Formation of all-cis-5-Aryl-2,3,5-trisubstituted N-Hydroxypyrrolidines
Dimethyl (2S*,4S*,5R*)-1-Hydroxy-5-(4-nitrophenyl)pyrrolidine-
2,4-dicarboxylate (3c): Method A (0.162 g, 50% yield); Method B
(0.284 g, 88% yield). Yellow solid; m.p. 132–134 °C. 1H NMR
(400 MHz): δ = 2.09–2.30 (m, 2 H), 2.85 (s, 3 H), 3.14 (ddd, J =
Dimethyl (2S*,4S*,5R*)-5-(4-Chlorophenyl)-1-hydroxypyrrolidine-
2,4-dicarboxylate (3g): Method A (0.289 g, 92% yield); Method B
(0.292 g, 93% yield). White solid; m.p. 125–127 °C. 1H NMR
(400 MHz): δ = 2.30 (ddd, J = 13.3, 9.2, 8.6 Hz, 1 H), 2.42 (ddd,
10.2, 9.3, 6.9 Hz, 1 H), 3.49 (dd, J = 7.8, 2.5 Hz, 1 H), 3.52 (s, 3 J = 13.3, 10.7, 6.9 Hz, 1 H), 3.09 (s, 3 H), 3.27 (ddd, J = 10.2, 9.2,
H), 4.11 (d, J = 10.2 Hz, 1 H), 5.62 (br. s, 1 H), 7.27–7.33 (m, 2 6.9 Hz, 1 H), 3.67 (dd, J = 10.7, 8.6 Hz, 1 H), 3.71 (s, 3 H), 4.19
H), 7.85–7.92 (m, 2 H) ppm. 13C NMR (100 MHz): δ = 27.1, 45.0, (d, J = 10.2 Hz, 1 H), 5.74 (br. s, 1 H), 7.19–7.28 (m, 4 H) ppm.
51.7, 52.4, 67.7, 71.4, 123.2, 128.9, 141.6, 145.4, 171.4, 171.9 ppm.
C14H16N2O7 (324.29): calcd. C 51.85, H 4.97, N 8.64; found C
51.73, H 4.84, N 8.49.
13C NMR (100 MHz): δ = 26.9, 44.9, 51.5, 52.2, 67.6, 71.6, 128.1,
129.3, 133.5, 136.2, 171.7, 171.9 ppm. C14H16ClNO5 (313.74):
calcd. C 53.60, H 5.14, Cl 11.30, N 4.46; found C 53.39, H 4.88,
N 4.71.
Dimethyl
(2S*,4R*,5S*)-1-Hydroxy-5-(4-nitrophenyl)pyrrolidine-
2,4-dicarboxylate (4c): Method A (0.107 g, 33% yield). Yellow so-
lid; m.p. 130–132 °C. 1H NMR (400 MHz): δ = 2.21 (ddd, J = 13.7,
9.4, 1.9 Hz, 1 H), 2.70 (ddd, J = 13.7, 7.8, 7.8 Hz, 1 H), 3.13 (s, 3
H), 3.62–3.71 (m, 1 H), 3.80 (s, 3 H), 4.35 (dd, J = 7.8, 1.9 Hz, 1
H), 5.06 (d, J = 10.4 Hz, 1 H), 5.14 (s, 1 H), 7.50–7.58 (m, 2 H),
8.15–8.22 (m, 2 H) ppm. 13C NMR (100 MHz): δ = 27.7, 45.6, 51.6,
52.1, 65.9, 69.3, 123.3, 129.0, 146.0, 147.5, 172.0, 172.6 ppm.
C14H16N2O7 (324.29): calcd. C 51.85, H 4.97, N 8.64; found C
51.92, H 4.75, N 8.89.
Dimethyl (2S*,4S*,5R*)-5-(4-Bromophenyl)-1-hydroxypyrrolidine-
2,4-dicarboxylate (3h): Method A (0.333 g, 93% yield); Method B
(0.322 g, 90% yield). White solid; m.p. 125–127 °C. 1H NMR
(400 MHz): δ = 2.35 (ddd, J = 13.4, 9.4, 8.1 Hz, 1 H), 2.50 (ddd,
J = 13.4, 10.5, 7.2 Hz, 1 H), 3.10 (s, 3 H), 3.34 (ddd, J = 10.3, 9.4,
7.2 Hz, 1 H), 3.72 (dd, J = 10.5, 8.1 Hz, 1 H), 3.79 (s, 3 H), 4.25
(d, J = 10.3 Hz, 1 H), 5.52 (br. s, 1 H), 7.21–7.43 (m, 4 H) ppm.
13C NMR (100 MHz): δ = 26.9, 45.1, 51.6, 52.2, 67.6, 72.3, 127.8,
129.6, 131.2, 136.8, 171.9, 172.0 ppm. C14H16BrNO5 (358.19):
calcd. C 46.95, H 4.50, Br 22.31, N 3.91; found C 47.19, H 4.28,
N 4.25.
Dimethyl
(2S*,4S*,5R*)-1-Hydroxy-5-(4-methoxyphenyl)pyrrol-
idine-2,4-dicarboxylate (3d): Method A (0.288 g, 93% yield);
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Method B (0.278 g, 90% yield); viscous oil. H NMR (400 MHz):
Dimethyl (2S*,4S*,5R*)-5-(4-Cyanophenyl)-1-hydroxypyrrolidine-
2,4-dicarboxylate (3i): Method A (0.3 g, 91% yield); Method B
(0.316 g, 96% yield). White solid; m.p. 127–129 °C. 1H NMR
(400 MHz): δ = 2.40 (ddd, J = 13.3, 9.2, 8.6 Hz, 1 H), 2.49 (ddd,
J = 13.3, 10.6, 6.9 Hz, 1 H), 3.11 (s, 3 H), 3.39 (ddd, J = 10.2, 9.3,
6.9 Hz, 1 H), 3.75 (s, 3 H), 3.72–3.78 (m, 1 H), 4.33 (d, J = 10.2 Hz,
1 H), 5.99 (br. s, 1 H), 7.50–7.54 (m, 2 H), 7.58–7.62 (m, 2 H) ppm.
13C NMR (100 MHz): δ = 27.0, 44.9, 51.5, 52.2, 67.5, 71.7, 111.4,
118.7, 128.7, 131.8, 143.4, 171.4, 171.7 ppm. C15H16N2O5 (304.30):
calcd. C 59.21, H 5.30, N 9.21; found C 59.32, H 5.16, N 9.45.
δ = 2.33 (ddd, J = 13.2, 9.3, 8.5 Hz, 1 H), 2.49 (ddd, J = 13.2, 10.7,
7.0 Hz, 1 H), 3.15 (m, 3 H), 3.30 (ddd, J = 10.2, 9.3, 7.0 Hz, 1 H),
3.69 (dd, J = 10.6, 2.2 Hz, 1 H), 3.77 (s, 6 H), 4.21 (d, J = 10.2 Hz,
1 H), 5.66 (s, 1 H), 6.80–6.85 (m, 2 H), 7.25–7.30 (m, 2 H) ppm.
13C NMR (100 MHz): δ = 26.8, 45.0, 51.4, 52.0, 55.1, 67.5, 71.8,
113.3, 128.9, 129.6, 159.1, 172.0, 172.0 ppm. C15H19NO6 (309.32):
calcd. C 58.25, H 6.19, N 4.53; found C 58.47, H 5.90, N 4.72.
Dimethyl
(2S*,4S*,5R*)-1-Hydroxy-5-(biphenyl-4-yl)pyrrolidine-
2,4-dicarboxylate (3e): Method A (0.213 g, 60% yield); Method B
(0.224 g, 63% yield). White solid; m.p. 132–134 °C. 1H NMR
(400 MHz): δ = 2.40 (ddd, J = 13.2, 9.3, 8.5 Hz, 1 H), 2.55 (ddd,
J = 13.3, 10.7, 6.9 Hz, 1 H), 3.14 (s, 3 H), 3.38 (ddd, J = 10.2, 9.3,
6.9 Hz, 1 H), 3.74–3.80 (m, 1 H), 3.81 (s, 3 H), 4.34 (d, J = 10.2 Hz,
1 H), 5.59 (s, 1 H), 7.31–7.37 (m, 1 H), 7.40–7.49 (m, 4 H), 7.57–
7.62 (m, 4 H) ppm. 13C NMR (100 MHz): δ = 26.9, 45.1, 51.5,
52.2, 67.7, 72.1, 126.8, 127.0, 127.3, 128.3, 128.7, 136.7, 140.7,
140.8, 172.0, 172.0 ppm. C20H21NO5 (355.39): calcd. C 67.59, H
5.96, N 3.94; found C 67.72, H 6.11, N 4.27.
Dimethyl (2S*,4S*,5R*)-1-Hydroxy-5-(naphth-1-yl)pyrrolidine-2,4-
dicarboxylate (3j): Method A (0.256 g, 84% yield); Method B
(0.268 g, 88% yield); viscous oil. 1H NMR (400 MHz): δ = 2.47
(ddd, J = 13.3, 9.2, 9.2 Hz, 1 H), 2.58 (ddd, J = 13.1, 10.7, 6.4 Hz,
1 H), 2.75 (s, 3 H), 3.60 (ddd, J = 9.7, 9.6, 6.6 Hz, 1 H), 3.80 (s, 3
H), 3.88 (dd, J = 10.3, 9.0 Hz, 1 H), 5.06 (d, J = 9.8 Hz, 1 H), 5.85
(br. s, 1 H), 7.43–7.54 (m, 3 H), 7.73–7.77 (m, 1 H), 7.82–7.92 (m,
2 H), 7.94–8.04 (m, 1 H) ppm. 13C NMR (100 MHz): δ = 26.8,
44.4, 51.0, 52.1, 67.7 (2 C), 125.3, 125.3 (2 C), 125.8 (2 C), 127.9,
128.6, 131.7, 133.1, 133.4, 171.9, 172.1 ppm. C18H19NO5 (329.35):
calcd. C 65.64, H 5.81, N 4.25; found C 65.78, H 5.93, N 4.10.
Dimethyl
(2S*,4R*,5R*)-1-Hydroxy-5-(biphenyl-4-yl)pyrrolidine-
2,4-dicarboxylate (4e): Method A (53 mg, 15% yield); Method B
(57 mg, 16% yield); viscous oil. 1H NMR (400 MHz): δ = 2.19
(ddd, J = 13.7, 9.5, 2.4 Hz, 1 H), 2.71 (dt, J = 13.7, 7.8 Hz, 1 H),
3.15 (s, 3 H), 3.65 (dt, J = 9.5, 7.8 Hz, 1 H), 3.80 (s, 3 H), 4.32 (dd,
J = 7.8, 2.4 Hz, 1 H), 4.90 (d, J = 10.2 Hz, 1 H), 5.40 (br. s, 1 H),
7.28–7.46 (m, 5 H), 7.50–7.58 (m, 4 H) ppm. 13C NMR (100 MHz):
δ = 27.4, 45.6, 51.5, 52.0, 65.8, 70.0, 126.8, 127.0, 127.3, 128.6,
128.8, 136.7, 140.6, 140.8, 172.1, 172.9 ppm. C20H21NO5 (355.39):
calcd. C 67.59, H 5.96, N 3.94; found C 67.73, H 6.26, N 3.78.
4-tert-Butyl 2-Methyl (2S*,4S*,5R*)-1-Hydroxy-5-phenylpyrrolid-
ine-2,4-dicarboxylate (3k): Method A (0.247 g, 77% yield);
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Method B (0.241 g, 75% yield); oil. H NMR (400 MHz): δ = 0.91
(s, 9 H), 2.28 (ddd, J = 13.1, 9.3, 8.1 Hz, 1 H), 2.42 (ddd, J = 13.1,
11.0, 7.6 Hz, 1 H), 3.23 (ddd, J = 10.7, 9.3, 7.6 Hz, 1 H), 3.67 (dd,
J = 11.0, 8.1 Hz, 1 H), 3.73 (s, 3 H), 4.21 (d, J = 10.7 Hz, 1 H),
5.51 (br. s, 1 H), 7.18–7.29 (m, 3 H), 7.35–7.40 (m, 2 H) ppm. 13C
NMR (100 MHz): δ = 27.3, 27.6, 45.4, 52.1, 67.7, 72.2, 80.7, 127.7,
128.1, 128.5, 138.0, 170.5, 170.9 ppm. C17H23NO5 (321.37): calcd.
C 63.54, H 7.21, N 4.36; found C 63.76, H 7.48, N 4.22.
Dimethyl (2S*,4S*,5R*)-5-(3-Chlorophenyl)-1-hydroxypyrrolidine-
2,4-dicarboxylate (3f): Method A (0.292 g, 93% yield); Method B
(0.295 g, 94% yield). White solid; m.p. 138–140 °C. 1H NMR
(400 MHz): δ = 2.40 (ddd, J = 13.3, 9.3, 8.6 Hz, 1 H), 2.52 (ddd,
J = 13.3, 10.6, 6.8 Hz, 1 H), 3.20 (s, 3 H), 3.37 (ddd, J = 10.2, 9.3,
4-tert-Butyl 2-Methyl (2S*,4R*,5S*)-1-Hydroxy-5-phenylpyrrolid-
ine-2,4-dicarboxylate (4k): Method A (60 mg, 19% yield);
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6.8 Hz, 1 H), 3.78 (dd, J = 10.6, 8.6 Hz, 1 H), 3.81 (s, 3 H), 4.28 Method B (60 mg, 19% yield); oil. H NMR (400 MHz): δ = 0.91
(d, J = 10.2 Hz, 1 H), 5.90 (br. s, 1 H), 7.24–7.30 (m, 3 H), 7.42– (s, 9 H), 2.06 (ddd, J = 13.6, 9.5, 2.6 Hz, 1 H), 2.51 (dt, J = 13.6,
7.45 (m, 1 H) ppm. 13C NMR (100 MHz): δ = 26.9, 45.0, 51.5,
52.2, 67.6, 71.7, 126.1, 127.8, 127.9, 129.3, 134.0, 139.8, 171.7,
171.9 ppm. C14H16ClNO5 (313.74): calcd. C 53.60, H 5.14, Cl
11.30, N 4.46; found C 53.51, H 5.02, N 4.69.
8.3 Hz, 1 H), 3.53 (ddd, J = 10.2, 9.5, 8.3 Hz, 1 H), 3.72 (s, 3 H),
4.22 (dd, J = 8.3, 2.6 Hz, 1 H), 4.80 (d, J = 10.2 Hz, 1 H), 5.34 (br.
s, 1 H), 7.20–7.30 (m, 3 H), 7.36–7.41 (m, 2 H) ppm. 13C NMR
(100 MHz): δ = 27.4, 28.0, 45.8, 51.9, 65.9, 70.4, 80.7, 128.2, 128.5,
Eur. J. Org. Chem. 2011, 6567–6573
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