6838
C. Cai et al. / Tetrahedron 61 (2005) 6836–6838
preparation of 4a while methylamine hydrochloride was
used instead of NH4Cl. 100%; white solid; mp 200.5–
201.5 8C; 1H NMR (300 MHz, CD3CN): d 1.34 (9H, s), 2.38
(6H, s), 2.85 (3H, d, JZ4.7 Hz), 3.06 (1H, dd, JZ9.4,
14.0 Hz), 3.16 (1H, dd, JZ7.9, 14.2 Hz), 3.63 (3H, s), 4.38
(1H, m), 5.69 (1H, d, JZ8.3 Hz), 6.88 (1H, s), 7.43 (2H, s);
13C NMR (300 MHz, DMSO-d6): d 19.7, 26.1, 28.0, 30.9,
51.7, 52.9, 78.2, 126.5, 132.2, 136.7, 137.5, 155.1, 166.5,
172.3; HRMS(ESC) [MCH]C calcd. For C19H29N2O5:
365.2076, found, 365.2101; MS(ESC) (relative intensity):
365.0 (15) (MCH)C.
3.2.2. 40-Methylcarbamoyl N-Boc-20,60-dimethyl-L-
phenylalanine (5b). 100%; white foam; mpO210 8C; H
1
NMR (300 MHz, DMSO-d6): d 1.30 (9H, s), 2.32 (6H, s),
2.74 (3H, d, JZ4.5 Hz), 2.94 (1H, dd, JZ6.0, 14.4 Hz),
3.10 (1H, dd, JZ6.5, 14.1 Hz), 4.02–4.12 (1H, m), 7.21
(1H, d, JZ8.4 Hz), 7.44 (2H, s), 8.27 (1H, d, JZ4.5 Hz);
13C NMR (300 MHz, DMSO-d6): d 19.1, 26.1, 28.0, 31.2,
53.1, 78.0, 126.5, 132.0, 136.7, 138.1, 155.2, 166.6, 173.4;
HRMS(ESC) [MCH]C calcd. For C18H27N2O5: 351.1920,
found, 351.1909; MS(ESC) (relative intensity): 351.0 (15)
(MCH)C.
3.1.5. 40-Ethylcarbamoyl N-Boc-20,60-dimethyl-L-phenyl-
alanine methyl ester (4c). Similar method to preparation of
4a while ethylamine hydrochloride was used instead of
3.2.3. 40-Ethylcarbamoyl N-Boc-20,60-dimethyl-L-phenyl-
alanine (5c). 100%; white foam; mpO210 8C; H NMR
1
(300 MHz, DMSO-d6): d 1.10 (3H, t, JZ7.2 Hz), 1.31 (9H,
s), 2.33 (6H, s), 2.94 (1H, dd, JZ6.0, 14.4 Hz), 3.10 (1H,
dd, JZ6.0, 14.1 Hz), 3.30–3.23 (2H, m), 4.04–4.11 (1H, m),
7.17 (1H, d, JZ8.4 Hz), 7.45 (2H, s), 8.30 (1H, t, JZ
5.4 Hz); 13C NMR (300 MHz, DMSO-d6): d 14.8, 20.0,
28.1, 31.3, 33.7, 53.3, 78.0, 126.6, 132.2, 136.9, 138.2,
155.2, 165.9, 173.5; HRMS(ESC) [MCH]C calcd. For
C19H29N2O5: 365.2076, found, 365.2099; MS(ESC)
(relative intensity): 365.0 (16) (MCH)C.
1
NH4Cl. 100%; white solid; mp 176.0–177.0 8C; H NMR
(300 MHz, CD3CN): d 1.20 (3H, t, JZ7.2 Hz), 1.34 (9H, s),
2.38 (6H, s), 3.05 (1H, dd, JZ7.2, 14.8 Hz), 3.18 (1H, dd,
JZ6.4, 14.0 Hz), 3.36 (2H, m), 3.63 (3H, s), 4.38 (1H, m),
5.96 (1H, d, JZ8.3 Hz), 6.94 (1H, s), 7.44 (2H, s); 13C
NMR (300 MHz, DMSO-d6): d 14.8, 19.8, 28.1, 31.0, 33.9,
51.7, 53.0, 78.3, 126.6, 132.4, 136.7, 137.5, 155.2, 165.8,
172.4; HRMS(ESC) [MCH]C calcd. For C20H31N2O5:
379.2233, found, 379.2190; MS(ESC) (relative intensity):
379.0 (15) (MCH)C.
3.2.4. 40-Morpholinylcarbamoyl N-Boc-20,60-dimethyl-L-
1
phenylalanine (5d). White foam; mpO210 8C; H NMR
3.1.6. 40-Morpholinylcarbonyl N-Boc-20,60-dimethyl-L-
phenylalanine methyl ester (4d). Similar method to
preparation of 4a while morpholine was used instead of
NH4Cl. 99%; white solid; mp 97.0–98.0 8C; 1H NMR
(300 MHz, CDCl3): d 1.34 (9H, s), 2.37 (6H, s), 3.09 (2H,
m), 3.35–3.90 (8H, m), 3.68 (3H, s), 4.54 (1H, m), 5.09 (1H,
d, JZ8.4 Hz), 7.02 (2H, s); 13C NMR (300 MHz, CD3OD):
d 20.3, 28.7, 33.1, 43.9, 52.7, 54.6, 67.8, 80.6, 127.7, 134.6,
137.9, 139.1, 157.2, 172.7, 174.1; HRMS(ESC) [MCH]C
calcd. For C22H33N2O6: 421.2339, found, 421,2373;
MS(ESC) (relative intensity): 421.0 (40) (MCH)C.
(300 MHz, DMSO-d6): d 1.29 (9H, s), 2.31 (6H, s), 2.93
(1H, dd, JZ9.0, 14.1 Hz), 3.10 (1H, dd, JZ5.8, 14.0 Hz),
3.30–3.85 (8H, m), 4.11 (1H, m), 6.99 (2H, s), 7.19 (1H, d,
JZ8.7 Hz); 13C NMR (300 MHz, CD3OD): d 18.8, 27.1,
32.0, 42.3, 53.1, 66.3, 78.9, 126.5, 133.6, 136.8, 137.7,
156.1, 171.3, 173.9; HRMS(ESC) [MCH]C calcd. For
C21H31N2O6: 407.2182, found, 407.2180; MS(ESC)
(relative intensity): 407.1 (38) (MCH)C.
References and notes
3.2. General procedure for hydrolysis of amino acid
methyl esters 4a–d
1. Bryant, S. D.; Jinsmaa, Y.; Salvadori, S.; Okada, Y.; Lazarus,
L. H. Biopolymers (Pept. Sci.) 2003, 71, 86–102.
2. Jinsmaa, Y.; Okada, Y.; Tsuda, Y.; Shiotani, K.; Sasaki, Y.;
Ambo, A.; Bryant, S. D.; Lazarus, L. H. J. Pharmacol. Exp.
Ther. 2004, 309, 432–438 and literatures cited in this article.
3. Stresser, D. M.; Kupfer, D. Biochemistry 1997, 36, 2203–2210.
4. Wentland, M. P.; Lou, R.; Dehnhardt, C. M.; Duan, W.; Cohen,
D. J.; Bidlack, J. M. Bioorg. Med. Chem. Lett. 2001, 11,
1717–1721.
Into an ice-cooled solution of methyl ester 4 (8.54 mmol) in
THF (50 mL) was added an aqueous LiOH solution (1 N,
50 mL) and stirred at 0 8C. Upon disappearance of starting
materials (monitored by TLC), the organic solvents were
removed and the aqueous phase was neutralized with cooled
1 N HCl at 0 8C, and extracted with EtOAc, finally dried
over Na2SO4 overnight. Filtration and evaporation to
dryness led to the acid 5.
5. Breslin, H. J.; He, W.; Kavash, R. W. PCT Int. Appl., WO 2003,
2003092688.
3.2.1. 40-Carbamoyl N-Boc-20,60-dimethyl-L-phenyl-
alanine (5a). White solid; mpO210 8C; 1H NMR
(300 MHz, DMSO-d6): d 1.30 (9H, s), 2.32 (6H, s), 2.95
(1H, dd, JZ8.8, 13.9 Hz), 3.10 (1H, dd, JZ6.2, 14.0 Hz),
4.02–4.12 (1H, m), 7.18–7.23 (2H, m), 7.48 (2H, s), 7.80
(1H, s); 13C NMR (300 MHz, DMSO-d6): d 19.8, 28.0, 31.2,
53.1, 78.0, 126.9, 131.7, 136.6, 138.3, 155.2, 167.8, 173.4;
HRMS(ESC) [MCH]C calcd. For C17H25N2O5: 337.1763,
found, 337.1780; MS(ESC) (relative intensity): 236.9 (6)
(MKBoc)C.
6. Dolle, R. E.; Machaut, M.; Martinez-Teipel, B.; Belanger, S.;
Cassel, J. A.; Stabley, G. J.; Graczyk, T. M.; DeHaven, R. N.
Bioorg. Med. Chem. Lett. 2004, 14, 3545–3548.
7. Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14,
4607–4610.
8. Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 3931–3934.
9. Wang, W.; McMurray, J. S. Tetrahedron Lett. 1999, 40,
2501–2504.