Asymmetric Synthesis of (Trifluoromethyl)piperidines: Preparation of Highly Enantioenriched α′-(Trifluoromethyl)pipecolic Acids

Wahid B. Jatoi; Annabelle Bariau; Cécile Esparcieux; Gilles Figueredo; Yves Troin; Jean-Louis Canet

doi:10.1055/s-2008-1072768

LETTER

Asymmetric Synthesis of (Trifluoromethyl)piperidines: Preparation of Highly Enantioenriched α′-(Trifluoromethyl)pipecolic Acids

Wahid B. Jatoi, Annabelle Bariau, Cécile Esparcieux, Gilles Figueredo, Yves Troin, Jean-Louis Canet*
Laboratoire de Chimie des Hétérocycles et des Glucides, EA 987, Ecole Nationale Supérieure de Chimie de Clermont-Ferrand, Université Blaise Pascal, BP 187, 63174 Aubière Cedex, France
Fax: +33(4)73407008; e-Mail: j-louis.canet@univ-bpclermont.fr;

Abstract

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Abstract

The first asymmetric synthesis of (trifluoromethyl)pipecolic acids is reported. The synthetic strategy involves as key step an intramolecular Mannich reaction of a homochiral α-Tfm-β-amino ketal, prepared with a high stereoselectively in four steps from a fluoral hemiacetal.

Key words

fluorine - piperidines - cyclic amino acids - stereoselectivity - intramolecular Mannich reaction

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References

References and Notes

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Selected Data for Compounds 20, 22, and 23
(-)-(2 S ,6 R )-6-Trifluoromethyl-pipecolic Acid (20)
White solid; mp 118 °C; [α]_D ²⁵ -11.2 (c 1.00, MeOH). ¹H NMR (400 MHz, D₂O): δ = 3.61 (m, 1 H), 3.37 (dd, J = 12, 3 Hz, 1 H), 2.11 (m, 1 H), 2.06-1.95 (m, 2 H), 1.65-1.37 (m, 3 H). ¹³C NMR (100 MHz, D₂O): δ = 177.2, 124.6 (q, J _CF = 277 Hz), 60.3, 56.7 (q, J _CF = 30 Hz), 27.4, 22.5, 22.0. ¹⁹F NMR (376 MHz, CD₃OD): δ = -78.0. HRMS: m/z calcd for C₇H₁₁F₃NO₂ [M + H⁺]: 198.0742; found: 198.0724.
(-)-(2 S ,6 R )-4,4-Dihydroxy-6-trifluoromethyl-pipecolic Acid (22)
White solid; mp 95 °C; [α]_D ²⁵ -2.1 (c 1.00, MeOH). ¹H NMR (400 MHz, D₂O): δ = 4.34 (m, 1 H), 4.23 (dd, J = 13.0, 3.5 Hz, 1 H), 2.53 (dt, J = 14.0, 3.5 Hz, 1 H), 2.37 (dt, J = 14.0, 3.0 Hz, 1 H), 2.08 (t, J = 13.5 Hz, 2 H). ¹³C NMR (100 MHz, D₂O): δ = 169.5, 122.6 (q, J _CF = 279 Hz), 90.4, 56.1, 54.6 (q, J _CF = 33 Hz), 36.8, 33.2. ¹⁹F NMR (376 MHz, CD₃OD): δ = -75.1. HRMS: m/z calcd for C₇H₉NO₃F₃ [(M - H₂O) + H⁺]: 212.0535; found: 212.0545.
(-)-(2 S ,4 S ,6 R )-4-Hydroxy-6-trifluoromethyl-pipecolic Acid (23)
White solid; mp 145 °C; [α]_D ²⁵ -9.3 (c 0.95, MeOH). ¹H NMR (400 MHz, D₂O): δ = 3.92 (tt, J = 11.5, 4.5 Hz, 1 H), 3.62 (m, 2 H), 3.40 (dd, J = 12.5, 3.0 Hz, 1 H), 2.37 (m, 1 H), 2.26 (m, 1 H), 1.44 (q, J = 12.0 Hz, 1 H), 1.38 (td, J = 12.5, 11.0 Hz, 1 H). ¹³C NMR (100 MHz, D₂O): δ = 176.6, 124.4 (q, J _CF = 277 Hz), 66.3, 58.3, 54.9 (q, J _CF = 30 Hz), 36.2, 31.3. ¹⁹F NMR (376 MHz, CD₃OD): δ = -77.8. HRMS: m/z calcd for C₇H₁₁F₃NO₃ [M + H⁺]: 214.0691; found: 214.0700.