[Studies on the stereochemistry and structure-activity relationship of cholinolytic compounds 3-(2-phenyl-2-cyclopentyl-2-hydroxyl-ethoxy)-quinuclidines].
Four optical isomers of the new cholinolytic compound 3-(2-phenyl-2-cyclopentyl-2-hydroxyl-ethoxy)-quinuclidine (I) have been asymmetrically synthesized by two methods. Method one: Recemic 1-phenyl-1-cyclopentylepoxyethane reacting with 3R or 3S-quinuclidinol produces a mixture of (R-1) and (R-2) or (S-1) and (S-2) respectively. The chemical yields varied from 57% to 78%. The highest % de is 22 and the major product is (R-1) or (S-1). Method two: Grignard reaction of 3R or 3S-benzoyl-methoxy-quinuclidine with cyclopentyl magnesium bromide yields a mixture of (R-1) and (R-2) or (S-1) and (S-2). The chemical yield is 80%. The highest % de is 81 and the major product is (R-2) or (S-2). Preliminary evaluation of the four new optical isomers revealed the following series of biological potencies: (R-2) greater than (I) greater than (S-1) greater than (R-1) greater than (S-2). In the coupling of the compounds with the active centers of M receptors, the absolute configurations in carbon-3 of the quinuclidinyl group and carbon-2 of the substituted ethyl group play an important role. The influence of carbon-2R is greater than that of carbon-3R on cholinolytic potency.
Gao
J H
JH
Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing.
Wen
G L
GL
Zhang
Q K
QK
D000818:Animals; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D006168:Guinea Pigs; D051379:Mice; D010276:Parasympatholytics / Q000138:chemical synthesis*; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003517:Cyclopentanes; D010276:Parasympatholytics; D011812:Quinuclidines; C066419:3-(2'-phenyl-2'-cyclopentyl-2'-hydroxyethoxy)quinuclidine