8
V. Tolman, P. Sedmera / Journal of Fluorine Chemistry 101 (2000) 5±10
J 32.0, 14.6, 6.7, 3.9 Hz, H-3d), 4.090 (1 H, d, 8.2, 6.7 Hz,
H-2), 4.910 (1 H, ddd, J 49.5, 8.9, 3.9, H-4), 7.129 (1 H, d,
J 8.2 Hz, 2-NH), 7.499 (1 H, s, amide NH), 7.605 (1 H, s,
amide NH). 13C NMR (d6-DMSO): 28.25 Q (3 C, t-Bu),
34.37 Td (JC,F 21.1 Hz, C-3), 50.21 Dd (JC,F 2.4 Hz,
C-2), 78.31 S (C-Me3), 88.59 Dd (JC,F 183.7 Hz, C-4),
155.35 S (OCONH), 171.06 Sd (JC,F 20.1 Hz, C-5),
173.15 S (C-1). 19F NMR (d6-DMSO): 193.2 m.
Analysis: Calculated for C10H17FN2O5 (264.26): C,
45.45; H, 6.49; N, 10.60%. Found: C, 45.49; H, 6.50; N,
10.31%.
1H NMR (D2O): 2.421±2.592 (2 H, m, 2 Â H-3), 3.977 (1
H, dd, J 6.0, 5.8 Hz, H-2), 5.198 (1 H, ddd, J 48.8, 8.4,
4.1 Hz, H-4). 13C NMR (D2O): 35.89 Td (JC,F 20.8 Hz,
C-3), 54.57 D (C-2), 91.37 Dd (JC,F 183.7 Hz, C-4),
175.83 S (C-1), 176.81 Sd (JC,F 63.0 Hz, C-1). 19F
NMR (D2O): 186.3 (ddd, J 48.8, 30.3, 22.9 Hz).
Analysis: Calculated for C5H9FN2O3 (164.14): C, 36.59;
H, 5.52; F, 11.57; N, 17.07%. Found: C, 36.30; H, 5.28; F,
11.50; N, 16.91%.
3.6. Trans-4-fluoro-5-pyrrolidone-2-carboxamide (9a)
3.3. Threo-Na-(t-Butyloxycarbonyl)-4-fluoroglutamine
(6b)
To the erythro-dimethyl ester hydrochloride 8a (918 mg,
4 mmol), dissolved in dry methanol (3 ml), triethylamine
(445 mg, 4.4 mmol) was added, after 5 min the mixture was
diluted with dry ether (25 ml) and the suspension was kept
in the freezer for 3 h. The ®ltered solution was taken to
dryness, the free oily diester was dissolved in saturated
methanolic ammonia (5 ml) and allowed to stand overnight.
After evaporation a semisolid material resulted, which was
again dissolved in methanolic ammonia (5 ml) and the
whole operation was repeated. Yield, 498 mg (85%), m.p.
140±1458C (from water).
Using the same procedure as for 6a, the compound 6b
was prepared on 1 mmol scale in a yield of 150 mg (57%) of
a white foam.
1H NMR (d6-DMSO): 1.386 (9 H, s, t-Bu), 2.021±2.137
(2 H, m, 2 Â H-3), 4.036 (l H, dt, J 8.6, 7.4 Hz, H-2),
4.479 (1 H, ddd, J 50.3, 9.8, 3.2 Hz, H-4), 7.153 (1 H, d,
J 8.6 Hz, 2-NH), 7.436 (1 H, s, amide NH), 7.603 (1 H, s,
amide NH).
1H NMR (d6-DMSO): 2.288 (1 H, dddd, J 13.8, 13.7,
8.4, 6.7 Hz, H-3u), 2.384 (1 H, dddd, J 13.9, 13.7, 7.8,
3.1, H-3d), 4.059 (1 H, ddd, J 8.4, 4.5, 3.1 Hz, H-2), 5.107
(1 H, ddd, J 53.7, 7.8, 6.7 Hz, H-4), 7.200 (1 H, s, amide
NH), 7.592 (1 H, s, amide NH), 8.446 (1 H, s, pyrrolidone
NH). 13C NMR (d6-DMSO): 32.68 Td (JC,F 20.1 Hz,
No analysis was performed.
3.4. Erythro-4-fluoroglutamine (2a)
A solution of 6a (124 mg, 0.47 mmol) in tri¯uoroacetic
acid (1 ml) was allowed to stand for 1 h at 208C, evaporated
in vacuo, dissolved in water (1 ml), applied on a small
C-3), 52.70 Dd (JC,F 4.0 Hz, C-2), 88.16 Dd (JC,F
179.1 Hz, C-4), 171.80 Sd (JC,F 19.8 Hz, C-5), 173.41
Sd (JC,F 2.1 Hz, C-1). 19F NMR (d6-DMSO): 184.7
(ddd, J 53.7, 13.9, 13.8, 4.5 Hz).
column of Dowex 50 Â 8 (H cycle, 200±400 mesh,
0.9 Â 4.0 cm), washed with water and the product eluted
with 5% aqueous ammonia. The ninhydrin-positive frac-
tions were pooled, evaporated and dried in vacuo over
phosphorus pentoxide. Yield, 71 mg (92%), m.p. 165±
1688C. Recrystallization may be achieved by dissolution
in hot water (1 ml) and rapid cooling; 41 mg (53%) of
crystals, m.p. 173±1758C were recovered.
Analysis: Calculated for C5H7FN2O2 (146.13): C, 41.09;
H, 4.83; F, 13.00; N, 19.45%. Found: C, 41.25; H, 4.69; F,
12.78; N, 19.47%.
3.7. Cis-4-fluoro-5-pyrrolidone-2-carboxamide (9b)
1H NMR (D2O): 2.355 (1 H, dddd, J 15.6, 15.6, 10.2,
7.1 Hz, H-3u), 2.577 (1 H, dddd, J 37.6, 15.6, 6.0, 3.0 Hz,
H-3d), 3.957 (1 H, dd, J 7.1, 6.0 Hz, H-2), 5.278 (1 H,
ddd, J 48.9, 10.2, 3.0 Hz, H-4). 13C NMR (D2O): 36.25
Td (JC,F 20.2 Hz, C-3), 54.88 Dd (JC,F 1.8 Hz, C-2),
In the same way as used for 9a, the threo-dimethylester
hydrochloride 8b was converted into 9b in a yield of 355 mg
(81%), m.p. 204±2068C (water).
1H NMR (d6-DMSO): 1.914 (1 H, dddd, J 27.9, 13.4,
6.8, 6.7 Hz, H-3u), 2.759 (1 H, dddd, J 13.4, 12.7, 8.2,
7.4, H-3d), 3.912 (1 H, ddd, J 7.4, 6.8, 3.3 Hz, H-2), 5.060
(1 H, ddd, J 53.1, 8.2, 6.7 Hz, H-4), 7.179 (1 H, s, amide
NH), 7.496 (1 H, s, amide NH), 8.398 (1 H, s, pyrrolidone
NH). 13C NMR (d6-DMSO): 32.19 Td (JC,F 19.5 Hz,
91.77 Dd (JC,F 184.3 Hz, C-4), 176.42 Sd (JC,F
67.2 Hz, C-5), 178.10 S (C-1). 19F NMR (D2O): 186.4
(ddd, J 48.9, 37.6, 15.6 Hz).
Analysis: Calculated for C5H9FN2O3 (164.14): C, 36.59;
H, 5.52; F, 11.57; N, 17.07%. Found: C, 36.41; H, 5.59; F,
11.32; N, 17.19%.
C-3), 51.88 Dd (JC,F 4.0 Hz, C-2), 88.10 Dd (JC,F
180.7 Hz, C-4), 171.20 Sd (JC,F 20.1 Hz, C-5), 172.67
S (C-1). 19F NMR (d6-DMSO): 184.2 (ddd, J 53.1,
27.9, 12.7, 3.3 Hz). Cis-con®guration follows from the
ROESY crosspeak between H-2 and H-4.
3.5. Threo-4-fluoroglutamine (2b)
Analysis: Calculated for C5H7FN2O2 (146.13): C, 41.09;
H, 4.83; F, 13.00; N, 19.45%. Found: C, 40.87; H, 4.99; F,
12.92; N, 19.63%.
Following the same procedure, the crude compound 6b
(150 mg, 0.57 mmol) was deprotected to give 69 mg (74%)
of crystalline 2b, m.p. 168±1698C (from aqueous ethanol).