N. Girard, J.-P. Hurvois / Tetrahedron Letters 48 (2007) 4097–4099
4099
of methanol containing 2 g of lithium acetate dihydrate
and 1.07 g (26.8 mmol, 7.0 equiv) of sodium cyanide. The
resulting solution was placed in a divided cell and oxidized
at a planar vitreous graphite electrode at (+0.9 V/SCE).
After the consumption of 870 coulomb (2.35 F/mol), the
electrolysis was stopped. The solvent was evaporated in
vacuo and the crude material was taken up with water
(100 mL) and extracted with ether (100 mL · 2). The
combined organic layers were dried over MgSO4 and
concentrated. The crude reaction mixture was purified by
silica column chromatography (diethyl ether/petroleum
ether, 1:1) to afford (2S*,4S*)-8 (0.820 g, 75%, yellow oil)
45% yield as a single stereoisomer (99% de). Several at-
tempts were made to improve the conversion yield, but
all of them remain unsuccessful. Although a single ad-
duct was detected by spectroscopic means (1H and 13C
NMR), it was not possible to univocally determine the
stereochemistry at this stage. However, one can assume
that the substituents were all in a cis configuration as
drawn in Scheme 3. Completion of the synthesis of
( )-1 was made as follows. The acidic cleavage of the
tetrahydropyranyl ether resulted in the formation of 2-
methyl-6-nonyl-1-phenyl-piperidin-4-ol whose phenyl
ring was reduced with Li (100 equiv) in a mixture of
THF and liquid ammonia in the presence of EtOH as
proton donor (Scheme 3).14 After work-up, the interme-
diate crude dienamine mixture was immediately hydro-
lyzed in aqueous acidic ethanol to produce ( )-1 (73%
yield from 13) as a white solid which melted at 97 ꢁC.
Spectral data of ( )-1 (1H, 13C NMR, and m/z) were
identical with those reported in the literature.5b
1
as the major diastereomer. H NMR (300 MHz, CDCl3):
d = 1.45–1.62 (m, 5H), 1.63–2.08 (m, 4H), 2.10–2.42 (m,
2H), 3.02–3.13 (m, 1H), 3.43–3.58 (m, 1H), 3.84–4.04
(m, 2H), 4.60–4.65 (m, 1H), 4.66–4.70 (m, 1H), 6.95–6.98
(m, 3H), 7.25–7.31 (m, 2H). 13C NMR (75 MHz, CDCl3):
d = 19.87, 25.32, 31.05, 31.08, 31.18, 32.94, 34.59, 35.80,
45.07, 45.23, 50.97, 51.02, 62.94, 69.98, 70.64, 97.41, 98.12,
118.25, 122.27, 129.34. HRMS: m/z calcd for C17H22N2O2
[M+]: 286.1681; found, 286.1665.
10. Husson, H. P.; Royer, J. Chem. Soc. Rev. 1999, 6, 383–394.
11. (a) Deslongchamps, P. In Stereoelectronic Effects in
Organic Chemistry; Baldwin, J., Ed.; Pergamon Press:
Oxford, 1983; (b) Stevens, R. V. Acc. Chem. Res. 1984, 17,
289–296.
12. Malassene, R.; Vanquelef, E.; Toupet, L.; Hurvois, J. P.;
Moinet, C. Org. Biomol. Chem. 2003, 1, 547–551.
13. For the regioselective methoxylation of 2-substituted
piperidines see: (a) Laurent, P.; Braekman, J. C.; Daloze,
D. Eur. J. Org. Chem. 2000, 2057–2062; (b) Bodmann, K.;
Bug, T.; Steinbeisser, S.; Kreuder, R.; Reiser, O. Tetrahe-
In summary, a stereoselective synthesis of ( )-alkaloid
241D has been developed. The alkylation–reduction
steps were performed stereoselectively to place the sub-
stituents in a cis relative configuration.
Acknowledgement
N.G. thanks the MENRT for a grant.
´
dron Lett. 2006, 47, 2061–2064; (c) Driessens, F.; Hootele,
C. Can. J. Chem. 1992, 70, 2722–2725.
References and notes
14. Synthesis of alkaloid ( )-241D. Compound 13 (0.36 g,
1.31 mmol) was dissolved in a THF–H2SO4 1.5 N (10:1)
mixture and stirred at +65 ꢁC for 6 h. Work-up and
purification by column chromatography (diethyl ether/
petroleum ether, 1:1) afforded 2-methyl-6-nonyl-1-phenyl-
piperidin-4-ol (0.26 g, 96%), which was dissolved in a
mixture of liquid ammonia (20 mL) THF (10 mL) and
ethanol (6 mL). Then, Li (0.55 g, 80 mmol) was added in
small pieces over a 1 h period upon which the solution
became blue. Stirring was continued for 2 h and the
solution was quenched with an excess of ethanol (5 mL)
and ammonia was allowed to evaporate under a well
ventilated hood. Water (20 mL) was added and the
resulting aqueous mixture was extracted with cyclohexane
(50 mL · 2). The combined organic layers were dried with
MgSO4 and concentrated in vacuo to afford a mixture of
crude enamines which were dissolved in a H2SO4/H2O/
EtOH (0.5:5.0:4.5) mixture. The solution was heated at
60 ꢁC for 1 h and the solvents were evaporated. The
sulfate of ( )-1 was dissolved in water and the solution
was made basic by the addition of NaOH pellets. The free
amine was extracted with diethyl ether (50 mL · 2) and the
combined organic phases were dried over MgSO4 and
concentrated. Purification by column chromatography
with diethyl ether saturated with gaseous ammonia gave
( )-1 (0.14 g, 76%) as a white solid, mp = 97 ꢁC. 1H NMR
(300 MHz, CDCl3): d = 1.47 (t, 3J = 7.10 Hz, 3H), 1.62
1. Edwards, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188–
1197.
2. For a review on the solenopsins see: Leclercq, S.; Daloze,
D.; Braekman, J. C. Org. Prep. Proced. Int. 1996, 28, 501–
503.
3. Attygale, A. B.; Xu, S. C.; McCormick, K. D.; Meinwald,
J.; Blankespoor, C. L.; Eisner, T. Tetrahedron 1993, 49,
9333–9342.
4. Edwards, M. W.; Garraffo, H. M.; Daly, J. W. Synthesis
1994, 1167–1170.
5. (a) Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503–2505; (b)
Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem.
Soc., Perkin Trans.1 2000, 353–357; (c) Davis, F. A.;
Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169–3171; (d)
Monfray, J.; Gelas-Miahle, Y.; Gramain, J.-C.; Remuson,
R. Tetrahedron: Asymmetry 2005, 16, 1025–1034.
6. Girard, N.; Gautier, C.; Malassene, R.; Hurvois, J.-P.;
Moinet, C.; Toupet, L. Synlett 2004, 2005–2009.
7. (a) Girard, N.; Hurvois, J.-P.; Moinet, C.; Toupet, L. Eur.
J. Org. Chem. 2005, 1, 2269–2280, and references cited
therein; For a recent metal-catalyzed synthesis of N-aryl
piperidones see: (b) Scho¨n, U.; Messinger, J.; Buckendahl,
M.; Prabhu, M. S.; Konda, A. Tetrahedron Lett. 2007, 48,
2519–2525.
8. For a general survey on the oxidation of nitrogen-
containing compounds see: (a) Steckan, E. In Organic
Electrochemistry; Lund, E., Hammerich, O., Eds.; Marcel
Dekker: New York, 2001; pp 545–588; (b) Shono, T.
Tetrahedron 1984, 40, 811–850.
3
3
(sext, J = 12.5 Hz, 2H), 1.80 (d, J = 6.5 Hz, 3H), 2.65–
3.20 (s, br, 2H), 1.95–1.42 (m, 16H), 1.83–1.88 (m, 2H),
2.45–2.55 (m, 1H), 2.60–2.64 (m, 1H), 3.57–3.62 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 14.06, 22.43, 22.63,
26.02, 29.28, 29.52, 29.54, 29.73, 31.85, 36.77, 41.69, 43.85,
50.17, 54.87, 68.96. HRMS: m/z calcd for C15H31NO
[M+]: 240.2327; found, 240.2325.
9. Procedure for the synthesis of (2S*,4S*)-1-phenyl-4(tetra-
hydro-2H-pyran-2-yloxy)piperidine-2-carbonitrile
Compound 7 (1.0 g, 3.83 mmol) was dissolved in 100 mL
(8).