A simple and stereospecfic route to 2,6-disubstituted 4-hydroxypiperidines. Synthesis of dendrobate alkaloid (+)-241D and formal synthesis of (-)-indolizidine 167B.

Article abstract of DOI:10.1021/ol006176n

The condensation of enantiopure beta-amino esters with beta-ketoesters followed by cyclization and decarboxylation afforded 2,3-dihydro-4-pyridones 3, which were selectively hydrogenated to provide 2,6-disubstituted 4-hydroxypiperdines.

Full text of DOI:10.1021/ol006176n

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2503-2505
A Simple and Stereospecfic Route to
2,6-Disubstituted 4-Hydroxypiperidines.
Synthesis of Dendrobate Alkaloid
(+)-241D and Formal Synthesis of
(−)-Indolizidine 167B
Dawei Ma* and Haiying Sun
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
madw@pub.sioc.ac.cn
Received June 8, 2000
ABSTRACT
The condensation of enantiopure â-amino esters with â-ketoesters followed by cyclization and decarboxylation afforded 2,3-dihydro-4-pyridones
3, which were selectively hydrogenated to provide 2,6-disubstituted 4-hydroxypiperdines.
2,6-Disubstituted 4-hydroxypiperidine and 2,6-disubstituted
4-oxopiperidine ring systems are found embedded within the
frameworks of many biologically active natural products such
as lasubine II,1 lyfoline,2 myrtine,3 and dendrobate alkaloid
(+)-241D4 (Figure 1). In addition, they also serve as the key
intermediates in the synthesis of other alkaloids such as 2,6-
disubstituted piperidines and indolizidines.5,6 Several methods
for asymmetrically synthesizing this class of compounds have
appeared, which include Comins’s 2,3-dihydro-4-pyridone
methodology,5b Kunz’s Mannich-Michael reaction strategy,7
and Chenevert’s enzymatic route.4c In connection with our
studies on the synthesis from enantiopure â-amino esters,8
we have reported a method for diastereoselective synthesis
(5) For review, see (a) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675. (b)
Comins, D. L.; Joseph, S. P.; Hong, H.; Al-awer, R. S.; Foti, C. J.; Zhang,
Y.; Chen. X.; Lamunyon, D. H.; Guerra-Weltzien, M. Pure Appl. Chem.
1997, 69, 477. (c) Michael, J. P. Nat. Prod. Rep. 1997, 14, 619.
(6) (a) Kuethe, J. T.; Comins, D. L. Org. Lett. 1999, 1, 1031. (b) Comins,
D. L.; Zhang, Y. J. Am. Chem. Soc. 1996, 118, 12248.
(1) Isolation: Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Chem. Pharm.
Bull. 1978, 26, 2515. Synthesis: Brown, J. D.; Foley, M. A.; Comins, D.
L. J. Am. Chem. Soc. 1988, 110, 7445 and references therein.
(2) (a) Rother, A. Phytochemistry 1990, 29, 1683. (b) Xie, X.-Q.; Rother,
A.; Edwards, J. M. J. Nat. Prod. 1995, 58, 1876.
(3) Isolation: Slosse, P.; Hootele, C. Tetrahedron Lett. 1978, 397.
Synthesis: Gelas-Mialhe, Y.; Gramain, J. C.; Louver, A.; Remuson, R.
Tetrahedron Lett. 1992, 33, 73.
(4) Isolation: (a) Edwards, M. W.; Daly, J. W.; Mters, C. W. J. Nat.
Prod. 1988, 51, 1188. Synthesis: (b) Edwards, M. W.; Garraffo, M.; Daly,
J. W. Synthesis 1994, 1167. (c) Chenevert, R.; Dickman, M. J. Org. Chem.
1996, 61, 3332. (d) Ciblat S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem.
Soc., Perkin Trans. 1 2000, 353.
(7) (a) Weymann, M.; Pfrengle, W.; Schollmeyer, D.; Kunz, H. Synthesis
1997, 1151. (b) Weymann, M.; Schultz-Kukula, M.; Kunz, H. Tetrahedron
Lett. 1998, 39, 7835.
(8) (a) Ma, D.; Sun, H. Tetrahedron Lett. 2000, 41, 1947. (b) Ma, D.;
Sun, H. Tetrahedron Lett. 1999, 40, 3609. (c) Ma, D.; Zhang, J. J. Chem.
Soc., Perkin Trans. 1 1999, 1703. (d) Ma, D.; Zhang, J. Tetrahedron Lett.
1998, 39, 9067. (e) Ma, D.; Jiang, J. Tetrahedron: Asymmetry 1998, 9,
1137. (f) Ma, D.; Jiang, J. Tetrahedron: Asymmetry 1998, 9, 575.
10.1021/ol006176n CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/18/2000

treated with sodium methoxide or sodium ethoxide to afford
cyclization products 2.12 Removal of the ester moiety in 2
by refluxing these â-ketoesters in a mixture of ethanol and
aqueous NaOH (1/1) provided 2,3-dihydropyridones 3 in high
yields. Reduction of 3 was obtained with NaBH4 or
hydrogenation catalyzed by Pd/C under ordinary pressure
in order to reduce both the C-C double bond and the C-O
double bond. Under these conditions it was found that the
reaction either did not occur or gave a complicated mixture.
After some experimentation, we found that under 50 atm at
50 °C the hydrogenation of 3b or 3c provided 4a or 4b as
a single product. Thus, we have established a simple method
to obtain enantiopure 2,6-disubstituted 4-hydroxypiperidines.
The overall yields for these four steps were over 55%.
To assign the stereochemistry of two new stereogenic
centers, we undertook the total synthesis of dendrobate
alkaloid (+)-241D using the present strategy. As shown in
Scheme 2, â-amino ester 6, obtained from ethyl 2E-
Figure 1. Structures of alkaloids possessing 2,4,6-trisubstituted
piperidine moiety.
Scheme 2
of 2,4,5-trisubstituted piperidines.8b Herein we wish to
describe a simple and efficient method for preparing 2,6-
disubstituted 4-hydroxypiperidines and its application to the
synthesis of dendrobate alkaloid (+)-241D and (-)-indolizi-
dine 167B.7,9,10
As outlined in Scheme 1, our approach to 2,6-disubstituted
4-hydroxypiperidines started from enantiopure â-amino esters
Scheme 1
dodecenoate 5 by a known procedure, was condensed with
ethyl acetoacetate and then treated with sodium ethoxide to
afford the cyclic product 7. After removal of the ester moiety
of 7, the generated 2,3-dihydropyridone was hydrogenated
to provide the target molecule.13 Its spectral data were all
identical with those reported. In addition, by converting this
product to the corresponding Mosher ester, we determined
its enantiopurity to be greater than 97%. This synthetic result
indicated that the three substituents in this piperidine are all
cis to each other. Therefore, we could conclude that during
the hydrogenation the active species attack the two double
bonds exclusively from the back face of 2-alkyl or aryl group
of enones 3. It is notable that the present synthetic route
only involves six workup steps to give dendrobate alkaloid
(+)-241D in 46% overall yield and is much more efficient
than those reported by Chenevert,4c Troin4d and their co-
workers.
1, which were conveniently prepared on large scales accord-
ing to Davies’ procedure.11 After 1a and 1b were condensed
with â-ketoesters, the vinylogous urethanes generated were
(11) (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,
183. (b) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1141.
(9) Isolation: Aronstam, R. S.; Daly, S. W.; Spande, T. F.; Narayanan,
T. K.; Albuquerque, E. X. Neurochem. Res. 1986, 11, 1227.
(12) (a) Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902.
(b) Backer, H. G. O. J. Prakt. Chem. 1961,12, 294.
(10) Synthesis: (a) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990,
55, 4688. (b) Jefford, C. W.; Tang, Q.; Zaslona, A. J. Am. Chem. Soc.
1991, 113, 3513. (c) Takahata, H.; Bandoh, H.; Momose, T. Heterocycles
1995, 41, 1797. (d) Lee, E.; Li, K. S.; Lim, J. Tetrahedron Lett. 1996, 37,
1445. (e) Michael, J. P.; Gravestock, D. Eur. J. Org. Chem. 1998, 865. (f)
Angle, S. R.; Henry, R. M. J. Org. Chem. 1997, 62, 8549.
(13) Selected data: [R]25 +7.2 (c 2.0, MeOH) (lit.4c [R]25 +6.5 (c
D
D
2.0, MeOH); IR (neat) 3271, 3182, 2962, 2921, 2852 cm-1; 1H NMR (300
MHz, CDCl3) δ 3.67 (m, 1H), 2.70 (m, 1H), 2.55 (m, 1H), 1.98 (m, 2H),
1.41 (m, 2H), 1.27 (m, 14H), 1.15 (d, J ) 6.2 Hz, 3H), 1.02 (m, 2H), 0.89
(t, J ) 7.0 Hz, 3H); EIMS m/z 241 (M+).
2504
Org. Lett., Vol. 2, No. 16, 2000

To demonstrate the ability of the present method for
synthesis of indolizidine alkaloids, we report the formal
synthesis of (-)-indolizidine 167B as outlined in Scheme
3. After the deprotection of â-amino ester 88c using Pd/C-
alcohol of 10 with benzyl chloformate, the secondary alcohol
was converted into the corresponding ketone by Dess-
Martin oxidation. Hydrogenation of this ketone to remove
the Cbz protecting group provided 11, which could be
transformed into the (-)-indolizidine 167B by known
procedure.7a Its spectral data were same with those reported.14
In summary, we have developed a method for synthesizing
2,6-disubstituted 4-hydroxypiperidines from enantiopure
â-amino esters in four workup steps. Considering its simplic-
ity and that both enantiopure â-amino esters and â-ketoesters
are conveniently available, this method should be valuable
for preparing enantiopure polysubstituted piperidines as well
as some related alkaloids. The further application of this
method to the synthesis of other alkaloids is being pursued
in our laboratory and will be reported in due course.
Scheme 3
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (grant 29725205), and Qiu Shi Science & Tech-
nologies Foundation for their financial support.
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL006176N
(14) Selected data for 11: [R]25D -10.2 (c 1.5, CHCl3); IR (neat) 3289,
catalyzed hydrogenation, the generated ester was transformed
into diol 10 following the procedure given above. After
selective protection of the amine moiety and the primary
1
2959, 2930, 1712 cm-1; H NMR (300 MHz, D2O) δ 3.62 (m, 2H), 3.10
(br s, 1H), 2.85 (m, 2H), 2.42 (m, 2H), 2.12 (m, 2H), 1.62 (m, 8H), 0.95
(t, J ) 7.2 Hz, 3H); EIMS m/z 200 (M+ + H+).
Org. Lett., Vol. 2, No. 16, 2000
2505