Bisol et al.
JOCArticle
CH2Cl2 (3.0 mL) at 25 °C was added EtI (0.61 mL, 7.7 mmol)
and Ag2O (1.77 g, 7.66 mmol) then the reaction was refluxed for
24 h in the absence of light. Next, another portion of EtI (0.61
mL, 7.7 mmol) was added and the reaction was stirred under
reflux for an additional period of 18 h. After cooling to room
temperature, the solid was separated by filtration through a pad
of Celite and the filtrate was concentrated under reduced
pressure to give a yellow oil. Filtration on a pad of silica gel
(hexane/EtOAc 4:1) gave a 60:40 mixture of (()-17-anti:(()-18-
anti (274 mg, 80%) as a pale yellow oil. Analytical data: IR
(neat) 3031, 2978, 2104, 1738, 1252, 1172, 701 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.39-7.31 (m, 5H major, 5H minor), 4.73
(d, J=5.1 Hz, 1H major), 4.72 (d, J=5.1 Hz, 1H minor), 4.10 (q,
J=7.2 Hz, 2H minor), 4.01-3.97 (m, 1H major, 1H minor), 3.63
(s, 3H major), 3.57-3.46 (m, 2H major, 2H minor), 2.61-2.53
(m, 1H major, 1H minor), 2.42 (dd, J=15.9, 3.8 Hz, 1H major),
2.41 (dd, J=15.8, 3.9 Hz, 1H minor), 1.23 (t, J=7.2 Hz, 3H
minor), 1.10 (t, J=7.0 Hz, 3H major, 3H minor); 13C NMR
(CDCl3, 100 MHz) δ 171.9 (C), 171.4 (C), 136.5 (C), 136.4 (C),
128.7 (CH), 128.4 (CH), 128.3 (CH), 127.5 (CH), 80.0 (CH), 79.9
(CH), 67.3 (CH2), 67.2 (CH2), 66.6 (CH), 66.5 (CH), 60.7 (CH2),
51.8 (CH3), 36.3 (CH2), 36.0 (CH2), 15.4 (CH3), 14.2 (CH3).
Methyl syn-4-Azido-3-ethoxy-4-phenylbutanoate [(()-17-syn] þ
Ethyl syn-4-Azido-3-ethoxy-4-phenylbutanoate [(()-18-syn]. To a
stirred solution of a 98:2 mixture of (()-3a-syn:(()-3a-anti
(330 mg, 1.40 mmol) in CH2Cl2 (3.3 mL) at 25 °C was added
EtI (0.67 mL, 8.4 mmol) and Ag2O (1.95 g, 8.42 mmol) then the
reaction was refluxed for 23 h in the absence of light. After cooling
toroom temperature, the solidwas separated by filtration through
a pad of Celite and the filtrate was concentrated under reduced
pressure to give a yellow oil. Filtration on a pad of silica gel
(hexane/EtOAc 4:1) gave a 70:30 mixture of (()-17-syn:(()-18-
syn (343 mg, 93%) as a pale yellow oil. Analytical data: IR (neat)
syn-4-Hydroxy-5-phenylpyrrolidin-2-one [(()-16a-syn]. (()-
16a-syn was prepared from the 98:2 mixture of (()-3a-syn:(()-
3a-anti. Purification by column chromatography on silica gel
(EtOAc) gave pure (()-16a-syn (87%) as a white solid, mp
138-139 °C. Analytical data: IR (KBr) 3338, 3215, 3086, 1672,
1358, 1108, 700 cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 7.91
(br s, exchanges with D2O, 1H), 7.25-7.13 (m, 5H), 4.73 (d, J=
5.1 Hz, exchanges with D2O, 1H), 4.59 (d, J=5.1 Hz, 1H), 4.29
(ddt, J=6.2, 5.1, 2.9 Hz, 1H), 2.43 (dd, J=16.5, 6.2 Hz, 1H), 1.98
(dd, J=16.5, 2.9 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
175.9 (C), 138.2 (C), 127.8 (2 ꢀ CH), 127.7 (2 ꢀ CH), 127.1
(CH), 68.8 (CH), 62.7 (CH), 40.4 (CH2). Anal. Calcd for
C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 68.15; H,
6.37; N, 7.72.
anti-5-Ethyl-4-hydroxypyrrolidin-2-one [(()-16b-anti]. (()-16b-
anti was obtained in 94% yield as a white solid, mp 132-134 °C.
Analytical data: IR (KBr) 3351, 3212, 3076, 2927, 1674, 1070 cm-1
;
1H NMR (DMSO-d6, 400 MHz) δ 7.75 (br s, exchanges with D2O,
1H), 5.16 (br s, exchanges with D2O, 1H), 3.90 (appdt, J=6.5, 3.0
Hz, 1H), 3.11 (dt, J = 6.7, 2.5 Hz, 1H), 2.44 (dd, J=16.8, 6.5 Hz,
1H), 1.91 (dd, J=16.8, 3.5 Hz, 1H), 1.50-1.25 (m, 2H), 0.86 (t, J=
7.4 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 174.6 (C), 70.6
(CH), 64.1 (CH), 39.7 (CH2), 26.8 (CH2), 10.1 (CH3). Anal. Calcd
for C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found: C, 55.57; H,
8.96; N, 10.52.
syn-5-Ethyl-4-hydroxypyrrolidin-2-one [(()-16b-syn]. (()-16b-
syn was prepared from the 98:2 mixture of (()-3b-syn:(()-3b-anti
in 95% yield as a white solid, mp 179-181 °C. Analytical data: IR
(KBr) 3310 (broad), 3205 (broad), 2967, 1668, 1185, 1078 cm-1; 1H
NMR (DMSO-d6, 400 MHz) δ 7.65 (br s, exchanges with D2O,
1H),5.01(d, J=5.0 Hz, exchanges with D2O, 1H), 4.18 (ddt, J=6.0,
5.0, 2.5 Hz, 1H), 3.30 (dt, J=7.0, 5.0 Hz, 1H), 2.38 (dd, J=16.8, 6.0
Hz, 1H), 1.94 (dd, J=16.8, 2.5 Hz, 1H), 1.60-1.30 (m, 2H), 0.87 (t,
J=7.4 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 175.2 (C), 67.0
(CH), 60.4 (CH), 40.8 (CH2), 21.9 (CH2), 10.5 (CH3). Anal. Calcd
for C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found: C, 55.71; H,
8.72; N, 10.81.
1
3032, 2977, 2104, 1738, 1253, 1169, 701 cm-1; H NMR (400
MHz, CDCl3) δ 7.38-7.30 (m, 5H major, 5H minor), 4.58 (d, J=
7.2 Hz, 1H major, 1H minor), 4.10-4.04 (m, 2H minor),
3.97-3.92 (m, 1H major, 1H minor), 3.68-3.63 (m, 2H major,
2H minor), 3.61 (s, 3H major), 2.38-2.35 (m, 2H major, 2H
minor), 1.22 (t, J=7.2 Hz, 3H minor), 1.19 (t, J=7.0 Hz, 3H
major), 1.10 (t, J=7.0 Hz, 3H minor); 13C NMR (CDCl3, 100
MHz) δ 171.5 (C), 136.7 (C), 136.6 (C), 128.9 (CH), 128.7 (CH),
127.8 (CH), 79.7 (CH), 79.6 (CH), 69.1 (CH), 67.5 (CH2), 60.7
(CH2), 51.8 (CH3), 37.5 (CH2), 37.2 (CH2), 15.6 (CH3), 14.3
(CH3).
General Procedure for Reductive Cyclization of γ-Azido Es-
ters. To a stirred solution of the γ-azido ester (1.00 mmol) in
MeOH (20 mL) was added 10 mol % Pd/C (10% w/w) then the
system was charged with H2 (balloon). The mixture was stirred
at 25 °C until the reaction was complete (monitored by TLC).
The catalyst was separated by filtration on a filter paper and the
filtrate was eluted through a pad of Celite and concentrated
under reduced pressure. Unless otherwise noted, the purifica-
tion of each γ-lactam was achieved by addition of Et2O followed
by grinding the insoluble residue with a spatula to induce
precipitation of a solid that was separated by filtration under
reduced pressure (this procedure was repeated until no more
solid was precipitated from the filtrate).
anti-4-Hydroxy-5-phenylpyrrolidin-2-one [(()-16a-anti]. (()-
16a-anti was obtained in 91% yield as a white solid, mp 119-
121 °C. Analytical data: IR (KBr) 3232 (broad), 3050, 2915, 1694,
1668, 1352, 703 cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 8.10 (br
s, exchanges with D2O, 1H), 7.39-7.36 (m, 2H), 7.31-7.27 (m,
3H), 5.56 (br s, exchanges with D2O, 1H), 4.36 (d, J=3.4 Hz, 1H),
4.01-3.98 (m, 1H), 2.51 (dd, J = 16.5, 6.8 Hz, 1H), 2.03 (dd, J=
16.5, 4.1 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 174.9 (C),
141.4 (C), 128.5(2ꢀ CH), 127.4(CH), 125.9 (2ꢀ CH), 74.4 (CH),
66.2 (CH), 39.5 (CH2). Anal. Calcd for C10H11NO2: C, 67.78; H,
6.26; N, 7.90. Found: C, 68.16; H, 6.34; N, 7.54.
anti-4-Ethoxy-5-phenylpyrrolidin-2-one [(()-19-anti]. (()-19-
anti was prepared from the 60:40 mixture of (()-17-anti:(()-18-
anti in 83% yield as a white solid, mp 84-85 °C. Analytical data:
IR (KBr) 3191 (broad), 3097, 2918, 2866, 1712, 1085, 698 cm-1
;
1H NMR (DMSO-d6, 400 MHz) δ 8.19 (br s, exchanges with
D2O, 1H), 7.41-7.28 (m, 5H), 4.55 (d, J=2.5 Hz, 1H), 3.85
(appdt, J=6.5, 3.2 Hz, 1H), 3.55 (dq, J=9.3, 7.0 Hz, 1H), 3.43
(dq, J=9.3, 7.0 Hz, 1H), 2.61 (dd, J=17.0, 6.7 Hz, 1H), 2.11 (dd,
J=17.0, 3.5 Hz, 1H), 1.11 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-
d6, 100 MHz) δ 174.9 (C), 141.2 (C), 128.8 (2 ꢀ CH), 127.6 (CH),
126.1 (2 ꢀ CH), 81.9 (CH2), 64.0 (CH), 63.3 (CH), 36.7 (CH2),
15.3 (CH3). Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N,
6.82. Found: C, 69.90; H, 7.09; N, 6.72.
syn-4-Ethoxy-5-phenylpyrrolidin-2-one [(()-19-syn]. (()-19-
syn was prepared from the 70:30 mixture of (()-17-syn:(()-18-
syn. The reaction was carried out at 25 °C for 2 h then the balloon
with H2 was removed and the mixture was refluxed for 20 h.
Purification by column chromatography on silica gel (hexane/
EtOAc 1:1) gave pure (()-19-syn (61%) as a white solid, mp
80-82 °C. Analytical data: IR (KBr) 3191 (broad), 3086, 2923,
1
1691, 1121,1089, 699 cm-1; H NMR (DMSO-d6, 400 MHz) δ
8.12 (br s, exchanges with D2O, 1H), 7.36-7.28 (m, 5H), 4.84 (d,
J=5.7 Hz, 1H), 4.25-4.22 (m, 1H), 3.20 (dq, J=9.4, 7.0 Hz, 1H),
2.89 (dq, J=9.4, 7.0 Hz, 1H), 2.55 (dd, J = 16.7, 6.7 Hz, 1H), 2.20
(dd, J=16.7, 4.2 Hz, 1H), 0.75 (t, J=7.0 Hz, 3H); 13C NMR
(DMSO-d6, 100 MHz) δ 175.2 (C), 138.1 (C), 127.9 (2 ꢀ CH),
127.8 (2 ꢀ CH), 127.4 (CH), 76.7 (CH2), 64.4 (CH), 61.4 (CH),
37.8 (CH2), 14.9 (CH3). Anal. Calcd for C12H15NO2: C, 70.22; H,
7.37; N, 6.82. Found: C, 69.84; H, 7.75; N, 6.60.
4-Hydroxypyrrolidin-2-one. To a stirred solution of ethyl
4-azido-3-oxobutanoate44 (3.80 g, 22.2 mmol) in absolute EtOH
960 J. Org. Chem. Vol. 76, No. 3, 2011