Total synthesis of (±)-epibatidine using a biocatalytic approach

Full text of DOI:10.1021/jo991141q

8968
J . Org. Chem. 1999, 64, 8968-8969
independently by J ohnson’s group and ourselves.5 We
recently reported that easily prepared 7-azanorbornanes
carrying an appropriate N-substituent are microbially
oxidized stereoselectively on an unfunctionalized meth-
ylene carbon.5,6 In this note, we communicate our total
synthesis of epibatidine using a selected metabolite
generated from this biotransformation.
Tota l Syn th esis of (()-Ep iba tid in e Usin g a
Bioca ta lytic Ap p r oa ch
Horacio F. Olivo * and Michael S. Hemenway
Division of Medicinal and Natural Products Chemistry,
College of Pharmacy, and The Center for Biocatalysis and
Bioprocessing, The University of Iowa,
Iowa City, Iowa 52242
Resu lts a n d Discu ssion
Received J uly 19, 1999
We selected the N-benzoyl group as the anchoring/
directing group in the microbial oxidation of 7-azanor-
bornane because of the reproducibility of the biotrans-
formation experiments, good yield, and minimal production
of side products.5b The desired N-benzoyl-7-azanorbor-
nane (2a ) was easily prepared in three steps from
commercially available trans-4-aminocyclohexanol hy-
drochloride (Scheme 1). Microbial hydroxylation of sub-
strate 2a utilizing B. bassiana furnished stereoselectively
2-endo-hydroxy-7-azanorbornane (3a ) in 56% yield and
22% ee.5b Optical rotation experiments showed that the
slightly favored enantiomer generated in the microbial
transformation was (-)-(1R). NMR spectra of substrate
2a and metabolite 3a showed the presence of a mixture
of rotamers. Thus, we reduced the benzamides 2a and
3a to their corresponding benzylic amines with lithium
aluminum hydride to facilitate their structural assign-
Epibatidine (1) is a natural product that was isolated
from the skin of the Ecuadorian poison frog Epipedobates
tricolor in trace amounts (less than 1 mg from 700 frogs).1
This alkaloid has attracted a lot of attention because it
showed remarkable analgesic activity (200-500 times
more potent than morphine) and displayed a very distinct
mode of action.2 Interestingly, both optical isomers
displayed similar activity.3 Since its structural elucida-
tion by Daly in 1992, a surprisingly large number of
syntheses have appeared in the literature.4 However, no
total synthesis using a biocatalytic approach has yet been
described.5
1
ment. H- and 13C NMR spectra of the benzylic amine
3b were identical to those reported by Fletcher.7 We have
also studied the effect of several phosphorus-containing
N-substituents on the microbial hydroxylation of 7-aza-
norbornanes.6 We and J ohnson’s group have found that
B. bassiana is able to accept a variety of functionalities
on the heteroatom of the substrate.5,6 We found that good
reproducible yields are obtained when the N-substituent
is a benzoyl group and therefore selected the correspond-
ing metabolite as the intermediate to complete a synthe-
sis of epibatidine. We might attribute the low enantiose-
lectivity of the microbial oxidation to the hindered
rotation of the N-benzoyl group, which was improved
when utilizing phosphorus-containing N-substituents
albeit in slightly lower isolated yields.6
Thus, oxidation of microbially hydroxylated 7-azanor-
bornane 3a with TPAP-NMO gave ketone 4 (Scheme 2).
Transmetalation of 2-chloro-5-iodopyridine8 with n-bu-
tyllithium and addition to ketone 4 at - 78 °C yielded
exclusively endo-alcohol 5. Deoxygenation of tertiary
alcohol 5 was carried out successfully in two steps
following a modification of the Dolan-MacMillan proto-
col.9 Alcohol 5 was esterified to the mixed anhydride 6
in quantitative yield. Methyl oxalate 6 was treated with
tributyltin hydride to furnish exclusively endo-chloropy-
ridyl isomer 7a . Equilibration to a mixture of separable
Microbial oxidation of unfunctionalized carbons can be
a powerful tool for providing hydroxylated molecules that
otherwise might not be easily accessible. We envisioned
that an appropriately N-substituted 7-azanorbornane
derivative would be a good substrate for oxidation of an
unfunctionalized carbon and that the metabolite would
make a valuable intermediate for a total synthesis of
epibatidine. Oxidation of N-substituted 7-azanorbornanes
with the fungus Beauveria bassiana has been studied
*
To whom correspondence should be addressed. Fax: 319-335-
8766. E-mail: Horacio-Olivo@uiowa.edu.
(1) (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J .
C.; Pannell, L.; Daly, J . W. J . Am. Chem. Soc. 1992, 114, 3475. (b)
Daly, J . W. J . Nat. Prod. 1998, 61, 162.
(2) (a) Li, T. C.; Qian, C. G.; Eckman, J .; Huang, D. F.; Shen, T. Y.
Bioorg. Med. Chem. Lett. 1993, 3, 2759. (b) Qian, C. G.; Li, T. C.; Shen,
T. Y.; Libertinegarahan, L.; Eckman, J .; Biftu, T.; Ip, S. Eur. J . Pharm.
1993, 250, R13-R14. (c) Fisher, M.; Huangfu, D.; Shen, T. Y.; Guyenet,
P. G. J . Pharmacol. Exp. Ther. 1994, 270, 702.
(3) Similar activity: (a) Bai, D.; Chu, G.; Xu, R.; Zhu, X. J . Org.
Chem. 1996, 61, 4600. (b) Badio, B.; Daly, J . W. Mol. Pharmacol. 1994,
45, 563.
(4) For recent syntheses of epibatidine see: (a) Habermann, J .; Ley,
S. V.; Scott, J . S. J . Chem. Soc., Perkin Trans. 1 1999, 1253. (b) Zhang,
C. M.; Ballay, C. J .; Trudell, M. L. J . Chem. Soc., Perkin Trans. 1 1999,
675. (c) Namyslo, J . C.; Kaufmann, D. E. Synlett 1999, 114. (d)
Palmgren, A.; Larsson, A. L. E.; Backvall, J . E.; Helquist, P. J . Org.
Chem. 1999, 64, 836. (e) Barros, M. T.; Maycock, C. D.; Ventura, M.
R. Tetrahedron Lett. 1999, 40, 557.
(5) (a) Davis, C. R.; J ohnson, R. A.; Cialdella, J . I.; Liggett, W. F.;
Mizsak, S. A.; Marshall, V. P. J . Org. Chem. 1997, 62, 2244. (b). Olivo,
H. F.; Hemenway, M. S.; Gezginci, M. H. Tetrahedron Lett. 1998, 39,
1309.
(6) Hemenway, M. S.; Olivo, H. F. J . Org. Chem. 1999, 64, 6312.
(7) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.;
Hobbs, S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball, R. G. J .
Org. Chem. 1994, 59, 1771.
(8) Preparation of 2-chloro-5-iodopyridine: (a) Hama, Y.; Nobuhara,
Y.; Aso, Y.; Otsubo, T. Bull. Chem. Soc. J pn. 1988, 61, 1683. (b)
Magidson, O.; Menschikoff, G. Chem. Ber. 1925, 113, 3.
(9) The Dolan-MacMillan deoxygenation has been applied previ-
ously in syntheses of epibatidine and analogues: (a) Zhang, C. M.;
Trudell, M. L. J . Org. Chem. 1996, 61, 7189. (b) Olivo, H. F.; Colby, D.
A.; Hemenway, M. S. J . Org. Chem. 1999, 64, 4966.
10.1021/jo991141q CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/09/1999

Notes
Sch em e 1. P r ep a r a tion of Su bstr a te a n d
J . Org. Chem., Vol. 64, No. 24, 1999 8969
in tert-butyl alcohol at 100 °C in a sealed tube.9a Removal
of the N-benzoyl group was achieved using acid hydroly-
sis to afford epibatidine (1).10
Micr obia l Tr a n sfor m a tion
In summary, we have synthesized epibatidine in 10
steps from commercially available trans-4-aminocyclo-
hexanol. The three key steps involve an intramolecular
nucleophilic displacement of a trans-4-aminocyclohexanol
derivative, microbial oxidation of an unfunctionalized
carbon, and coupling of the chloropyridyl ring to a
7-azanorbornanone. We have shown how biocatalysis can
be a useful tool to provide access to molecules that
otherwise may require lengthier synthetic sequences.
This work demonstrates how preparative biotransforma-
tions can be successfully blended with modern synthetic
organic chemistry to prepare a molecule of great biologi-
cal interest.
Sch em e 2. Syn th esis of Ep iba tid in e fr om
Hyd r oxyla ted Meta bolite
Ack n ow led gm en t. The authors wish to thank The
Central Investment Fund for Research Enhancement
at The University of Iowa for financial support and The
American Foundation for Pharmaceutical Education for
a fellowship to M.S.H.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for the preparation of compounds 2a -7b and H and
13C NMR spectra for compounds 1-7b. This material is
available free of charge from the Internet at http://pubs.acs.org.
J O991141Q
endo- and exo-isomers was possible when the endo-isomer
7a was subjected to 6 equiv of potassium tert-butoxide
(10) Avenoza, A.; Busto, J . H.; Cativiela, C.; Peregrina, J . M.
Synthesis 1998, 1335.