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

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.

O6C-20-nor-salvinorin A is a stable and potent KOR agonist

“…5,6,7,8 We recently identified angular methyl C20 as a main contributor to scaffold instability due to a 1,3-diaxial interaction with the C12 hydrogen, which is relieved by epimerization. 9 We found that deletion of C20 reversed the stability of the SalA scaffold and caused the potent isomer to predominate (1:2.5). This new lead compound, 20-nor-SalA, retained the high potency and selectivity of SalA itself, and its facile synthesis allowed the generation of new aryl analogs using a carboxylate-directed Heck reaction.…”

“…This new lead compound, 20-nor-SalA, retained the high potency and selectivity of SalA itself, and its facile synthesis allowed the generation of new aryl analogs using a carboxylate-directed Heck reaction. 9 We hypothesized that further scaffold stabilization might be possible by removing the restriction of the small dihedral angle (0° ideal) 10 enforced by the C-ring lactone. Here we show that O→C replacement (lactone→cyclo-hexanone), combined with C20 deletion, stabilizes the SalA scaffold to the point where no epimerization is observed under conditions that equilibrate SalA.…”

“…Although the structural complexity of 20-nor-SalA is equivalent to that of SalA, its synthetic complexity is markedly reduced – a relationship we identified through dynamic retrosynthetic analysis. 9 Furthermore, 20-nor-SalA is significantly more stable, resulting in reduced epimerization of its C8 carbon. Epimerization is not, however, completely eliminated.…”

“…We wondered if part of the driving force for C8 epimerization derives from the embedded ester, which strains the ring system due to semi-planarity, but cannot reach full planarity given the trans -ring junction (25° dihedral angle C12→C8, determined by x-ray crystallography, Ref. 9). Epimerization to a cis -fused junction relieves angle strain and allows better overlap of the O6 lonepair with the C17 carbonyl (7° dihedral angle C12→C8 in x-ray structure of 8- epi - 1 , Ref.…”

“…We could easily access intermediate 5 in only 6 steps from commercially available Hagemann’s ester ( 4 ), as reported previously. 9 In our original route, introduction of the A-ring oxygen substituent was achieved by deprotonation with LDA, followed by oxidation with Davis’ oxaziridine. However, removal of sulfonamide byproducts proved difficult, so we instead explored the use of diatomic oxygen.…”