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Enantioselective Synthesis and Physicochemical Properties of Libraries of 3‐Amino‐ and 3‐Amidofluoropiperidines |
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| Authors: | Dr Aurélie Orliac Dr Julie Routier Dr Fabienne Burgat?Charvillon Dr Wolfgang H B Sauer Dr Agnes Bombrun Dr Santosh S Kulkarni Dr Domingo Gomez?Pardo Prof Janine Cossy |
| Affiliation: | 1. Laboratoire de Chimie Organique, ESPCI ParisTech, 10 Rue Vauquelin, 75231 Paris Cedex 05 (France), Fax: (+33)?1‐40‐79‐46‐60;2. Merck Serono S.A. Geneva, 9 Chemin des mines 1202 Geneva (Switzerland);3. Syngene International Ltd, Plot Nos.?2 and 3, Bommasandra IV Phase, Jigani Link Road, Bangalore, 560 100 (India) |
| 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. |
| Keywords: | basicity enantioselectivity fluorine lipophilicity stereoelectronic effects |
