title: Development of a catalytic enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes for the synthesis of endothelin-A antagonist ABT-546. Scope, mechanism, and further application to the synthesis of the antidepressant rolipram.
abstract: The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol % bis(oxazoline)-Mg(OTf)(2) complex with an amine cocatalyst, we obtained the product nitroketone with 88% selectivity at the aryl-bearing stereocenter and in good yield on scales ranging to 13 mol. The effects of ligand structure, metal salt, and solvent on the reaction are described. Particularly important to the reaction is the water content. While water is necessary during the generation of the catalyst, the water must be then removed to maximize stereoselectivity and reactivity. The reaction has been extended to other dicarbonyl substrates, and a variety of substitution patterns are tolerated on the nitroolefin partner. The reaction has also been employed in the synthesis of the antidepressant rolipram. Investigations relating to the mechanism of the reaction are also described.
authors.affiliation: GPRD Process Research and Development, Abbott Laboratories, Building R8/1, 1401 Sheridan Road, North Chicago, Illinois 60064-6285, USA. david.barnes@abbott.com
authors.forename: David M
authors.initials: DM
authors.lastname: Barnes
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fickes
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fitzgerald
authors.forename: Steven A
authors.initials: SA
authors.lastname: King
authors.forename: Howard E
authors.initials: HE
authors.lastname: Morton
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Plagge
authors.forename: Margo
authors.initials: M
authors.lastname: Preskill
authors.forename: Seble H
authors.initials: SH
authors.lastname: Wagaw
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Wittenberger
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000928:Antidepressive Agents / Q000138:chemical synthesis; D002384:Catalysis; D065128:Endothelin Receptor Antagonists; D009574:Nitro Compounds / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis*; D044022:Receptor, Endothelin A; D020889:Rolipram / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013343:Styrenes / Q000737:chemistry
chemical_list: C467892:ABT 546; D000475:Alkenes; D000928:Antidepressive Agents; D065128:Endothelin Receptor Antagonists; D009574:Nitro Compounds; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D013343:Styrenes; D020889:Rolipram