N-Methyl Amino Acids
and the residue was purified by column chromatography,
concentrated at reduced pressure and the residue was taken
up in ether. The ethereal solution was extracted with saturated
aqueous sodium bicarbonate solution (3 × 10 mL). The
combined aqueous extracts were acidified with dilute hydro-
chloric acid and extracted with dichloromethane (3 × 20 mL).
The extracts were dried (MgSO4), filtered, and evaporated at
reduced pressure. The residue was purified by column chro-
matography, eluting with 95:5:0.5:0.2 chloroform-methanol-
water-acetic acid to give first the â-carboline 74 as an oil (340
mg, 68%). The â-carboline can be converted to the tert-
butylammonium salt 75 by taking it up in ether and adding
an equivalent of tert-butylamine. The precipitated tert-butyl-
ammonium salt 75 can be recrystallized from hot methanol.
eluting with 80% ethyl acetate-dichloromethane to afford the
oxazolidinone 66 as a colorless foam (750 mg, 67%). [R]22
D
+117.8° (c 1.0, CH2Cl2). 1H NMR [300 MHz, d6-DMSO, 298
K] δ 9.76 (s, 1H), 7.93-7.34 (m, 8H), 5.35 (s, 2H), 4.94-4.93
(m, 4H), 4.52 (br s, 2H), 4.32 (t, 1H, J ) 5.4 Hz), 3.57-3.44
(m, 2H), 3.27 (s, 1H), 1.90-1.25 (br s, 4H). 1H NMR [300 MHz,
d6-DMSO, 333 K] 9.60 (s, 1H), 7.86-7.31 (m, 8H), 5.26 (dd,
2H, J ) 20.0, 4.1 Hz), 4.90 (d, 2H, J ) 1.2 Hz), 4.84 (s, 2H),
4.54 (m, 2H), 4.28 (t, 1H, J ) 5.6 Hz), 4.04 (t, J ) 6.4 Hz),
3.24-3.18 (m, 2H), 1.58-1.39 (m, 4H). 13C NMR [75 MHz, d6-
DMSO, 298 K] δ 172.45, 153.74, 152.75, 143.67, 143.59, 140.87,
127.73, 127.21, 124.98, 120.14, 77.75, 77.55, 73.26, 66.82,
54.33, 46.61, 44.98, 26.87, 22.38. 13C NMR [75 MHz, d6-DMSO,
333 K] δ 171.95, 153.84, 152.44, 143.41 and 143.32, 140.62,
127.39, 126.85, 124.59, 124.56, 119.73, 77.34, 72.99, 66.57,
53.98, 46.49, 44.79, 26.69, 22.17. IR (KBr disk) ν 3289 (OH),
3066, 3041, 3015 and 3007 (CH, aromatic), 3000-2800 (CH,
saturated), 1798 (CdO, oxazolidinone), 1713 (CdO, carbam-
ate), 1588, 1557, 1412, 1346, 1196, 1136, 1048, 940, 742, 709
cm-1. HRMS calcd for C24H26N5O7 (M + H) 498.1842, found
496.1816.
Mp 162-165 °C. [R]24 +41.3° (c 1.0, MeOH). 1H NMR [300
D
MHz, d6-DMSO] δ 9.68, 9.32 and 8.21-7.93 (2 × br s and m,
4H), 7.48-7.23 (m, 9H), 5.17-4.71 (m, 5H), 3.44-3.39 (m, 1H),
2.78-2.72 (m, 1H), 1.06 (s, 9H). 13C NMR (75 MHz, CDCl3)
(rotamers) δ 172.56, 159.08, 155.94, 155.77, 137.14, 136.06,
135.27, 130.34, 128.33, 127.70, 127.62, 127.42, 127.18, 123.75,
118.41, 114.77, 110.76, 66.07, 54.19, 50.06, 42.12, 27.19, 23.44,
23.21. IR (KBr disk) ν 3000-2800 (CH, saturated), 2743, 2636
and 2554 (NH3+), 1711 (CdO, carbamate), 1637 (CO2-), 1568,
1422, 1386, 1358, 1301, 1222, 1102, 1066, 748, 697 cm-1. Anal.
Calcd for C25H29N3O5: C, 66.50; H, 6.47; N, 9.31. Found: C,
66.67; H, 6.54; N, 9.20. Further elution afforded the N-methyl
(2S)-2-[(9H-Flu or en -9-ylm eth ylm eth oxycar bon yl)-m eth -
yl-am in o]-5-[h ydr oxym eth yl-(2-oxy-6H-[1,2,3,5]oxatr iazin -
4-yl-a m in o)p en ta n oic Acid (68). The oxazolidinone 66 (100
mg, 0.2 mmol) was dissolved in dichloromethane (4 mL),
triethylsilane (0.3 mL) was added followed by trifluoroacetic
acid (4 mL), and the reaction mixture was stirred under a
nitrogen atmosphere overnight. The mixture was concentrated
at reduced pressure. The residue was purified by column
chromatography, eluting with 10% methanol-dichloromethane,
to afford the N-methyl compound 68 as a colorless foam (60
tryptophan 73 as a solid (110 mg, 22%). Mp 129-130 °C. [R]25
D
1
-49.6° (c 0.5, CHCl3). H NMR (300 MHz, CDCl3) (rotamers)
δ 9.35, 8.83 and 8.38-8.36 (2 × br s and m, 2H), 7.63-6.94
(m, 9H), 5.14-5.01 (m, 3H), 3.50-3.09 (m, 2H), 2.89-2.83 (m,
3H). 13C NMR (75 MHz, CDCl3) (rotamers) δ 175.25, 159.41,
156.88, 155.94, 136.29, 135.92, 134.33, 130.96, 128.52, 128.19,
127.79, 125.55, 124.89, 124.67, 124.21, 122.75, 119.75, 118.58,
116.26, 109.71, 67.83, 67.71, 58.66, 58.39, 31.97, 31.81, 24.68,
24.16. IR (KBr disk) ν 3600-3200 (CO2H), 3091 and 3056 (CH,
aromatic), 3000-2800 (CH, saturated), 1749 (CdO, acid), 1675
(CO, carbamate), 1605, 1459, 1392, 1319, 1251, 1191, 1135,
983, 795, 755, 699 cm-1. Anal. Calcd for C21H20N2O5: C, 66.31;
H, 5.30; N, 7.36. Found: C, 66.20; H, 5.39; N, 7.16.
mg, 60%). [R]22 -12.9° (c 1.0, CH2Cl2). 1H NMR [300 MHz,
D
d6-DMSO, 300 K] δ 9.60 (s, 1H), 7.84-7.26 (m, 8H), 4.90 (s,
2H), 4.88 (s, 2H), 4.35-3.97 (m, 4H), 3.30 (s, 2H), 2.72 (s, 3H),
1.70-1.40 (m, 4H). 13C NMR [75 MHz, d6-DMSO, 300 K] δ
171.97, 155.63, 153.90, 143.64 and 143.59, 140.54, 127.30,
126.76, 124.65, 119.70, 77.41, 73.04, 66.56, 57.94, 46.62, 44.95,
30.16, 25.10, 24.05. IR (KBr disk) ν 3700-2700 (COOH), 3300-
3200 (dNH), 3064, 3039, 3018 and 3009 (CH, aromatic), 1739
(CdO), 1696 (CdO, carbamate), 1589, 1555, 1451, 1409, 1315,
1263, 1195, 1158, 1131, 1028, 992, 760, 741 cm-1. HRMS calcd
for C24H28N5O7 (M + H) 498.1989, found 498.1969.
(S)-3-Ca r bon ylben zyloxy-4-[1-ca r bon ylben zyloxy-2,3-
d ih yd r oin d ol-3(R,S)-ylm eth yl]oxa zolid in -5-on e (77). The
dihydrotryptophan 7630 (2.0 g, 4.2 mmol) was dissolved in
toluene (100 mL) and the solution was treated with camphor-
sulfonic acid (60 mg) and paraformaldehyde (5 g) and heated
at reflux for 1 h. The clear solution was concentrated in vacuo
and the residue was taken up in ethyl acetate and washed
with saturated aqueous sodium bicarbonate solution. The
organic layer was dried (MgSO4), filtered, and evaporated at
reduced pressure to give a tan oil (1.56 g). The oil was purified
by column chromatography, eluting with 20% ethyl acetate-
hexane, to give the oxazolidinone 77 as a colorless oil (1.38 g,
(S)-3-Ca r bon ylben zyloxy-4-(1-for m yl-1H-in d ol-3-ylm e-
th yl)oxa zolid in -5-on e (72). A mixture of the tryptophan
carbamate 71 (3.0 g, 8.2 mmol), benzene (200 mL), camphor-
sulfonic acid (100 mg), and paraformaldehyde (5 g) was heated
to reflux for 1.5 h. The reaction mixture was concentrated
under reduced pressure and the residue was taken up in ether.
The ethereal layer was washed with saturated aqueous sodium
bicarbonate solution, dried (MgSO4), filtered, and concentrated
in vacuo to give an oil. The oil was further purified by column
chromatography, eluting with 60% ether-hexane, to give the
1
67%). H NMR (300 MHz, CDCl3) δ 7.89-6.93 (m, 14H), 5.53
(br s, 1H), 5.26-5.09 (m, 5H), 4.22-4.18 and 3.78-3.35 (2 ×
m, 4H), 2.31-2.12 (m, 2H). 13C NMR (75 MHz, CDCl3) δ
171.71, 153.18, 152.78, 142.01, 136.16, 135.01, 132.87, 128.65,
128.49, 128.32, 128.12, 127.98, 123.86, 122.70, 114.84, 77.63,
68.21, 68.11, 66.92, 53.56, 53.16, 36.76, 36.38, 35.66. IR (NaCl)
ν 3000-2800 (CH, saturated), 1798 (CdO, oxazolidinone), 1712
(CO, carbamate), 1599, 1457, 1412, 1347, 1261, 1140, 1032,
752 cm-1. Anal. Calcd for C28H26N2O6: C, 69.12; H, 5.39; N,
5.76. Found: C, 69.37; H, 5.67; N, 5.57.
oxazolidinone 72 as a colorless foam (2.67 g, 86%). [R]25
D
+154.0° (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 9.31, 8.89
and 8.33-8.31 (2 × br s and m, 2H), 7.58-7.04 (m, 9H), 5.21
(br s, 3H), 4.59-4.46 (m, 2H), 3.57-3.22 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 171.73, 159.13, 155.53, 152.36, 135.25,
134.07, 130.74, 128.65, 125.40, 124.67, 124.27, 120.91, 119.68,
118.70, 116.69, 115.91, 109.49, 77.81, 67.86, 55.64, 26.11,
25.06. IR (KBr disk) ν 3100 and 3063 (CH, aromatic), 3000-
2800 (CH, saturated), 1801 (CdO, oxazolidinone), 1712
(CdO, carbamate), 1604, 1459, 1417, 1370, 1241, 1198, 1163,
1127, 1047, 1001, 753, 696 cm-1. Anal. Calcd for C21H18N2O5:
C, 66.66; H, 4.79; N, 7.40. Found: C, 66.87; H, 5.06; N, 7.50.
N,N′-Bis-ca r bon ylben zyloxy-3(R,S)-3-[2(S)-2-ca r boxy-
2-m eth yla m in o-eth yl]-N-m eth yl-2,3-d ih yd r oin d ole (78).
To a solution of the dihydrotryptophan oxazolidinone 77 (1.2
g, 2.5 mmol) in chloroform (13 mL) was added triethylsilane
(1.2 mL) and trifluoroacetic acid (13 mL). The mixture was
left to stand for 2 d and then diluted with toluene and
concentrated under reduced pressure. The greenish residue
was chromatographed on a short silica gel column, eluting with
chloroform-methanol-water 93:6.5:0.5. The appropriate frac-
tions were collected and the solvent was removed in vacuo.
The residue was further purified by chromatography, eluting
with the same solvent system, to give the N-methyl dihydro-
(S)-N-Ca r bon ylben zyloxy-N-m eth yl-N′-for m yl-L-tr yp -
toph an (73) an d (S)-2-Car bon ylben zyloxy-9-for m yl-1,3,4,9-
tetr a h yd r o-â-ca r bolin e-3-ca r boxylic Acid ter t-Bu tyl Am -
m on iu m Sa lt (75). To a mixture of the oxazolidinone 72 (500
mg, 1.3 mmol), chloroform (8 mL), and triethylsilane (0.6 mL)
was added trifluoroacetic acid (8 mL) and the whole was left
to stand at room temperature for 2 d. The mixture was then
J . Org. Chem, Vol. 68, No. 7, 2003 2665