Catalytic asymmetric synthesis of an HIV integrase inhibitor.
An efficient synthesis of HIV integrase inhibitor (S)-(-)-1 via a unique asymmetric hydrogenation of a mixture of imines/enamine 5a-5b/5c is described. Hydrogenation of the imines/enamine by a Rh(I)-Josiphos complex afforded 6 in 90% yield and 90% ee. Amide formation completed the synthesis of 1 in 58% overall yield from 2, which is readily available from 3,4-dihydro-2H-pyran in a seven-step sequence. A deuterium labeling study suggests the asymmetric hydrogenation proceeds predominantly via the enamine tautomer.
Zhong
Yong-Li
YL
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
Krska
Shane W
SW
Zhou
Hua
H
Reamer
Robert A
RA
Lee
Jaemoon
J
Sun
Yongkui
Y
Askin
David
D
D000588:Amines / Q000737:chemistry; D002384:Catalysis; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006865:Hydrogenation; D007097:Imines / Q000737:chemistry; D013237:Stereoisomerism
D000588:Amines; D019428:HIV Integrase Inhibitors; D007097:Imines; D019427:HIV Integrase