Approaches to syn-7-substituted 2-azanorbornanes as potential nicotinic agonists; synthesis of syn- and anti-isoepibatidine

Article abstract of DOI:10.1021/ol0510365

(Chemical Equation Presented) Coupling of N-Boc-7-bromo-2-azabicyclo[2.2.1] heptane with aryl and pyridyl boronic acids incorporates aryl and heterocyclic substituents at the 7-position and leads to a preference for syn over anti stereoisomers. Incorporat

Full text of DOI:10.1021/ol0510365

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2759-2762
Approaches to Syn-7-Substituted
2-Azanorbornanes as Potential Nicotinic
Agonists; Synthesis of syn- and
anti-Isoepibatidine
John R. Malpass,* Sandeep Handa, and Richard White
Department of Chemistry, UniVersity of Leicester, Leicester LE1 7RH, United Kingdom
jrm@le.ac.uk
Received May 5, 2005
ABSTRACT
Coupling of N-Boc-7-bromo-2-azabicyclo[2.2.1]heptane with aryl and pyridyl boronic acids incorporates aryl and heterocyclic substituents at
the 7-position and leads to a preference for syn over anti stereoisomers. Incorporation of a chloropyridyl group followed by N-deprotection
gives syn-isoepibatidine. Facial selectivity in attack on 7-keto-2-azanorbornanes depends heavily on the N-protecting group leading to the first
syn-7-hydroxy-2-azabicyclo[2.2.1]heptane derivative.
The discovery of epibatidine 1, a naturally occurring deriva-
tive of the 7-azabicyclo[2.2.1]heptane (7-azanorbornane) ring
system that has unusually high activity at the nicotinic
acetylcholine receptor (nAChR),1 has stimulated intense
synthetic activity. The search for therapeutically useful
compounds having higher nAChR subtype selectivity and
lower toxicity has encouraged the synthesis of a wide range
of analogues and isomers.2
the heterocycle are simply reversed. Other epibatidine
isomers 2 and 3 (having the heterocycle attached to the 5-
and 6-endo positions of 2-azanorbornane)3a retain high
nAChR affinity, as do many homologues and analogues.4
The exo orientation of the heterocycle in the isomers 4
and 5 leads to a much greater N-N distance and reduced
nAChR affinity as anticipated.3a
We have recently reported the synthesis of novel syn- and
anti-7-derivatives of 2-azanorbornane, including syn-
isoepiboxidine 7 (and the anti stereoisomer) via the corre-
(1) 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. For
leading references to epibatidine analogue synthesis, see: Carroll, F. I.;
Lee, J. R.; Navarro, H. A.; Ma, W.; Brieaddy, L. E.; Abraham, P.; Damaj,
M. I.; Martin, B. R. J. Med. Chem. 2002, 45, 4755-4761.
(2) For reviews and leading references to analogues and to nAChR
affinities, see: Carroll, F. I. Bioorg. Med. Chem. Lett. 2004, 14, 1889-
1896. Bunnelle, W. H.; Dart, M. J.; Schrimpf, M. R. Curr. Top. Med. Chem.
2004, 4, 299-334.
(3) See: (a) Cox, C. D.; Malpass, J. R.; Rosen, A.; Gordon, J. J. Chem.
Soc., Perkin Trans. 1 2001, 2372-2379 (2-5). (b) Hodgson, D. M.;
Maxwell, C. R.; Wisedale, R.; Matthews, I. R.; Carpenter, K. J.; Dickenson,
A. H.; Wonnacott, S. J. Chem. Soc., Perkin Trans. 1 2001, 3150-3158
(3).
(4) Malpass, J. R.; Hemmings, D. A.; Wallis, A. L.; Fletcher, S.; Patel,
S. J. Chem. Soc., Perkin Trans. 1 2001, 1044-1050. Malpass, J. R.; Patel,
A. B.; Davies, J. W.; Fulford, S. Y. J. Org. Chem. 2003, 68, 9348-9355.
We have been intrigued by the potential of the elusive
isomer isoepibatidine 6 in which all the key features of 1
are retained but the positions of the bicyclic nitrogen and
10.1021/ol0510365 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/02/2005

sponding 7-ethoxycarbonyl derivatives.5 Interest in 7-sub-
stituted 2-azanorbornanes has also been extended to their
use as precursors to R-kainic acids.6 We now report the first
successful direct attachment of aryl and heterocyclic rings
to the 7-position of 2-azanorbornanes via metal-catalyzed
coupling reactions, opening the way to syn-isoepibatidine 6
and a wider range of analogues.2,7 Additionally, further
investigation of the manipulation of syn/anti stereochemistry
in 7-substituted 2-azanorbornanes has allowed us to resolve
a disagreement over the stereochemical assignment of the
7-hydroxy compounds unambiguously.
The key anti-7-substituted intermediate 9a is available
from N-benzyl-2-azanorborn-5-ene 8 as described earlier.5
The conversion of 9a into 10a and modification to give the
N-Boc and N-Cbz examples 10c and 10d was achieved using
standard methods5 (Scheme 1).
A significant recent report describing the coupling of
nonactivated secondary bromo- and iodo- compounds with
aryl boronic acids using a Ni(0) catalyst illustrates recent
developments that are increasing the versatility of cross-
coupling reactions substantially.9 This work included ex-
amples of two (thiophene- and indole-based) heterocyclic
boronic acids, and we applied this procedure to our more
complex substrates, despite earlier observations on difficulties
using functionalized alkyl electrophiles.9
We had intended to use the syn-7-bromo isomers of 9 as
precursors but based our initial studies on the Boc-protected
anti isomer 9c, which was prepared from the readily available
9a in 70% yield (Scheme 1). Coupling with phenylboronic
acid required modification of the conditions described by
Zhou and Fu.9 A significantly higher catalyst loading was
used (20 mol % instead of 4 mol %), and the low reactivity
of 9c necessitated a temperature of 100 °C for 48 h (rather
than 60 °C for 5 h). Flash chromatography provided both
epimers 11 and 12 in a total yield of 50%. The syn/anti ratio
was 60:40 (Scheme 2).
Scheme 1
Scheme 2
The anti stereochemistry is retained at C-7 during the
substitution owing to neighboring group participation by the
2-azanorbornyl nitrogen. This allows smooth exchange of
the bromine by a range of other nucleophilic groups5 but
clearly precludes direct SN2 displacement with inversion,
leading to the syn compounds which we had chosen as
precursors for coupling chemistry. This is a problem since
the syn-7-substituted derivatives are of much greater interest
pharmacologically, bearing in mind the importance of N-N
distances in achieving high nAChR affinity and the current
level of understanding of the nAChR pharmacophore.2 Our
earlier synthesis of syn- and anti-isoepiboxidines involved
the construction of the methylisoxazole ring in situ from a
nitrile substituent via an ester group of established syn
configuration.5
The same conditions were applied to the coupling of
3-pyridyl boronic acid with 9c and gave 13 and 14 in a
combined isolated yield of 33%. The syn epimer was again
preferred (syn/anti ratio of 75:25). Yields were generally in
line with those reported by Zhou and Fu.9
The key objective of the present work was the direct
incorporation of pyridyl heterocycles at the 7-position of
2-azanorbornanes, preferably with control of syn stereo-
chemistry. We hoped to use metal-catalyzed cross-coupling
reactions to couple the heterocycle and the syn-bromo
compound but were faced by two issues. First, studies of
this type of reaction involving nonprimary sp3 centers are
in their infancy;8 second, only the anti-7-bromo precursors
9 were available.
The fact that â-elimination is impossible in our system
may contribute to the success of our reactions. Having
demonstrated that this catalytic system can be utilized
successfully with pyridyl boronic acids and functionalized
secondary bromides, we applied similar conditions to the
coupling of 4-chloro-3-pyridyl boronic acid10 with 9c. The
(8) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525-
1532. Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674-
688. Coupling of pyridylboronic acids and heteroaryl systems has been
reported: Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B.
J. Org. Chem. 2002, 67, 7541-7543.
(9) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. This
report concentrated on secondary alkyl halides that lacked functionality. A
footnote in the paper states that “reactions of functionalized alkyl electro-
philes proceed in lower yield”.
(5) Malpass, J. R.; White, R. J. Org. Chem. 2004, 69, 5328-5334.
(6) Hodgson D. M.; Hachisu, S.; Andrews, M. D. Org. Lett. 2005, 7,
815-817.
(7) For recent examples of alternative heterocycles incorporated into the
epibatidine framework and into analogues, see leading references in: Carroll,
F. I.; Ma, W.; Yokota, T.; Lee, J. R.; Brieaddy, L. E.; Navarro, H. A.;
Damaj, M. I.; Martin, B. R. J. Med. Chem. 2005, 48, 1221-1228. See also
citations 2 and 4 in ref 5.
(10) Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy, P. R.; Rault, S.
Tetrahedron 2002, 58, 2885-2890. This reagent is now commercially
available.
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Org. Lett., Vol. 7, No. 13, 2005

isolated material contained some of the desired products, but
there was also evidence of defunctionalization11 and sol-
volysis (incorporation of a 2-butoxy group in place of the
2-chloropyridyl substituent). Lowering the temperature to 50
°C and the reaction time to 12 h avoided loss of the pyridyl
chlorine and produced the desired 15 and 16 in an overall
30% yield (Scheme 3).
tion5,12 and made the question of stereocontrol in the actual
coupling reactions somewhat academic.
Nevertheless, we performed a chloropyridyl coupling at
room temperature and interrupted the conversion after 3 h
(ca. 10% conversion). The ratio of 15 and 16 in the isolated
sample was 75 anti:25 syn. When this same mixture was
treated with base (KOtBu/BuOH) at 50 °C, the ratio reversed
in favor of the syn isomer (25 anti:75 syn). This is in
agreement with initial retention of configuration at C-7
followed by base-induced epimerization.
Scheme 3
While it is now clear that syn-7 isomers of 9 are not
required for synthesis of 6, our early development work
toward the syn-7-hydroxy isomers of 10 has allowed us to
extend the range of syn derivatives and to resolve a recent
disagreement over the orientation of the hydroxyl group.5,13
We approached the syn-7-hydroxy compounds 18 via a
simple oxidation/reduction strategy (Scheme 4).
Scheme 4
The mixture of N-protected products was not easy to
separate, but the major epimer 16 was isolated by careful
chromatography and characterized with the aid of a crystal
structure (Figure 1). Removal of the N-Boc group was
Swern oxidation of 10a,c,d provided the corresponding
7-keto-compounds 17a,c,d, but perversely, hydride reduction
of the latter two derivatives using borohydride occurred only
from the syn face, re-forming the starting compounds 10.
Fortunately, the facial selectivity was reversed in the case
of the N-benzyl aminoketone 17a and led to a substantial
preference for the syn-hydroxy derivative 18a.
The syn stereochemistry of 18a was confirmed by an X-ray
crystal structure of the 3,5-dinitrobenzoate derivative (Figure
2).
Standard methods allow attachment of a range of O-linked
heterocycles using the oxy-anions of 10a,c,d,13 and it is now
clear that a range of claimed syn derivatives that were
synthesized as potential muscarinic antagonists13 are in fact
the anti isomers 19. The availability of the syn compounds
18 now opens the way to the preferred range of syn
derivatives 20.
These include novel analogues of ABT-59414 that contain
the chloropyridyloxy group and have the same sequence of
atoms between the two nitrogens.
(11) Quantities of defunctionalised N-Boc-2-azanorbornane (ca. 20%)
were isolated from each of the coupling reactions.
Figure 1. X-ray crystal structure of N-Boc isoepibatidine 16.
(12) This situation recalls early syntheses of epibatidine 1 that gave
predominantly the unwanted endo stereoisomer, requiring subsequent
epimerization at the 2-position of the 7-azanorbornyl ring system, for
example: 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, 1771-1778. For a significant improvement to the
epimerization methodology for epibatidine, see: Habermann, J.; Ley, S.
V.; Scott, J. S. J. Chem. Soc., Perkin Trans. 1 1999, 1253-1256.
(13) Mitch, C. H.; Quimby, S. J. Patent WO 00/75140 A1, 2000; U.S.
Patent 6, 559, 171 B1 2003.
straightforward (using acetyl chloride in ethanol/ethyl
acetate5), giving syn-isoepibatidine as the hydrochloride salt
6:HCl in 88% isolated yield.
The use of strong base and elevated temperatures inevi-
tably raised the likelihood of epimerization at the 7-posi-
Org. Lett., Vol. 7, No. 13, 2005
2761

explore this area and examine the factors that determine facial
selectivity in attack on the 7-keto group.15
In summary, facial selectivity in attack on 7-keto-2-
azanorbornanes is profoundly dependent on the N-protecting
group and allows isolation and characterization of syn-7-
hydroxy-2-azanorbornane (a precursor of novel potential
nicotinic and muscarinic ligands). Significantly, we have
demonstrated the first successful coupling of 4-chloro-3-
pyridyl boronic acid with the functionalized secondary alkyl
bromo compound 9c and have shown that epimerization
occurs under the reaction conditions. The observed thermo-
dynamic preference for the syn-7-chloropyridyl derivative
allows the use of the more readily accessible anti-7-bromo
compound as the substrate in the synthesis of the novel
epibatidine isomer syn-isoepibatidine 6. This compound is
a potential nicotinic agonist and will be screened for nAChR
subtype selectivity. The coupling reaction itself has signifi-
cance for the direct synthesis of other epibatidine analogues.
Figure 2. X-ray crystal structure of the 3,5-dinitrobenzoate of 18a.
Syn-7 isomers have N-N distances that are more condu-
cive to nAChR activity than the anti isomers but have less
conformational freedom than ABT-594. We continue to
Acknowledgment. We are grateful to Dr. John Fawcett
for the crystal structures and to Dr. Gerry Griffith for NMR
data.
(14) Holladay, M. W.; Wasicak, J. T.; Lin, N. H.; He, Y.; Ryther, K.
B.; Bannon, A. W.; Buckley, M. J.; Kim, D. J. B.; Decker, M. W.; Anderson,
D. J.; Campbell, J. E.; Kuntzweiler, T. A.; Donnelly-Roberts, D. L.; Piattoni-
Kaplan, M.; Briggs, C. A.; Williams, M.; Arneric, S. P. J. Med. Chem.
1998, 41, 407-412.
(15) For significant work on facial selectivity in attack on carbonyl groups
in bicyclic environments, see: Kaselj, M.; Wen-Sheng, C.; Le Noble, W.
J. Chem. ReV. 1999, 99, 1387-1413.
Supporting Information Available: Experimental pro-
cedures for coupling reactions and spectroscopic data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0510365
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