title: Stereoselective preparation of a cyclopentane-based NK1 receptor antagonist bearing an unsymmetrically substituted sec-sec ether.
abstract: A highly efficient synthesis of the potent and selective NK-1 receptor antagonist 1 is described. The key transformation involved the etherification reaction between cyclopentanol 12 and chiral imidate 30 which was catalyzed by HBF4 to initially give ether 14 as a 17:1 mixture of diastereomers and in 75% combined yield. The diastereoselectivity was upgraded to 109:1 by crystallization of the triethylamine solvate 44 which was isolated in 54% yield from 12. Mechanistic studies confirmed that the etherification reaction proceeds through an unprecedented S(N)2 reaction pathway under typical S(N)1 reaction conditions.
authors.affiliation: Department of Process Research, Merck and Company, Incorporated, P.O. Box 2000, Rahway, New Jersey 07065, USA. Jeffrey_Kuethe@Merck.com
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kuethe
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Marcoux
authors.forename: Audrey
authors.initials: A
authors.lastname: Wong
authors.forename: Jimmy
authors.initials: J
authors.lastname: Wu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hillier
authors.forename: Peter G
authors.initials: PG
authors.lastname: Dormer
authors.forename: Ian W
authors.initials: IW
authors.lastname: Davies
authors.forename: David L
authors.initials: DL
authors.lastname: Hughes
mesh_terms: D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D004987:Ethers; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists
chemical_list: D003517:Cyclopentanes; D004987:Ethers; D064729:Neurokinin-1 Receptor Antagonists