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

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

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

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