Total Syntheses of Ibogamine, Tabernanthine, Ervaoffine J, and Ervaoffine K

Abstract

The roots of the central African iboga shrub (Tabernanthe iboga) induce a hallucinogenic response that has been used for centuries in the Bwiti religion in West Central Africa. The alkaloids contained in this root are commonly referred to as iboga alkaloids and over one hundred unique structures have been isolated. Their distinctive structure and psychotropic properties have captured the eyes of chemists for the last fifty years. Most notably, the ability of these compounds to weaken the abuse of controlled substances (such as alcohol and morphine) has garnered considerable attention despite a vague molecular understanding. Herein, we describe the gram scale total synthesis of (±) – ibogamine in nine steps and 24% overall yield. This route features a Mitsunobu fragment coupling and macrocyclic Friedel–Crafts alkylation to establish the nitrogen-containing core of ibogamine. A regio- and diastereoselective hydroboration allows for simultaneous formation of the tetrahydroazepine and isoquinuclidine ring systems via sulfonamide deprotection and concomitant intramolecular cyclization. This robust synthesis of ibogamine enabled the completion of thirteen ibogamine analogs including (±) – tabernanthine. These compounds are currently being evaluated for biological activity. In addition to analog synthesis, we leveraged our synthesis of ibogamine to access Ervaoffine J and Ervaoffine K from a central intermediate. Ervaoffine J was synthesized in eight steps in 14% yield. Our strategy features an aerobic Winterfeldt oxidation to introduce the 4-quinolone moiety. Ervaoffine K was produced in ten steps and 10% yield. The synthesis leveraged (bromodifluoromethyl)-trimethylsilane to induce a regioselective von Braun-type C-N bond fragmentation. This C-N bond cleavage unveiled the tetrasubstituted all-syn cyclohexane core of ervaoffine K and enabled the completion of its synthesis.