Enantioselective Synthesis of Pyrrolidine- and Piperidinecarboxylic Acids
FULL PAPERS
1-(4-Toluenesulfonyl)-piperidine-4-carboxylic acid amide
(2b-Ts): White solid, mp 212–2158C partial decomposition;
1H NMR (DMSO-d6): d=1.47–1.55 (m, 2H), 1.71–1.75 (dd,
2H, J=2.7, 13.4 Hz), 1.98–2.03 (tt, 1H, J=3.8, 10.9 Hz),
2.20–2.25 (dt, 2H, J=2.4, 11.7 Hz), 2.39 (s, 3H), 3.51 (m,
2H, dublet-like, J=12.2 Hz), 6.79 (s, br., 1H, NH2), 7.17 (s,
br., 1H, NH2), 7.42 (d, 2H, J=8.1 Hz), 7.59 (d, 2H, J=
8.1 Hz); 13C NMR (DMSO-d6): d=21.70 , 28.31, 46.09,
128.17, 130.50, 133.13, 144.17, 176.19; MS (EI): m/z=264
(5), 199 (1), 155 (21), 127 (31), 109 (100), 91 (95), 82 (56), 65
(31).
128.11, 130.14, 133.50, 144.84; MS (EI): m/z=264 [M+] (2),
212 (100), 155 (70), 91 (69). Chiral separation on Chiralcel
OD-H, n-heptane/2-propanol 1:1, 0.38 mLminÀ1, 208C.
(Æ)-1-(4-Toluenesulfonyl)-piperidine-2-carboxylic
acid
amide (4b-Ts): White solid, mp 126–1368C under decompo-
1
sition; H NMR (DMSO-d6): d=1.11 (m, 1H), 1.18–1.33 (m,
2H), 1.41 (m, 2H), 1.89 (d, 1H, J=12.7 Hz), 2.36 (s, 3H),
3.30–3.37 (m, 1H), 3.63 (d, 1H, J=12.2 Hz), 4.38 (d, 1H,
J=4.4 Hz), 7.08 (s, br., 1H, CONH2), 7.28 (s, br., 1H,
CONH2), 7.35 (d, 2H, J=8.3 Hz), 7.64 (d, 2H, J=8.3 Hz);
13C NMR (DMSO-d6): d=19.88, 21.45, 24.38, 27.60, 43.19,
55.11, 127.51, 130.32, 138.07, 143.52, 172.53; MS (EI): m/z=
238 (81), 155 (66), 126 (15), 91 (100); anal. calcd. for
C13H18N2O3S: C 55.30, H 6.43, N 9.92; found: C 54.61, H
6.35, N 9.76.
1-(4-Toluenesulfonyl)-piperidine-4-carboxylic acid (2c-Ts):
White solid, mp 169–1718C (partial decomposition); yield:
54 mg (85% at 86% conversion) from 59 mg (2.24 mM) of
1
2a-Ts with NIT-108 (1.42 g/L); H NMR (CDCl3): d=1.77–
(Æ)-1-(4-Toluenesulfonyl)-piperidine-2-carboxylic
acid
1.85 (m, 2H), 1.97–2.00 (m, 2H), 2.09 (m, 1H), 2.25–2.30
(m, 1H), 2.43 (s, 3H), 2.41–2.46 (m, 1H), 3.63–3.66 (m, 2H),
7.31 (d, 2H, J=8.3 Hz), 7.63 (d, 2H, J=8.3 Hz), 9.32 (s, br.,
1H, COOH); 13C NMR (CDCl3): d=21.78, 27.41, 40.02,
45.59, 127.91, 129.95, 133.18, 143.92, 180.11; MS (EI): m/z=
266 (1), 238 (1), 155 (7), 142 (96), 91 (43), 82 (100); anal.
calcd. for C13H17NO4S: C 55.11, H 6.06, N 4.94; found: C
54.98, H 6.06, N 4.85.
(4c-Ts): White solid, mp 101–1028C; chemical hydrolysis,
1
yield: 20%; H NMR (CDCl3): d=1.30–1.47 (m, 2H), 1.60–
1.75 (m, 3H), 2.15 (m, 1H), 2.41 (s, 3H), 3.20 (dt, 1H, J=
2.4, 12.7 Hz), 3.73 (d, 1H, J=12.7 Hz), 4.76 (d, 1H, J=
5.3 Hz), 7.26 (d, 2H, J=7.8 Hz), 7.68 (d, 2H, J=7.8 Hz),
8.70 (s, br., 1H, COOH); 13C NMR (CDCl3): d=21.04,
21.75, 24.69, 27.73, 42.77, 55.08, 127.40, 129.72, 137.17,
143.57, 176.95; MS (EI): m/z=283 [M+] (0.02), 238 (100),
155 (17), 91 (26).
(Æ)-1-(4-Toluenesulfonyl)-piperidine-3-carbonitrile
(3a-
Ts): White solid, mp 130–1318C; 1H NMR (CDCl3): d=
1.59–1.70 (m, 2H), 1.84–1.86 (m, 1H), 1.95–1.99 (m, 1H),
2.45 (s, 3H), 2.64 (t, 1H, J=9.5 Hz), 2.81 (m, 2H), 3.4–3.42
(m, 1H), 3.65 (d, 1H, J=8.8 Hz), 7.35 (d, 2H, J=8.2 Hz),
7.65 (d, 2H, J=8.2 Hz); 13C NMR (CDCl3): d=21.81, 23.40,
27.50, 27.62, 46.11, 47.97, 119.62, 127.88, 130.15, 133.18,
144.40; MS (EI): m/z=264 [M+] (42), 198 (12), 155 (34), 109
(100), 91 (72); anal. calcd. for C13H16N2O2S: C 59.07; H 6.10;
N 10.60. Found: C 58.34; H 6.04; N 10.54; Chiral separation
on Chiralpak ADH, n-heptane/2-propanol 1:1, 0.5 mLminÀ1,
208C.
References
[1] For the incorporation of b-proline in bioactive com-
pounds consult references in: a) C. Thomas, F. Oercher,
P. Gmeiner, Synthesis 1998, 1491–1496; b) A. Dermata-
kis, K.-C. Luk, W. DePinto, Bioorg. Med. Chem. 2003,
11, 1873–1881.
[2] For the incorporation of pipecolic acid in bioactive
compounds see: a) S. Nazabadioko, R. J. PØrez, R.
Brieva, V. Gotor, Tetrahedron: Asymmetry 1998, 9,
1597–1604, and references cited therein; b) E. Eich-
horn, J.-P. Roduit, N. Shaw, K. Heinzmann, A. Kiener,
Tetrahedron: Asymmetry 1997, 8, 2533–2536, and refer-
ences cited therein; c) G. J. Gatto, Jr., M. T. Boyne, II,
N. L. Kelleher, C. T. Walsh, J. Am. Chem. Soc. 2006,
128, 3838–3847; d) J. F. Berrien, J. Royer, H. P.
Husson, J. Org. Chem. 1994, 59, 3769–3774.
[3] For nipecotic and isonipecotic acids as GABA agonists
and GABA uptake inhibitors see: a) K. E. Andersen,
J. L. Sørensen, J. Lau, B. F. Lundt, H. Petersen, P. O.
Huusfeldt, P. D. Suzdak, M. D. B. Swedberg, J. Med.
Chem. 2001, 44, 2152–2163; b) L. Nielsen, L. Brehm, P.
Krogsgaard-Larsen, J. Med. Chem. 1990, 33, 71–77;
c) B. Frølund, U. Kristiansen, L. Brehm, A. B. Hansen,
P. Krogsgaard-Larsen, E. Falch, J. Med. Chem. 1995,
38, 3287–3296.
1-(Toluene-4-sulfonyl)-piperidine-3-carboxylic acid (3c-
Ts): White solid, mp 135–1388C; yield 38 mg (40% at 50%
conversion; ee=93%) from 101 mg (0.382 mM) of (Æ)-3a-
1
Ts with NIT-107 (0.29 g/L); H NMR (CDCl3): d=1.36–1.44
(m, 1H), 1.62–1.69 (m, 1H), 1.79–1.82 (m, 1H), 1.98–2.01
(m, 1H), 2.36 (t, 1H, J=10.2 Hz), 2.43 (s, 3H), 2.52 (t, 1H,
J=10.7 Hz), 2.66 (m, 1H), 3.58 (d, 1H, J=11.7 Hz), 3.81 (d,
1H, J=11.2 Hz), 7.33 (d, 2H, J=7.8 Hz), 7.64 (d, 2H, J=
7.8 Hz), 9.30 (s, br., 1H, COOH); 13C NMR (CDCl3): d=
21.79, 24.11, 26.47, 40.97, 46.48, 47.60, 127.91, 130.00, 133.15,
143.98, 178.87; MS (EI): m/z=283[M+] (0.2), 238 (100), 155
(20), 128 (5), 91 (32).
2-Cyano-piperidine-1-carboxylic acid benzyl ester (4a-
Cbo): Colorless oil; 1H NMR (CDCl3): d=1.46 (m, 1H),
1.73 (m, 3H), 1.84 (m, 1H), 1.95 (m, 1H), 3.04 (m, 1H),
4.13 (m, 1H), 5.16 (s, 2H), 5.30 (m, 1H), 7.29–7.50 (m, 5H);
13C NMR (CDCl3): d=20.47, 24.74, 28.68, 41.96, 44.55,
68.33, 117.71, 128.37, 128.64, 128.87, 136.04; MS (EI): m/z=
244[M+] (4), 153 (9), 128 (11), 109 (12), 91 (100); anal. calcd
for C14H16N2O2: C 68.83, H 6.60, N 11.47; found: C 68.66, H
6.58, N 10.99.
[4] For representative examples see: a) P. D. Bailey, P. A.
Millwood, P. Smith, Chem. Commun. 1998, 633–640,
ˇ
and references cited therein; b) A. Stoncius, M. Nahr-
(Æ)-1-(4-Toluenesulfonyl)-piperidine-2-carbonitrile
(4a-
wold, N. Sewald, Synthesis 2005, 11, 1829–1837; c) P.
Gmeiner, F. Oercher, C. Thomas, K. Weber, Tetrahe-
dron Lett. 1995, 36, 381–382; d) H. Zang, M. Mifsud, F.
Tanaka, C. F. Barbas, III, J. Am. Chem. Soc. 2006, 128,
9630–9631; e) A. Lei, M. Chen, M. He, X. Zhang,
Eur. J. Org. Chem. 2006, 4343–4347; f) J. F. Berrien, J.
Ts): White solid, mp 121–1228C; 1H NMR (CDCl3): d=
1.54–1.68 (m, 2H), 1.80 (m, 2H), 1.87–1.98 (m, 2H), 2.44 (s,
3H), 2.67 (m, 1H), 3.84 (d, 1H, J=11.7 Hz), 4.98 (s, 1H),
7.36 (d, 2H, J=8.2 Hz), 7.70 (d, 2H, J=8.2 Hz); 13C NMR
(CDCl3): d=19.95, 21.90, 24.70, 29.65, 43.38, 46.02, 115.46,
Adv. Synth. Catal. 2007, 349, 1475 – 1480
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