312 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Fisher et al.
39.0, 52.5, 52.8, 57.6, 57.8, 67.1, 67.4, 67.6, 78.0, 78.3, 78.5, 128.3,
128.8, 135.3, 135.6, 153.5, 154.0, 171.8, 172.1.
present, gHMQC assignment) δ 27.7, 28.9, 34.0, 34.6, 49.3, 49.7,
50.1, 59.4, 59.9, 82.2, 82.3, 155.6, 155.7, 170.1.
(2S,4S)-1-(tert-Butoxycarbonyl)-4-bromoproline Benzyl Ester
(6b). Compound 519 (3.22 g, 10.0 mmol) and carbon tetrabromide
(3.43 g, 10.3 mmol) were dissolved in 30 mL of dry THF (0.33
M). Then, 1,2-bis(diphenylphosphino)ethane (diphos,21 2.40 g, 6.0
mmol) was added. The reaction was allowed to stir at room
temperature for 20 h, at which time the suspension was filtered
through a pad of Celite. The pad was rinsed with THF and the
filtrate was evaporated to give a yellow oil. The crude product was
purified on a silica gel column (4.5 × 50 cm) with elution initiated
with hexanes/Et2O (4:1) and then increasing to hexanes/Et2O (1:1)
to afford 3.14 g (82%) of 6b as a clear oil: TLC Rf ) 0.16 (hexanes/
(2S,4S)-1-(tert-Butoxycarbonyl)-4-(N-benzyloxycarbonyl)ami-
noproline (9a). Compound 8a (0.37 g, 1.61 mmol) was dissolved
in H2O (∼6 mL), and then a 2 N NaOH solution (0.065 g, 1.61
mmol in 0.75 mL of H2O) was added. The reaction mixture was
cooled to 0 °C and then CbzCl (0.30 g, 1.77 mmol) was added
dropwise. One more equivalent of a 2 N NaOH solution was added
to the reaction and the reaction was stirred at 0 °C for 1 h. The
reaction mixture was stirred at room temperature overnight. The
next day another 2 equiv of 2 N NaOH and 1.1 equiv of CbzCl at
0 °C were added. The reaction mixture was stirred overnight, where
it eventually warmed to room temperature. The reaction mixture
was stirred for two more days. The reaction mixture was washed
with Et2O to remove excess CbzCl. The water layer was acidified
to pH ∼3 with solid citric acid and this solution then was extracted
with EtOAc (3×). The organic layers were combined and washed
with water and brine. They were then dried over MgSO4, filtered,
and concentrated to afford 0.47 g (80%) of a pale yellow glassy
solid: mp 59-61 °C; TLC Rf ) 0.58 (1-propanol/NH4OH, 4:1);
1
Et2O, 4:1); [R]D -41.3 (c 1.5 CH2Cl2); H NMR (CDCl3, COSY
assignment, rotamers present) δ 1.20 and 1.32 (2s, 9H), 2.24-
2.30 (m, 1H), 2.57-2.71 (m, 1H), 3.53-3.61 (m, 1 H), 3.82-3.93
(m, 1H), 4.11-4.34 (m, 2H), 4.91-5.16 (m, 2H), 7.19-7.22 (m,
5H); 13C NMR (CDCl3, HMQC assignment, rotamers present) δ
27.9, 28.3, 28.5, 40.2, 41.1, 41.8, 42.8, 55.5, 55.9, 58.2, 58.5, 67.3,
80.8, 128.4, 128.7, 128.8, 135.6, 135.8, 153.3, 153.8, 171.4, 171.7.
(2S,4S)-1-(tert-Butoxycarbonyl)-4-azidoproline Benzyl Ester
(7a). Compound 6a (0.93 g, 2.35 mmol) and NaN3 (0.70 g, 10.8
mmol) were suspended in 40 mL of dry DMF. This mixture was
heated at 55 °C in an oil bath for 18.5 h. The mixture was allowed
to cool to room temperature, whereupon it was poured into ice cold
water. The mixture was extracted with EtOAc, and the combined
organic layers were washed with H2O and brine and then dried
over MgSO4, filtered, and concentrated to give 0.78 g (96%) of 7a
as a dark oil: TLC Rf ) 0.67 (hexanes/EtOAc, 1:1); [R]D -32.2
1
[R]D -24.3 (c 1.0, CH3OH); H NMR (CDCl3, rotamers present,
gCOSY assignment) δ 1.38 and 1.43 (2s, 9H), 1.9-2.12 (m, 1H),
2.30-2.46 (m, 1H), 3.42 (t, 1H, J ) 12.3 Hz), 3.58-3.63 (m, 1H),
4.20-4.35 (m, 2H), 5.05-5.12 (m, 2H), 5.90 and 5.97 (2d, 0.75H,
J ) 7.5 and 8.4 Hz), 6.53 (br s, 0.25H, NH30), 7.26-7.30 (m, 5H),
9.33 (br s, 1H); 13C NMR (CDCl3, rotamers present, gHMQC
assignment) δ 28.5, 28.7, 34.8, 36.9, 49.9, 50.8, 52.6, 53.8, 58.0,
58.2, 67.1, 81.3, 82.0, 128.3, 128.5, 128.7, 136.4, 154.0, 155.8,
156.2, 175.3, 176.9; HRFAB MS m/z 365.1720 [M + H]+,
C18H24N2O6 + H+ requires 365.1712.
1
(c 1.5, CH2Cl2); H NMR (CDCl3, rotamers present) δ 1.31 and
1.43 (2s, 9H), 2.11-2.21 (m, 1H), 2.33-2.48 (m, 1H), 3.39-3.50
(m, 1H), 3.60-3.72 (m, 1H), 4.00-4.12 (m, 1H), 4.31 and 4.34
(2d, 0.6H, J ) 3.6 and 3.9 Hz), 4.44 and 4.47 (2d, 0.4H, J ) 3.0
and 3.6 Hz), 5.04-5.26 (m, 2H), 7.32-7.33 (5H); 13C NMR
(CDCl3, rotamers present, gHMQC assignment) δ 28.4, 28.7, 35.4,
36.4, 51.2, 51.6, 57.8, 58.1, 58.6, 59.6, 67.3, 80.7, 128.3, 128.4,
128.6, 128.7, 128.8, 135.6, 135.7, 153.6, 154.0, 171.4, 171.6; IR
(neat): 2976, 2105 (N3), 1751, 1700 cm-1.
(2S,4R)-1-(tert-Butoxycarbonyl)-4-(N-benzyloxycarbonyl)ami-
noproline (9b). The same procedures used above to make 9a were
used to convert 8b (1.0 g, 4.34 mmol) to 1.0 g (63%) of 9b as a
white foamy solid: mp 69-71 °C; TLC Rf ) 0.64 (1-propanol/
1
NH4OH, 4:1); [R]D -21.7 (c 1.32, CH3OH); H NMR (CDCl3,
rotamers present, gCOSY assignment) δ 1.37 and 1.41 (2s, 9H)
1.84-2.24 (m, 2H), 3.29-3.70 (m, 2H), 4.26-4.36 (m, 2H), 5.04
(br s, 2H), 5.56 and 5.67 (2 br s, 0.7 H, NH), 6.56 (br s, 0.3 H,
NH30), 7.29 (s, 5H), 9.76 (br s, 1H); 13C NMR (CDCl3, rotamers
present, gHMQC assignment) δ 28.5, 28.7, 35.5, 37.0, 49.7, 50.2,
51.4, 52.3, 57.7, 58.0, 81.3, 128.2, 128.4, 128.7, 136.3, 154.2, 155.2,
156.2, 175.3, 176.7; FAB MS m/z 365.1 [M + H]+.
(2S,4R)-1-(tert-Butoxycarbonyl)-4-azidoproline Benzyl Ester
(7b). Compound 6b (1.13 g, 2.94 mmol) was treated in a manner
similar to that used to convert 6a to 7a to afford 1.01 g (99%) of
7b as a yellow oil: TLC Rf ) 0.75 (CH2Cl2/MeOH, 20:1); [R]D
-49.3 (c 1.0, CH2Cl2); 1H NMR (CDCl3, rotamers present) δ 1.26
and 1.39 (2s, 9 H), 2.01-2.10 (m, 1H), 2.16-2.29 (m, 1H), 3.36-
3.61 (m, 2H), 4.04-4.08 (m, 1H), 4.28 (t, 0.6H, J ) 7.5 Hz), 4.36-
4.41 (apparent t, 0.4H, J ) 6.6 and 8.1 Hz), 4.98-5.19 (m, 2H),
7.25-7.27 (m, 5H); 13C NMR (CDCl3, rotamers present) δ 28.2,
28.3, 28.5, 35.4, 36.4, 51.4, 51.6, 57.8, 58.0, 58.9, 59.4, 67.0, 80.6,
128.6, 135.6, 135.8, 153.5, 154.1, 172.1 172.3; IR (neat): 2978,
Methyl 3(R)-[(4(S)-(4-Benzyloxycarbonylamino)-1-(tert-bu-
toxycarbonyl)-2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrro-
lidineacetate (11a). Compound 9a (0.35 g, 0.95 mmol), the TFA
salt of 3(R)-2-oxo-1-pyrrolidineacetic acid methyl ester22,23 (10, 0.27
g, 0.95 mmol), Et3N (0.33 g, 3.4 mmol), and 2-chloro-1-methylpy-
ridinium iodide (0.26 g, 1.03 mmol) were dissolved in 50 mL of
CH2Cl2. The reaction mixture was heated at reflux for 2.5 days.
The reaction mixture was allowed to cool and then it was washed
with 10% citric acid, 1 M NaHCO3, H2O, and brine. The solution
was dried over MgSO4, filtered, and then concentrated to give a
yellow oil. This oil was purified on a silica gel column (2.5 × 30
cm) by eluting initially with hexanes/EtOAc (1:1) and then
increasing to EtOAc/hexanes (5:1). Crystallization from EtOAc/
petroleum ether (bp 60-70 °C) afforded 0.30 g (61%) of 11a: mp
92-95 °C; [R]D -25.0 (c 0.5, MeOH); 1H NMR (CD3OD, gCOSY
assignment, rotamers present) δ 1.44 (s, 9H), 1.86-2.11 (m, 2H),
2.39-2.61 (m, 2H), 3.25-3.31 (m, 1H), 3.42-3.50 (m, 2H), 3.71-
3.79 (m with s at 3.71, 4H), 3.99 (br d, 1H, J ) 18 Hz), 4.15-
4.25 (m, 3H), 4.43-4.49 (m, 1H), 5.01-5.10 (m, 2H), 7.33-7.34
(m, 5H); 13C NMR (CD3OD, gHMQC assignment, rotamers present)
δ 25.8, 27.1, 27.5, 27.8, 35.3, 36.6, 44.2, 44.7, 49.3, 50.1, 51.0,
51.6, 52.1, 52.7, 59.4, 66.3, 80.5, 80.85, 127.7, 128.0, 128.3, 137.0,
154.6, 156.9, 169.4, 173.3, 174.4; ESI MS m/z 541.2 [M + Na]+.
Anal. (C25H34N4O8) C, H, N.
2105 (N3), 1748, 1701 cm-1
.
(2S,4S)-1-(tert-Butoxycarbonyl)-4-aminoproline (8a). Com-
pound 7a (1.0 g, 2.89 mmol) was dissolved in 50 mL of 10% H2O/
EtOH that contained 136 mg of 10% Pd/C. The reaction was
hydrogenated at 75 psi for 28 h. The mixture was filtered through
a pad of Celite and the pad was washed with a mixture of H2O/
EtOH (1:1). The filtrate was then concentrated to give a solid, which
was triturated with absolute ethanol to yield 0.61 g (91%) of 8a as
a white solid: mp 225-228 °C (dec) [lit.20 mp 225-227 °C (dec)];
[R]D 21 (c 0.98, H2O) [lit.20 [R]D 21 (c 0.24, H2O)]; 1H NMR (D2O,
rotamers present, gCOSY assignment) δ 1.24 and 1.28 (2s, 9H),
1.90-1.96 (m, 1H), 2.43-2.53 (m, 1H), 3.53-2.65 (m, 2H), 3.81-
3.83 (m, 1H), 3.96-4.00 (m, 1H); 13C NMR (D2O, rotamers
present) δ 27.7, 27.8, 33.9, 50.0, 49.8, 60.7, 82.5, 155.8, 180.4.
(2S,4R)-1-(tert-Butoxycarbonyl)-4-aminoproline (8b). In pro-
cedures analogous to that used to make 8a, 7b (0.87 g, 2.51 mmol)
yielded 0.57 g (95%) of 8b as a white solid: mp 240-241 °C (dec)
[lit.20 228-229 °C (dec)]; [R]D -35.9 (c 1.0, H2O) [lit.20 -35 (c
0.17, H2O)]; 1H NMR (D2O, rotamers present, COSY assignment)
δ 1.22 and 1.27 (2s, 9H), 2.05-2.14 (m, 1H), 2.23-2.32 (m, 1H),
3.36-3.47 (m, 1H), 3.57-3.65 (m, 1H), 3.77-3.84 (m, 1H), 4.01-
4.06 (apparent t, 1H, J ) 7.5 and 8.1 Hz); 13C NMR (D2O, rotamers
Methyl 3(R)-[(4(R)-(4-Benzyloxycarbonylamino)-1-(tert-bu-
toxycarbonyl)-2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrro-
lidineacetate (11b). Compound 9b (2.1 g, 5.76 mmol) was
dissolved in 50 mL of dry THF. This solution was placed under
Ar and then cooled to -23 °C. N-Methylpiperidine (0.57 g, 5.76