A new asymmetric synthesis of (S)-(+)-pipecoline and (S)-(+)- and (R)-(-)-coniine by reductive photocyclization of dienamides

Article abstract of DOI:10.1016/S0040-4039(00)01549-5

(S)-(+)-Pipecoline and both enantiomers of coniine were synthesized, in good yields, by a reductive photocyclization of chiral dienamides. Enantioselectivities of up to 75% were obtained. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01549-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8769–8772
A new asymmetric synthesis of (S)-(+)-pipecoline and
(S)-(+)- and (R)-(−)-coniine by reductive photocyclization of
dienamides
Fanny Bois, Daniel Gardette and Jean-Claude Gramain*
´
Equipe Synthe`se Organique, CNRS et Universite´ Blaise Pascal, 24 avenue des Landais, 63170 Aubie`re, France
Received 16 June 2000; accepted 12 September 2000
Abstract
(S)-(+)-Pipecoline and both enantiomers of coniine were synthesized, in good yields, by a reductive
photocyclization of chiral dienamides. Enantioselectivities of up to 75% were obtained. © 2000 Published
by Elsevier Science Ltd.
Keywords: reductive photocyclization; dienamides; 2-substituted piperidines; (S)-(+)- and (R)-(−)-coniine; (S)-(+)-
pipecoline.
The development of synthetic routes to 2-substituted piperidine alkaloids 1 is of great interest
due to their occurrence in nature and their significant biological and pharmacological
properties.1
Numerous asymmetric syntheses of optically active piperidines with a stereogenic carbon at
the 2-position have been described. Most of them involved chiral intermediates which were
cyclized into enantioenriched or enantiopure 2-substituted piperidines. These intermediates were
prepared from a variety of chiral auxiliaries derived from phenylglycinol,2 2-substituted pyrro-
lidines,3 8-phenyl menthol,4 sultam,5 a-methylbenzylamine6 or amino acids.7 Other methodolo-
gies involved catalytic methods8 or the chiral lithiation–intramolecular cyclization sequence of
appropriate N-Boc-N-(3-halopropyl)-allylamines.9
More recently, different strategies to prepare 2-substituted piperidines from an already built
piperidine ring have been reported, such as asymmetric reduction of cyclic imines,10 enzymatic
resolution,11 alkylation of chiral 1,3,4-oxadiazinane12 or nucleophilic addition on N-acyliminium
ion.13
Moreover, since the work of Ninomiya14 little attention has been paid to photochemical
methods to synthesize monocyclic piperidine alkaloids.
* Corresponding author. Fax: +33(0) 4 73 40 77 17; e-mail: gramain@chisg2.univ-bpclermont.fr
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01549-5

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We now report a new, short and enantioselective synthesis of (S)-(+)-pipecoline,2b,15 an
alkaloid of P. sabiniana Dougl. and of both enantiomers of coniine,2b,10–12,15 a hemlock alkaloid,
based on the reductive photocyclization of the readily available chiral dienamides 3 (Scheme 1).
The chiral auxiliary was (R)- or (S)-a-methylbenzylamine, allowing access to both enantiomers
of the desired piperidines.
Scheme 1. Reagents: i, benzene, ZnCl2, reflux, Dean–Stark; ii, acryloyl chloride, NEt3 (1.5 equiv.), THF, rt; iii, hw,
quartz reactor, low pressure mercury lamp, NaBH4 in benzene:toluene:methanol; 58:28:14; iv, LAH, THF, reflux; v,
H2, Pd(OH)2, Boc2O, MeOH; vi, TFA, anisole, CH2Cl2
The imine 2 was obtained in excellent yield (2a, 77%; 2b, 74%) by condensation of
(R)-a-methylbenzylamine on acetone or pentan-2-one. N-acylation of the imine 2 with acryloyl
chloride in the presence of 1.5 equivalents of triethylamine at room temperature gave the
dienamide 3, which is the key intermediate in our synthesis (3a, 77%; 3b, 51%).
The photocyclization of the dienamide 3 was the crucial step and its irradiation led to the
intermediate acyliminium ion 4 which was reduced in situ by sodium borohydride to give the
piperidin-2-one 516 (50%).
The solvents and the temperature of irradiation were chosen after optimization trials. The best
results, in chemical yield and stereoselectivity, were obtained when the irradiation of the
dienamide 3 was run in a mixture of benzene:toluene:methanol (58:28:14) at −20°C in a quartz
1
reactor with a low pressure mercury lamp. The diastereomeric excess, determined by H and by
using an 13C inverse gated decoupling sequence, was 75%.
The stereochemical outcome of this reaction could be explained by the nucleophilic addition
of hydride on the non-isolated intermediate iminium ion 4 by the less hindered of its two
diastereotopic faces.17,18
The lactam 5 was then reduced to piperidine 6 with LiAlH4 (6a, 91%; 6b, 77%). The piperidine
6 was debenzylated and the alkaloids thus obtained, (S)-(+)-pipecoline and (S)-(+)-coniine, were
converted in situ to their tert-butoxycarbamate derivatives 7a and 7b in order to avoid the
manipulation of volatile and toxic alkaloids.19

8771
The antipodal (R)-(−)-N-Boc-coniine 7c was obtained by the same procedure using (S)-a-
methylbenzylamine as the chiral auxiliary.
Cleavage of the carbamoyl group by treatment of small quantities of compound 7 with
trifluoroacetic acid and anisole led to (S)-(+)-pipecoline, (S)-(+)- and (R)-(−)-coniine in 90%
enantiomeric excess.20
In conclusion, we described a short, efficient and enantioselective synthesis of 2-substituted
piperidines: (S)-(+)-pipecoline, (S)-(+)- and (R)-(−)-coniine, in excellent enantiomeric excess, by
means of reductive photocyclization of dienamides prepared from (R)- or (S)-a-methylbenzyl-
amine as chiral auxiliary.
References
1. For reviews on piperidines and piperidine alkaloids see: (a) Harrison, T. Contemporary Organic Synthesis; 1995;
Vol. 2, pp. 209–224. (b) Ibid. 1996; Vol. 3, pp. 259–275. (c) Angle, S. R.; Breitenbucher, J. G. In Studies in
Natural Product Chemistry: Stereoselective Synthesis (Part J); Atta-ur-Rahman, Ed.; Elsevier: Oxford, 1995; Vol.
16, pp. 453–502.
2. (a) Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383–394 and references cited therein. (b) Freville, S.;
Ce´le´rier, J.-P.; Thery, V. M.; Lhommet, G. Tetrahedron: Asymmetry 1995, 6, 2651–2654.
3. Enders, D.; Tiebes, J. Liebigs Ann. Chem. 1993, 173–177.
4. Al-awar, R. S.; Joseph, S. P.; Comins, D. L. Tetrahedron Lett. 1992, 33, 7635–7638.
5. Oppolzer, W.; Bochet, C. G.; Merifield, E. Tetrahedron Lett. 1994, 35, 7015–7018.
6. (a) Kiguchi, T.; Nakazano, Y.; Kotera, S.; Ninomiya, I.; Naito, T. Heterocycles 1990, 31, 1525–1535. (b) Marx,
E.; El Bouz, M.; Ce´le´rier, J.-P.; Lhommet, G. Tetrahedron Lett. 1992, 33, 4307–4310.
7. Kunz, H.; Pfrergle, W. Angew. Chem., Int. Ed. Engl. 1989, 28, 1067–1069.
8. Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahedron: Asymmetry 1996, 7, 3047–3054.
9. Serino, C.; Stehle, N.; Park, Y. S.; Florio, S.; Beak, P. J. Org. Chem. 1999, 64, 1160–1165.
10. Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1998, 63, 6344–6347.
11. Sa´nchez-Sancho, F.; Herrado´n, B. Tetrahedron: Asymmetry 1998, 9, 1951–1965.
12. Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1997, 38, 4623–4626.
13. Pilli, R. A.; de Fa´tima Alves, C.; Bo¨ckelmann, M. A.; Mascarentas, Y. P.; Nery, J. G.; Vencato, I. Tetrahedron
Lett. 1999, 40, 2891–2894.
14. Ninomiya, I.; Naito, T. Heterocycles 1981, 15, 1433–1462.
15. For recent synthesis of (S)-(+)-pipecoline and (S)-(+)- and (R)-(−)-coniine see: (a) Meyers, A. I.; Munchhof, M.
J. J. Org. Chem. 1995, 60, 7084–7085. (b) Doller, D.; Davies, R.; Chakalamanil, S. Tetrahedron: Asymmetry 1997,
8, 1275–1278. (c) Wu, X.-D.; Khim, S.-K.; Zhang, X.; Cederstrom, E. M.; Mariano, P. S. J. Org. Chem. 1998,
63, 841–859.
16. A typical procedure is given for the preparation of N-(a-methylbenzyl)-6-propylpiperidin-2-one 5b: sodium
borohydride (660 mg, 17.4 mmol) was added to a stirred solution of the dienamide 3b (500 mg, 2.05 mmol) in
a mixture of benzene (85 ml)/toluene (45 ml)/methanol (20 ml) at −20°C. When the added sodium borohydride
was dissolved, the resulting solution was irradiated, in a quartz reactor with a low pressure mercury lamp, for 48
hours. The reaction mixture was then evaporated. Water was added to the residue and the mixture was extracted
with CH2Cl2 (3×15 ml). The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo.
Flash chromatography on SiO2 (AcOEt:hexane; 30:70) of the crude product gave the compound 5b (250 mg, 1.02
1
mmol), shown to be a mixture of two diastereoisomers (ratio=87:12) as determined by H and 13C NMR; IR
(CHCl3) 1635 cm−1; 1H NMR (CDCl3 400 MHz) l 0.58 (t, 3H, J=7.5 Hz), 0.63–0.67 (m, 1H), 0.77–0.90 (m, 1H),
1.01–1.13 (m, 1H), 1.17–1.28 (m, 1H), 1.54 (d, 3H, J=7.0 Hz), 1.56–1.71 (m, 2H), 1.73–1.84 (m, 2H), 2.32–2.46
(m, 2H), 3.32–3.40 (m, 1H), 5.67 (q, 1H, J=7.0 Hz), 7.05–7.35 (m, 5H); 13C NMR (CDCl3 100 MHz) l 13.9,
15.9, 16.3, 19.4, 25.6, 31.0, 34.5, 52.5, 53.1, 127.1–128.2, 140.9, 169.8. The spectral data for this compound
matched in all aspects those reported in the literature17.
17. Polniaszek, R. P.; Belmont, S. E.; Alvarez, R. J. Org. Chem. 1990, 55, 215–223.
18. Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett. 1999, 40, 739–742.

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19. Preparation of (S)-(+)-N-Boc-2-propylpiperidine 7b: to a solution of piperidine 6b (220 mg, 0.96 mmol) in 10 ml
of AcOEt was added Boc2O (230 mg, 1.05 mmol) and Pd(OH)2 (22 mg). The suspension was vigorously stirred
in a Paar apparatus under hydrogene (4 atm.) at room temperature for 15 hours. After filtration of catalyst, the
solvent was evaporated. A solution of NaOH (4N) (5 ml) and THF (10 ml) was added to the residue and the
mixture was stirred at room temperature for 1 hour. After addition of ether to the mixture and extraction, the
extract was dried and evaporated. Chromatography on SiO2 (AcOEt:hexane; 1:20 with a few drops of NEt3) of
the crude product gave the expected piperidine 7b with an enantiomeric excess better than 90%; [h]2D0 28.5 (c 1.35
1
CHCl3) {lit.10 [h]D20 30.5 (c 1.30 CHCl3)}; H NMR (CDCl3 400 MHz) l 0.90 (t, 3H, J=7.2 Hz), 1.20–1.67 (m,
6H), 1.44 (s, 9H), 2.73 (t, 1H, J=13.3 Hz), 3.95 (m, 1H), 4.19 (m, 1H); 13C NMR (CDCl3 100 MHz) l 14.1, 19.1,
19.5, 25.7, 28.5, 31.9, 38.7, 50.2, 78.9, 155.2. Specific rotation of other N-Boc-piperidines: (S)-(+)-N-Boc-2-
methylpiperidine 7a: [h]2D0 46 (c 0.86 CHCl3) {lit.15 [h]D20 50.9 (c 0.83 CHCl3)}; (R)-(−)-N-Boc-2-propylpiperidine
7c: [h]2D3 −28.4 (c 1.36 CHCl3) {lit.3 [h]D23 −31.5 (c 0.86 CHCl3)}.
20. 1H and 13C spectroscopic data are in agreement with those reported in literature.15
.