title: Enzymatic- and iridium-catalyzed asymmetric synthesis of a benzothiazepinylphosphonate bile acid transporter inhibitor.
abstract: 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.
authors.affiliation: GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cowan
authors.forename: Jon L
authors.initials: JL
authors.lastname: Collins
authors.forename: Mark B
authors.initials: MB
authors.lastname: Mitchell
authors.forename: John A
authors.initials: JA
authors.lastname: Ray
authors.forename: Peter W
authors.initials: PW
authors.lastname: Sutton
authors.forename: Amy A
authors.initials: AA
authors.lastname: Sarjeant
authors.forename: Eric E
authors.initials: EE
authors.lastname: Boros
mesh_terms: D000818:Animals; D002384:Catalysis; D018360:Crystallography, X-Ray; D004950:Esterases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007495:Iridium / Q000737:chemistry*; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013552:Swine; D027981:Symporters / Q000037:antagonists & inhibitors*; D013841:Thiazepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D013841:Thiazepines; C071908:sodium-bile acid cotransporter; D007495:Iridium; D004950:Esterases