Asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes as key components of substance p antagonists.
An efficient asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes is described. Three methods were developed for the preparation of the 2,3-disubstituted cyclopentenones and cyclohexenones, which are key achiral building blocks. These intermediates are reduced catalytically with (R)-2-methyloxazaborolidine in high yield (82-98%) and excellent ee (89-96%). Directed reduction of the chiral allylic alcohols using Red-Al gives exclusively the 1,2-anti stereochemistry (>99:1). Epimerization of the ester center followed by saponification/crystallization affords the desired hydroxyacids in good yield (65-70%) and in high enantiomeric excess (>99%).
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, USA. Jeffrey_Kuethe@merke.com
Jeffrey T
JT
Kuethe
Audrey
A
Wong
Jimmy
J
Wu
Ian W
IW
Davies
Peter G
PG
Dormer
Christopher J
CJ
Welch
Michael C
MC
Hillier
David L
DL
Hughes
Paul J
PJ
Reider
D002384:Catalysis; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003510:Cyclohexanes / Q000138:chemical synthesis*; D003517:Cyclopentanes / Q000138:chemical synthesis*; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism; D013373:Substance P / Q000037:antagonists & inhibitors*
D003510:Cyclohexanes; D003517:Cyclopentanes; D013373:Substance P