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B. L. Rao et al. / Tetrahedron: Asymmetry 27 (2016) 487–491
O
O
O
O
ASUD-diphenyl
phosphate
O
BnNH2
MeO
OH
Boc
N
MeO
NHBn
Boc
MeO
HN
HN
HN
O
Boc
Ib
Ic
Ia
O
O
HCl
Ac2O
MeO
NHBn
MeO
NHBn
NH2
(R)-lacosamide
Id
Scheme 5.
(m, 10H); 13C NMR (75 MHz, CDCl3): dC 21.44, 25.50, 32.47, 37.76,
44.31, 120.35, 120.42, 125.78, 129.67, 150.43, 150.53, 165.73;
DEPT 135: dC 21.43, 25.49, 35.74, 44.27 (–CH2), 120.35, 120.42,
125.82, 129.69 (–CH); 31P NMR (121 MHz, CDCl3): d –11.57 (s);
MS: m/z 430.20 [M+H]+.
(2.36 g, 82%); mp 113–115 °C (lit.10 114–116 °C); [
(c 1, CH3OH) [lit.10 À13.9].
a
]
20 = À13.8
D
The other dipeptides listed in Table 2 were prepared in a similar
manner and characterized.
4.5. Synthesis of lacosamide
4.3. Synthesis of N-ASUD esters of N-substituted amino acids
To a solution of N-(tert-butoxycarbonyl)-O-methyl-D-serine Ia,
4.3.1. Synthesis of 2,4-dioxo-3-azaspiro[5.5]undecan-3-yl (tert-
(Scheme 5) (5.0 g, 22.8 mmol) in dichloromethane (25 mL) was
added triethyl amine (2.54 g, 25.1 mmol) and the reaction mixture
was stirred under an N2 atmosphere. After 10 min, ASUD-Di phenyl
phosphate (10.8 g, 25.1 mmol) was added and the reaction mixture
was stirred at ambient temperature for 5 h. After completion of the
reaction, the reaction mixture was washed with water (15 ml),
brine (15 mL), dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by column chromatography
(silica gel, n-hexane/ethyl acetate, 80:20) to afford 2,4-dioxo-3-
butoxycarbonyl)-
L
-phenyl-alaninate (Table 1, entry 6)
-Phenyl alanine (5.0 g, 18.8 mmol) was dis-
At first, N-Boc-
L
solved in dichloromethane (50 mL); to the clear solution were
added ASUD-diphenyl phosphate (8.1 g, 18.8 mmol) and triethy-
lamine (2.1 g, 20.73 mmol). The reaction mixture was stirred at
room temperature for 4 h and washed with water (2 Â 25 mL),
brine (2 Â 25 mL). The DCM layer was dried over anhydrous
Na2SO4, filtered and concentrated in vacuum to yield 8.5 g
(>100%) of viscous oil. The oil was purified by silica gel
chromatography (ethyl acetate: hexane = 3: 7) and crystallized
from n-propanol to give the product as a white solid (7.12 g,
85%); mp 127–129 °C; TLC: Single, Rf 0.7 (Hexanes:EtOAc-2:1);
100% Purity by HPLC (Method b, Table 1);% ee: 99.35% (Method f,
azaspiro[5.5]undecan-3-yl N-(tert-butoxycarbonyl)-O-methyl-
serinate Ib as a colorless oil (8.3 g, 91.3%); 98.37% purity by HPLC
(Method d, Table 1);% ee: 99.21% (Method j, Table 1) ( -isomer
Rt = 11.89 min;
-isomer Rt = 14.74 min); IR (CHCl3, cmÀ1): vmax
D-
D
L
3441, 3019, 2980, 2933, 2859, 1812, 1750, 1715, 1502, 1455,
1393, 1368, 1342, 1282, 1244, 1215, 1196, 1170, 1135, 1116,
1107, 1064, 966, 926, 878, 851, 758, 668; 1H NMR (300 MHz,
CDCl3): dH 1.45–1.59 (m, 19H), 2.60–2.69 (m, 2H), 2.76–2.82 (m,
2H), 3.42 (s, 3H), 3.74–3.78 (dd, J = 9.6, 3.6 HZ, 1H), 3.86–3.91,
J = 9.6, 3.6 HZ, 1H), 4.82 (m, 1H), 5.37 (d, 1H); 13C NMR (75 MHz,
CDCl3): dC 167.5, 165.5, 154.8, 80.2, 72.0, 59.2, 52.3, 44.1, 36.6,
35.0, 32.6, 28.2, 25.5, 21.4; MS: m/z 398.58 [M]+, 415.79 [M
+H2O]+, 420.9 [M+Na]+.
Table 1) (D-isomer Rt = 13.1 min; L-isomer Rt = 22.1 min); IR (KBr,
cmÀ1): vmax 3421, 3288, 2983, 2934, 1802, 1791, 1748, 1714,
1698, 1604, 1526, 1497, 1455, 1389, 1365, 1240; 1H NMR
(300 MHz, CDCl3): dH 1.38 (s, 9H), 1.48–1.59 (m, 10H), 2.64–2.83
(m, 4H), 3.12–3.16 (dd, 1H), 3.32–3.39 (dd, 1H), 4.90–4.95 (m,
2H), 7.27–7.34 (m, 5H); 13C NMR (75 MHz, CDCl3): dC 20.44,
24.53, 27.20, 31.65, 34.14, 35.53, 37.23, 43.15, 51.64, 79.17,
126.10, 127.51, 128.68, 134.29, 153.58, 164.53, 164.76, 167.62;
MS: m/z 461.96 [M+H2O]+.
A mixture of 2,4-dioxo-3-azaspiro[5.5]undecan-3-yl N-(tert-
The other active esters given in Table 1 were prepared and char-
acterized in a similar manner.
butoxycarbonyl)-O-methyl-D-serinate Ib (Scheme 5) (3.0 g,
7.53 mmol) and benzyl amine (0.97 g, 9.05 mmol) was vigorously
stirred for 3 h at ambient temperature. After completion of the
reaction, methyl tert-butyl ether (20 mL) was added and stirred
at room temperature for 1 h. The reaction mixture was filtered,
and washed with methyl tert-butyl ether (5 mL). The filtrate was
washed with 5% aq HCl solution (10 mL), water (2 Â 10 mL), brine
(10 mL), dried over Na2SO4, and evaporated under reduced pres-
sure. The crude product solidified while standing overnight at
room temperature to yield tert-butyl (R)-(1-(benzylamino)-3-
methoxy-1-oxopropan-2-yl) carbamate Ic as a colorless solid
4.4. Synthesis of dipeptides
4.4.1. Synthesis of Boc-
A mixture of Boc- -phenyl alanine-ASUDester (Table 1, entry 6)
(3.0 g, 6.7 mmol), -phenyl alanine methyl ester hydrochloride
L-Phe-Phe-OMe (Table 2, entry 1)
L
L
(1.46 g, 6.7 mmol), and triethylamine (1.71 g, 16.9 mmol) in dry
THF (15 mL) was stirred overnight at room temperature (15 h).
After completion of the reaction, the reaction mixture was filtered
(remove TEAÁHCl salt) and washed with THF (5 mL). The filtrate
was concentrated under vacuum to obtain an oily crude. The oily
crude was dissolved in ethyl acetate, washed with 1.0% NaHCO3
solution and water. The ethyl acetate layer was dried over Na2SO4
and distilled under vacuum to give an oily crude product. The oily
crude product obtained was crystallized using ethyl acetate and
(2.1 g, 90.4%); mp 62–64 °C (lit.23 63–64 °C); [
a
]
25 = À20.8 (c 0.9,
D
CHCl3) [lit.23 À20.5]; 97.68% purity by HPLC (Method-d, Table 1);
ee%: 99.44% (Method-j, Table 1) [(R)-isomer Rt = 7.65 min; (S)-iso-
mer Rt = 8.51 min]. IR (KBr, cmÀ1): vmax 3326, 3030, 2971, 2950,
2927, 2852, 2824, 1684, 1650, 1528, 1496, 1453, 1393, 1364,
1351, 1317, 1284, 1252, 1227, 1171, 1115, 1095, 1046, 1021,
919, 870, 750, 697, 652; 1H NMR (300 MHz, CDCl3): dH 1.43
hexanes to yield Boc-L-Phe-Phe-OMe as a white crystalline solid