N-Methyl Amino Acids via Oxazolidinones
431
CO carbamate; 135.90, quaternary ArC; 128.48, 128.13, 127.73
5×ArC; 67.90, ArCH2; 61.56, CHCH2OH; 60.98, 60.45, NCHCO;
33.20, NCH3.
82), 288 (43), 274 (32), 256 (35), 235 (26), 218 (100), 188 (33), 174
(42). ␦H (rotamers) 10.52, s, 1H, CO2H; 7.34, s, 10H, ArH; 6.18, 6.02,
2m, 1H, NCHCO; 5.23, s, 2H, ArCH2; 2.78, s, 3H, NCH3. ␦C (rotamers)
175.30, CO2H; 157.35, CO, carbamate; 136.01, 133.58, 2×quaternary
ArC; 129.09, 128.76, 128.62, 128.45, 128.07, 127.79, 10×ArC; 67.95,
2×ArCH2; 62.46, NCHCO; 31.43, 30.97, NCH3.
N-Benzyloxycarbonyl-N-methyl-L-tyrosine (18c)
The compound was isolated as an oil (60% yield) (Found: M+H,
330.1352. C18H20NO5 requires M+H, 330.1341). max/cm–1 (NaCl)
3400–2700 (CO2H), 3092, 3067 and 3034 (CH, aromatic), 3000–2900
(CH, saturated), 1760 (C=O), 1708 (C=O, carbamate), 1509, 1454,
1402, 1218, 1018, 738, 698. [␣]D27 –47.2° (c, 1.0 in CHCl3). m/z
(e.s.m.s.) 344 (25%), 330 (M+1, 8%), 316 (14), 288 (16), 279 (54), 214
(100), 129 (24). ␦H [300 MHz, (D6)dimethyl sulfoxide, 333 K]
7.45–7.27, m, 5H, ArH; 7.24, d, JAB 8.3 Hz, 2H, ArH; 7.10, d, J 8.3 Hz,
2H, ArH; 5.04, d, JAB 10.0 Hz, 1H, ArCHH; 5.01, d, JAB 10.0 Hz, 1H,
ArCHH; 4.84–4.77, m, 1H, NCHCO; 3.29–3.01, m, 2H, CH2PhOH;
2.78, s, 3H, NCH3. ␦C [75 MHz, (D6)dimethyl sulfoxide, 333 K,
rotamers] 171.07, CO2H; 155.24, 152.39, 149.14, carbamate CO, C 6;
136.43, 135.34, 134.76, 2×quaternary ArC; 129.35, 129.08, 128.02,
127.94, 127.76, 127.59, 127.13, 126.75, 5×ArC; 120.08, C 4; 114.83,
C 5; 65.96, ArCH2; 59.83, NCHCO; 33.40, CH2PhOH; 31.28, NCH3.
N␣–Benzyloxycarbonyl-N␣-methyl-N -phthaloyl-L-lysine (18j)33
The compound was isolated as an oil (79% yield) (Found: M+H,
425.1724. Calc. for C23H25N2O6: M+H, 425.1713). max/cm–1 (NaCl)
3700–3200 (CO2H), 3091, 3064 and 3032 (CH, aromatic), 3000–2800
(CH, saturated), 1770 (C=O, Phth), 1711 (C=O, carbamate), 1439,
1398, 1368, 1326, 1213, 1154, 1088, 1046, 965, 870, 753, 721, 698.
[␣]D25 –13.7° (c, 1.0 in CHCl3). ␦H (rotamers) 8.13, m, 1H, CO2H;
7.75–7.74, 7.63–7.60, m, 4H, Phth.; 7.32–7.19, m, 5H, ArH; 5.13–5.02,
m, 2H, ArCH2; 4.74–4.72, 4.59–4.57, m, 1H, NCHCO; 3.62–3.54, m,
2H, NCHCH2; 2.82, s, 3H, NCH3; 1.99–1.94, 1.75–1.57, m, 4H,
2×CH2; 1.33–1.29, m, 2H, CH2. ␦C (rotamers) 175.46, 175.23, C 5;
168.21, C=O, Phth; 157.06, 156.29, OCON; 136.13, 136.03, quaternary
ArC; 133.74, CH, Phth; 131.73, quaternary ArC, Phth; 128.22, 127.76,
127.60, 127.45, 5×ArC; 122.98, CH, Phth; 67.39, ArCH2; 58.21, C 4;
37.30, CH2; 30.75, 30.33, NCH3; 27.98, CH2; 27.70, CH2; 23.14, CH2.
N-Benzyloxycarbonyl-N-methyl-L-glutamine (18d)
The compound was isolated as an oil (62% yield) (Found: M+H,
295.1296. C14H19N2O5 requires M+H, 295.1294). max/cm–1 (NaCl)
3500–3000 (CO2H), 3349 and 3220 (NH2), 3094, 3069 and 3044 (CH,
aromatic), 3000–2900 (CH, saturated), 1680 (C=O), 1612, 1454, 1403,
1321, 1187, 1145, 771, 698. [␣]D28 –17.6° (c, 1.0, CHCl3). m/z (e.s.m.s.)
296 (M+2, 22%), 295 (M+1, 100), 277 (14), 251 (18), 204 (23), 186
(13), 161 (17). ␦H (rotamers) 9.70, s, 1H, CO2H; 7.30, s, 5H, ArH; 6.80,
6.35, 6.04, 3s, 2H, CONH2; 5.09, s, 2H, ArCH2; 4.73, 4.62, 2m, 1H,
NCHCO; 2.80, s, 3H, NCH3; 2.24, 2.04, 2m, 4H, CH2CH2CONH2. ␦C
(rotamers) 176.78, 176.41, CO2H; 174.40, CONH2; 157.40, C=O, car-
bamate; 136.19, quaternary ArC; 128.51, 128.14, 127.95, 127.73,
ArC; 67.79, ArCH2; 58.48, NCHCO; 32.18, 31.07, NCH3; 24.36,
CH2CONH2; 20.76, CH2CH2CONH2.
CF3COOH/Et3SiH Reductive Cleavage of the Threonine
Oxazolidinone (7b)
The oxazolidinone (7b) (1.71 g, 6.4 mmol) was dissolved in chloro-
form (32 ml) in a round-bottom flask followed by addition of trifluo-
roacetic acid (32 ml) and triethylsilane (3.0 ml, 19.2 mmol) and the
mixture was left to stir for 3 days. The reaction mixture was concen-
trated from ethanol (×3) under reduced pressure. The residue was taken
up in a mixture of ether (50 ml) and 5% sodium bicarbonate solution (50
ml). The ethereal solution was extracted with 5% sodium bicarbonate
solution (2×20 ml). The combined aqueous layers were washed with
ether (2×20 ml) and the aqueous layer was then acidified with 5 mol
dm–3 HCl to pH 2 and extracted with ethyl acetate (3×20 ml). The com-
bined ethyl acetate layers were dried (MgSO4), filtered and concen-
trated to give an oil. The oil was further purified by silica gel
chromatography, with CHCl3/MeOH/Acetic acid (95: 4.9: 0.1) as the
eluting solvent to afford firstly the by-product (8b)32 as an oil (540 mg,
32%). max (NaCl)/cm–1 3400–2700 (CO2H), 3094, 3064 and 3035 (CH,
aromatic), 3000–2800 (CH, saturated), 1715 (C=O), 1500, 1424, 1358,
1219, 1150, 1107, 973, 766, 698; [␣]D29 –70.9° (c, 1.0 in CHCl3). m/z
(e.s.m.s.) 288 (M+Na, 74%), 266 (M+1, 100), 238 (17), 222 (24), 219
(19). ␦H 10.30, s, 1H, CO2H; 7.32, m, 5H, ArH; 5.16, m, 3H, ArCH2,
NCHHO; 4.84, m, 1H, NCHHO; 4.29–4.21, m, 1H, CH3CHOH;
4.05–4.01, m, 1H, NCHCO; 1.44, d, J 6.1 Hz, 3H, CH3. ␦C (rotamers)
174.29, 173.77, CO2H; 153.54, 152.91, carbamate CO; 135.58, quater-
nary ArC; 128.39, 128.18, 127.95, 127.61, 5×ArC; 79.28, 79.04, 78.44,
NCH2O; 67.75, ArCH2; 67.50, CH3CHOH; 63.26, NCHCO; 18.32,
CH3. Further elution gave N-Cbz N-methyl-L-threonine (18b) as an oil
(600 mg, 35%). max/cm–1 (NaCl) 3600–3250 (CO2H), 3094, 3069 and
3035 (CH, aromatic), 3000–2900 (CH, saturated), 1725 (C=O, acid),
1680 (C=O, carbamate), 1454, 1403, 1310, 1157, 1028, 981, 881, 771,
698. [␣]D30 –28.2° (c, 1.0 in CHCl3). m/z (e.s.m.s.) 268 (M+1, 100%),
224 (28), 214 (13). ␦H (rotamers) 7.56, s, 1H, CO2H; 7.36, s, 5H, ArH;
5.14, s, 2H, ArCH2; 4.61, s, 1H, CHOHCH3; 4.48–4.39, m, 1H,
NCHCO; 3.04, m, 3H, NCH3; 1.27–1.17, m, 3H, CH3. ␦C (rotamers)
172.86, CO2H; 157.88, 156.70, CO carbamate; 135.94, quaternaryArC;
128.33, 127.93, 127.70, 127.47, 5×ArC; 67.82, ArCH2; 66.95, CHOH;
64.56, 63.40, NCHCO; 33.94, 33.19, NCH3; 19.29, CH3.
N-Benzyloxycarbonyl-N-methyl-DL-glutamic Acid (18e)35
The compound was isolated as an oil (63% yield) (Found: M+H,
296.1126. Calc. for C14H18NO6: M+H, 296.1134). max/cm–1 (NaCl)
3500–2750 (CO2H), 3093, 3066 and 3035 (CH, aromatic), 3000–2900
(CH, saturated), 1710 (C=O), 1486, 1453, 1405, 1322, 1189, 1143, 770,
698. m/z (e.s.m.s.) 296 (M+1, 100%), 277 (23), 252 (41), 204 (37), 160
(26). ␦H (rotamers) 10.42, s, 2H, 2×CO2H; 7.20, s, 5H, ArH; 4.99, s, 2H,
ArCH2; 4.65–4.61, 4.52–4.49, 2m, 1H, NCHCO; 2.74, s, 3H, NCH3;
2.24–2.17, 1.92–1.86, 2m, 4H, CH2CH2CO2H. ␦C (rotamers) 175.13,
174.98, 172.85, 2×CO2H; 156.60, 156.00, CO carbamate; 136.06, qua-
ternary ArC; 128.01, 127.49, 127.13, 5×ArC; 66.96, ArCH2; 57.78,
NCHCO; 30.95, 30.41, 30.24, NCH3; 23.75, 23.45, CH2CH2CO2H.
4-Benzyl Hydrogen N-Benzyloxycarbonyl-N-methyl-L-aspartate (18f)
The compound was isolated as an oil (65% yield) (Found: M+H,
372.1439. C20H22NO6 requires M+H, 372.1447). max/cm–1 (NaCl)
3600–3250 (CO2H), 3092, 3064 and 3033 (CH, aromatic), 3000–2900
(CH, saturated), 1735 (C=O, acid), 1702, 1681 (C=O), 1454, 1401,
1316, 1261, 1167, 1001, 737, 697. m/z (e.s.m.s.) 372 (M+1, 12%), 342
(12), 288 (57), 274 (44), 218 (100), 188 (67), 174 (33). ␦H 7.25, 7.24,
2s, 10H, ArH; 5.11–4.39, 4.75, 2m, 5H, NCHCO, 2×ArCH2; 3.12–3.07,
2.84–2.73, 2m, 5H, CH2CO2Bn, NCH3. ␦C (rotamers) 176.07, CO2H;
171.34, 170.91, COOCH2; 157.16, C=O, carbamate; 136.18, 135.61,
2×quaternary ArC; 128.33, 128.09, 127.86, 127.69, 10×ArC; 67.67,
67.41, 66.48, 2×ArCH2; 58.46, 57.37, NCHCO; 35.19, 34.46,
CH2CO2Bn; 33.23, NCH3.
Hydrogenolysis of the N-t-Butoxycarbonyloxazolidin-5-one (13)
A sample of the oxazolidinone (13) (2.21 g, 6.3 mmol) was dis-
solved in methanol (150 ml) and 10% Pd-on-charcoal catalyst (165 mg)
was added, and the resulting solution was stirred in a hydrogen atmo-
sphere for 3 days. Only half the theoretical amount of hydrogen was
absorbed. The solution was filtered through a sintered glass funnel to
remove the catalyst and the filtrate was concentrated under vacuum to
give an oil, which contained two compounds by t.l.c.. The mixture was
N-Benzyloxycarbonyl-N-methyl-L-phenylglycine (18g)
The compound was isolated as an oil (64% yield). max/cm–1 (NaCl)
3400–2750 (CO2H), 3094, 3069, 3033 (CH, aromatic), 3000–2900
(CH, saturated), 1746 (C=O, acid), 1697 and 1674 (C=O), 1586, 1454,
1399, 1361, 1311, 1149, 1080, 1049, 972, 916, 769, 699, 649, 616. [␣]D28
+120.1° (c, 1.0 in CHCl3). m/z (e.s.m.s.) 322 (M+Na, 13%), 300 (M+1,