J¢ = 4.1 Hz, 1H, CH2b), 3.61–3.63 (m, 4H, NCH2morph), 3.70–3.72
(m, 4H, OCH2morph), 4.19–4.23 (m, 3H, CHFmoc and OCH2), 4.32–
4.37 (m, 1H, CHa), 6.97 (d, J = 5.4 Hz, 1H, H(5)pyrim), 7.21–7.27
(m, 2H, CHaryl), 7.34–7.39 (m, 2H, CHaryl), 7.61–7.64 (t, J = 6.9 Hz,
2H, CHaryl), 7.70 (d, J = 8.2 Hz, 1H, NH), 7.77 (s, 1H, H(4)imid),
7.83 (d, J = 6.8 Hz, 2H, CHaryl), 8.43 (d, J = 5.4 Hz, 1H, H(6)pyrim),
8.64 (s, 1H, H(2)imid), 12.79 (br, 1H, OH); 13C-NMR (100 MHz,
DMSO-d6) d 29.6 (t), 43.8 (t, 2C), 46.5 (d), 53.5 (d), 65.6 (t), 65.8
(t, 2C), 97.1 (d), 113.5 (d), 120.1 (d, 2C), 125.16 (d), 125.22 (d),
126.98 (d), 127.0 (d), 127.6 (d, 2C), 135.2 (d), 139.3 (s), 140.64 (s),
140.67 (s), 143.7 (s, 2C), 154.8 (s), 155.9 (s), 160.6 (d), 160.9 (s),
173.2 (s); HRMS (ESI) m/z: calculated for C29H29N6O5 [M+H]+
541.2194, found 541.2183.
Acknowledgements
Abdelatif ElMarrouni is the recipient of a predoctoral fellowship
(FI) from the Generalitat of Catalonia. This work was supported
by grant AGL2006-13564-C02-02/AGR from MICINN of Spain.
We are also grateful to the Serveis Te`cnics de Recerca of the
University of Girona for NMR spectra.
Notes and references
1 (a) W. L. Scott, J. Alsina, C. O. Audu, E. Babaev, L. Cook, J. L. Dage,
L. A. Goodwin, J. G. Martynow, D. Matosiuk, M. Royo, J. G. Smith,
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(c) G. Beck, Synlett, 2002, 837–850 and references cited therein.
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(b) A. Wu, Y. Xy and X. Qian, Bioorg. Med. Chem., 2009, 17, 592–599;
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V. Jger, Org. Lett., 2005, 7, 2317–2320.
(S)-Na-Fmoc-6-(1-(2-morpholinopyrimidin-N-ylamino)-2-amino-
hexanoic acid (18c). By the general procedure, Na-Boc-
pyrimidin-4-yl amino ester 12c (100 mg, 0.24 mmol) provided 18c
(117 mg, 93%) as a colorless solid: mp 96–98 ◦C; TLC: Rf (ethyl
acetate/methanol/acetic acid, 2 : 3 : 0.3): 0.57; [a]2D5 -2.99 (c 0.30,
MeOH); IR (neat) 3269br (OH), 1688 (CO), 1656 (CC), 1583
1
(CN), 1198, 1176, 1125, 1024 (CO) cm-1; H-NMR (400 MHz,
3 (a) C. C. Liu and P. G. Schultz, Annu. Rev. Biochem., 2010, 79, 413–
444; (b) N. D. Jabre, T. Respondek, S. A. Ulku, N. Korostelova and
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Curr. Med. Chem., 2009, 16, 4399–4418; (d) R. P. Hicks, J. B. Bhonsle,
D. Venugopal, B. W. Koser and A. L. Magill, J. Med. Chem., 2007,
50, 3026–3036; (e) N. Sitaram, Curr. Med. Chem., 2006, 13, 679–
696.
DMSO-d6) d 1.41–1.47 (m, 2H, CH2), 1.50–1.52 (m, 2H, CH2),
1.60–1.64 (m, 1H, CH2), 1.66–1.74 (m, 1H, CH2b), 3.22 (m, 2H,
NCH2b), 3.58 (s, 8H, CH2morph), 3.91 (dd, J = 8.8 Hz, J¢ = 4.8 Hz,
1H, CHa), 4.20–4.29 (m, 3H, CHFmoc and OCH2), 5.76 (d, J =
5.8 Hz, 1H, H(5)pyrim), 7.05 (br, 1H, NH), 7.32 (m, 2H, CHaryl),
7.40 (m, 2H, CHaryl), 7.54 (br, 1H, NH), 7.72 (m, 3H, CHaryl and
H(6)pyrim), 7.88 (d, J = 7.4 Hz, 2H, CHaryl), 12.56 (br, 1H, OH);
13C-NMR (100 MHz, DMSO-d6) d 23.2 (t), 25.2 (t), 28.4 (t), 30.7
(t), 43.9 (t, 2C), 46.7 (d), 53.9 (d), 65.5 (t), 66.1 (t, 2C), 96.2 (d),
120.1 (d, 2C), 125.26 (d), 125.29 (d), 127.1 (d, 2C), 127.6 (d, 2C),
140.71 (s), 140.73 (s), 143.81 (s), 143.88 (s), 154.2 (d), 156.1 (s),
161.2 (s), 162.4 (s), 174.3 (s); HRMS (ESI) m/z: calculated for
C29H34N5O5 [M+H]+ 532.2554, found 532.2570.
4 For recent reviews on the synthesis of unnatural a-amino acids, see:
(a) P. Jana, S. Maity and D. Haldar, Curr. Org. Synth., 2010, 7, 224–234;
(b) C. Cativiela and M. Ordonez, Tetrahedron: Asymmetry, 2009, 20,
1–63; (c) D. Haldar, Curr. Org. Synth., 2008, 5, 61–80; (d) A. Perdih and
M. D. Sollner, Curr. Org. Chem., 2007, 11, 801–832; (e) C. Najera and
J. M. Sansano, Chem. Rev., 2007, 107, 4584–4671; (f) V. J. Hruby and V.
A. Soloshonok, Asymmetric synthesis of novel sterically constrained
amino acids, Tetrahedron Symposia-in-print, 2001, 57, 6329–6650.
5 For some representative examples, see: (a) A.-N. R. Alba, X. Com-
panyo´, G. Valero, A. Moyano and R. Rios, Chem.–Eur. J., 2010,
16, 5354–5361; (b) V. Iosub, A. R. Haberl, J. Leung, M. Tang, K.
Vembaiyan, M. Parvez and T. Back, J. Org. Chem., 2010, 75, 1612–
1619; (c) S. Kno¨r, B. Laufer and H. Kessler, J. Org. Chem., 2006, 71,
5625–5630.
´ ˜
Synthesis of (S)-1-(2-morpholinopyrimidin-4-yl)pyrrolidine-2-
carboxylic acid (18e). To a solution of methyl ester 12e (90 mg,
0.31 mmol, 1 equiv.) in THF/MeOH/H2O (1 : 2 : 2) (8 mL mmol-1)
was added LiOH monohydrate (44.7 mg, 0.77 mmol, 2.5 equiv.)
and the reaction mixture was stirred at room temperature for 4 h.
Upon completion of the reaction (TLC monitoring), the organic
solvents were removed under reduced pressure. The pH of the
resulting aqueous solution was then adjusted to 4 with glacial
acetic acid, and the solution was extracted with CH2Cl2 (3 ¥
5 mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated under reduced pressure. The resulting residue
was purified by flash chromatography with a gradient elution
n-hexane/ethyl acetate/acetic acid from (4 : 1 : 0) to (0 : 20 : 1) to
afford 61 mg (70%) of pyrimidin-4-yl amino acids 18e as a colorless
solid: mp 193–106 ◦C; TLC: Rf (ethyl acetate/methanol/acetic
6 For some representative examples, see: (a) F. Tao, Y. Luo, Q. Huang,
Y. Liu, B. Li and G. Zhang, Amino Acids, 2009, 37, 603–607; (b) M.
Suhartono, M. Weidlich, T. Stein, M. Karas, G. Du¨rner and M. W.
Go¨bel, Eur. J. Org. Chem., 2008, 1608–1614.
7 A. ElMarrouni, M. Gu¨ell, C. Collell and M. Heras, Tetrahedron, 2010,
66, 612–623.
8 (a) D. Font, M. Herasand and J. M. Villalgordo, Tetrahedron, 2008,
64, 5226–5235; (b) D. Font, M. Heras and J. M. Villalgordo, J. Comb.
Chem., 2003, 5, 311–321; (c) D. Font, M. Heras and J. M. Villalgordo,
Synthesis, 2002, 1833–1842.
9 R. J. Cherney and L. Wang, J. Org. Chem., 1996, 61, 2544–2546.
10 For recent reviews on phosphonium coupling, see: (a) T. S. Mansour, S.
Bardhan and Z.-K. Wan, Synlett, 2010, 1143–1169; (b) F.-A. Kang, Z.
Sui and W. V. Murray, Eur. J. Org. Chem., 2009, 461–479 and references
cited therein.
11 F.-A. Kang, J. Kodah, Q. Guan, X. Li and W. V. Murray, J. Org. Chem.,
1
acid, 1 : 3 : 0.5): 0.21; H-NMR (200 MHz, CDCl3) d 2.07–2.30
2005, 70, 1957–1960.
12 (a) M. K. Lakshman and J. Frank, Org. Biomol. Chem., 2009, 7, 2933–
2940; (b) Z.-K. Wan, S. Wacharansindhu, C. G. Levins, M. Lin, K.
Tabei and T. S. Mansour, J. Org. Chem., 2007, 72, 10194–10210.
13 The optical purity of compounds 10 and 12 were verified by coupling
with both D/L-phenylalamine and L-phenylalanine in order to measure
the degree of racemization by HPLC (see ESI†).
14 T. D. Ashton and P. J. Scammells, Aust. J. Chem., 2008, 61, 49–58.
15 Compound 12a and amino ester 9a have the same Rf . Without this
work-up the purification of compound 12a proved to be problematic.
(m, 4H, 2 ¥ CH2), 3.62–3.77 (m, 10H, CH2morph and NCH2pro),
4.50 (br, 1H, CHa), 5.92 (d, J = 6.6 Hz,1H, H(5)pyrim), 8.02 (d, J =
6.6 Hz, 1H, H(6)pyrim), 9.98 (br, 1H, COOH); 13C-NMR (50 MHz,
DMSO-d6) d 23.6 (t), 28.8 (t), 42.0 (t, 2C), 46.5 (t), 59.0 (d), 65.5
(t, 2C), 94.6 (d), 151.1 (d), 157.0 (s), 159.0 (s), 173.4 (s); HRMS
(ESI) m/z: calculated for C13H19N4O3 [M+H]+ 279.1379, found:
279.1452.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5967–5977 | 5977
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