A Scalable Synthesis of an Azabicyclooctanyl Derivative, a Novel DPP-4 Inhibitor

• Published in: Journal of organic chemistry Vol. 73; no. 22; pp. 9016 - 9021
• Main Authors: Fei, Zhongbo, Wu, Quanbing, Zhang, Fei, Cao, Yudong, Liu, Chuanqin, Shieh, Wen-Chung, Xue, Song, McKenna, Joe, Prasad, Kapa, Prashad, Mahavir, Baeschlin, Daniel, Namoto, Kenji
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.11.2008; Amer Chemical Soc
• Subjects: Aldehydes - chemistry; Azabicyclo Compounds - chemical synthesis; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - pharmacology; Butanes - chemistry; Chemistry; Chemistry, Organic; Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Imines - chemistry; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; Sulfonium Compounds - chemistry; AMINES; TERT-BUTANESULFINYL IMINES; ASYMMETRIC-SYNTHESIS; Chemical rearrangement; Corey-Chaykovsky reaction; Enzyme; Nitrogen heterocycle; Sulfinamide; Enzyme inhibitor; Steric hindrance; Chiral compound; Dipeptidyl-peptidase II; Diastereoselectivity; Peptidases; Grignard reagent; Amine; Benzylic compound; Hydrolases; Carboxamide; Chemical synthesis; Nucleophile
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo801830x

A practical synthetic strategy to a chiral azabicycclooctanyl derivative (1), a potent DPP-4 inhibitor, starting from a commercially available nortropine is described. The stereogenic center of 1 was established employing a modified protocol of Ellman’s diastereoselective addition of a benzylic nucleophile to tert-butanesulfinimine. Other key steps include Corey−Chaykovsky reaction, Meinwald rearrangement, and CDMT-promoted amide bond formation involving a sterically hindered amine 2.