title: Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations.
abstract: An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH(2)Cl(2) at -78 degrees C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94:6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl(2) in CH(2)Cl(2) or CHCl(3) at temperatures of between 20-60 degrees C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99:1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl(2) proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.
authors.affiliation: School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, UK B15 2TT.
authors.forename: Claire A M
authors.initials: CA
authors.lastname: Cariou
authors.forename: Benson M
authors.initials: BM
authors.lastname: Kariuki
authors.forename: John S
authors.initials: JS
authors.lastname: Snaith
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D002255:Carbonic Acid / Q000737:chemistry*; D002384:Catalysis; D003500:Cyclization; D006851:Hydrochloric Acid / Q000737:chemistry; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry; D010875:Pipecolic Acids / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D000588:Amines; D000596:Amino Acids; D009570:Nitriles; D010875:Pipecolic Acids; D010880:Piperidines; D002255:Carbonic Acid; C031345:pipecolic acid; D006851:Hydrochloric Acid