On the mechanism of an asymmetric alpha,beta-unsaturated carboxylic acid hydrogenation: application to the synthesis of a PGD2 receptor antagonist.
Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2, a prostaglandin D2 (PGD2) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl2]2 (3, S-BINAP = (S)-(+)-2,2'-bis(diphenylphospino)-1,1'-binapthyl), it was discovered that low hydrogen pressures (<30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal-carbon cleavage, while under basic conditions, hydrogenolysis of the metal-carbon bond was predominant.
Tellers
David M
DM
Department of Process Research, Merck and Co. Inc., P.O. Box 2000, Rahway, NJ 07065-0900, USA. david_tellers@merck.com
McWilliams
J Christopher
JC
Humphrey
Guy
G
Journet
Michel
M
DiMichele
Lisa
L
Hinksmon
Joseph
J
McKeown
Arlene E
AE
Rosner
Thorsten
T
Sun
Yongkui
Y
Tillyer
Richard D
RD
D000475:Alkenes / Q000737:chemistry; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003903:Deuterium / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry; D006865:Hydrogenation; D007700:Kinetics; D015394:Molecular Structure; D011312:Pressure; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013696:Temperature
D000475:Alkenes; D002264:Carboxylic Acids; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D006859:Hydrogen; D003903:Deuterium; C036293:prostaglandin D2 receptor