Valbenazine (Ingrezza), a potent compound that selectively inhibits VMAT2 through an active metabolite HTBZ, has been approved for the treatment of tardive dyskinesia and very recently for chorea associated with Huntington's disease. In this report, a practical synthesis of HTBZ and valbenazine has been achieved, featuring a highly stereoselective 1,3-dipolar cycloaddition and an enzymatic kinetic resolution. The cascade process toward pyrido[2,1-a]isoquinoline including cycloaddition, cleavage of the N—O bond, and lactamization proved to be operationally feasible. The allure of enzymatic resolution developed in this work provides a rapid access to THIQ-fused piperidine in various bioactive substances.

Comprehensive Summary

Valbenazine (Ingrezza), a potent and highly selective inhibitor of vesicular monoamine transporter type 2 (VMAT2) through the active metabolite hydrotetrabenazine (HTBZ), has been approved for the treatment of tardive dyskinesia and, very recently, for chorea, which is associated with Huntington's disease. Despite numerous synthetic efforts dedicated to the synthesis of HTBZ, the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone reduction. Herein, we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3-dipolar cycloaddition and enzymatic kinetic resolution. The cascade process includes cycloaddition, N—O bond cleavage, and lactamization, which proved to be operationally simple. The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline (THIQ)-fused piperidine in the production of medically significant compounds, such as yohimbine and reserpine.