Synthesis of bridged analogs of epibatidine. 3-Chloro-5,7,8,9,9a,10-hexahydro-7,10-methanopyrrolo[1,2-b]-2,6-naphthyridine and 2-chloro-5,5a,6,7,8,10-hexahydro-5,8-methanopyrrolo[2,1-b]-1,7-naphthyridine

Article abstract of DOI:10.1016/S0040-4039(01)00575-5

The synthesis of conformationally locked analogs of epibatidine are described in which the key step is an intramolecular reductive palladium-catalyzed Heck-type coupling.

Full text of DOI:10.1016/S0040-4039(01)00575-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3795–3797
Synthesis of bridged analogs of epibatidine.
3-Chloro-5,7,8,9,9a,10-hexahydro-7,10-methanopyrrolo[1,2-b]-
2,6-naphthyridine and
2-chloro-5,5a,6,7,8,10-hexahydro-5,8-methanopyrrolo[2,1-b]-
1,7-naphthyridine
Lawrence E. Brieaddy,a S. Wayne Mascarella,a Herna´n A. Navarro,a Robert N. Atkinson,a
M. I. Damaj,b Billy R. Martinb and F. Ivy Carrolla,*
aChemistry and Life Sciences, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, USA
bDepartment of Pharmacology and Toxicology, Medical College of Virginia Commonwealth University, Richmond,
VA 23298, USA
Received 15 February 2001; accepted 6 April 2001
Abstract—The synthesis of conformationally locked analogs of epibatidine are described in which the key step is an intramolecular
reductive palladium-catalyzed Heck-type coupling. © 2001 Elsevier Science Ltd. All rights reserved.
nitrogen group. Molecular modeling studies show that
the nitrogen–nitrogen distance in nicotine (1) is 4.8 A,
whereas the nitrogen distance in the two local energy
The alkaloid nicotine (1) interacts with nicotinic acetyl-
choline receptors (nAChRs) to produce a number of
biological effects including antinociception.1–3 Nicotine
(1) is composed of a pyridine ring and a N-methyl
pyrrolidine ring connected via the 3- and 2%-positions,
respectively. In 1992, Daly and co-workers reported the
isolation and structure determination of epibatidine (2,
exo-2-(2%-chloro-5%-pyridinyl)-7-azabicyclo[2.2.1]hept-
ane) from the skin of the Ecuadorian poison frog,
Epipedobates tricolor,4 and along with other laborato-
ries showed that 2 was a potent analgesic acting
through the nAChRs.5,6 There are a number of similar-
ities between nicotine (1) and epibatidine (2); the most
prominent being that both compounds possess a pyri-
dine ring connected to a second ring containing a
,
minimum conformations 2A and 2B for epibatidine is
7–9
,
4.5 and 5.5 A.
The unique structure of 2 combined with its novel
pharmacological activity has attracted considerable
interest in the synthesis of 2 and analogs. In previous
reports from our laboratory, we have presented
improved methods for the synthesis of epibatidine and
its analogs.10–12 Since the synthesis and evaluation of
bridged analogs of nicotine have provided insight into
the pharmacophore for the nAChR,13,14 we envisioned
that similar studies directed toward epibatidine analogs
* Corresponding author. Tel.: 919-541-6679; fax: 919-541-8868; e-mail: fic@rti.org
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00575-5

3796
L. E. Brieaddy et al. / Tetrahedron Letters 42 (2001) 3795–3797
,
would also provide useful information. Thus, in this
study, we report the synthesis of 3-chloro-5,7,8,9,9a,
10-hexahydro-7,10-methanopyrrolo[1,2-b]-2,6-naph-
thyridine (3) and 2-chloro-5,5a,6,7,8,10-hexahydro-5,8-
methanopyrrolo[2,1-g]-1,7-naphthyridine (4). Com-
pounds 3 and 4 can be viewed as conformationally
locked analogs of epibatidine (2) and are comparable to
the two principle low energy conformations of the
freely rotating pyridine ring in epibatidine.7–9,15 In the
‘syn’ conformation of epibatidine the N-C1-C2-N dihe-
dral angle is ꢀ42° while in compound 4 the corre-
sponding dihedral angle is ꢀ43°.16 In the ‘anti’
conformation of epibatidine the N-C1-C2-N dihedral
angle is ꢀ133° while in compound 3 the corresponding
dihedral angle is ꢀ138°. The nitrogen-to-nitrogen dis-
tances are somewhat shorter in the bridged analogs
than in the corresponding epibatidine conformations
compound 3 in particular is within the 4.5 to 5.5 A
range that has been proposed by several authors for the
nicotinic pharmacophore.7–9,15
The epibatidine analog 3 was synthesized as shown in
Scheme 1 starting with 2-amino-4-methylpyridine (5).
Iodination of 5 using iodine in a periodic, sulfuric,
acetic acid mixture afforded a 71% yield of 2-amino-5-
iodo-4-methylpyridine (6). The structure of 6 was estab-
lished by analysis of the 1HNMR spectrum, which
showed singlets at l 2.23, 6.46, and 8.27 ppm for the
C4-methyl, H-3, and H-6 protons, respectively. Reac-
tion of 6 with meta-chloroperbenzoic acid in acetone
gave the N-oxide 7, which was isolated as the hydro-
chloride salt in 85% yield. We treated the hydrochloride
salt of 7 with acetic anhydride in dioxane expecting to
obtain the 4-acetoxymethyl or 4-hydroxymethyl com-
pounds 8a and 8b, respectively. Surprisingly, 2-acetam-
ido-4-chloromethyl-5-iodopyridine (8c) was isolated in
56% yield. Apparently, chloride ion displaced the ace-
,
(3.8 versus 4.6 A for compound 4 ‘syn’ epibatidine pair
,
and 5.1 versus 5.6 A for compound 3 ‘anti’ epibatidine
pair). However, the nitrogen-to-nitrogen distance for
Scheme 1. Conditions: (a) H5IO6, I2, H2SO4, HOAc, H2O, 80°C; (b) MCPBA; (c) ethereal HCl; (d) Ac2O, dioxane; (e) (CH3)3 SiI,
CHCl3; (f) NaOMe, MeOH; (g) KO2CH, Pd(OAc)2, Bu4NCl, DMF, 90°C; (h) 3N HCl, reflux; (i) NaNO2, conc. HCl
Scheme 2. Conditions: (a) H5IO6, I2, H2SO4, HOAc, H2O, 80°C; (b) MCPBA; (c) ethereal HCl; (d) Ac2O, dioxane; (e) (CH3)3 SiI,
CHCl3; (f) NaOMe, MeOH; (g) KO2CH, Pd(OAc)2, Bu4NCl, DMF, 90°C; (h) 3N HCl, reflux; (i) NaNO2, conc. HCl

L. E. Brieaddy et al. / Tetrahedron Letters 42 (2001) 3795–3797
3797
toxy or hydroxy group from the expected 4-ace-
toxymethyl or 4-hydroxymethyl intermediate to give 8c.
Alkylation of 7-azabicyclo[2.2.1]hept-2-ene (9a),17 gen-
Liss: New York, 1998; pp. 359–378.
2. Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med.
Chem. 1997, 40, 4169–4194.
erated
from
tert-butoxycarbonyl-7-azabicy-
3. Lloyd, G. K.; Williams, M. J. Pharmacol. Exp. Ther.
clo[2.2.1]hept-2-ene (9b) using trimethylsilyl iodide in
chloroform, with 8c provided the N-alkylated product
10 in 43% yield. Two possible approaches for the
conversion of 10 to 11 were Heck cyclization18–20 and
radical initiated cyclization.21,22 We found that
intramolecular cyclization of 10 using reductive Heck
conditions similar to that used for intermolecular
coupling12 (palladium diacetate, potassium formate,
and tetrabutyl ammonium chloride in DMF at 90°C)
provided the hexahydro-7,10-methanopyrrolo-2-[1,2-b]-
2,6-naphthyridine 11 in 45% yield. Hydrolysis of 11
using refluxing 3N hydrochloric acid effected aminoly-
sis of the 3-acetylamino group to give 90% of the
3-amino analog 12. Diazotization of 12 using sodium
nitrite in concentrated hydrochloric acid yielded the
desired epibatidine analog 3 in 28% yield.
2000, 292, 461–467.
4. Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh,
H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992,
114, 3475–3478.
5. Badio, B.; Daly, J. W. Mol. Pharmacol. 1994, 45, 563–
569.
6. Badio, B.; Shi, D.; Garraffo, M.; Daly, J. W. Drug Dev.
Res. 1995, 36, 46–59.
7. Campillo, N.; Paez, J. A.; Alkorta, I.; Goya, P. J. Chem.
Soc., Perkin Trans. 2 1998, 2665–2670.
8. Glennon, R. A.; Dukat, M. In Neuronal Nicotinic Recep-
tors: Pharmacology and Therapeutic Opportunities;
Americ, S. P.; Brioni, J. D., Eds. Nicotinic cholinergic
receptor pharmacophores. Wiley-Liss: New York, 1998;
pp. 271–284.
9. Glennon, R. A.; Dukat, M. Pharm. Acta Helv. 2000, 74,
103–114.
Epibatidine analog 4 was synthesized from 2-amino-6-
methylpyridine (13) by a set of reactions exactly
analogous to those used to prepare analog 3 (see
Scheme 2). The yield in each step was similar to the
analogous step in the synthesis of 3.
10. Brieaddy, L. E.; Liang, F.; Abraham, P.; Lee, J. R.;
Carroll, F. I. Tetrahedron Lett. 1998, 39, 5321–5322.
11. Kotian, P. L.; Carroll, F. I. Synth. Commun. 1995, 25,
63–71.
12. Liang, F.; Navarro, H. A.; Abraham, P.; Kotian, P.;
Ding, Y.-S.; Fowler, J.; Volkow, N.; Kuhar, M. J.;
Carroll, F. I. J. Med. Chem. 1997, 40, 2293–2295.
13. Holladay, M. W.; Cosford, N. D. P.; McDonald, I. A. In
Neuronal Nicotinic Receptors: Pharmacology and Thera-
peutic Opportunities; Arneric, S. P.; Brioni, J. D., Eds.
Natural products as a source of nicotinic acetylcholine
receptor modulators and leads for drug discovery. Wiley-
Liss: New York, 1999; pp. 253–270.
Even though the analogs 3 and/or 4 possess several of
the structural features in proposed pharmacophores for
the a4b2 nAChR, they did not show high affinity for
this receptor site. This information provides important
insight into the design of new a4b2 nAChR ligands.
In summary, we have developed synthetic methods to
prepare the conformationally locked analogs of epiba-
tidine 3 and 4. The synthetic strategy provides interme-
diates 12 and 19 that can be manipulated to provide
access to additional epibatidine analogs.
14. Turner, S. C.; Hongbin, Z.; Rapoport, H. J. Org. Chem.
2000, 65, 861–870.
15. Meyer, M. D.; Decker, M. W.; Rueter, L. E.; Anderson,
D. J.; Dart, M. J.; Kim, K. H.; Sullivan, J. P.; Williams,
M. Eur. J. Pharmacol. 2000, 393, 171–177.
16. SYBYL, version 6.7.1; Tripos, Inc., 1699, S. Hanley Rd.,
St. Louis, MO 63144, 2000.
Acknowledgements
17. Marchand, A. P.; Allen, R. W. J. Org. Chem. 1975, 40,
2551–2552.
This research was supported by the National Institute
on Drug Abuse (Grant DA12001).
18. de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl.
1994, 33, 2379–2411.
19. Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J.
Chem. Rev. 1996, 96, 635–662.
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