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Enantioselective Synthesis and Physicochemical Properties of Libraries of 3‐Amino‐ and 3‐Amidofluoropiperidines
Author(s) -
Orliac Aurélie,
Routier Julie,
Burgat Charvillon Fabienne,
Sauer Wolfgang H. B.,
Bombrun Agnes,
Kulkarni Santosh S.,
Gomez Pardo Domingo,
Cossy Janine
Publication year - 2014
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201302423
Subject(s) - enantioselective synthesis , piperidine , chemistry , lipophilicity , fluorine , protonation , amino acid , stereochemistry , atom (system on chip) , ring (chemistry) , ring size , organic chemistry , catalysis , ion , biochemistry , embedded system , computer science
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 p K a 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 p K a due to conformationnal modifications induced by fluorine atom(s). In the protonated forms, the CF bond is in an axial position due to a dipole–dipole interaction between the N−H + and CF bonds. Predictions of the physicochemical properties using common software appeared to be limited to determine correct values of p K a and/or differences of p K a between cis‐ and trans‐ 3‐amino‐5‐fluoropiperidines.