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

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

References and Notes

• 1a Bégué J.-P. Bonnet-Delpon D. In Chimie Bioorganique et Médicinale du Fluor   EDP Sciences and CNRS Editions; Paris: 2005. 
• 1b Bégué J.-P. Bonnet-Delpon D. J. Fluorine Chem.  2006,  127:  992 
• 1c Kirk KL. J. Fluorine Chem.  2006,  127:  1013 
• 1d Isanbor C. O’Hagan D. J. Fluorine Chem.  2006,  127:  303 
• 2a Dolbier WR. J. Fluorine Chem.  2005,  126:  157 
• 2b Schofield H. J. Fluorine Chem.  1999,  100:  7 
• 3a Bariau A. Roblin J.-P. Troin Y. Canet J.-L. Synlett  2005,  1731 
• 3b Bariau A. Jatoi WB. Calinaud P. Troin Y. Canet J.-L. Eur. J. Org. Chem.  2006,  3421 
• For scarce examples of preparation of α-Tfm-piperidines, see:
• 4a Jiang J. DeVita RJ. Doss GA. Goulet MT. Wyvratt MJ. J. Am. Chem. Soc.  1999,  121:  593 
• 4b Crousse B. Bégué J.-P. Bonnet-Delpon D. J. Org. Chem.  2000,  65:  5009 
• 4c Gille S. Ferry A. Billard T. Langlois BR. J. Org. Chem.  2003,  68:  8932 
• 4d Spanedda MV. Ourévitch M. Crousse B. Bégué J.-P. Bonnet-Delpon D. Tetrahedron Lett.  2004,  45:  5023 
• 4e Magueur G. Legros J. Meyer F. Ourévitch M. Crousse B. Bonnet-Delpon D. Eur. J. Org. Chem.  2005,  1258 
• 4f Kim G. Kim J. Tetrahedron Lett.  2005,  46:  423 
• 4g Gheorghe A. Quiclet-Sire B. Vila X. Zard SZ. Tetrahedron  2007,  63:  7187 
• 4h Dobbs AP. Parker PJ. Skidmore J. Tetrahedron Lett.  2008,  49:  827 
• 5 Plenkiewicz H. Dmowski W. Lipinski M. J. Fluorine Chem.  2001,  111:  227 
• 6 Wabnitz TC. Spencer JB. Org. Lett.  2003,  5:  2141 
• 7 Parker D. Chem. Rev.  1991,  91:  1441 
• 8 Huguenot F. Brigaud T. J. Org. Chem.  2006,  71:  2159 
• 9 Higashiyama K. Ishii A. Mikami K. Synlett  1997,  1381 
• 11 For a recent review concerning pipecolic acids and derivatives, see: Kadouri-Puchot C. Comesse S. Amino Acids  2005,  29:  101 
• For a recent review concerning fluorinated amino acids, see:
• 12a Qiu X.-L. Meng W.-D. Qing F.-L. Tetrahedron  2004,  60:  6711 
• 12b See also: Jäckel C. Koksch B. Eur. J. Org. Chem.  2005,  4483 
• For approaches to racemic Tfm-pipecolic acids, see ref. 4h and:
• 13a Kobelkova NM. Osipov SN. Kolomiets AF. Russ. Chem. Bull.  2002,  51:  1298 
• 13b Osipov SN. Artyushin OI. Kolomiets AF. Bruneau C. Picquet M. Dixneuf PH. Eur. J. Org. Chem.  2001,  3891 
• For selective synthesis of fluorine-containing homoprolines, see:
• 13c Golubev AS. Schedel H. Radics G. Sieler J. Burger K. Tetrahedron Lett.  2001,  42:  7941 
• 13d Golubev AS. Schedel H. Radics G. Fiorini M. Thust S. Burger K. Tetrahedron Lett.  2004,  45:  1445 
• For 4-oxo-pipecolic acid, see:
• 14a

  Ref. 11.

• 14b Partogyan-Halim K. Besson L. Aitken DJ. Husson HP. Eur. J. Org. Chem.  2003,  268 ; and references cited therein
• For 4-hydroxy-pipecolic acid, see ref. 11 and:
• 15a Cordero FM. Bonollo S. Machetti F. Brandi A. Eur. J. Org. Chem.  2006,  3235 ; and references cited therein
• 15b Occhiato EG. Scarpi D. Guarna A. Eur. J. Org. Chem.  2008,  524 ; and references cited therein
• 16 Huang H. Iwasawa N. Mukaiyama T. Chem. Lett.  1984,  1465 
• 17 Ates A. Gautier A. Leroy B. Plancher J.-M. Quesnel Y. Markò IE. Tetrahedron Lett.  1999,  40:  1799 

10

R-(+)-1, [α]_D ²⁵ 16.0 (c 1.30, CHCl₃); S-(-)-1, [α]_D ²⁵ -16.5 (c 1.15, CHCl₃).

18

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.