Concise route to the chiral pyrrolidine core of selective inhibitors of neuronal nitric oxide.
2-(((3R,4R)-4-(Allyloxy)-1-benzylpyrrolidin-3-yl)methyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine (2), a key intermediate for the preparation of novel neuronal nitric oxide synthase (nNOS) inhibitors, is synthesized using diisopropyl (R)-(+)-malate as the starting material. The key steps involve a Frater-Seebach diastereoselective alkylation and a fast intramolecular cyclization.
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, USA.
Fengtian
F
Xue
Wenxin
W
Gu
Richard B
RB
Silverman
D000478:Alkylation; D000498:Allyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000498:Allyl Compounds; D004791:Enzyme Inhibitors; D011725:Pyridines; D052248:Nitric Oxide Synthase Type I