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J. Spengler et al.
PAPER
(MgSO4) and evaporated. Triturating with pentane gave a crystal-
line powder, which was washed with pentane (2 30 mL). Filtration
and drying in vacuo gave 6 as a white crystalline powder. Yield:
1.74 g (47%); mp 183–186 °C; [ ]D25 –101.8 (c = 1.0, CHCl3); ee
>99.9% (HPLC).
1H NMR (200 MHz, acetone-d6): = 3.05 (1 H, m, CH2), 3.24 (1
H, m, CH2), 5.04 (1 H, m, CH), 5.11 (1 H, s, CHCO2H), 7.29–7.58
(4 H, m, C6H4).
1H NMR (200 MHz, DMSO-d6): = 2.68 (1 H, m, CH2Phe), 2.93 (3
H, m, CHCH2, CH2Phe), 4.14 (1 H, m, CH), 4.47 (1 H, m, CHPhe),
4.55 (1 H, s, CHCO2H), 7.00–7.43 (10 H, m, C6H4, C6H5 and
CONH2), 7.67 (1 H, s, CONH2), 8.58 (1 H, m, CONH).
13C NMR (50 MHz, DMSO-d6): = 30.2 (CHCH2), 37.6 (CH2Phe),
52.3 (CH), 54.0 (CHPhe), 57.7 (CHCO2H), 126.0, 126.5, 127.0,
128.0, 128.2, 128.4, 129.3, 131.8, 132.4, 137.9 (C6H4 and C6H5),
170.8, 171.3, 173.0 (CONH, CONH2, CO2H).
13C NMR (50 MHz, acetone-d6): = 30.2 (CH2), 49.7 (CH), 56.4
(CHCO2H), 89.5 [m, C(CF3)2], 120.3 (q, J = 286 Hz, CF3), 121.5
(q, J = 294 Hz, CF3), 127.6, 127.9, 128.5, 129.4, 130.7, 131.5
(C6H4), 169.8 (CO), 177.1 (CO2H).
MS (ESI+): m/z = 368.1607 ([M + H]+ requires 368.1605).
(10aS)-3,3-Bis(trifluoromethyl)-1-oxo-(1,2,3,4-tetrahydro-
isoquinolino)[2,3-c]oxazolidine (8)
Compound 5 (1.56 g, 5 mmol) and paraformaldehyde (0.3 g, 10
mmol) were dissolved in CHCl3 (2 mL)–TFA (2 mL). After 30 min
(reaction control by 19F NMR or TLC) the solvents were removed
in vacuo. Recrystallization from hexane gave 8 as a solid. Yield:
1.33 g (82%); mp 81–82 °C; [ ]D25 –114.3 (c = 1.0, CHCl3).
19F NMR (188 MHz, acetone-d6): = 0.43 (q, J = 8.6 Hz, CF3),
1.32 (q, J = 8.6 Hz, CF3).
IR (KBr): = 1838 (C=O), 1725 cm–1.
MS (EI): m/z (%) = 369 (4) [M]+, 324 (33) [M – CO2H]+, 302 (5),
1H NMR (300 MHz, CDCl3): = 3.07 (1 H, m, CHCH2), 3.20 (1 H,
m, CHCH2), 3.89 (1 H, m, CH), 4.32 (1 H, m, CH2), 4.43 (1 H, m,
CH2), 7.12–7.28 (4 H, m, C6H4).
226 (10), 130 (100).
Anal. Calcd for C14H9F6NO4: C, 45.54; H, 2.46; N, 3.79. Found: C,
45.14; H, 2.79; N, 3.78.
13C NMR (75 MHz, CDCl3): = 31.2 (CH2CH), 47.3 (CH2), 54.1
(CH), 89.7 [m, C(CF3)2], 120.5 (q, J = 285 Hz, CF3), 121.7 (q,
J = 293 Hz, CF3), 126.6, 127.1, 127.4, 129.8, 131.2, 131.8 (C6H4),
168.6 (CO).
19F NMR (282 MHz, CDCl3): = –0.26 (q, J = 8.7 Hz, CF3), 3.76
(q, J = 8.7 Hz, CF3).
IR (KBr): = 1820 (C=O) cm–1.
MS (EI): m/z (%) = 325 (46) [M]+, 278 (6), 256 (7), 228 (39), 104
X-ray Crystallographic Data: Single crystals were grown from
CHCl3–hexane. Monoclinic, space group P21/c, T = 223 K;
a = 13.391(1) Å, b = 7.009(1) Å, c = 15.627(1) Å, = 93.77(1)°;
V = 1464.5(2) Å3; Z = 4; Dc = 1.676 gcm–3; CCD-Diffractometer
(BRUKER AXS), -scans (0.3°), 7982 data collected, 5260 inde-
pendent reflections (Rint = 0.037), structure solution by direct meth-
ods,21 anisotropic refinement22 for all nonhydrogen atoms,
hydrogen atoms refined isotropic, R1 = 0,0476; wR2 = 0,1232 [I
>2 (I)]; and R1 = 0,0647; wR2 = 0.1398 for all data.23
(100).
(5R,10aR)-3,3-Bis(trifluoromethyl)-1-oxo-(1,2,3,4-
tetrahydroisoquinolino)[2,3-c]oxazolidin-5-carboxylic Acid
(6b)
Anal. Calcd for C13H9F6NO2: C, 48.01; H, 2.79; N, 4.31. Found: C,
47.94; H, 2.84; N, 4.23.
Compound 6b was prepared analogous to 6a starting from (R)-phe-
nylalanine. [ ]D25 +110 (c = 1, CHCl3); ee >99.9% (HPLC). Other
characteristic data are in agreement with compound 6a.
(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (1)
Compound 8 (0.65 g, 2 mmol) was dissolved in a mixture of propan-
2-ol (2 mL)–H2O (2 mL) and stirred for several days. After con-
sumption of the starting material (reaction control by 19F NMR or
TLC) the solvents were removed in vacuo. Recrystallization from
EtOH–H2O gave 1 as a white solid. Yield: 0.25 g (72%); mp 304–
310 °C (Lit.1 mp 325 °C); [ ]D25 –134 (c = 1.0, 0.1 N HCl) (Lit.13
[ ]D25 –139 (c = 1.0, 0.1 N HCl).
(1S,3S)-1,2,3,4-Tetrahydroisoquinoline-1,3-dicarboxylic Acid
(3)
Compound 6a (0.74 g, 2 mmol) was dissolved in a mixture of pro-
pan-2-ol (2 mL)–H2O (2 mL) and stirred for several days. After con-
sumption of the starting material (reaction control by 19F NMR or
TLC) the solvents were removed in vacuo. Recrystallization from
EtOH–H2O gave 3 as a white solid. Yield: 0.33 g (75%); mp 209–
211 °C (dec.); [ ]D25 –27 (c = 3, DMSO).
1H NMR (200 MHz, D2O): = 3.04 (1 H, m, CHCH2), 3.22 (1 H,
m, CHCH2), 4.01 (1 H, m, CH), 5.07 (1 H, s, CHCO2H), 7.11–7.39
(4 H, m, C6H4).
MS (EI): m/z (%) = 177 (7) [M]+, 132 (100) [M – CO2H]+).
(2S)-N -[(3S)-3-(1,2,3,4-tetrahydroisoquinolyl)carbonyl]-
phenylalanine tert-Butyl Ester (9)
Compound 8 (0.65 g, 2 mmol) and (S)-phenylalanine tert-butyl es-
ter (0.67 g, 3 mmol) were dissolved in Et2O (4 mL) and stirred for
several days. After consumption of the starting material (reaction
control by 19F NMR or TLC) the precipitate was filtered and stirred
vigorously with Et2O to give 9 as a white powder. Yield: 0.53 g
(69%); mp 142–145 °C; [ ]D25 –5.3 (c = 1.0, CHCl3).
13C NMR (DMSO-d6): = 29.3 (CHCH2), 51.9 (CH2CH), 57.2
(CH), 126.1, 127.1, 128.1, 128.6, 130.0, 132.0 (C6H4), 170.1, 171.4
(2 CO2H).
MS (EI): m/z (%) = 221 (5) [M]+, 176 (59) [M – CO2H]+, 130 (100).
1H NMR (200 MHz, CDCl3): = 1.45 [9 H, s, C(CH3)3], 2.73 (1 H,
m, CH2Phe), 3.00–3.24 (3 H, m, CHCH2, CH2Phe), 3.56 (1 H, m,
CHPhe), 3.85 (1 H, m, CH2), 3.96 (1 H, m, CH2), 4.79 (1 H, m, CH),
7.04–7.27 (9 H, m, C6H4, C6H5), 7.70 (1 H, m, CONH).
Anal. Calcd for C11H11NO4 1.5H2O: C, 57.38; H, 5.25; N, 6.08.
Found: C, 57.20; H, 5.01; N, 5.77.
(2S)-N -[(1S,3S)-3-(1-Carboxy-1,2,3,4-tetrahydroisoquinolyl)-
carbonyl]phenylalanine Amide (7)
13C NMR (50 MHz, CDCl3): = 28.5 [C(CH3)3], 31.4 (CHCH2),
38.6 (CH2Phe), 47.6 (CH2), 53.6 (CHPhe), 56.7 (CH), 82.7 [C(CH3)3],
126.0, 126.7, 127.1, 127.4, 128.8, 129.5, 130.0, 134.8, 136.7, 136.8
(C6H4, C6H5), 171.2 (CONH), 173.2 (CO2Bu-t).
Compound 6a (0.74 g (2 mmol) and (S)-phenylalanine amide (0.48
g, 3 mmol) were dissolved in propan-2-ol (4 mL) and stirred for sev-
eral days. After consumption of the starting material (reaction con-
trol by 19F NMR or TLC) the precipitate was filtered and
recrystallized (EtOH–H2O) to give 7. Yield: 0.34 g (47%); mp 218–
221 °C; [ ]D25 –43 (c = 0.8, DMSO).
MS (EI): m/z (%) = 380 (20) [M]+, 324 (71), 132 (100).
Anal. Calcd for C23H28N2O3: C, 72.60; H, 7.42; N, 7.36. Found: C,
72.84; H, 7.29; N, 7.72.
Synthesis 2001, No. 10, 1513–1518 ISSN 0039-7881 © Thieme Stuttgart · New York