PAPER
Novel Trifluoromethylated Amino Acids
907
give a brown oil; yield: 28.5 g (0.110 mol, quant); purity ~90%. The
product was used in the next step without further purification.
1H NMR (500 MHz, CDCl3): d (isomeric mixture) = 2.33–2.63 [m,
4 H, (CH2)2], 2.94–3.20 [m, 5 H, (CH2)2, CH], 3.71 (s, 3 H, CH3),
4.40–4.41 (2 s, 2 H, PhCH2, E + Z), 7.21–7.42 (m, 5 H, C6H5).
(2) (a) Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais,
S.; Duong, L. T.; Falgueyret, J.-P.; Kimmel, D. B.;
Lamontagne, S.; Léger, S.; LeRiche, T.; Li, C. S.; Massé, F.;
McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer,
J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan,
G. A.; Rodan, S. B.; Seto, C.; Thérien, M.; Truong, V.-L.;
Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.;
Black, W. C. Bioorg. Med. Chem. Lett. 2008, 18, 923.
(b) Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.;
Falgueyret, J.-P.; Léger, S.; Li, C. S.; Massé, F.; McKay, D.
J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.;
Zamboni, R. Bioorg. Med. Chem. Lett. 2005, 15, 4741.
(3) For reviews on applications of the trifluoroethyl group in
biochemistry, see: (a) Bravo, P.; Bruche, L.; Pesenti, C.;
Viani, F.; Volonterio, A.; Zanda, M. J. Fluorine Chem.
2001, 112, 153. (b) Zanda, M. New J. Chem. 2004, 28,
1401. (c) Sani, M.; Volonterio, A.; Zanda, M.
Methyl 6-(Benzylamino)-6-(trifluoromethyl)spiro[3.3]heptane-
2-carboxylate (11)
TFA (10.9 mL, 0.143 mol) was added to a mixture of imine 9 (28.5
g, 0.110 mol) and NaHF2 (5.5 g, 0.088 mol) in MeCN (300 mL) and
DMF (25 mL, 0.33 mol) at 0 °C, and the suspension was stirred for
5 min. TMSCF3 (23.5 g, 0.165 mol) was added and the mixture was
stirred at r.t. for 12 h then sat. aq Na2CO3 (50 mL) was added and
the mixture was stirred for a further 5 min. The mixture was diluted
with H2O (500 mL) and extracted with EtOAc (3 × 300 mL). The
combined organic phases were washed with H2O and brine, dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by flash column chromatography [hexane–EtOAc
(3:1)] to give a colorless oil; yield: 17.0 g (0.052 mol, 47%);
Rf = 0.3.
1H NMR (500 MHz, CDCl3): d = 1.58 (br s, 1 H, NH), 2.08 (d,
J = 12.0 Hz, 1 H), 2.14 (d, J = 12.5 Hz, 1 H), 2.27–2.50 (m, 6 H),
3.06 (quin, J = 8.5 Hz, 1 H, CH), 3.70 (s, 3 H, CH3), 3.81 (s, 2 H,
PhCH2), 7.25–7.41 (m, 5 H, C6H5).
13C NMR (125 MHz, CDCl3): d = 32.86 (s), 33.54 (s), 37.81 (s),
39.34 (s), 39.59 (s), 40.17 (s), 47.33 (s), 51.66 (s, CH3), 56.75 [q,
2J(C,F) = 28.9 Hz, CCF3], 127.06 (s, CH, Ph), 127.09 [q,
1J(C,F) = 285.3 Hz, CF3], 127.89 (s, CH, Ph), 128.41 (s, CH, Ph),
140.63 (s, tert-C, Ph), 175.65 (s, COOCH3).
ChemMedChem 2007, 2, 1693.
(4) (a) Volonterio, A.; Bellosta, S.; Bravin, F.; Bellucci, M. C.;
Bruche, L.; Colombo, G.; Malpezzi, L.; Mazzini, S.; Meille,
S. V.; Meli, M.; Arellano, C. R.; Zanda, M. Chem. Eur. J.
2003, 9, 4510. (b) Molteni, M.; Pesenti, C.; Sani, M.;
Volonterio, A.; Zanda, M. J. Fluorine Chem. 2004, 125,
1735. (c) Binkert, C.; Frigerio, M.; Jones, A.; Meyer, S.;
Pesenti, C.; Prade, L.; Viani, F.; Zanda, M. ChemBioChem
2006, 7, 181.
(5) For recent reviews on the synthesis of fluorinated b-amino
acids, see (a) Acena, J. L.; Simon-Fuentes, A.; Fustero, S.
Curr. Org. Chem. 2010, 14, 928. (b) Mikami, K.; Fustero,
S.; Sánchez-Roselló, M.; Acena, J.-L.; Soloshonok, V.;
Sorochinsky, A. Synthesis 2011, 3045.
(6) (a) Bravo, P.; Corradi, E.; Pesenti, C.; Vergani, B.; Viani, F.;
Volonterio, A.; Zanda, M. Tetrahedron Asymmetry 1998, 9,
3731. (b) Sergeeva, N. N.; Golubev, A. S.; Hennig, L.;
Burger, K. Synthesis 2002, 2579. (c) Wan, W.; Hou, J.;
Jiang, H.; Yuan, Z.; Ma, G.; Zhao, G.; Hao, J. Eur. J. Org.
Chem. 2010, 1778. (d) Bezdudny, A. V.; Alekseenko, A. N.;
Mykhailiuk, P. K.; Manoilenko, O. V.; Shishkin, O. V.;
Pustovit, Y. M. Eur. J. Org. Chem. 2011, 1782.
(7) (a) Sato, K.; Tarui, A.; Omote, M.; Ando, A.; Kumadaki, I.
Synthesis 2010, 1865. (b) Shibata, N.; Matsnev, A.; Cahard,
D. Beilstein J. Org. Chem. 2010, 6, 65. (c) Nie, J.; Guo,
H.-C.; Cahard, D.; Ma, J. Chem. Rev. 2011, 111, 455.
(8) (a) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7631.
(b) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757.
(9) Under standard conditions for the Ruppert reaction, only
activated imines such as azirines, imines of perfluorinated
ketones, N-sulfonylated aldimines, or nitrones react with
trifluoromethyl(trimethyl)silane; see: (a) Felix, C. P.;
Khatimi, N.; Laurent, A. Tetrahedron Lett. 1994, 35, 3303.
(b) Banks, R. E.; Besheesh, M.; Lawrence, N. J.; Tovell, D.
J. J. Fluorine Chem. 1999, 97, 79. (c) Petrov, V. A.
Tetrahedron Lett. 2000, 41, 6959. (d) Kawano, Y.;
Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005, 34, 422.
(e) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem.
2001, 66, 2572. (f) Nelson, D. W.; Easley, R. A.; Pintea, B.
N. V. Tetrahedron Lett. 1999, 40, 25.
(10) Several uncommon examples of reactions of nonactivated
imines with trifluoromethyl(trimethyl)silane have been
reported; these involve the use of tetraalkylammonium
fluoride or basic phosphines as initiators, the addition
of(trimethylsilyl)imidazole as an activator, or the initial
generation of a boron complex; see: (a) Prakash, G. K. S.;
Mogi, R.; Olah, G. A. Org. Lett. 2006, 8, 3589. (b) Kirij, N.
V.; Babadzhanova, L. A.; Movchun, V. N.; Yagupolskii, Y.
19F NMR (470 MHz, CDCl3): d = –78.44 (br s, CF3).
MS: m/z = 327 (M+).
6-Amino-6-(trifluoromethyl)spiro[3.3]heptane-2-carboxylic
Acid Hydrochloride (2·HCl)
A soln of ester 11 (8.2 g, 0.025 mol) and 6 M aq HCl (0.5 mL) in
MeOH (150 mL) was hydrogenated at r.t. at 10 atm for 12 h using
10% Pd/C (100 mg) as the catalyst. The soln was filtered, and the
filtrate was concentrated under vacuum. 6 M aq HCl (100 mL) was
added to the residue and the mixture was refluxed for 1 h. The soln
was then concentrated under vacuum and the residue was triturated
with MeCN (20 mL). The white solid was filtered off and dried in
air; yield: 5.45 g (0.021 mmol, 84%); mp >200 °C.
1H NMR (500 MHz, D2O): d = 2.13–2.32 (m, 4 H), 2.36 (d, J = 15.2
Hz, 1 H), 2.43 (d, J = 14.8 Hz, 1 H), 2.55 (dd, J = 14.8, 2.8 Hz, 1
H), 2.66 (dd, J = 14.4, 2.4 Hz, 1 H), 2.93 (quin, J = 8.2 Hz, 1 H,
CH).
13C NMR (125 MHz, D2O): d = 31.80 (s), 32.27 (s), 37.13 (s), 37.19
2
(s), 38.38 (s), 38.81 (s), 53.13 [quin, J(C,F) = 32.7 Hz, CCF3],
124.61 [quin, 1J(C,F) = 279.1, CF3], 180.0 (s, COOH).
19F NMR (470 MHz, DMSO-d6): d = –79.01 (br s, CF3).
Anal. Calcd for C9H12F3NO2·HCl: C, 41.63; H, 5.05; N, 5.39.
Found: C, 41.33; H, 5.00; N, 5.22.
Supporting Information for this article is available online at
References
(1) For reviews on bioisosteric replacements, see:
(a) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
(b) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147.
(c) Venkatesan, N.; Kim, B. H. Curr. Med. Chem. 2002, 9,
2243. (d) Zajc, B.; Kumar, R. Synthesis 2010, 1822.
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Synthesis 2012, 44, 903–908