Rapid Synthesis of Psychoplastogenic Tropane Alkaloids

A general chemical synthesis method for tropane alkaloids—compounds with a characteristic 8-azabicyclo[3.2.1]octane core—enables late-stage structural diversification at positions N8, C3, C6, and C7, which are important for biological activity. The approach constructs the core via aziridination of a cycloheptadiene intermediate followed by vinyl aziridine rearrangement, yielding six tropane alkaloids and several analogues in 5-7 steps. Testing five tropane-containing compounds in cultured cortical neurons for dendritic spine growth—a marker of structural neuroplasticity—suggests that the orientation of the C3 substituent may influence psychoplastogenic effects. This platform supports future structure-activity relationship studies.

Study at a glance

Abstract

Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous medicinal applications, microbial biosynthesis and a variety of chemical syntheses have been designed for individual family members. However, current approaches are not amenable to late-stage structural diversification at N8, C3, C6, or C7, positions that are critical for modulating the biological properties of these molecules. Here, we describe a general approach to the synthesis of tropane alkaloids and their analogues that relies on the construction of the 8-azabicyclo[3.2.1]octane core through aziridination of a cycloheptadiene intermediate, followed by vinyl aziridine rearrangement. Using this strategy, we synthesized six tropane alkaloids and several analogues in only 5-7 steps. Given that the tropane alkaloid scopolamine has been reported to promote structural neuroplasticity and produce antidepressant effects, we tested five tropane-containing compounds for their ability to promote dendritic spine growth in cultured cortical neurons. We found that the orientation of the C3 substituent may play a role in the psychoplastogenic effects of tropane alkaloids. Our work provides a robust platform for producing tropane analogs for future structure-activity relationship studies.