A Protecting‐Group‐Free Synthesis of (−)‐Salvinorin A

Abstract

A concise enantioselective total synthesis of the neoclerodane diterpene (À )-salvinorin A is reported. The stereogenic center at C-12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels-Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2-diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (À )-salvinorin A was synthesized in only 16 steps starting from 3-furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels-Alder strategy employing a 2-bromo-1,3-diene moiety was investigated.

Sharpless Asymmetric Dihydroxylation: An Impressive Gadget for the Synthesis of Natural Products: A Review

“…Owing to its wide medicinal importance, various research groups have reported different routes for its synthesis. Recently, in 2021, Zimdar et al [ 52 ] devised an efficient strategy for the total synthesis of salvinorin. The total synthesis was initiated with the synthesis of lactone via a number of steps resulting in the generation of lactone 60 in 87% yield.…”

A Route to Potent, Selective, and Biased Salvinorin Chemical Space

“…Prior syntheses − and medicinal chemistry campaigns struggled with the configurational lability of C8, which underwent epimerization ( K eq = 2.5) to generate the low potency 8 -epi -SalA under acidic, basic, and thermal conditions . Whereas total syntheses might provide more analogs for property optimization, they have ranged from 16–29 steps (1.3–0.3% yield) − generated no analogs and retained, by definition, the C8 configurational lability of SalA itself . As a result, two syntheses targeted stabilized SalA scaffolds that would not epimerize.…”

A route to potent, selective and biased salvinorin chemical space

“…Prior syntheses [14][15][16][17][18][19][20] and medicinal chemistry campaigns struggled with the configurational lability of C8, which underwent epimerization (Keq = 2.5) to generate the low potency 8-epi-SalA under acidic, basic and thermal conditions. 5 Whereas total syntheses might provide more analogs for property optimization, they have ranged from 16-29 steps (1.3-0.3% yield) [14][15][16][17][18][19][20][21][22] generated no analogs and retained, by definition, the C8 configurational lability of SalA itself. 22 As a result, two syntheses targeted stabilized SalA scaffolds that would not epimerize.…”

“…Prior binding models suggested a hydrogen bond in this region as necessary for high potency; 57 a recent furan-tophenyl replacement retained affinity but lost potency. 24 To probe in-plane hydrogen bonding, we replaced the 3-furyl with strong acceptors 58 like 3-and 4-pyridyl (20)(21), but these led to potency losses (Figure 4C). Instead, 3-thiophenyl (19) and phenyl (25a) led to increased potency, which might have suggested important cation-π or π-π interactions 59 perpendicular to the plane of the electron-rich rings.…”