Enantioselective synthesis of the trans-2,6-dialkylpiperidine alkaloids (2R,6R)-lupetidine and (2R,6R)-solenopsin A

Article abstract of DOI:10.1016/S0957-4166(98)00249-3

The enantioselective synthesis of the trans-2,6-dialkylpiperidine alkaloids (2R,6R)-lupetidine and (2R,6R)-solenopsin A from 6-methyl-2- piperidone 1 is described. The key step of this synthesis consists of the addition of a dialkylcopper derivative to the thioimidate salt 3 followed by sodium borohydride reduction of the resulting iminium salt.

Full text of DOI:10.1016/S0957-4166(98)00249-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2419–2422
Enantioselective synthesis of the trans-2,6-dialkylpiperidine
alkaloids (2R,6R)-lupetidine and (2R,6R)-solenopsin A
Mercedes Amat,∗ José Hidalgo, Núria Llor and Joan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 5 June 1998; accepted 19 June 1998
Abstract
The enantioselective synthesis of the trans-2,6-dialkylpiperidine alkaloids (2R,6R)-lupetidine and (2R,6R)-
solenopsin A from 6-methyl-2-piperidone 1 is described. The key step of this synthesis consists of the addition
of a dialkylcopper derivative to the thioimidate salt 3 followed by sodium borohydride reduction of the resulting
iminium salt. © 1998 Elsevier Science Ltd. All rights reserved.
The stereoselective synthesis of substituted piperidines, which are widespread skeletal fragments
of important biologically active natural products, has attracted considerable attention in the last few
decades1. In particular, the 2,6-disubstituted piperidine ring structure has been found in certain members
of the pine and fire ant species. However, although cis-2,6-dialkylpiperidines are easily accessible,
efficient stereoselective methods for the synthesis of trans-2,6-disubstituted piperidines are relatively
scarce. Solenopsin A [(2R,6R)-2-methyl-6-undecylpiperidine]2 and solenopsin B [(2R,6R)-2-methyl-6-
tridecylpiperidine],2 isolated from the venom secreted by the fire ant Solenopsis invicta, have been
a vehicle for the testing of several different synthetic methods.3 These methods include: (i) hydride
reduction of 1-piperideines4 or the corresponding iminium salts;5 (ii) intramolecular aminomercuration;6
(iii) alkene nitrone cycloadditions;7 (iv) alkylation of α-lithiated piperidine derivatives;8 (v) addi-
tion of organocerium reagents to 6-alkyl-1-piperideines;9 (vi) reductive decyanation of 2,6-dialkyl-2-
cyanopiperidines;10 (vii) intramolecular addition of allylsilanes to nitrones;11 (viii) isomerization of N-
nitroso-cis-2,6-dialkylpiperidines;12 and (ix) nucleophilic amine substitution of mesylates.13,14 Some of
these procedures have been extended to the enantioselective synthesis of solenopsins.15
In a previous paper16 we reported the enantioselective synthesis of the cis-2,6-dialkylpiperidine
alkaloid (2R,6S)-dihydropinidine from 6-methyl-2-piperidone 1 (Scheme 1). The key step was the
addition of propylmagnesium bromide to the iminium salt A (R=H), generated by partial reduction of the
amide carbonyl of 1. The observed stereoselectivity is a consequence of the stereoelectronically preferred
axial approach17 of the nucleophile to the most stable half chair conformation of A (Scheme 2), which
∗
Corresponding author. E-mail: amat@farmacia.far.ub.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00249-3

2420
M. Amat et al. / Tetrahedron: Asymmetry 9 (1998) 2419–2422
incorporates a methyl group in a pseudoaxial orientation to relieve the A(1,2) strain.18 Reversal of this
sequence, i.e. addition of an organometallic reagent to the lactam 1, followed by hydride addition to the
resulting iminiun salts A (R=Me or R=n-C11H23), also under stereoelectronic control, would lead to the
trans-2,6-dialkylpiperidine alkaloids (2R,6R)-lupetidine and (2R,6R)-solenopsin A, respectively.
Scheme 1.
Scheme 2.
Our initial attempts to prepare trans-2,6-dialkylpiperidines by treatment of lactam 1 (easily
prepared16 from the chiral non-racemic bicyclic lactam 2, Scheme 3) with Grignard, organolithium,19 or
organocerium20 reagents, followed by reduction with lithium aluminium hydride or sodium borohydride,
resulted in failure. These results prompted us to use the more reactive thioimidate salt 4:21 addition of an
organometallic reagent to the iminium moiety of 4, followed by elimination of the methylsulfanyl group,
would also lead to the desired iminium salts 5 (i.e. A, R=alkyl).
Scheme 3.
Compound 4 was obtained in good yield by protection of the hydroxyl group of lactam 1, followed
by treatment with Lawesson reagent and subsequent alkylation of the resulting thioamide 3 with methyl
iodide. However, treatment of 4 with methyllithium or methylmagnesium bromide, followed by addition
of NaBH4, afforded the reduced piperidine 6a as the only identifiable product. This result can be
attributed to the basicity of the above organometallic reagents, which deprotonate the α position of
thioimidate 4 yielding the corresponding ketene S,N-acetal;22 subsequent addition of a hydride affords
piperidine 6a. However, addition of the less basic23 organometallic derivative lithium dimethylcuprate
to the salt 4 at 0°C, followed by treatment of the reaction mixture with NaBH4, afforded the desired
2,6-dimethylpiperidine 6b (92:8 trans:cis ratio) in 55% overall yield from thioamide 3. Piperidine 6a
was also formed in about 17% yield in all cases. Finally, hydrogenolysis of the benzylic substituent of 6b

M. Amat et al. / Tetrahedron: Asymmetry 9 (1998) 2419–2422
2421
gave trans-2,6-dimethylpiperidine 7b, whose hydrochloride showed mp 243–244°C and [α]D +12.4 (c
3.0, EtOH) {lit.24 mp 247–249°C and [α]D +12.8 (c 3.06, EtOH)} and possessed data identical to those
reported for the alkaloid (2R,6R)-lupetidine,24 isolated from Nanophyton erinaceum.25
The above methodology provides a general synthetic entry to enantiopure trans-2,6-dialkylpiperidines.
This was exemplified by an enantioselective synthesis of the fire ant venom solenopsin A. Thus, treatment
of the thioimidate salt 4 with di-n-undecylcopper(I)-magnesium bromide, followed by reduction with
NaBH4, afforded the corresponding 2-methyl-6-undecylpiperidine in 54% overall yield from thioamide
3 as a 7:3 mixture of trans-6c and its cis-isomer,26 which could be separated by column chromatography
after desilylation (n-Bu4NF). Debenzylation of the major isomer afforded (2R,6R)-solenopsin A 7c,
which was isolated as the hydrochloride {mp 141–142°C and [α]D −7.0 (c 1.3, CHCl3); lit.8b mp
141–142°C and [α]D −7.6 (c 0.5, CHCl3)}. The spectral data (1H-NMR and 13C-NMR) of our synthetic
solenopsin A were identical with those reported.5g
The above results expand the potential of chiral non-racemic bicyclic lactam 2 for the enantioselective
synthesis of diversely substituted piperidines.27
Acknowledgements
Financial support from the DGICYT, Spain (project PB94-0214) is gratefully acknowledged. Thanks
are also due to the ‘Comissionat per a Universitats i Recerca’, Generalitat de Catalunya, for Grant 1997-
SGR-0018, and to the ‘Ministerio de Educación y Cultura’ for a fellowship to J.H.
References
1. (a) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York,
1985; Vol. 3, pp. 1–90. (b) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando,
1985; Vol. 26, pp. 89–183. (c) Wang, C.-L. J.; Wuonola, M. A. Org. Prep. Proced. Int. 1992, 24, 585–621. (d) Angle, S.
R.; Breitenbucher, J. G. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam,
1995; Vol. 16, pp. 453–502. (e) Schneider, M. J. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon: Oxford, 1996; Vol. 10, pp. 155–299.
2. (a) MacConnell, J. G.; Blum, M. S.; Fales, H. M. Tetrahedron 1971, 26, 1129–1139. (b) Jones, T. H.; Blum, M. S.; Fales, H.
M. Tetrahedron 1982, 38, 1949–1958. (c) Leclercq, S.; Thirionet, I.; Broeders, F.; Daloze, D.; Vander Meer, R.; Braekman,
J. C. Tetrahedron 1994, 50, 8465–8478.
3. For a review, see: Leclercq, S.; Daloze, D.; Braekman, J.-C. Org. Prep. Proced. Int. 1996, 28, 501–543.
4. (a) Hill, R. K.; Yuri, T. Tetrahedron 1977, 33, 1569–1571. (b) Sakane, S.; Matsumura, Y.; Yamamura, Y.; Ishida, Y.;
Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 672–674. (c) Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura,
Y.; Sakane, S.; Hattori, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 2831–2843. (d) Meyers, A. I.; Edwards, P. D.;
Bailey, T. R.; Jagdmann, G. E. J. Org. Chem. 1985, 50, 1019–1026. (e) Yamaguchi, R.; Nakazono, Y.; Matsuki, T.; Hata,
E.; Kawanisi, M. Bull. Chem. Soc. Jpn 1987, 60, 215–222. (f) Ryckman, D. M.; Stevens, R. V. J. Org. Chem. 1987, 52,
4274–4279. (g) Taber, D. F.; Deker, P. B.; Fales, H. M.; Jones, T. H.; Lloyd, H. A. J. Org. Chem. 1988, 53, 2968–2971. (h)
Bacos, D.; Célérier, J. P.; Marx, E.; Rosset, S.; Lhommet, G. J. Heterocyclic Chem. 1990, 27, 1387–1392. (i) Fukuda, Y.;
Utimoto, K. Synthesis 1991, 975–978. (j) Fukuda, Y.; Matsubara, S.; Utimoto, K. J. Org. Chem. 1991, 56, 5812–5816. (k)
Ukaji, Y.; Watai, T.; Sumi, T.; Fujisawa, T. Chem. Lett. 1991, 1555–1558.
5. (a) Bonin, M.; Romero, J. R.; Grierson, D. S.; Husson, H.-P. Tetrahedron Lett. 1982, 23, 3369–3372. (b) Takahashi, K.;
Kurita, H.; Ogura, K.; Iida, H. J. Org. Chem. 1985, 50, 4368–4371. (c) Grierson, D. S.; Royer, J.; Guerier, L.; Husson,
H.-P. J. Org. Chem. 1986, 51, 4475–4477. (d) Wasserman, H. H.; Rusiecki, V. Tetrahedron Lett. 1988, 29, 4977–4980. (e)
Comins, D. L.; Weglarz, M. A. J. Org. Chem. 1991, 56, 2506–2512. (f) Kotsuki, H.; Kusumi, T.; Inoue, M.; Ushio, Y.;
Ochi, M. Tetrahedron Lett. 1991, 32, 4159–4162. (g) Jefford, C. W.; Bo Wang, J. Tetrahedron Lett. 1993, 34, 2911–2914.
6. (a) Moriyama, Y.; Doan-Huynh, D.; Monneret, C.; Khuong-Huu, Q. Tetrahedron Lett. 1977, 825–828. (b) Adams, D.
R.; Carruthers, W.; Williams, M. J.; Crowley, P. J. J. Chem. Soc., Perkin Trans. 1 1989, 1507–1513. (c) Mundy, B. P.;

2422
M. Amat et al. / Tetrahedron: Asymmetry 9 (1998) 2419–2422
Bjorklund, M. Tetrahedron Lett. 1985, 26, 3899–3902. (d) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem. Soc. 1990, 112,
3100–3109.
7. (a) Carruthers, W.; Williams, M. J. J. Chem. Soc., Chem. Commun. 1986, 1287–1288. (b) Chackalamannil, S.; Wang, Y.
Tetrahedron 1997, 53, 11203–11210.
8. (a) Beak, P.; Koo Lee, W. J. Org. Chem. 1993, 58, 1109–1117. (b) Comins, D. L.; Radi Benjelloun, N. Tetrahedron Lett.
1994, 35, 829–832.
9. Oppolzer, W.; Bochet, C. G.; Merifield, E. Tetrahedron Lett. 1994, 35, 7015–7018.
10. Nagasaka, T.; Hayashi, H.; Kumakawa, M.; Sakamoto, M.; Mizuno, M.; Hamaguchi, F. Heterocycles 1989, 29, 2157–2166.
See also Refs. 2c and 5a.
11. Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 1957–1965.
12. Fuji, K.; Ichikawa, K.; Fujita, E. Chem. Pharm. Bull. 1979, 27, 3183–3185.
13. (a) Takahata, H.; Inose, K.; Araya, N.; Momose, T. Heterocycles 1994, 38, 1961–1964. (b) Solladié, G.; Huser, N. Recl.
Trav. Chim. Pays-Bas 1995, 114, 153–156.
14. Lupetidine [(2R,6R)-2,6-dimethylpiperidine] has also been synthesized following this method: Najdi, S.; Kurth, M. J.
Tetrahedron Lett. 1990, 31, 3279–3282.
15. See Refs. 2c, 4g, 4k, 5c, 5f, 5g, 7b, 8b, 9, 13a and 13b.
16. Amat, M.; Llor, N.; Hidalgo, J.; Hernández, A.; Bosch, J. Tetrahedron: Asymmetry 1996, 7, 977–980.
17. Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon: New York, 1983; p. 211.
18. (a) Johnson, F. Chem. Rev. 1968, 68, 375–412. (b) Hoffman, R. W. Chem. Rev. 1989, 89, 1841–1860.
19. Cervinka, O. In The Chemistry of Enamines, Part I; Rappoport, Z., Ed. In The Chemistry of Functional Groups; Patai, S.;
Rappoport, Z., Eds.; Wiley: Chichester, 1994; p. 489.
20. (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984,
49, 3904–3912. (b) Denmark, S. E.; Edwards, J. P.; Nicaise, O. J. Org. Chem. 1993, 58, 569–578.
21. Kantlehner, W. In Iminium Salts in Organic Chemistry; Böhme, H.; Viehe, H. G., Eds.; Wiley: New York, 1979; Part 2, p.
279.
22. Gompper, R.; Elser, W. Org. Synth. 1968, 48, 97–101.
23. For the alkylation of the α-position of cyclic amines via thioimidate salts with lithium acetylides, see: (a) Takahata, H.;
Yamazaki, T. Heterocycles 1988, 27, 1953–1973. (b) Takahata, H.; Takahashi, K.; Wang, E.-C.; Yamazaki, T. J. Chem.
Soc., Perkin Trans. 1 1989, 1211–1214.
24. Najdi, S.; Kurth, M. J. Tetrahedron Lett. 1990, 31, 3279–3282.
25. (a) Kuzovkov, A. D.; Menshikov, G. P. Zhur. Obshchei Khim. 1950, 20, 1524 [Chem. Abstr. 1951, 45, 2485g]. (b) Hill, R.
K.; Morgan, J. W. J. Org. Chem. 1966, 31, 3451–3452. (c) Perrone, R.; Tortorella, V. Tetrahedron 1978, 34, 2533–2536.
26. The lower stereoselectivity in the hydride reduction of the R–C_N bond of related 1-piperidinium salts when R is an alkyl
group larger than CH3 has previously been observed.4c,d,k
27. (a) 2-Alkyl: Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994, 35, 2223–2226. (b) 3-Alkyl: Amat, M.; Pshenichnyi,
G.; Bosch, J.; Molins, E.; Miravitlles, C. Tetrahedron: Asymmetry 1996, 7, 3091–3094. (c) cis-2,6-Dialkyl: see Ref. 16.
(d) trans-3,4-Dialkyl: Amat, M.; Hidalgo, J.; Bosch, J. Tetrahedron: Asymmetry 1996, 7, 1591–1594 and 1845. See also
(e) Amat, M.; Llor, N.; Bosch, J.; Solans, X. Tetrahedron 1997, 53, 719–730. (f) Amat, M.; Llor, N.; Hidalgo, J.; Bosch,
J.; Molins, E.; Miravitlles, C. Tetrahedron: Asymmetry 1996, 7, 2501–2504.