Optically Active 3-Aminopiperidines
concentrated under reduced pressure. After purification by flash
chromatography on silica gel (PE/EtOAc, 95:5 to 90:10), methyl 1-
benzyl-2-ethylpyrrolidine-2-carboxylate (759 mg, 3.07 mmol, 77%)
(100 mg, 0.31 mmol, 1 equiv.) afforded an oil that was purified by
flash column chromatography on silica gel (PE/Et2O, 95:5) to give
a mixture of 37 and 38 (44 mg, 0.13 mmol, 41%, 37/38, 40:60). 37:
was isolated as a yellow oil. IR (neat): ν = 2967, 2803, 1722, 1454,
IR (neat): ν = 2953, 2929, 2857, 2100, 1471, 1454, 1372, 1295, 1254,
˜
˜
1
1224, 1170, 1134, 1108 cm–1. 1H NMR: δ = 7.37–7.18 (m, 5 H), 1103, 1048, 907, 834 cm–1. H NMR: δ = 7.29–7.13 (m, 5 H), 3.43
3.96 (d, J = 13.9 Hz, 1 H), 3.73 (s, 3 H), 3.29 (d, J = 13.7 Hz, 1
H), 2.90 (m, 1 H), 2.50 (ddd, J = 8.7, 7.5, 7.5 Hz, 1 H), 2.22 (m, 1
H), 2.02 (dq, J = 14.6, 7.3 Hz, 1 H), 1.88–1.70 (m, 3 H), 1.63 (dq,
(s, 2 H), 3.37 (m, 1 H), 3.28 (ddd, J = 9.7, 8.1, 4.3 Hz, 1 H), 2.84
(m, 1 H), 2.65 (dddd, J = 11.6, 4.2, 4.2, 2.0 Hz, 1 H), 1.98 (ddd, J
= 11.4, 11.4, 2.8 Hz, 1 H), 1.86 (m, 1 H), 1.76 (m, 1 H), 1.56 (m,
J = 13.8, 7.4 Hz, 1 H), 0.96 (dd, J = 7.4, 7.4 Hz, 3 H) ppm. 13C 1 H), 0.83 (s, 9 H), 0.04 (s, 3 H), 0.00 (s, 3 H) ppm. 38: IR (neat):
NMR: δ = 175.0 (s), 140.5 (s), 128.3 (d, 2 C), 128.2 (d, 2 C), 126.6
(d), 71.1 (s), 53.4 (t), 51.4 (t), 51.0 (q), 33.3 (t), 27.6 (t), 21.7 (t),
8.7 (q) ppm. MS: m/z(%) = 247 (0.1) [M+·], 189 (7), 188 (54), 92
(8), 91 (100), 65 (10). HRMS (ESI): calcd. for C15H22NO2 [M +
H+] 248.16451; found 248.16404. To a suspension of LiAlH4 (233,
ν = 2953, 2929, 2857, 2100, 1471, 1454, 1372, 1295, 1254, 1103,
˜
1
1048, 907, 834, 775 cm–1. H NMR: δ = 7.29–7.13 (m, 5 H), 4.08
(ddd, J = 6.2, 2.9, 2.9 Hz, 1 H), 3.90 (d, J = 13.0 Hz, 1 H), 3.44
(d, J = 13.0 Hz, 1 H), 3.18 (dd, J = 12.8, 5.4 Hz, 1 H), 3.06 (dd, J
= 12.9, 3.8 Hz, 1 H), 2.84 (m, 1 H), 2.55 (ddd, J = 5.4, 3.5, 3.5 Hz,
6.14 mmol, 2 equiv.) in THF (20 mL) at 0 °C was added dropwise 1 H), 2.48 (ddd, J = 10.7, 8.9, 7.0 Hz, 1 H), 1.86 (m, 1 H), 1.56
a solution of the previously synthesized methyl 1-benzyl-2-ethylpyr-
rolidine-2-carboxylate (759 mg, 3.07 mmol, 1 equiv.) in THF
(15 mL). After 2 h at room temp., H2O (0.12 mL), NaOH (3.75 m,
(m, 1 H), 0.82 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H) ppm. MS: m/z
(%) = 291 (14), 290 (61) [M+· – CH2N3 ], 92 (8), 91 (100), 75 (12),
·
73 (40). 37 + 38: 13C NMR: δ = 139.2 (s), 138.0 (s), 128.9 (d), 128.8
0.12 mL), and water (0.28 mL) were added dropwise at 0 °C. After (d), 128.3 (d), 127.2 (d), 127.1 (d), 74.8 (d), 73.3 (d), 72.5 (d), 64.4
1 h at room temp., the mixture was filtered through a pad of Celite,
the filtrate was concentrated under reduced pressure and 33
(d), 62.3 (t), 59.6 (t), 55.4 (t), 52.0 (t), 51.9 (t), 50.8 (t), 33.5 (t),
33.3 (t), 25.8 (q), 25.8 (q), 18.0 (s), –4.5 (q), –4.6 (q), –4.8 (q),–4.9
(q) ppm.
(405 mg, 1.85 mmol, 60%) was isolated as an oil. IR (neat): ν =
˜
3416, 2963, 2878, 2804, 1454, 1412, 1365, 1308, 1141, 1054,
1027 cm–1. 1H NMR: δ = 7.35–7.21 (m, 5 H), 3.83 (d, J = 13.0 Hz,
1 H), 3.74 (d, J = 10.5 Hz, 1 H), 3.37 (d, J = 10.7 Hz, 1 H), 3.34
(d, J = 13.3 Hz, 1 H), 2.91 (ddd, J = 9.1, 7.5, 3.0 Hz, 1 H), 2.51
(ddd, J = 9.1, 9.1, 7.7 Hz, 1 H), 1.93 (ddd, J = 12.7, 10.0, 5.3 Hz,
1 H), 1.82 (m, 1 H), 1.76–1.60 (m, 2 H), 1.60–1.40 (m, 2 H), 0.91
(t, J = 7.5 Hz, 3 H) ppm. 13C NMR: δ = 140.0 (s), 128.6 (d, 2 C),
128.4 (d, 2 C), 127.0 (d), 66.5 (s), 63.6 (t), 51.9 (t), 51.3 (t), 31.4
(t), 24.5 (t), 22.3 (t), 8.7 (q) ppm. MS: m/z (%) = 219 (0.04) [M+·],
189 (5), 188 (37), 98 (4), 92 (8), 91 (100), 65 (9). HRMS (ESI):
calcd. for C14H22NO [M + H+] 220.16959; found 220.16885.
[(2R,3R)-1-Benzyl-3-(tert-butyldiphenylsilyloxy)pyrrolidin-2-yl]meth-
anol (39): To a suspension of trans-3-hydroxy-l-proline (1.4 g,
10.69 mmol, 1.0 equiv.) in MeOH (70 mL) was added SOCl2
(1.54 mL, 21.37 mmol, 2.0 equiv.) at 0 °C. After 2 d at room temp.,
the reaction mixture was concentrated under reduced pressure. To
a solution of the crude material in CH2Cl2 (40 mL) were added
Et3N (5.78 mL, 42.11 mmol, 3.9 equiv.) and benzyl bromide
(1.51 mL, 12.70 mmol, 1.2 equiv.). After 18 h at room temp., a satu-
rated solution of NaHCO3 (15 mL) was added to the reaction mix-
ture. The aqueous layer was extracted with CH2Cl2 (3ϫ30 mL),
the organic layer was dried with MgSO4 and concentrated under
reduced pressure. After purification by flash chromatography on
silica gel (PE/EtOAc, 50:50), methyl (2S,3S)-1-benzyl-3-hydroxy-
pyrrolidine-2-carboxylate (1.81 g, 7.7 mmol, 72%) was isolated as
3-Azido-1-benzyl-3-ethylpiperidine (34) and 2-(Azidomethyl)-1-benz-
yl-2-ethylpyrrolidine (35): Following the general procedure with
nBu4NN3 (94 mg, 0.33 mmol, 1.1 equiv., 0 °C, 3.5 h) and Xtal-
Fluor-E (76 mg, 0.33 mmol, 1.1 equiv.), the transformation of 33
(65 mg, 0.30 mmol, 1 equiv.) afforded an oil that was purified by
flash column chromatography on silica gel (PE/Et2O, 98:2 to 90:10)
to give 34 (23 mg, 0.09 mmol, 31%) and 35 (16 mg, 0.07 mmol,
a pale-yellow oil. [α]2D0 = –52.2 (c = 1.0, CHCl ). IR (neat): ν = 49,
˜
3
2810, 1731, 1436, 1201, 1170, 1134, 1075, 989 cm–1. H NMR: δ =
1
7.34–7.22 (m, 5 H), 4.41 (ddd, J = 6.6, 2.9, 2.9 Hz, 1 H), 3.92 (d,
J = 12.8 Hz, 1 H), 3.68 (s, 3 H), 3.64 (d, J = 12.8 Hz, 1 H), 3.23
(d, J = 3.7 Hz, 1 H), 2.99 (ddd, J = 8.6, 8.6, 2.8 Hz, 1 H), 2.73–
2.59 (m, 2 H), 2.18 (m, 1 H), 1.75 (dddd, J = 13.4, 7.4, 2.6, 2.6 Hz,
1 H) ppm. 13C NMR: δ = 173.1 (s), 137.9 (s), 129.2 (d, 2 C), 128.3
(d, 2 C), 127.3 (d), 75.5 (d), 74.2 (d), 58.6 (t), 52.0 (q), 51.0 (t), 33.3
(t) ppm. MS: m/z= 235 (0.8) [M+·], 176 (40), 92 (8), 91 (100), 65
(11). To a solution of methyl (2S,3S)-1-benzyl-3-hydroxypyrrol-
idine-2-carboxylate (500 mg, 2.13 mmol, 1 equiv.) in CH2Cl2
(10 mL) were added Et3N (0.36 mL, 2.60 mmol, 1.2 equiv.), DMAP
(16 mg, 0.13 mmol, 0.6 equiv.), and TBDPSCl (0.68 mL,
2.60 mmol, 1.2 equiv.). After 18 h at room temp., a saturated solu-
tion of Na2CO3 (20 mL) was added. The aqueous layer was ex-
tracted with CH2Cl2 (3ϫ20 mL), the organic layer was dried with
MgSO4, filtered, and then concentrated under reduced pressure.
After purification by flash chromatography on silica gel (PE/
EtOAc, 90:10), methyl (2S,3S)-1-benzyl-3-(tert-butyldiphenylsilyl-
oxy)pyrrolidine-2-carboxylate (693 mg, 1.47 mmol, 69) was isolated
22%). 34: IR (neat): ν = 2940, 2093, 1763, 1455, 1310, 1275, 1124,
˜
1
875 cm–1. H NMR: δ = 7.36–7.22 (m, 5 H), 3.54 (d, J = 13.0 Hz,
1 H), 3.48 (d, J = 13.0 Hz, 1 H), 2.65–2.50 (m, 2 H), 2.24–2.09 (m,
2 H), 1.78 (m, 1 H), 1.70–1.52 (m, 4 H), 1.40 (m, 1 H), 0.89 (t, J
= 7.5 Hz, 3 H) ppm. 13C NMR: δ = 138.1 (s), 129.0 (d, 2 C), 128.2
(d, 2 C), 127.1 (d), 63.0 (t), 63.0 (s), 60.4 (t), 53.4 (t), 33.0 (t), 30.8
(t), 22.2 (t), 7.6 (q) ppm. MS: m/z(%) = 244 (0.1) [M+·], 188 (3),
160 (19), 92 (13), 91 (100), 70 (37), 65 (15). HRMS (ESI): calcd.
for C H N [M + H+] 245.1761; found 245.1755; 35: IR (neat): ν
˜
14 21
4
= 2965, 2925, 2095, 1726, 1494, 1453, 1360, 1282, 1153 cm–1. 1H
NMR: δ = 7.37–7.18 (m, 5 H), 3.75 (d, J = 13.4 Hz, 1 H), 3.69 (d,
J = 13.4 Hz, 1 H), 3.39 (d, J = 12.3 Hz, 1 H), 3.25 (d, J = 12.5 Hz,
1 H), 2.72–2.66 (m, 2 H), 1.85–1.46 (m, 6 H), 0.95 (t, J = 7.4 Hz,
3 H) ppm. 13C NMR: δ = 140.7 (s), 128.2 (d, 2 C), 128.2 (d, 2 C),
126.6 (d), 65.3 (s), 56.8 (t), 52.3 (t), 51.5 (t), 32.6 (t), 26.6 (t), 22.0
(t), 8.8 (q) ppm. MS: m/z(%) = 188 (36) [M+. –CH2N3 ], 130 (4),
·
104 (7), 92 (8), 91 (100), 65 (13). HRMS (ESI): calcd. for C14H21N4
as a colorless oil. [α]2D0 = –14.0 (c = 1.1, CHCl ). IR (neat): ν = 32,
˜
3
[M + H+] 245.1761; found 245.1755.
2857, 1737, 1428, 1202, 1111, 1061, 1028, 822 cm–1. H NMR: δ =
1
(3S,4S)-3-Azido-1-benzyl-4-(tert-butyldimethylsilyloxy)piperidine (37)
7.65–7.59 (m, 4 H), 7.44–7.20 (m, 11 H), 4.47 (ddd, J = 6.1, 2.8,
2.8 Hz, 1 H), 3.87 (d, J = 13.0 Hz, 1 H), 3.68 (d, J = 13.0 Hz, 1
H), 3.45 (s, 3 H), 3.34 (d, J = 3.3 Hz, 1 H), 2.96 (ddd, J = 8.7, 7.7,
2.3 Hz, 1 H), 2.73 (ddd, J = 10.2, 8.6, 6.8 Hz, 1 H), 1.87 (dddd, J
= 13.1, 10.3, 7.7, 6.4 Hz, 1 H), 1.69 (dddd, J = 13.0, 6.6, 2.3, 2.3 Hz,
and
(2R,3S)-2-(Azidomethyl)-1-benzyl-3-(tert-butyldimethylsilyl-
oxy)pyrrolidine (38): Following the general procedure with
nBu4NN3 (97 mg, 0.34 mmol, 1.1 equiv., 0 °C, 3.5 h) and Xtal-
Fluor-E (78 mg, 0.34 mmol, 1.1 equiv.), the transformation of 36[24]
Eur. J. Org. Chem. 2012, 2023–2040
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