Directed Biosynthesis of Mitragynine Stereoisomers

Abstract

Mitragyna speciosa (Kratom) is used as a natural remedy for pain and management of opioid dependence. The pharmacological properties of Kratom have been linked to a complex mixture of monoterpene indole alkaloids, most notably mitragynine. Here, we report the central biosynthetic steps responsible for the scaffold formation of mitragynine and related corynanthe-type alkaloids. We illuminate the mechanistic basis by which the key stereogenic centre of this scaffold is formed. These discoveries were leveraged for the enzymatic production of mitragynine, the C-20 epimer speciogynine, and a series of fluorinated analogues.

Syntheses and structural plasticity of kratom pseudoindoxyl metabolites

“…24 Finally, we believed that our secologanin analog could further broaden the synthetic landscape, as it could provide access to both diastereomeric kratom pseudoindoxyls of the corynanthe-type, allo (mitragynine) and normal (speciogynine) isomers, by selective hydrogenation of its olefinic bond. 25,26 As such, this synthetic study was designed to mimic the manner through which nature assembles mitragynine pseudoindoxyl (3), including rapid complexity generation via cascade reactions of tryptamine and secologanin analogs, step-and redox economy, divergency and protecting group-free assembly. 27 Herein, we report the first total synthesis of mitragynine pseudoindoxyl (3) and its diastereomer, speciogynine pseudoindoxyl (4).…”