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R. Roy et al. / Tetrahedron: Asymmetry 24 (2013) 1502–1513
4.1.4. Benzyl 7-allyl-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]-
pyridine-5(6H)-carboxylate I
(125 MHz, CDCl3): d 14.4, 20.0, 26.7, 26.8, 27.0, 33.0, 41.9, 47.7,
49.1, 83.8, 109.3. HRMS calcd for C11H22NO2 [M+H]+ 200.1650;
found 200.1656.
Compound 24 (400 mg, 0.94 mmol) was dissolved in dry THF
(10 mL) at 0 °C and t-BuOK (296 mg, 2.64 mmol) was added to it.
The reaction mixture was stirred for 1 h at the same temperature
and finally quenched by the dropwise addition of water. Work-
up was carried out by ethyl acetate (3 ꢂ 10 mL). The organic layer
was washed with water followed by brine and dried over Na2SO4.
The solvent was removed under reduced pressure to give a crude
product as a mixture of diastereomers which was further purified
by silica gel column chromatography to give pure 25 (117 mg)
and 26 (233 mg) as a colourless liquid with a 1:2 diastereomeric
ratio, respectively. Yield: (350 mg, 88%).
4.1.8. (3R,4R,5S)-5-Propylpiperidine-3,4-diol 11
To a solution of amine 27 (30 mg, 0.15 mmol) in distilled meth-
anol (1.5 mL) was added concentrated HCl (3 drops) and the result-
ing mixture was stirred for 3 h. After completion of the reaction, it
was neutralized by the addition of aq NH4OH solution. Evaporation
of the whole mixture to dryness gave a crude product, which was
purified by repeated washing with ethyl acetate (3 ꢂ 5 mL) to
obtain a white solid 11 (23 mg, 96% yield). Mp 123–125 °C, Rf:
0.32 (ethyl acetate: methanol, 9: 1),½a D25
¼ þ25:6 (c 1.25, EtOH)
ꢃ
IR (KBr) m
max cmꢀ1: 1062, 1452, 1625, 2820, 2925, 2954, 3344. 1H
4.1.5. (3aR,7S,7aR)-Benzyl 7-allyl-2,2-dimethyltetrahydro-[1,3]-
dioxolo-[4,5-c]pyridine-5(6H)-carboxylate 25
NMR (500 MHz, D2O): d 0.76 (t, J = 7.1 Hz, 3H), 1.10–1.17 (m,
2H), 1.26–1.30 (m, 1H), 1.59–1.67 (m, 2H), 2.67 (t, J = 12.6 Hz,
1H), 2.71–2.75 (m, 1H), 3.19–3.23 (m, 1H), 3.32–3.39 (m, 2H),
3.56–3.61 (m, 1H). 13C NMR (125 MHz, D2O): d 13.3, 18.7, 30.1,
38.4, 46.4, 46.6, 68.5, 74.5. HRMS calcd for C8H18NO2 [M+H]+
160.1337; found 160.1339.
Rf: 0.57 (hexane:ethyl acetate, 24: 1), ½a D25
¼ ꢀ30:0 (c 0.90,
ꢃ
CH2Cl2); IR (neat)
m
max cmꢀ1: 1091, 1229, 1370, 1423, 1705,
2872, 2928, 3434. 1H NMR (500 MHz, CDCl3, 50% mixture of rota-
mers): d 1.40–1.44 (m, 12H, both rotamers), 1.81–2.03 (m, 2H, both
rotamers), 2.15–2.19 (m, 2H, both rotamers), 2.32–2.35 (m, 2H,
both rotamers), 2.71–2.83 (m, 4H, both rotamers), 3.48–3.53 (m,
4H, both rotamers), 4.25 (d, J = 14.0 Hz, 1H, single rotamer), 4.37
(d, J = 14.0 Hz, 1H, single rotamer), 4.56 (d, J = 9.1 Hz, 1H, single
rotamer), 4.68 (d, J = 10.1 Hz, 1H, single rotamer), 4.89–4.94 (m,
2H, both rotamers), 5.05–5.16 (m, 6H, both rotamers), 5.68–5.83
(m, 2H, both rotamers), 7.30–7.34 (m, 10H, ArH, both rotamers).
13C NMR (125 MHz, CDCl3): d 26.6, 26.8, 28.6, 28.7, 37.8, 44.9,
45.1, 47.4, 67.6, 67.7, 70.3, 70.4, 81.5, 81.8, 110.0, 110.1, 117.0,
117.4, 128.0, 128.2, 128.6, 136.1, 136.3, 136.4, 156.1. HRMS calcd
for C19H25NNaO4 [M+Na]+ 354.1676; found 354.1680.
4.1.9. (3aR,7S,7aR)-5-Butyl-2,2-dimethyl-7-propylhexahydro-[1,3]-
dioxo-lo[4,5-c]pyridine 28
Substrate 27 (60 mg, 0.30 mmol) was dissolved in 6 mL of EtOH/
H2O (2:1) solution and to it were added 20% Pd(OH)2/C followed by
butyraldehyde (108.2 mg, 1.50 mmol). The reaction mixture was
stirred for 2 h under 1 atm of H2 at room temperature. It was then
filtered through a pad of Celite and the filtrate was evaporated
under reduced pressure to afford a crude liquid which was purified
by silica gel column chromatography to give 28 (75 mg, 97% yield)
as
a
viscous liquid. Rf: 0.52 (hexane:ethyl acetate, 99: 1),
½
a 2D5
ꢃ
¼ þ2:7 (c 0.75, CH2Cl2);, IR (neat)
m
max cmꢀ1: 1093, 1231,
1379, 1466, 1707, 2872, 2931, 2957. 1H NMR (500 MHz, CDCl3): d
0.87–0.90 (m, 6H), 1.12–1.17 (m, 1H), 1.26–1.45 (m, 12H),
1.51–1.57 (m, 1H), 1.71 (t, J = 11.1 Hz, 1H, H-6), 1.82–1.89 (m, 1H,
H-7), 2.05 (t, J = 10.1 Hz, 1H, H-4), 2.37–2.48 (m, 2H),
2.93–2.98 (m, 2H), 3.22 (dd, J = 3.9, J = 9.7 Hz, 1H, H-40),
3.47–3.52 (m, 1H, H-3a). 13C NMR (125 MHz, CDCl3): d 14.1, 14.4,
20.1, 20.7, 26.8, 27.0, 29.4, 33.4, 39.1, 54.7, 57.6, 57.7, 84.7, 110.0.
HRMS calcd for C15H30NO2 [M+H]+ 256.2276; found 256.2276.
4.1.6. (3aR,7R,7aR)-Benzyl 7-allyl-2,2-dimethyltetrahydro-[1,3]-
dioxolo-[4,5-c]pyridine-5(6H)-carboxylate 26
Rf: 0.56 (hexane:ethyl acetate, 24: 1), ½a D25
¼ ꢀ25:0 (c 0.40,
ꢃ
CH2Cl2); IR (neat)
m
max cmꢀ1: 1086, 1222, 1428, 1703, 2854,
2924, 3442. 1H NMR (500 MHz, CDCl3, 50% mixture of rotamers):
d 1.40–1.45 (m, 12H, both rotamers), 1.85–1.86 (m, 2H, both rota-
mers), 1.96–1.97 (m, 2H, both isomers), 2.33–2.44 (m, 4H, both
rotamers), 2.73–2.83 (m, 2H, both rotamers), 3.12–3.16 (m, 2H,
both rotamers), 3.29 (m, 2H, both rotamers), 4.28 (d,
J = 16.5 Hz, 1H, single rotamer), 4.39 (d, J = 11.3 Hz, 1H, single rot-
amer), 4.52 (d, J = 8.8 Hz, 1H, single rotamer), 4.63 (d, J = 10.1 Hz,
1H, single rotamer), 5.04–5.11 (m, 8H, both rotamers), 5.77–5.82
(m, 2H, both rotamers), 7.31–7.37 (m, 10H, both rotamers). 13C
NMR (125 MHz, CDCl3): d 26.7, 27.0, 29.7, 29.8, 34.3, 34.5, 39.2,
39.7, 46.8, 47.2, 67.6, 75.6, 75.7, 83.4, 83.6, 110.4, 110.5, 117.3,
117.4, 127.8, 128.0, 128.2, 128.6, 134.6, 136.4, 136.6, 155.5.
4.1.10. (3R,4R,5S)-1-Butyl-5-propylpiperidine-3,4-diol 12
Compound 12 (39 mg, 94% yield) was obtained as a white amor-
phous solid from 28 (50 mg, 0.19 mmol) following the same proce-
dure as used to prepare 11. Mp 115–117 °C Rf: 0.52 (ethyl acetate:
methanol, 9: 1), ½a D25
ꢃ
¼ þ37:5 (c 0.20, EtOH); IR (KBr)
m :
max cmꢀ1
1067, 1460, 2599, 2690, 2962, 3377. 1H NMR (500 MHz, D2O): d
0.73–0.79 (m, 6H), 1.08–1.29 (m, 5H), 1.52–1.65 (m, 4H), 2.68–
2.70 (m, 2H), 3.00 (br s, 2H), 3.19 (t, J = 9.6 Hz, 1H), 3.37–3.46 (m,
2H), 3.57 (br s, 1H). 13C NMR (125 MHz, D2O): d 12.7, 13.3, 18.6,
19.2, 25.6, 30.1, 38.3, 54.4, 54.9, 57.0, 68.6, 74.3. C12H26NO2
[M+H]+ 216.1963; found 216.1968.
HRMS calcd for
354.1680.
C
19H25NNaO4 [M+Na]+ 354.1676; found
4.1.7. (3aR,7S,7aR)-2,2-Dimethyl-7-propylhexahydro-[1,3]dioxolo-
[4,5-c]-pyridine 27
Compound 25 (80 mg, 0.24 mmol) was dissolved in methanol
(4 mL) and was stirred under 1 atm of H2 in the presence of 20%
Pd(OH)2/C (10 mg) at room temperature for 6 h. After completion
of the reaction, the reaction mixture was filtered through a Celite
pad and the filtrate was concentrated to give a crude product
which was purified by silica gel column chromatography to give
a viscous liquid 27 (46 mg, 95% yield). Rf: 0.52 (ethyl acetate:
4.1.11. (3R,4R,5R)-5-Propylpiperidine-3,4-diol 13
Compound 13 (26 mg, 95% yield) was prepared from 29
(35 mg, 0.18 mmol) using the same procedure as used to obtain
11 as a white solid. Mp 128–130 °C, Rf: 0.30 (ethyl acetate: meth-
anol, 9: 1), ½a 2D5
ꢃ
¼ þ3:3 (c 0.30, EtOH). IR (KBr)
m
max cmꢀ1: 1147,
1460, 1558, 2871, 2931, 2959, 3431. 1H NMR (500 MHz, D2O): d
0.73–0.76 (m, 3H), 1.10–1.24 (m, 4H), 2.04–2.06 (m, 1H), 2.71–
2.76 (m, 1H), 2.98 (dd, J = 4.3, J = 12.6 Hz, 1H), 3.06 (d,
J = 13.45 Hz, 1H), 3.14 (d, J = 13.45 Hz, 1H), 3.74 (s, 1H), 3.89 (s,
1H). 13C NMR (125 MHz, D2O): d 13.2, 18.6, 29.7, 31.7, 43.0,
44.1, 65.4, 66.3. HRMS calcd for C8H18NO2 [M+H]+ 160.1337;
found 160.1335.
methanol, 9: 1), ½a D25
ꢃ
¼ þ6:7 (c 0.15, CH2Cl2); IR (neat)
m :
max cmꢀ1
1092, 1233, 1382, 1568, 2932, 2960, 3403. 1H NMR (500 MHz,
CDCl3): d 0.89 (t, J = 7.3 Hz, 3H), 1.13–1.19 (m, 1H), 1.29–1.41 (m,
8H), 1.53–1.58 (m, 1H), 1.74–1.78 (m, 1H), 1.98 (s, 1H), 2.17–
2.22 (m, 1H), 2.66 (t, J = 10.8 Hz, 1H), 3.03–3.07 (m, 1H), 3.17
(dd, J = 4.0 Hz, J = 13.4 Hz, 1H), 3.30–3.39 (m, 2H). 13C NMR