Practical Synthesis of Valbenazine via 1,3-Dipolar Cycloaddition

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 facile. The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroi-soquinoline (THIQ)-fused piperidine to access key frameworks in the production of medically significant compounds, such as yohimbine and reserpine.