Gram-Scale Total Synthesis of (±)-Ibogamine

Abstract

We describe the gram-scale total synthesis of (±)-ibogamine in nine steps and 24% overall yield. The approach 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.

Figure 1.

Representative Iboga Alkaloids.

Scheme 1.

Synthetic Analysis of Ibogamine

Scheme 2.

Synthesis of Macrocycle (6)^{a a}Reagents and conditions: (a) TBSCl (1.05 equiv), ImH (2.2 equiv), DMF, 0 to 23 °C, 16 h, 96%; (b) EtMgBr (2.50 equiv), THF, 0 to 23 °C, 2h, then 6N HCl (5 equiv), 16h, 85%; (c) 8 (2.0 equiv), 9 (1.0 equiv), PPh3 (1.60 equiv), DIAD (1.60 equiv), 1:1 THF/PhMe, 0 to 23 °C, 16h, 93%; (d) NaBH4 (1.20 equiv), CeCl3•7H2O (1.20 equiv), 1:1 THF/MeOH, 0 to 23 °C, 1h; (e) Ac2O (1.20 equiv), DMAP (1.50 equiv), DCM, 0 to 23 °C, 1h (96%, 2 steps); (f) Mg(ClO4)2 (2.0 equiv), CSA (1.0 equiv), DCM, 23 °C, 4h, 49%.

Scheme 3.

Total Synthesis of (±)-Ibogamine^{a a}Reagents and conditions: (a) BH3•DMS (5.0 equiv), 3N NaOH (30.0 equiv), H2O2 (20.0 equiv), THF, 0 to 23 °C, 2h, (96%); (b) MsCl (4.0 equiv), DMAP (1.0 equiv), pyridine, 23 °C; (c) HSCH2CO2H (4.0 equiv), DBU (8.0 equiv), 8:1 MeCN/DMF 0 to 23 °C, 1h, 77% over 2 steps.