title: Stereoselective synthesis of cis-3,4-disubstituted piperidines through ring transformation of 2-(2-mesyloxyethyl)azetidines.
abstract: The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding β-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation of a variety of new 4-acetoxy-, 4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone to undergo an S(N)2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines, providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid hydrolysis.
authors.affiliation: Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Mollet
authors.forename: Saron
authors.initials: S
authors.lastname: Catak
authors.forename: Michel
authors.initials: M
authors.lastname: Waroquier
authors.forename: Veronique
authors.initials: V
authors.lastname: Van Speybroeck
authors.forename: Matthias
authors.initials: M
authors.lastname: D'hooghe
authors.forename: Norbert
authors.initials: N
authors.lastname: De Kimpe
mesh_terms: D001372:Aza Compounds; D001384:Azetidines / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D054879:Halogenation; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008698:Mesylates / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis*; D013237:Stereoisomerism; D047090:beta-Lactams / Q000737:chemistry*
chemical_list: D001372:Aza Compounds; D001384:Azetidines; D008698:Mesylates; D010880:Piperidines; D047090:beta-Lactams