A Protecting-Group-Free Synthesis of (-)-Salvinorin A

A concise enantioselective total synthesis of the neoclerodane diterpene (-)-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, (-)-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.

Automated summary

A concise and effective total synthesis of (-)-salvinorin A was achieved with high enantioselectivity and diastereoselectivity, using catalytic asymmetric propargylation and substrate-controlled reactions. The synthesis involved intramolecular Diels-Alder reactions and chemoselective Mitsunobu inversion, resulting in a streamlined reaction sequence with only 16 steps and 1.4% total yield. Additionally, an alternative strategy with a 2-bromo-1,3-diene moiety was explored.