Enzymatic- and Iridium-Catalyzed Asymmetric Synthesis of a Benzo­thiazepinyl­phos­phonate Bile Acid Transporter Inhibitor

A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)­norleucinate (4) with porcine liver esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which was used for construction of the benzo­thiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11, enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydro­benzo­thiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir­(COD)2BArF] (26) and Taniaphos ligand P afforded the (3R,5R)-tetra­hydro­benzo­thiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield.