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.