title: Enantioselective synthesis and physicochemical properties of libraries of 3-amino- and 3-amidofluoropiperidines.
abstract: The enantioselective syntheses of 3-amino-5-fluoropiperidines and 3-amino-5,5-difluoropiperidines were developed using the ring enlargement of prolinols to access libraries of 3-amino- and 3-amidofluoropiperidines. The study of the physicochemical properties revealed that fluorine atom(s) decrease(s) the pKa and modulate(s) the lipophilicity of 3-aminopiperidines. The relative stereochemistry of the fluorine atoms with the amino groups at C3 on the piperidine core has a small effect on the pKa due to conformationnal modifications induced by fluorine atom(s). In the protonated forms, the C-F bond is in an axial position due to a dipole-dipole interaction between the N-H(+) and C-F bonds. Predictions of the physicochemical properties using common software appeared to be limited to determine correct values of pKa and/or differences of pKa between cis- and trans-3-amino-5-fluoropiperidines.
authors: Laboratoire de Chimie Organique, ESPCI ParisTech, 10 Rue Vauquelin, 75231 Paris Cedex 05 (France), Fax: (+33) 1-40-79-46-60.
authors: Aurélie
authors: A
authors: Orliac
authors: Julie
authors: J
authors: Routier
authors: Fabienne Burgat
authors: FB
authors: Charvillon
authors: Wolfgang H B
authors: WH
authors: Sauer
authors: Agnes
authors: A
authors: Bombrun
authors: Santosh S
authors: SS
authors: Kulkarni
authors: Domingo Gomez
authors: DG
authors: Pardo
authors: Janine
authors: J
authors: Cossy
mesh_terms: D020650:Combinatorial Chemistry Techniques; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D006845:Hydrocarbons, Fluorinated; D010880:Piperidines
keywords: basicity; enantioselectivity; fluorine; lipophilicity; stereoelectronic effects