C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3141–3152
3147
H-2a), 2.97 (s, 3H, OMs), 3.05 (m, 1H, H-5), 3.34 (dd,
1H, J=10.2, 5.5 Hz, H-2b), 3.55 (m, 2H,
CH2OSi(CH3)2tBu/NCH2Ph), 3.66 (dd, 1H, J=10.1,
4.6 Hz, CH2OSi(CH3)2tBu), 4.12 (d, 1H, J=13.4 Hz,
4.13. Ethyl (2S,4S)-1-benzyl-4-cyanoprolinate 14
6
A mixture of 3 (275.7 mg, 0.68 mmol) and NaCN (50.1
mg, 1.02 mmol) in DMSO (10 mL) was stirred at 60°C
for 4 h. After cooling to rt, saturated aqueous NaHCO3
was added and the mixture extracted with Et2O. The
organic layer was dried over MgSO4 and evaporated.
The residue was purified by flash chromatography
(petroleum ether/EtOAc, 85:15) to give 14 (158.4 mg,
90%) as a colorless oil: EI-MS m/z=258 [M+]; TLC:
Rf=0.51 (petroleum ether/EtOAc, 1:1); IR (film): w
6
NCH2Ph), 5.10 (m, 1H, H-3), 7.19–7.38 (m, 5H, Ar);
13C NMR (90.56 MHz, CDCl3): l 18.21 (C-Tbs), 25.87
(C-Tbs), 36.14 (C-4), 38.32 (C
6
H3(Ms)), 58.87
H2OTBS),
(NCH2Ph), 59.49 (C-2), 63.44 (C-5), 65.69 (C
6
6
79.34 (C-3), 127.17, 128.34, 128.72 (C-Ar); Anal. calcd
for C19H33NO4SSi (399.63): C, 57.11; H, 8.32; N, 3.50;
S, 8.02, found: C, 57.12; H, 8.37; N, 3.52; S, 8.09.
1
2981, 2241, 1730, 1454, 1186, 753, 701 cm−1; H NMR
4.11. (3S,5S)-1-Benzyl-5-(tert-butyldimethylsilyloxy-
methyl)pyrrolidine-3-carbonitrile 12
(360 MHz, CDCl3):
l 1.30 (t, 3H, J=7.1 Hz,
CO2CH2CH3), 2.34 (ddd, 1H, J=13.4, 5.5, 5.4 Hz,
6
H-3a), 2.53 (ddd, 1H, J=13.4, 9.6, 8.4 Hz, H-3b), 2.86
(dd, 1H, J=9.4, 7.7 Hz, H-5a), 3.05 (m, 1H, H-4), 3.24
(dd, 1H, J=9.4, 5.1 Hz, H-5b), 3.47 (dd, 1H, J=8.4,
5.4 Hz, H-2), 3.67 (d, 1H, J=13.1 Hz, NCH2Ph), 3.97
(d, 1H, J=13.1 Hz, NCH2Ph), 4.21 (q, 2H, J=7.1 Hz,
To a solution of 11 (16.2 mg, 0.041 mmol) in DMSO (6
mL) was added NaCN (8.5 mg, 0.17 mmol) and tetra-
butylammonium cyanide (10.99 mg, 0.041 mmol) under
N2 atmosphere in a glove box. The mixture was stirred
at 70°C for 24 h. Saturated aqueous NaHCO3 was then
added and the mixture extracted with Et2O. The
organic layer was dried over MgSO4 and evaporated.
The residue was purified by flash chromatography
(petroleum ether/EtOAc, 96:4) to give 12 (5.1 mg, 38%)
as a slightly yellowish oil: EI-MS m/z=330 [M+]; TLC:
Rf=0.07 (petroleum ether/EtOAc, 96:4); IR (film): w
CO2CH2
MHz, CDCl3): l 14.17 (CO2CH2C
33.48 (C-3), 55.01 (C-5), 56.35 (NC
(CO2CH2CH3), 63.41 (C-2), 121.22, 127.37, 128.63,
6
CH3), 7.24–7.35 (m, 5H, Ar); 13C NMR (90.56
6
H3), 25.90 (C-4),
H2Ph), 60.96
6
6
137.50, 171.94 (C-Ar); Anal. calcd for C15H18N2O2
(258.32): C, 69.74; H, 7.02; N, 10.84, found: C, 69.70;
H, 7.13; N, 10.92; [h]D20=−17.9 (c 1.0, CHCl3); ent-14
was prepared under the same reaction conditions, start-
ing from ent-3: [h]2D0=+17.9 (c 1.0, CHCl3).
1
2928, 2240, 1471, 1256, 1107, 837, 699 cm−1; H NMR
(360 MHz, CDCl3): l 0.05 (s, 6H, OSi(CH6 3)2tBu), 0.07
(s, 9H, OSi(CH3)2tBu), 2.01 (ddd, 1H, J=13.3, 5.7, 5.7
Hz, H-4a), 2.34 (ddd, 1H, J=13.3, 8.6, 8.6 Hz, H-4b),
2.54 (dd, 1H, J=9.6, 6.9 Hz, H-2a), 2.81 (m, 1H, H-3),
2.92 (m, 1H, H-5), 3.16 (dd, 1H, J=9.6, 3.4 Hz, H-2b),
3.46 (d, 1H, J=13.7 Hz, NCH2Ph), 3.61 (dd, 1H,
4.14. Ethyl (2S,4S)-4-azido-1-benzylprolinate 15
A mixture of 3 (269 mg, 0.66 mmol) and NaN3 (433
mg, 6.64 mmol) in DMF (20 mL) was stirred at 60°C
for 7 h. After cooling to rt, saturated aqueous NaHCO3
was added and the mixture extracted with Et2O. The
organic layer was dried over MgSO4 and evaporated.
The residue was purified by flash chromatography
(petroleum ether/EtOAc, 85:15) to give 15 (169 mg,
92%) as a slightly yellowish oil: EI-MS m/z=274 [M+];
TLC: Rf=0.67 (petroleum ether/EtOAc, 1:1); IR (film):
J=10.3, 6.2 Hz, CH6 2OSi(CH3)2tBu), 3.73 (dd, 1H,
J=10.3, 5.5 Hz, CH2OSi(CH3)2tBu), 4.12 (d, 1H, J=
13.7 Hz, NCH2Ph), 7.20–7.37 (m, 5H, Ar); Anal. calcd
for C19H30N2OSi (330.55): C, 69.04; H, 9.15; N, 8.47,
found: C, 69.09; H, 9.13; N, 8.41; [h]2D0=−67.5 (c 0.07,
CHCl3).
4.12. (2S,4S)-4-Azido-1-benzyl-2-(tert-butyldimethylsilyl-
oxymethyl)pyrrolidine 13
1
w 2984, 2105, 1740, 1265, 1182, 705 cm−1; H NMR
(360 MHz, CDCl3):
l 1.28 (t, 3H, J=7.0 Hz,
Compound 11 (24.40 mg, 0.06 mmol) and NaN3 (39.65
mg, 0.61 mmol) were dissolved in DMF (5 mL) and
heated to 60°C. After stirring for 4 h and then cooling
to rt water was added and the mixture extracted with
Et2O. The organic layer was separated, washed with
water (2×5 mL), dried (MgSO4) and evaporated. The
residue was purified by flash chromatography
(petroleum ether/EtOAc, 96:4) to give 13 (11.2 mg,
53%) as a colorless liquid: CI-MS m/z 347 [M+]; TLC:
Rf=0.64 (petroleum ether/EtOAc, 1:1); IR (film): w
CO2CH2CH3), 2.15 (ddd, 1H, J=14.1, 6.2, 3.3 Hz,
6
H-3a), 2.51 (ddd, 1H, J=14.1, 9.3, 7.9 Hz, H-3b), 2.63
(dd, 1H, J=10.3, 5.8 Hz, H-5a), 3.06 (dd, 1H, J=10.3,
2.0 Hz, H-5b), 3.32 (dd, 1H, J=9.3, 6.2 Hz, H-2), 3.54
(d, 1H, J=13.1 Hz, NCH2Ph), 3.88 (m, 1H, H-4), 4.05
(d, 1H, J=13.1 Hz, NCH2Ph), 4.18 (q, 2H, J=7.0 Hz,
CO2CH6 2CH3), 7.21–7.38 (m, 5H, Ar); Anal. calcd for
C14H18N4O2 (274.33): C, 61.30; H, 6.61; N, 20.42,
found: C, 61.37; H, 6.65; N, 20.71; [h]2D0=−57.5 (c 1.0,
CHCl3). ent-15 was prepared under the same reaction
conditions, starting from ent-3: [h]2D0=+55.2 (c 1.0,
CHCl3).
1
2954, 2104, 1257, 1108, 837, 776, 698 cm−1; H NMR
(360 MHz, CDCl3): l 0.07 (s, 6H, OSi(CH6 3)2tBu), 0.90
(s, 9H, OSi(CH3)2tBu), 1.78 (m, 1H, H-3a), 2.34 (ddd,
1H, J=14.8, 8.3, 7.8 Hz, H-3b), 2.43 (dd, 1H, J=10.6,
5.1 Hz, H-5a), 2.74 (m, 1H, H-2), 2.99 (brd, 1H,
J=10.6 Hz, H-5b), 3.38 (d, 1H, J=13.4 Hz, NCH2Ph),
4.15. (2S,4R)-(4-Aminomethyl-1-benzylpyrrolidin-2-
yl)methanol 16
3.58 (dd, 1H, J=9.9, 6.5 Hz, CH2
6
OH), 3.76 (m, 2H,
To a stirred solution of 14 (281 mg, 1.08 mmol) in THF
(10 mL) was added LiAlH4 (2.18 mL, 1 M solution in
THF) at 0°C. After 1.5 h the reaction was quenched
with saturated aqueous NaHCO3. The mixture was
filtered through Celite and the filter cake extracted with
CH2OH/H-4), 4.17 (d, 1H, J=13.4 Hz, NCH2Ph),
6
7.21–7.37 (m, 5H, Ar); Anal. calcd for C18H30N4OSi
(346.55): C, 62.39; H, 8.73; N, 16.17, found: C, 62.23;
H, 8.61; N, 16.25; [h]2D0=−79.0 (c 0.3, CHCl3).