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J. R. Casimir et al.
PAPER
sheets coated with silica gel 60 F254 (Merck, Darmstadt) in eluents
A: hexane/EtOAc/AcOH (70:30:5) and B: CHCl3/MeOH/
AcOH (40:2:1).
13C NMR (50 MHz, DMSO-d6): d = 14.8 (CH3), 48.0 (CH),122.9
(CH), 131.7 (C), 134.2 (CH), 167.4 (C), 170.5 (C).
MS: m/z = 219 (M + H)+, 241 (M + Na)+, 257 (M + K)+.
Na-[(o-Methoxycarbonyl)benzoyl]-(S)-isoleucinamide (3f)
This compound was obtained as a white solid (0.27 g, 92%) by the
reaction of 2f (0.167 g, 1.0 mmol) with monomethylphthalate 1
(0.181 g, 1.0 mmol) in the presence of BOP (0.443 g, 1.0 mmol),
HOBt (0.153 g, 1.0 mmol) and i-Pr2NEt (0.68 mL, 4.0 mmol) in
CH2Cl2 (25 mL) for 30 min followed by aqueous workup, drying
(Na2SO4) and concentration in vacuo; mp 193-195 °C; TLC:
Rf 0.22 (A), 0.72 (B); HPLC: Rt 10.28 min: [a]D -4.7 (c = 1.0,
MeOH).
Na-Phthaloyl-(S)-phenylalaninamide (4c)
Method A. White solid (0.752 g, 95%); mp 221 °C; TLC: Rf 0.27
(A), 0.62 (B); HPLC: Rt 12.52 min; [a]D -20.4 (c = 1.0, MeOH).
IR ATR, Ge: n = 3383, 3300, 3248, 3192, 3028, 2920, 1771, 1738,
1707, 1688, 1658, 1605, 1455, 1383, 1353, 720, 695 cm-1.
1H NMR (200 MHz, DMSO-d6): d = 3.34 (dd, J = 11.8, 14.0 Hz, 1
H), 3.53 (dd, J = 4.8, 14.0 Hz, 1 H), 4.93 (dd, J = 4.8, 11.8 Hz, 1 H),
7.12 (m, 5 H), 7.32 (s, 1 H), 7.72 (s, 1 H), 7.80 (s, 4 H).
13C NMR (50 MHz, DMSO-d6): d = 33.7 (CH2), 54.2 (CH), 122.9
(CH), 126.3 (CH), 128.2 (CH), 128.6 (CH), 131.2 (C), 134.4 (CH),
137.7 (C), 167.4 (C), 169.6 (C).
MS: m/z = 295 (M + H)+, 317 (M + Na)+, 333 (M + K)+.
Na-Phthaloyl-(S)-valinamide (4d)
IR ATR, Ge: n = 3365, 3281, 3184, 2959, 2875, 1722, 1631, 1581,
1592, 1522, 1270, 1083, 799, 706, 665 cm-1.
1H NMR (200 MHz, DMSO-d6): d = 0.86 (t, J = 7.5 Hz, 3 H), 0.91
(d, J = 6.9 Hz, 3 H), 1.18 (m, 1 H), 1.52 (m, 1 H), 1.86 (m, 1 H),
3.74 (s, 3 H), 4.27 (m, 1 H), 7.13 (s, 1 H), 7.35 (s, 1 H), 7.46-7.78
(m, 4 H), 8.37 (d, J = 8.7 Hz, 1 H).
13C NMR (50 MHz, DMSO-d6): d = 11.0 (CH3), 15.5 (CH3), 24.3
(CH2), 36.0 (CH), 52.1 (CH3), 57.4 (CH), 127.8 (CH), 128.9 (CH),
129.3 (CH), 129.6 (C), 131.5 (CH), 138.0 (C), 167.2 (C), 167.9 (C),
172.8 (C).
Method A. White solid (0.589 g, 89%); mp 191 °C; TLC: Rf 0.36
(A), 0.72 (B); HPLC: Rt 11.34 min; [a]D -1.2 (c = 1.1, MeOH).
IR ATR, Ge: n = 3396, 3200, 2959, 2927, 1773, 1705, 1693, 1644,
1471, 1387, 718, 694 cm-1.
1H NMR (200 MHz, DMSO-d6): d = 0.77 (d, J = 6.8 Hz, 3 H), 1.02
(d, J = 6.7 Hz, 3 H), 2.69 (m, 1 H), 4.29 (d, J = 8.6 Hz, 1 H), 7.11
(s, 1 H), 7.50 (s, 1 H), 7.88 (m, 4 H).
MS: m/z = 293 (M + H)+, 315 (M + Na)+, 331 (M + K)+.
EMM: m/z calcd for C15H20N2O4 293.1501 (MH+), found 293.1404.
13C NMR (50 MHz, DMSO-d6): d = 19.2 (CH3), 20.9 (CH3), 27.1
(CH), 58.4 (CH), 123.1 (CH), 131.3 (C), 134.5 (CH), 167.6 (C),
169.4 (C).
MS: m/z = 247 (M + H)+, 269 (M + Na)+, 285 (M + K)+.
Na-Phthaloyl-(S)-leucinamide (4e)
Method A. White solid (0.595 g, 85%); mp 160-161 °C; TLC:
Rf 0.37 (A), 0.64 (B); HPLC: Rt 12.61 min; [a]D -2.4 (c = 1.0,
MeOH).
N-Phthaloylation of a-Amino Carboxamides and Dipeptide Es-
ters or Amides
A solution of monomethyl phthalate 1 (0.49 g, 2.69 mmol), a-amino
carboxamide 2 (2.69 mmol, 1.0 equiv), BOP (1.31 g, 1.1 equiv),
ZnCl2 (0.92 g, 2.5 equiv) and i-Pr2NEt (4.6 mL, 10 equiv) in MeCN
(40 mL) was sonicated for 16 h in an ultrasound cleaning bath. The
solvent and i-Pr2NEt were removed under reduced pressure, then
the product was isolated by either Method A or B.
Method A: The residue was triturated in 1 N HCl (50 mL) and fil-
tered. This operation was repeated 3 to 4 times in order to get rid of
all the zinc salts. The crude product was washed with aq sat.
NaHCO3 (4 î 25 mL), brine (25 mL) and H2O (2 î 25 mL), then
dried in vacuo to afford the desired product as a white solid.
IR ATR, Ge: n = 3432, 3411, 3171, 2963, 2916, 1770, 1691, 1629,
1466, 1385, 715 cm-1.
1H NMR (200 MHz, DMSO-d6): d = 0.87 (d, J = 6.6 Hz, 3 H), 0.88
(d, J = 6.5 Hz, 3 H), 1.37 (m, 1 H), 1.90 (m, 1 H), 2.20 (m, 1 H),
4.67 (dd, J = 4.3, 11.8 Hz, 1 H), 7.23 (s, 1 H), 7.62 (s, 1 H), 7.89 (m,
4 H).
13C NMR (50 MHz, DMSO-d6): d = 20.7 (CH3), 23.1 (CH3), 24.8
(CH), 36.5 (CH2), 51.3 (CH), 123.1 (CH), 131.5 (C), 134.4 (CH),
167.7 (C), 170.4 (C).
MS: m/z = 261 (M + H)+, 283 (M + Na)+, 299 (M + K)+.
Na-Phthaloyl-(S)-isoleucinamide (4f)
Method A. White solid (0.637 g, 91%); mp 226 °C; TLC: Rf 0.41
(A), 0.67 (B); HPLC: Rt 12.43 min; [a]D +4.4 (c = 0.9, AcOH).
Method B: The residue was dissolved in EtOAc (100 mL), then the
solution was successively washed with 1 N HCl (3 î 75 mL), aq
satd NaHCO3 solution (3 î 75 mL), brine (75 mL) and H2O (75
mL). After evaporation and purification by flash chromatography in
hexane/EtOAc, the product was obtained as a white solid.
Na-Phthaloylglycinamide (4a)
Method A. White solid (0.291 g, 53%); mp 265 °C; TLC: Rf 0.16
(A), 0.15 (B); HPLC: Rt 8.07 min.
IR ATR, Ge: n = 3407, 3314, 3275, 3207, 1769, 1706, 1676, 1614,
1470, 1416, 1383, 952, 733, 714 cm-1.
IR ATR, Ge: n = 3400, 3200, 2963, 2925, 1775, 1707, 1693, 1643,
1470, 1456, 1386, 719, 694 cm-1.
1H NMR (200 MHz, DMSO-d6): d = 4.12 (s, 2 H), 7.22 (s, 1 H), 7.66
(s, 1 H), 7.80 (m, 4 H).
13C NMR (50 MHz, DMSO-d6): d = 39.9 (CH2), 123.1 (CH), 131.7
(C), 134.4 (CH), 167.5 (C), 167.9 (C).
MS: m/z = 205 (M + H)+, 227 (M + Na)+, 243 (M + K)+.
Na-Phthaloyl-(S)-alaninamide (4b)
Method A. White solid (0.411 g, 70%); mp 202-203 °C; TLC:
Rf 0.26 (A), 0.56 (B); HPLC: Rt 9.16 min; [a]D +0.31 (c = 1.1,
MeOH).
1H NMR (200 MHz, DMSO-d6): d = 0.79 (t, J = 7.1 Hz, 3 H), 0.90
(m, 1 H), 0.99 (d, J = 6.7 Hz, 3 H), 1.38 (m, 1 H), 2.52 (m, 1 H),
4.36 (d, J = 8.99 Hz, 1 H), 7.14 (s, 1 H), 7.51 (s, 1 H), 7.89 (m, 4 H).
13C NMR (50 MHz, DMSO-d6): d = 10.6 (CH3), 16.6 (CH3), 25.2
(CH2), 32.8 (CH), 57.9 (CH), 123.1 (CH), 131.2 (C), 134.5 (CH),
167.6 (C),169.5 (C).
MS: m/z = 261 (M + H)+, 283 (M + Na)+, 299 (M + K)+.
Na-Phthaloyl-a-allyl-(R,S)-alaninamide (4g)
Method A. White solid (0.576 g, 83%); mp 160-162 °C; TLC:
Rf 0.41 (A), 0.67 (B); HPLC: Rt 11.38 min.
IR ATR, Ge: n = 3421, 3174, 1774, 1706, 1675, 1610, 1465, 1387,
718, 690 cm-1.
IR (ATR, Ge): n = 3424, 3303, 3171, 2983, 2924, 1774, 1711, 1682,
1H NMR (200 MHz, DMSO-d6): d = 1.51 (d, J = 7.3 Hz, 3 H), 4.65
(q, J = 7.3 Hz, 1 H), 7.15 (s, 1 H), 7.53 (s, 1 H), 7.88 (m, 4 H).
1641, 1619, 1466, 1387, 721, 698 cm-1.
Synthesis 2001, No. 1, 75–80 ISSN 0039-7881 © Thieme Stuttgart · New York