Stereoselective synthesis of constrained azacyclic hydroxyethylene isosteres as aspartic protease inhibitors: dipolar cycloaddition and related methodologies toward branched pyrrolidine and pyrrolidinone carboxylic acids.
The synthesis of three vicinally substituted azacyclic carboxylic acids in enantiopure form was achieved from a common alpha-amino aldehyde originating from l-leucine. Pyrrolidines and pyrrolidinones were elaborated from alpha,beta-unsaturated gamma-hydroxy-delta-amino acids via azomethine ylide 1,3-dipolar addition and conjugate addition/cyclization strategies, respectively. The azacyclic amino acids were incorporated in a pseudopeptide now encompassing a hydroxyethylene isostere. Low nanomolar inhibition of BACE1, an enzyme implicated in the cascade of events leading to plaque formation in Alzheimer's disease, was found with a pyrrolidinone analogue.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, P. Q., Canada H3C 3J7. stephen.hanessian@umontreal.ca
Yun
Hongying
H
Hou
Yihua
Y
Tintelnot-Blomley
Marina
M
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002264:Carboxylic Acids / Q000737:chemistry*; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D011759:Pyrrolidines / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013237:Stereoisomerism
D002264:Carboxylic Acids; D011480:Protease Inhibitors; D011759:Pyrrolidines; D011760:Pyrrolidinones; D016282:Aspartic Acid Endopeptidases; C032519:pyrrolidine