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.
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.
Barnes
David M
DM
GPRD Process Research and Development, Abbott Laboratories, Building R8/1, 1401 Sheridan Road, North Chicago, Illinois 60064-6285, USA. david.barnes@abbott.com
Ji
Jianguo
J
Fickes
Michael G
MG
Fitzgerald
Michael A
MA
King
Steven A
SA
Morton
Howard E
HE
Plagge
Frederick A
FA
Preskill
Margo
M
Wagaw
Seble H
SH
Wittenberger
Steven J
SJ
Zhang
Ji
J
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
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