Chemical syntheses of the salvinorin chemotype of KOR agonist

Abstract

Covering: 2000 to 2020 The hallucinogenic diterpene salvinorin A potently and selectively agonizes the human kappa-opioid receptor (KOR). Its unique attributes-lack of a basic nitrogen, rapid brain penetrance, short half-life-combined with the potential of KOR as an emerging target for analgesics have stimulated extensive medicinal chemistry based on semi-synthesis from extracts of Salvia divinorum. Total synthesis efforts have delivered multiple, orthogonal routes to salvinorin A, its congeners and related analogs with the goal of optimizing its activity towards multiple functional endpoints. Here we review total syntheses of the salvinorin chemotype and discuss outstanding problems that synthesis can address in the future.

Figure 1.

Salvinorin diterpenes and select analogues.

Figure 2.

Rook’s approach to the A-ring of salvinorin A illustrated the difficulty of these substituted building blocks.

Figure 3.

Perlmutter established a remarkably concise 7-step approach to the salvinorin framework.

Figure 4.

Evans’ synthesis featured an unorthodox transannular Michael cascade to access the tricyclic core.

Figure 5.

Hagiwara’s first generation synthesis started from a Wieland-Miescher ketone derivative.

Figure 6.

Hagiwara’s second generation synthesis revised the C-ring synthesis.

Figure 7.

Hagiwara’s extension to salvinorin F, which suffers the same epimerization problem as salvinorin A.

Figure 8.

Forsyth’s synthesis features an intramolecular Diels-Alder reaction to establish the hindered decalin core of SalA

Figure 9.

Metz’s synthesis of SalA featured two intramolecular Diels-Alder reactions to relay stereochemistry from a chiral alcohol

Figure 10.

Prisanzano’s synthesis parlayed the Evans’ tranannular Michael cascade into a short route to a moderately active SalA analog.

Figure 11.

Shenvi’s synthesis of SalA analogs that retain high potency and selectivity at KOR but remove epimerization.

Figure 12.

Choice of dimensions for visualizing movement through a chemical space during total synthesis.

Figure 13.

Syntheses traversing a chemical space: a. information content (Cm) vs. target similarity (Tanimoto), b. oxidation state [O] vs. Cm, c. [O] vs. Tanimoto, d. [O] vs. Cm vs. Tanimoto.

Figure 14.

Scaffold hopping versus scaffold preservation/ alteration to reduce synthetic burden in natural product space.