19.08.2017by Jeremy Roach, Yusuke Sasano, Cullen Schmid, Saheem Zaidi, Vsevolod Katritch, Raymond Stevens, Laura Bohn, Ryan Shenvi
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