Conformationally Constrained Serine Analogues
J . Org. Chem., Vol. 65, No. 19, 2000 6141
δ 8.03-7.40 (m, 5 H), 6.46-6.34 (m, 2 H), 4.49 (d, J ) 2.0, 1
H), 3.92 (q, J ) 7.1, 2 H), 3.22 (bs, 1 H), 2.89 (bs, 1 H), 2.68 (d,
J ) 9.2, 1 H), 1.92 (dq, J ) 1.8, 3.5, 9.2, 1 H), 1.05 (t, J ) 7.1,
3 H); 13C NMR δ 14.1, 47.6, 47.7, 53.6, 64.5, 73.1, 83.9, 126.1,
128.0, 128.7, 132.8, 135.0, 136.3, 154.9, 161.9, 178.9. Anal.
Calcd: C, 66.05; H, 5.23; N, 4.28. Found: C, 65.91; H, 5.30; N
4.19.
mp 140 °C (dec) (CH2Cl2); IR νmax 3400-3200, 1695, 1620 cm-1
1H NMR (DMSO-d6) δ 8.15 (s, 1 H, exch.), 7.81-7.39 (m, 5 H),
6.14 (bs, 2 H), 6.00-5.60 (bm, 2 H, exch.), 4.35 (bs, 1 H), 3.58
(bs, 1 H), 2.71 (bs, 1 H), 1.89 (d, J ) 9.2, 1 H), 1.64 (d, J ) 9.2,
1 H); 13C NMR δ 45.8, 47.3, 49.3, 64.8, 74.1, 127.3, 128.8, 132.3,
133.4, 135.5, 136.3, 168.8, 172.3. Anal. Calcd: C, 65.92; H, 5.53;
N; 5.13. Found: C, 65.83; H, 5.61; N 5.00.
;
(1R *,2S *,3R *,4S *)-2-Be n zoyla m in o-3-e t h oxyca r b o-
n yloxybicyclo [2.2.1]h ep t-5-en e-2-ca r boxylic a cid 5: mp
Gen er a l P r oced u r e for th e Hyd r ogen a tion Rea ction .
The acid 5 or 6 (294 mg, 0.85 mmol) was suspended in EtOH
(50 mL) and reduced at room temperature and atmospheric
pressure with hydrogen over 10% Pd/C (91 mg, 0.85 mmol).
After 2 h the catalyst was filtered off and washed with EtOH
(10 mL). The solvent was eliminated and the solid crystallized,
giving pure compound 9 or 10.
152 °C (CH2Cl2/i-Pr2O); IR νmax 3350, 1740, 1720, 1620 cm-1
;
1H NMR δ 9.50-8.00 (bs, 1 H, exch.), 7.78-7.44 (m, 5 H), 6.99
(s, 1 H, exch.), 6.35-6.31, 6.18-6.14 (two m, 2 H), 6.02 (d, J
) 3.7, 1 H), 4.26 (q, J ) 7.1, 2 H), 3.93 (bs, 1 H), 3.39 (bs, 1
H), 1.84 (d, J ) 10.3, 1 H), 1.66 (dt, J ) 1.8, 10.3, 1 H), 1.33
(t, J ) 7.1, 3 H); 13C NMR δ 14.3, 42.7, 45.9, 49.8, 64.9, 66.8,
79.6, 127.4, 129.0, 132.1, 133.0, 135.4, 136.4, 153.2, 170.3,
171.9. Anal. Calcd: C, 62.60; H, 5.55; N, 4.06. Found: C, 62.33;
H, 5.49; N 3.84.
(1R *,2S *,3R *,4S *)-2-Be n zoyla m in o-3-e t h oxyca r b o-
n yloxybicyclo [2.2.1]h ep ta n e-2-ca r boxylic a cid 9: 296 mg,
100%; mp 143 °C (CH2Cl2/i-Pr2O); IR νmax 3350, 1695, 1630
1
cm-1; H NMR 7.87-7.46 (m, 5 H), 7.26 (s, 1 H, exch.), 5.71
(1R *,2R *,3S *,4S *)-2-Be n zoyla m in o-3-e t h oxyca r b o-
n yloxybicyclo [2.2.1]h ep t-5-en e-2-ca r boxylic a cid 6: mp
(d, J ) 4.0, 1 H), 4.28 (q, J ) 7.2, 2 H), 3.32 (bs, 1 H), 2.81 (bs,
1 H), 1.74 (d, J ) 11.0, 1 H), 1.80-1.40 (m, 5 H), 1.37 (t, J )
7.2, 3 H). Anal. Calcd: C, 62.24; H, 6.09; N, 4.03. Found: C,
62.18; H, 6.15; N 4.00.
183 °C (CH2Cl2/i-Pr2O); IR νmax 3350, 1740, 1720, 1620 cm-1
;
1H NMR δ 9.50-8.00 (bs, 1 H, exch.), 7.88-7.51 (m, 5 H), 7.00
(s, 1 H, exch.), 6.37-6.33, 6.24-6.20 (two m, 2 H), 5.46 (d, J
) 1.8, 1 H), 4.28 (q, J ) 7.1, 2 H), 3.88 (bs, 1 H), 3.08 (bs, 1
H), 2.00 (d, J ) 9.9, 1 H), 1.85 (dq, J ) 1.8, 3.5, 9.9, 1 H), 1.34
(t, J ) 7.1, 3 H); 13C NMR δ 14.3, 45.6, 47.5, 47.7, 65.0, 66.1,
78.8, 127.4, 129.0, 132.7, 132.9, 135.6, 136.5, 153.2, 169.7,
170.7. Anal. Calcd: C, 62.60; H, 5.55; N; 4.06. Found: C, 62.48;
H, 5.54; N 3.87.
(1R *,2R *,3S *,4S *)-2-Be n zoyla m in o-3-e t h oxyca r b o-
n yloxybicyclo [2.2.1]h ep ta n e-2-ca r boxylic a cid 10: 296
mg, 100%; mp 189 °C (CH2Cl2/i-Pr2O); IR νmax 3300, 1705,
1
1690, 1620 cm-1; H NMR 7.86-7.50 (m, 5 H), 7.56 (s, 1 H,
exch.), 5.57 (d, J ) 1.5, 1 H), 4.27 (q, J ) 7.1, 2 H), 3.29 (bs,
1 H), 2.50 (bs, 1 H), 1.94 (d, J ) 10.2, 1 H), 1.80-1.40 (m, 5
H), 1.35 (t, J ) 7.1, 3 H). Anal. Calcd: C, 62.24; H, 6.09; N;
4.03. Found: C, 62.10; H, 6.15; N 3.98.
Gen er a l P r oced u r e for Hyd r olysis of Sp ir ooxa zolon e.
Cycloadduct 3 or 4 (327 mg, 1 mmol) was dissolved in THF (5
mL) in the presence of a catalytic amount of HCl (37%). The
solution was stirred at room temperature for 0.30 h. The
solvent was evaporated, and the solid was taken up with in
CH2Cl2 (10 mL) and dried over Na2SO4. After solvent evapora-
tion, pure acid 5 or 6 was obtained in quantitative yield (345
mg).
Gen er a l P r oced u r e for Hyd r olysis of Ca r bon a te. The
acid 5 or 6 (345 mg, 1 mmol) was suspended in an ethanolic
solution of dimethylamine (5 mL, 33%) and the solution was
refluxed for 2 h. After solvent evaporation, the residue was
taken up with a solution of HCl (10 mL, 10%) and extracted
with AcOEt (3 × 15 mL). The organic layers were dried over
Na2SO4. After recrystallization, pure compound 7 or 8 was
obtained.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am in o
Acid s 11 a n d 12. Compound 9 or 10 (174 mg, 0.50 mmol) was
suspended in HCl (5 mL, 20%) in a sealed tube and placed in
an oven at 100 °C for 15 h. After cooling, the benzoic acid that
had separated was filtered. The aqueous layer was washed
with Et2O (5 mL) and then was evaporated to dryness under
reduced pressure, affording pure amino acid 11 or 12. Amino
acid derivative was drided with P2O5 in a vacuum.
(1R*,2S*,3R*,4S*)-2-Am in o-3-h yd r oxyb icyclo[2.2.1]-
h ep ta n e-2-ca r boxylic a cid h yd r och lor id e 11: yield 90 mg,
1
93%; mp 225 °C (dec); IR νmax 1710 cm-1; H NMR (D2O/CF3-
CO2D) 4.31 (d, J ) 4.0, 1 H), 2.52 (bs, 1 H), 2.31 (bs, 1 H),
1.80 (d, J ) 11.0, 1 H), 1.63-1.15 (m, 5 H); 13C NMR (D2O) δ
16.9, 22.5, 33.2, 40.6, 44.4, 63.2, 71.5, 173.5. Anal. Calcd: C,
46.27; H, 6.80; N, 6.75. Found: C, 46.00; H, 7.01; N 6.50.
(1R*,2S*,3R*,4S*)-2-Ben zoyla m in o-3-h yd r oxyb iciclo-
[2.2.1]h ep t-5-en e-2-ca r boxylic a cid 7: yield 166 mg, 61%;
(1R*,2R*,3S*,4S*)-2-Am in o-3-h yd r oxyb icyclo[2.2.1]-
h ep t a n e-2-ca r b oxylic a cid h yd r och lor id e 12: yield 92
mp 164 °C (dec) (CH2Cl2); IR νmax 3400-3200, 1695, 1620 cm-1
;
1H NMR (DMSO-d6) δ 12.4 (bs, 1 H, exch.), 7.85-7.37 (m, 5
H), 7.35 (s, 1 H, exch.), 6.25 (d, J ) 15.5, 1 H, exch.), 6.17-
6.13, 6.06-6.02 (two m, 2 H), 4.35 (bs, 1 H), 3.79 (bs, 1 H),
3.05 (bs, 1 H), 1.70 (d, J ) 9.7, 1 H), 1.55 (d, J ) 9.7, 1 H);
Anal. Calcd: C, 65.92; H, 5.53; N; 5.13. Found: C, 65.78; H,
5.60; N 5.05.
1
mg, 95%; mp 215 °C (dec); IR νmax 1700 cm-1; H NMR (D2O/
CF3CO2D) 4.20 (d, J ) 1.5, 1 H), 2.38 (bs, 1 H), 2.16 (bs, 1 H),
1.83 (d, J ) 11.4, 1 H), 1.58-1.10 (m, 5 H); 13C NMR (D2O) δ
22.8, 23.5, 34.5, 44.5, 45.3, 68.8, 75.5, 172.6. Anal. Calcd: C,
65.92; H, 5.53; N; 5.13. Anal. Calcd: C, 46.27; H, 6.80; N, 6.75.
Found: C, 45.93; H, 7.10; N 6.48.
(1R*,2R*,3S*,4S*)-2-Ben zoyla m in o-3-h yd r oxybycyclo-
[2.2.1]h ep t-5-en e-2-ca r boxylic a cid 8: yield 161 mg, 59%;
J O000595G