R.C.F. Jones et al. / Tetrahedron 67 (2011) 8925e8936
8929
was dried (Na2SO4) and evaporated under reduced pressure. The
residue was purified by column chromatography, eluting with ethyl
acetate/hexane/triethylamine (50:49:1 v/v/v) and on standing this
yielded the title compound as a colourless oil (93 mg, 42%): nmax
(film)/cmꢁ1 2952, 1731, 1655, 1454, 1068, 701; dH (270 MHz; CDCl3)
1.32 (3H, s, CCH3), 2.14 (1H, dd, J¼9.2, 13.2, 8-CHH), 2.37 (1H, d,
J¼9.6, NCHHC), 2.88 (1H, dd, J¼8.0, 13.2, 8-CHH), 3.15 (1H, dd, J¼3.5,
13.1, PhCHCHH), 3.30e3.40 (2H, m, NCHH and PhCHCHH), 3.67 (1H,
dd, J¼3.5,10.2, PhCHCH2), 3.71 (3H, s, OCH3), 4.11 (1H, dd, J¼8.0, 9.2,
8a-CH), 4.56, 4.73 (each 1H, d, J¼14.5, PhCH2), 7.24e7.35 (10H, m,
AreH); dC (68 MHz; CDCl3) 22.4 (CH3), 38.5 (CHCH2), 49.1 (CCH3),
49.7 (PhCH2), 52.2 (OCH3), 52.8 (PhCHCH2), 60.6 (PhCHCH2), 63.1
(NCH2C), 63.8 (CHCH2), 127.1, 127.7, 127.8, 128.2, 128.5, 128.7 (6ꢂ
AreCH), 136.7, 140.05 (2ꢂ AreC), 171.6 (CO2), 176.7 (CON); m/z 378
(Mþ, 8%), 350 (23), 308 (26), 249 (22), 105 (100), 104 (24), 91 (86).
HRMS: Mþ 378.1957; C23H26N2O3 requires Mþ 378.1943.
(CHCH2), 47.0 (CCH3), 51.4 (OCH3), 52.0 (PhCHCH2), 53.5 (PhCH2),
60.0 (NCH2), 60.5 (CHCO), 63.9 (PhCHCH2), 80.0 (C(CH3)3), 126.3,
127.0, 127.6, 127.8, 128.0, 128.1 (6ꢂ AreCH), 139.7, 139.95 (2ꢂ
AreC), 173.55, 176.4 (2ꢂ CO); m/z 351 (MþꢁC4H9CO2, 4%), 332 (37),
276 (100), 91 (70). HRMS: MþꢁC4H9CO2 351.2052; C27H36N2O4
requires MþꢁC4H9CO2 351.2072.
4.2.5. (2S,4R)-1-[(S)-2-Benzylamino-1-phenethyl]-2-tert-butox-
ycarbonyl-4-cyano-4-methylpyrrolidine (4f). Prepared from (3S,5S,
7R,7aS)-1-benzyl-5-tert-butoxycarbonyl-7-cyano-7-methyl-3-phen-
ylhexahydropyrrolo[1,2-a]imidazole (2f, 0.20 g, 0.48 mmol) by the
method described above for the preparation of 3a but using sodium
cyanoborohydride (33 mg, 0.53 mmol). Purification by column
chromatography, eluting with eluting with petroleum ether/ethyl
acetate/triethylamine (60:19.5:0.5 v/v/v) yielded the title compound
as a colourless oil (0.16 g, 80%): nmax (film)/cmꢁ1 3029, 2977, 2825,
2241,1715,1453,1368,1151, 732, 701; dH (400 MHz; CDCl3) 1.45 (10H,
s, NH and C(CH3)3), 1.47 (3H, s, CH3), 1.90 (1H, dd, J¼4.6,13.5, 3-CHH),
2.67 (1H, dd, J¼9.7, 13.5, 3-CHH), 2.90 (1H, dd, J¼6.8,11.7, PhCHCHH),
2.96 (1H, d, J¼9.3, NCHH), 3.01 (1H, dd, J¼6.8, 11.7, PhCHCHH), 3.08
(1H, d, J¼9.3, NCHH), 3.71, 3.79 (each 1H, d, J¼13.3, PhCH2), 3.83 (1H,
dd, J¼9.7, 4.6, CHCO) 4.09 (1H, t, J¼6.8, PhCHCH2), 7.30e7.36 (10H, m,
AreH); dC (68 MHz; CDCl3) 23.75 (CH3), 28.0 (C(CH3)3), 35.5 (CCH3),
42.6 (CHCH2), 52.4 (PhCHCH2), 53.9 (PhCH2), 60.4 (CHCO), 61.1
(NCH2), 63.7 (PhCHCH2), 81.4 (C(CH3)3), 125.0 (CN), 127.0, 127.9, 128.1,
128.3, 128.4, 128.7 (6ꢂ AreCH), 139.5, 139.93 (2ꢂ AreC), 173.15 (CO);
m/z 345 (MHþ, 6%), 299 (53), 243 (88), 210 (30), 120 (41), 104 (56), 91
(100). HRMS (FAB): MHþ 420.2657; C26H33N3O2 requires MHþ
420.2645.
4.2.2. (4R,7S,8aR)-2-Benzyl-7-methoxycarbonyl-7-methyl-4-
phenyloctahydropyrrolo[1,2-a]pyrazin-1-one (3b). Prepared from
(3R,5R,7S,7aR)-1-benzyl-5,7-bis(methoxycarbonyl)-7-methylhe誠-
xahydropyrrolo[1,2-a]imidazole (2b, 0.50 g, 1.22 mmol) by the
method described above for the preparation of 3a but using so-
dium cyanoborohydride (84.3 mg, 1.34 mmol) to afford the title
compound as a pale yellow oil (220 mg, 48%): spectroscopic data
were identical within experimental error to that recorded above
for enantiomer 3a.
4.2.3. (2S,4R)-1-[(S)-2-Benzylamino-1-phenethyl]-2-tert-butox-
ycarbonyl-4-methoxycarbonyl-4-methylpyrrolidine (4d). Prepared
from (3S,5S,7R,7aS)-1-benzyl-5-tert-butoxycarbonyl-7-methoxycar-
bonyl-7-methyl-3-phenylhexahydropyrrolo[1,2-a]imidazole
(2d,
4.2.6. (2R,4S)-1-[(R)-2-Benzylamino-1-phenethyl]-2-tert-butox-
ycarbonyl-4-cyano-4-methylpyrrolidine (4g). Prepared from (3R,5R,
7S,7aR)-1-benzyl-5-tert-butoxycarbonyl-7-cyano-7-methyl-3-phen-
ylhexahydropyrrolo[1,2-a]imidazole (2g, 0.33 g, 0.79 mmol) by the
method described above for the preparation of 3a but using sodium
cyanoborohydride (55 mg, 0.87 mmol) and ethanol (20 mL). Purifi-
cation by column chromatography, eluting with eluting with petro-
leum ether/ethyl acetate/triethylamine (60:19.5:0.5 v/v/v) yielded the
title compound as a colourless oil (0.17 g, 51%): nmax (film)/cmꢁ1 2976,
2236, 1714, 1452, 1368, 1154, 752, 702; dH (400 MHz; CDCl3) 1.44 (10H,
s, NH and C(CH3)3), 1.46 (3H, s, CH3), 1.89 (1H, dd, J¼4.6, 13.4, 3-CHH),
2.64 (1H, dd, J¼9.7, 13.4, 3-CHH), 2.89 (1H, dd, J¼6.8, 11.7, PhCHCHH),
2.94 (1H, d, J¼9.3, NCHH), 3.00 (1H, dd, J¼6.8, 11.7, PhCHCHH), 3.07
(1H, d, J¼9.3, NCHH), 3.68, 3.73 (each 1H, d, J¼13.3, PhCH2), 3.80 (1H,
dd, J¼9.7, 4.6, CHCO), 4.09 (1H, t, J¼6.8, PhCHCH2), 7.28e7.36 (10H, m,
AreH); dC (100 MHz; CDCl3) 23.7 (CH3), 28.0 (C(CH3)3), 35.0 (CCH3),
42.7 (CHCH2), 51.7 (PhCHCH2), 53.9 (PhCH2), 60.3 (CHCO), 61.1 (NCH2),
64.0 (PhCHCH2), 81.3 (C(CH3)3), 125.0 (CN), 128.0, 128.3, 128.4, 128.7,
128.8, 128.9 (6ꢂ AreCH), 139.4, 139.8 (2ꢂ AreC), 173.2 (CO); m/z 345
(MþꢁC4H10O, 7%), 299 (28), 243 (87), 210 (11), 120 (27), 104 (52), 91
0.37 g, 0.82mmol)by the method described above forthepreparation
of 3a but using sodium cyanoborohydride (56.8 mg, 0.90 mmol).
Purification by column chromatography, eluting with ethyl acetate
yielded the title compound as a pale yellow oil (0.27 g, 73%): nmax
(film)/cmꢁ1 3026, 2974, 1734, 1453, 1367, 1150, 1118, 700; dH
(400 MHz; CDCl3) 1.35 (3H, s, CH3), 1.41 (9H, s, C(CH3)3), 1.67 (1H, dd,
J¼4.5, 13.3, 3-CHH), 2.68 (1H, dd, J¼9.7, 13.3, 3-CHH), 2.81 (1H, dd,
J¼6.8, 11.7, PhCHCHH), 2.87 (1H, d, J¼9.1, NCHH), 2.95 (1H, dd, J¼6.8,
11.7, PhCHCHH), 3.05 (1H, d, J¼9.1, NCHH), 3.61 (3H, s, OCH3),
3.58e3.68 (2H, m, PhCHH and CHCO), 3.77 (1H, d, J¼13.3, PhCHH),
4.01 (1H, t, J 6.8, PhCHCH2), 7.21e7.29 (10H, m, AreH); dC (68 MHz;
CDCl3) 23.7 (CH3), 27.9 (C(CH3)3), 40.5 (CHCH2), 47.4 (CCH3), 51.9
(OCH3), 52.3 (PhCHCH2), 53.8 (PhCH2), 60.4 (NCH2), 60.8 (CHCO), 64.3
(PhCHCH2), 80.5 (C(CH3)3), 126.7, 127.4, 128.0, 128.1, 128.2, 128.5 (6ꢂ
AreCH), 139.6, 140.2 (2ꢂ AreC), 174.1, 177.0 (2ꢂCO); m/z 351
(MþꢁC4H9CO2, 2%), 332 (25), 276 (100), 91 (52). HRMS: MþꢁC4H9CO2
351.2076; C27H36N2O4 requires MþꢁC4H9CO2 351.2072. Found: C,
71.6; H, 8.3; N, 6.2%; C27H36N2O4 requires C, 71.7; H, 8.0; N, 6.2%.
4.2.4. (2R,4S)-1-[(R)-2-Benzylamino-1-phenethyl]-2-tert-butox-
ycarbonyl-4-methoxycarbonyl-4-methylpyrrolidine (4e). Prepared
from (3R,5R,7S,7aR)-1-benzyl-5-tert-butoxycarbonyl-7-methoxy-
carbonyl-7-methyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (2e,
106 mg, 0.24 mmol) by the method described above for the
preparation of 3a but using sodium cyanoborohydride (16.3 mg,
0.26 mmol). Purification by column chromatography, eluting with
ethyl acetate yielded the title compound as a pale yellow oil (81 mg,
76%): nmax (film)/cmꢁ1 3028, 2977, 2840, 1734, 1455, 1368, 1151,
1118, 734, 702; dH (400 MHz; CDCl3) 1.35 (3H, s, CH3), 1.41 (9H, s,
C(CH3)3), 1.67 (1H, dd, J¼4.5, 13.3, 3-CHH), 2.68 (1H, dd, J¼9.8, 13.3,
3-CHH), 2.81 (1H, dd, J¼6.8, 11.7, PhCHCHH), 2.87 (1H, d, J¼9.1,
NCHH), 2.95 (1H, dd, J 6.8, 11.7, PhCHCHH), 3.05 (1H, d, J 9.1, NCHH),
3.61 (3H, s, OCH3), 3.62e3.65 (2H, m, PhCHH and CHCO), 3.77 (1H,
d, J¼13.2, PhCHH), 4.01 (1H, t, J¼6.8, PhCHCH2), 7.21e7.30 (10H, m,
AreH); dC (68 MHz; CDCl3) 23.2 (CH3), 27.5 (C(CH3)3), 40.1
(100). HRMS: MþꢁC4H10
O
345.1870; C26H33N3O2 requires
MþꢁC4H10
O
345.1841. Found: C, 73.6; H, 8.1; N, 9.9%;
C26H33N3O2$0.3H2O requires C, 73.5; H, 8.0; N, 9.9%.
4.2.7. (2S,4R)- and (2S,4S)-1-[(S)-2-Benzylamino-1-phenethyl]-2-tert-
butoxycarbonyl-4-methoxycarbonylpyrrolidines (4h) and (4ha). So-
dium cyanoborohydride solution (1 M in THF; 0.23 mL, 0.23 mmol)
was added in one portion to (3S,5S,7R,7aS)-1-benzyl-5-tert-butox-
ycarbonyl-7-methoxycarbonyl-3-phenylhexahydropyrrolo[1,2-a]
imidazole (2h, 98 mg, 0.23 mmol) and hydrochloric acid (2 M; 2 mL)
in THF (10 mL) and the resultant mixture was stirred at room tem-
perature for 2 h. Workup as described for compound 3a afforded
a mixture of the trans pyrrolidine (4h) and the cis pyrrolidine (4ha)
as a colourless oil (97 mg, 99%): nmax (film)/cmꢁ1 3027, 2974, 2951,
1734, 1149, 701; dH (400 MHz; CDCl3; both diastereoisomers present,
cis-isomer A/trans-isomer B 1:5) 1.38, 1.43 (9H, s, C(CH3)3 isomers A