D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 2257–2260
2259
2. Experimental
2.1. (R)-3-Aminooctanol, 7
327, 281, 239, 168, 91; HRMS calcd for C23H35NO3
(M+) 373.2591, found 373.2576.
2.4. (1S,2S,6R)-1-(3-Hydroxypropyl)-2-ethoxycarbonyl-
6-pentylpiperidine, 11a
A mixture of the b-amino ester 6 (5.5 g, 15 mmol),
Pd/C (3 mmol) and acetic acid (1.5 mL) in methanol
(60 mL) was stirred under hydrogen (50 atm) at 50°C
for 20 h. The Pd/C was filtered off and the filtrate was
concentrated to dryness. The residual oil was dissolved
in THF (40 mL) and LAH (2.0 g, 50 mmol) was added
at 0°C in portion. The resulting mixture was stirred at
the same temperature for 2 h and then allowed to warm
to room temperature. The reaction was quenched by
adding water before the mixture was partitioned
between chloroform and water. The organic layer was
separated and the aqueous layer was extracted with
chloroform. The combined organic layers were dried
over Na2SO4, and concentrated to afford 2.0 g (91%) of
crude 7. [h]2D0=−14.4 (c 1.3, CHCl3); IR (KBr) 3554,
To a suspension of Raney Ni (60 mg) in ethanol (20
mL) was added a drop of triethylamine, and a solution
of 10 (150 mg, 0.4 mmol) in ethanol (1 mL). The
resulting mixture was stirred under hydrogen (70 atm)
at 60–70°C for 15 h. The cooled mixture was filtered
and the filtrate was concentrated. The residual oil was
chromatographed eluting with 1/10 methanol/ethyl ace-
tate to afford 11a (92 mg, 80%). [h]2D0=−11 (c 0.97,
1
CHCl3); IR (KBr) 3682, 1721, 11180 cm−1; H NMR
(300 MHz, CDCl3) l 4.21 (q, J=7.3 Hz, 2H), 3.70 (dt,
J=11.6, 3.6 Hz, 1H), 3.51 (dt, J=11.7, 3.6 Hz, 1H), 2.6
(d, J=10.7 Hz, 1H), 2.5 (m, 2H), 2.1 (dq, J=11.9, 2.2
Hz, 1H), 1.81–1.20 (m with t, J=6.5 Hz, 20H), 0.89 (t,
J=7.1 Hz, 3H); ESI-MS m/z 286 (M++H+); HRMS
calcd for C16H31NO3 (M+) 285.2303, found 285.2310.
1
3041, 2910, 1051 cm−1; H NMR (300 MHz, CDCl3) l
3.71–3.60 (m, 3H), 3.14 (br s, 3H), 2.85 (m, 1H),
1.63–1.21 (m, 10H), 0.89 (t, J=6.9 Hz, 3H); EI-MS m/z
146 (M+), 128, 102, 74, 56; HRMS calcd for C8H19NO
(M+) 145.1426, found 145.1428.
2.5. (5R,8S,8aS)-5-Pentyloctahydroindolizidine-8-car-
boxylic acid ethyl ester, 12
To a stirred solution of 11 (15 mg, 0.053 mmol) in
anhydrous methylene chloride (1.5 mL) was added
CBr4 (21 mg, 0.06 mmol) at 0°C. After all of the CBr4
was dissolved, Ph3P (21 mg, 0.06 mmol) was added.
The resulting solution was stirred at room temperature
for 17 h and the solvent was removed in vacuo. The
residue was extracted with n-hexane and the hexane
extract washed with brine. After removal of the solvent,
the residue was chromatographed to afford 12 (9 mg,
67%). [h]2D0=−31.5 (c 0.25, CHCl3); IR (KBr) 2781,
2.2. Condensation of 7 with b-keto ester, 8
A mixture of 7 (4.0 g, 27.6 mmol), b-keto ester 8 (7.3 g,
27.6 mmol) and freshly dried MgSO4 (1.5 g) was stirred
at room temperature for 2 days. Purification of the
resulting mixture directly by column chromatography
eluting with 1/3 ethyl acetate/n-hexane afforded 9 as a
colorless oil (7.5 g, 70%). [h]2D0=+8.9 (c 2.6, CHCl3); IR
(KBr) 3063, 2930, 1742, 1716, 1647 cm−1; 1H NMR
(300 MHz, CDCl3) l 8.51 (br d, J=7.8 Hz, 1H),
7.31–7.20 (m, 5H), 4.51 (s, 2H), 4.40 (s, 1H), 4.11 (q,
J=7.2 Hz, 2H), 3.60 (br m, 3H), 3.52 (m, 2H), 2.31 (m,
2H), 1.82 (m, 2H), 1.61–1.23 (m with t, J=6.3 Hz,
14H), 0.89 (t, J=7.3 Hz, 3H); EI-MS m/z 391 (M+),
341, 301, 213, 170, 156, 91; HRMS calcd for
C23H37NO4 (M+) 391.2721, found 391.2783.
1
1738, 1461 cm−1; H NMR (300 MHz, CDCl3) l 4.2 (q,
J=7.3 Hz, 2H), 3.5 (dt, J=7.7, 2.2 Hz, 1H), 2.67 (m,
1H), 2.15 (m, 2H), 1.91–1.21 (m with t, J=6.5 Hz,
20H), 0.89 (t, J=6.9 Hz, 3H); MS m/z 267 (M+), 197,
196, 238, 222, 168, 122, 70; HRMS calcd for
C16H29NO2 (M+) 267.2198, found 267.2207.
2.3. (R)-2-Pentyl-5-ethoxycarbonyl-6-(3-benzyloxy-
propyl)-1,2,3,4-tetrahydropyridine, 10
Acknowledgements
To a stirred solution of 9 (997 mg, 2.55 mmol) in
anhydrous acetonitrile (2.5 mL) was added CBr4 (1088
mg, 3.28 mmol) at 0°C. After all CBr4 was dissolved,
Ph3P (870 mg, 3.32 mmol) was added slowly. The
resulting mixture was warmed to room temperature and
stirring was continued until 9 disappeared (as indicated
by TLC). To this solution triethylamine (0.5 mL) was
added and the resulting solution was heated under
reflux for 5 h. The solvent was removed in vacuo and
the residue was chromatographed eluting with 1/15
ethyl acetate/n-hexane to afford 10 as a pale yellow oil
(675 g, 71%). [h]2D0=+86.5 (c 1.23, CHCl3); IR (KBr)
The authors are grateful to the Chinese Academy of
Sciences and National Natural Science Foundation of
China (grant 29725205) for their financial support.
References
1. For a review, see: Daly, J. W.; Garraffo, H. M.; Spande,
T. F. In Alkaloids: Chemical & Biological Perspectives;
Pelletier, S. W., Ed.; Pergamon Press: Oxford, 1999; Vol.
13; pp. 1–161.
2. Daly, J. W.; Nishizawa, Y.; Padgett, W. L.; Tokuyama, T.;
Smith, A. L.; Holmes, A. B.; Kibayashi, C.; Aronstam, R.
S. Neurochem. Res. 1991, 16, 1213.
3. For recent studies, see: (a) Shu, C.; Alcudia, A.; Yin, J.;
Liebeskind, L. S. J. Am. Chem. Soc. 2001, 123, 12477; (b)
Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543;
(c) Michael, J. P.; Gravestock, D. J. Chem. Soc., Perkin
1
2929, 1677, 1585 cm−1; H NMR (300 MHz, CDCl3) l
7.31–7.20 (m, 5H), 4.51 (s, 2H), 4.30 (br s, 1H), 4.15 (q,
J=7.1 Hz, 2H), 3.50 (t, J=6.3 Hz, 2H), 3.11 (m, 1H),
2.72 (t, J=7.3 Hz, 2H), 2.41 (dt, J=15, 5.1 Hz, 1H),
2.20 (m, J=5.5 Hz, 1H), 1.92 (m, 4H), 1.41–1.20 (m,
11H), 0.89 (t, J=7.0 Hz, 3H); EI-MS m/z 373 (M+),