924
S. G. Davies et al. / Tetrahedron: Asymmetry 23 (2012) 910–925
chromatography (Dowex 50 WX8-100, eluent 1.0 M aq NH4OH)
gave 99 as a pale yellow powder (187 mg, 95%); mp 228–230 °C;
chromatography (Dowex 50 WX8-100, eluent 1.0 M aq NH4OH)
gave 102 as a white solid (239 mg, 95%);22 mp 207–208 °C; {lit.22
½
a 2D5
ꢂ
ꢀ15.6 (c 0.5 in H2O); vmax (ATR) 3418 (O–H, N–H), 1647
mp 206 °C}; ½a 2D5
ꢀ2.2 (c 0.5 in H2O); dH (400 MHz, AcOH-d4)
ꢂ
(C@O); dH (400 MHz, AcOH-d4) 2.35 (3H, s, C(20)Me), 2.87–3.00
(1H, m, C(2)HA), 3.08–3.39 (1H, m, C(2)HB), 5.17–5.68 (1H, m,
C(3)H), 6.97–7.48 (3H, m, Ar); dC (100 MHz, AcOH-d4)33 9.5
(C(20)Me), 38.2 (C(2)), 48.0 (C(3)), 115.9, 122.2, 128.2 (C(40), C(50),
C(60)), 124.3, 136.9 (C(10), C(20)), 162.0 (d, J 226, C(30)); m/z (ESI+)
3.29 (1H, dd, J 17.6, 6.0, C(2)HA), 3.61 (1H, dd, J 17.6, 7.2, C(2)HB),
5.29–5.32 (1H, m, C(3)H), 7.48 (1H, app t, J 7.2, Ar), 7.78 (1H, app
t, J 7.0, Ar), 8.17 (1H, br s, Ar).
References and notes
220 ([M+Na]+, 92%), 198 ([M+H]+, 83%); HRMS (ESI+) C10H13FNO2
+
1. (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3; (b) Mikami, K.; Itoh, Y.; Yamanaka,
M. Chem. Rev. 2004, 104, 1; (c) O0Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
2. (a) Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27; (b) Böhm, H.-J.; Banner,
D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637; (c) Isanbor, C.; O0Hagan, D. J. Fluorine Chem.
2006, 127, 303; (d) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013; (e)
Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R.
E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider,
J.; Diederich, F.; Kansy, M.; Müller, K. ChemMedChem 2007, 2, 1100; (f)
Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (g) Kirk, K. L. Org.
Process Res. Dev. 2008, 12, 305; (h) Hagmann, W. K. J. Med. Chem. 2008, 51,
4359; (i) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320; (j) O0Hagan, D. J. Fluorine Chem. 2010, 131, 1071; (k)
Gourverneur, V.; Muller, K. Fluorine in Pharmaceutical and Medicinal
Chemistry; Imperial College Press: London, 2012.
3. Heidelberger, C.; Chaudhuri, N. K.; Danneberg, P.; Mooren, D.; Griesbach, L.;
Duschinsky, R.; Schnitzer, R. J. Nature 1957, 179, 663.
4. Takeuchi, Y.; Shiragami, T.; Kimura, K.; Suzuki, E.; Shibata, N. Org. Lett. 1999, 1,
1571.
5. Qui, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60, 6711.
6. Mikami, K.; Fuestero, S.; Sánchez-Roselló, M.; Aceña, J. L.; Soloshonok, V.;
Sorochinsky, A. Synthesis 2011, 3405.
7. Ohba, T.; Ikeda, E.; Takei, H. Bioorg. Med. Chem. Lett. 1996, 6, 1875.
8. (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574; (b) Middleton, W. J.; Bingham, E.
M. J. Org. Chem. 1980, 45, 2883.
([M+H]+) requires 198.0925; found 198.0925.
4.2.62. (S)-3-Amino-3-(20-fluoro-50-methoxyphenyl)propanoic
acid 100
NH2
MeO
CO2H
F
Following general procedure 4, 2.0 M aq HCl (20 mL) and 77
(276 mg, 1.03 mmol) followed by purification via ion exchange
chromatography (Dowex 50 WX8-100, eluent 1.0 M aq NH4OH)
gave 100 as a pale yellow powder (206 mg, 94%); mp 189–
191 °C; ½a 2D5
ꢀ3.8 (c 0.3 in H2O); vmax (ATR) 3425 (O–H, N–H),
ꢂ
1641 (C@O); dH (400 MHz, D2O) 2.85 (1H, dd, J 16.7, 6.8, C(2)HA),
2.96 (1H, dd, J 16.7, 7.8, C(2)HB), 3.73 (3H, s, OMe), 4.80–4.84
(1H, m, C(3)H), 6.93–7.l2 (3H, m, Ar); dC (125 MHz, D2O) 38.0
(C(2)), 46.7 (C(3)), 56.0 (OMe), 113.4, 116.4, 117.0 (C(30), C(40),
C(60)), 123.0 (C(10)), 154.6 (d, J 256, C(20)), 155.3 (C(50)), 175.1
(C(1)); m/z (ESI+) 236 ([M+Na]+, 87%), 214 ([M+H]+, 100%); HRMS
9. Peddie, V.; Pietsch, M.; Bromfield, K. M.; Pike, R. N.; Duggan, P. J.; Abell, A. D.
Synthesis 2010, 1845.
10. Davies, S. G.; Fletcher, A. M.; Lv, L.; Roberts, P. M.; Thomson, J. E. Tetrahedron
Lett. 2012, 53, 3052.
(ESI+) C10H13FNO3 ([M+H]+) requires 214.0874; found 214.0875.
+
11. (a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey,
G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M. E.; Patel, R.
A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang,
B. B.; Zhu, L.; Thornberry, N. A.; Wever, A. E. J. Med. Chem. 2005, 48, 141; (b)
Thornberry, N. A.; Weber, A. E. Curr. Top. Med. Chem. 2007, 7, 557.
12. For selected examples from this laboratory, see: (a) Davies, S. G.; Iwamoto, K.;
Smethurst, C. A. P.; Smith, A. D.; Rodríguez-Solla, H. Synlett 2002, 1146; (b)
Davies, S. G.; Kelly, R. J.; Price Mortimer, A. J. Chem. Commun. 2003, 2132; (c)
Davies, S. G.; Burke, A. J.; Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith, A.
D.; Rodríguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387; (d)
Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price Mortimer,
A. J.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 2630; (e) Abraham,
E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P.
M.; Russell, A. J.; Sánchez-Fernández, E. M.; Smith, A. D.; Thomson, J. E.
Tetrahedron: Asymmetry 2007, 18, 2510; (f) Abraham, E.; Davies, S. G.; Millican,
N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6,
1655; (g) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sánchez-
Fernández, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2008, 6, 1665; (h) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Tetrahedron 2009, 65, 10192; (i) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P.
M.; Thomson, J. E. Org. Lett. 2011, 13, 2544; (j) Davies, S. G.; Ichihara, O.;
Roberts, P. M.; Thomson, J. E. Tetrahedron 2011, 67, 216; (k) Davies, S. G.;
Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Tetrahedron 2011, 67, 9975; (l)
Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron Lett.
2011, 52, 6477; (m) Bagal, S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts,
P. M.; Scott, P. M.; Thomson, J. E. Tetrahedron Lett. 2011, 52, 2216; (n) Davies, S.
G.; Huckvale, R.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron:
Asymmetry 2011, 22, 1591; (o) Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Stonehouse, J. P.; Thomson, J. E. Tetrahedron Lett. 2012, 53, 1119; (p) Davies, S.
G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; Yin, J. Org. Lett. 2012, 14, 218; (q)
Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Russell, A. J.; Taylor, R. J.; Thomson, A. D.;
Thomson, J. E. Org. Lett. 2012, 14, 1672; (r) Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Thomson, J. E.; West, C. J. Tetrahedron 2012, 68, 4302; (s) Davies, S. G.; Garrido,
N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price Mortimer, A. J.;
Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17, 1793; (t) Davies, S.
G.; Mulvaney, A. W.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2007,
18, 1554.
4.2.63. (S)-3-Amino-3-(30-phenoxy-40-fluorophenyl)propanoic
acid 101
NH2
CO2H
F
OPh
Following general procedure 4, 2.0 M aq HCl (19 mL) and 78
(331 mg, 1.00 mmol) followed by purification via ion exchange
chromatography (Dowex 50 WX8-100, eluent 1.0 M aq NH4OH)
gave 101 as a white powder (267 mg, 97%); mp >370 °C; ½a D25
ꢂ
ꢀ12.0 (c 0.5 in H2O); vmax (ATR) 3418 (O–H, N–H), 1642 (C@O);
dH (400 MHz, AcOH-d4) 3.09 (1H, dd, J 17.4, 5.6, C(2)HA), 3.34
(1H, dd, J 17.4, 8.3, C(2)HB), 4.85–4.89 (1H, m, C(3)H), 7.00–7.38
(8H, m, Ar); dC (100 MHz, AcOH-d4) 37.8 (C(2)), 51.8 (C(3)), 117.5,
117.9, 121.9, 123.8, 124.8, 130.2 (C(20), C(50), C(60), o,m,p-Ph),
132.9, 143.0, 157.4 (C(10), (C(30), i-Ph), 154.6 (d, J 266, C(40)),
174.9 (C(1)); m/z (ESI+) 298 ([M+Na]+, 79%), 276 ([M+H]+, 100%);
HRMS (ESI+) C15H15FNO3 ([M+H]+) requires 276.1030; found
+
276.1032.
4.2.64. (S)-3-Amino-3-[20-fluoro-30-(trifluoromethyl)phenyl]-
propanoic acid 102
NH2
CO2H
13. Bull, S. D.; Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005,
16, 2833.
14. (a) Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.; Fenton, G.; Kelly, P. M.; Smith,
A. D. Synlett 2000, 1257; (b) Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.; Kelly,
P. M.; Kotchie, L. J.; Gianotti, M.; Laderas, M.; Smith, A. D. J. Chem. Soc., Perkin
Trans. 2001, 1, 3112.
F
CF3
Following general procedure 4, 2.0 M aq HCl (19 mL) and 79
(307 mg, 1.00 mmol) followed by purification via ion exchange