Pyridine analogs of (-)-cytisine and varenicline: cholinergic receptor probes

Article abstract of DOI:10.1016/j.tetlet.2008.03.133

A series of bicyclic pyridine containing alkaloids related to (-)-cytisine and varenicline are described. Synthetic access via regioisomeric metalation of alkoxy- and halo-pyridines gains entry to all four isomeric [3.3.1]-bicyclic targets. Regioselective

Full text of DOI:10.1016/j.tetlet.2008.03.133

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3368–3371
Pyridine analogs of (À)-cytisine and varenicline:
cholinergic receptor probes
Sebastien Demers, Heather Stevenson, John Candler, Crystal G. Bashore,
Eric P. Arnold, Brian T. O’Neill, Jotham W. Coe *
Pfizer Global Research and Development, Pfizer Inc., Groton, CT 06340, USA
Received 25 January 2008; revised 24 March 2008; accepted 25 March 2008
Available online 29 March 2008
Abstract
A series of bicyclic pyridine containing alkaloids related to (À)-cytisine and varenicline are described. Synthetic access via regio-
isomeric metalation of alkoxy- and halo-pyridines gains entry to all four isomeric [3.3.1]-bicyclic targets. Regioselective and sequential
oxidative cleavage of dicyclopentadiene generates a related [3.2.1]-bicyclic analog.
Ó 2008 Elsevier Ltd. All rights reserved.
Of the naturally occurring nicotinic acetylcholine recep-
tor (nAChR) ligands, the most potent and extensively stud-
ied include acetylcholine, nicotine, epibatidine and
anatoxin a (Fig. 1).1 All possess rotatable bonds that com-
promise their utility as pharmacophore probes. To better
establish receptor–ligand interactions, conformationally
restricted analogs of these inherently ‘flexible’ systems have
been prepared and studied.2,3 These derivatives often exhi-
bit decreased binding affinities due to newly imposed steric
restrictions or sub optimal alignment of pharmacophore
elements and thus fail to elucidate the ‘ideal’ orientation
of essential functionality. The pyridine analog by Kanne
et al. is a rare example that exhibits favored alignment
requirements for the anatoxin a system.4
(À)-Cytisine, a pyridone containing natural product
from the lupin alkaloid family,5 differs from these ligands.
Constrained by its bicyclic framework, a lack of rotatable
bonds fixes the pyridone carbonyl relative to the ‘basic’
piperidine nitrogen atom. We report herein the preparation
of cytisine mimics that are conformationally constrained
tools intended to ascertain specific interactions at nicotinic
receptor subtypes.6 Deviations within this compound-set
are restricted only to the position of the pyridine or
pyridone heteroatoms, thereby minimizing the ambiguity
as to spatial relationships of polar functionality and steric
perturbations between derivatives.
H
HN
N
N
O
N
O
CH3
N
O
(-)-cytisine
(-)-nicotine
acetylcholine
In the course of our work leading to the discovery of
varenicline,7 we generated the bicyclic pyridyl piperidine
50 (see Scheme 6), a derivative that exhibited particularly
high affinity at the muscle receptor subtype of the nAChR
(ꢀ47 nM @ a1bcd). Considerable work has been focused
on gaining insights into muscle receptor interactions since
the seminal work of Beers and Reich in the 1970s.8 Recent
contributions have markedly improved our understanding
of receptor–ligand topology, highlighted by the homology
HN
Cl
HN
HN
O
N
N
epibatidine
Fig. 1. Prototypical nicotinic receptor ligands (rotatable bonds, red).
anatoxin
a
Kanne's pyridine
*
Corresponding author. Tel.: +1 860 441 3271; fax: +1 860 686 0013.
E-mail address: jwcoe@pfizer.com (J. W. Coe).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.133

S. Demers et al. / Tetrahedron Letters 49 (2008) 3368–3371
3369
models based on the snail derived acetylcholine binding
protein (AChBP),9 which has triggered a surge of research
to further elucidate the structure—function relationships.10
These investigations herald a future with improved predic-
tive tools to impact the design of novel nAChRs ligands.
Inspired by the activity of 50 and the importance of this
receptor in drug discovery efforts, we have undertaken
the synthesis of this set of related analogs to examine the
effects of pyridine and piperidine nitrogen atom positional
relationships within this skeletal framework.
Olefin 7 was converted to its corresponding diol 8 by
dihydroxylation.16 Oxidative cleavage with NaIO4 pro-
vided an intermediate dialdehyde (or glycal, not shown)
that was condensed with benzylamine and reduced by
NaBH(OAc)3 to give 9.17 Benzyl group removal by transfer
hydrogenolysis and purification as the t-Boc derivative fol-
lowed by HCl mediated deprotection afforded the crystal-
line 3,11-diaza-pyridine derivative 10 as its bis-HCl salt.
The isomeric 3-alkoxy-4-keto-derivative 12 was accessed
using the directing effects described by Ronald (Scheme
2).18 LDA mediated metalation at the 4-position of 3-
alkoxyalkoxypyridine 11 and trapping with 2 proceeded
in 75% yield. Wolff–Kishner reduction not only generated
the expected reduced product, 13a, the 3-alkoxyalkyl group
was removed under these conditions to give phenol 13b
directly in 51% yield. Mixtures of 13a and 13b were
initially formed, along with the corresponding hydrazone
precursors; these ultimately converged to give 13b exclu-
sively with prolonged heating in hot KOH/ethylene glycol.
Though the displacement of 3-halopyridines by alkoxide is
known,19 the simultaneous reduction and dealkylation/
hydroxide displacement under Wolff–Kishner conditions
was an unexpected and fortuitous finding, making this
approach quite attractive. Activation of 13 as the triflate
provided 14, which was converted to the isomeric bicyclic
olefin 15 and ultimately the target 4,11-diazabicyclic pyri-
dine derivative 18 as described for 10.
We recently described the syntheses of (À)-cytisine.11
One approach employed a Heck cyclization to assemble
the requisite bicyclic core from the readily available mate-
rials.11a Herein, we extend the approach to generate hith-
erto unknown bicyclic [3.3.1]-pyridine and pyridone
derivatives. The closely related bicyclic [3.2.1]-bicyclic pyr-
idine 50 was prepared from dicyclopentadiene by a related
approach.
Directed orthometalation of alkoxypyridines described
by Comins achieves the regioselective introduction of pyr-
idine functionality (Scheme 1).12 By this approach, the
addition of 3-lithio-2-methoxypyridine 1 to 3-cyclopentyl-
carboxamide 2 gave access to keto-pyridine 3. Wolff–
Kishner reduction generated 4 (51%) and an undesired
diazindole derivative (40%), which was readily separated
(3-cyclopent-3-enyl-1H-pyrazolo[3,4-b]pyridine, not shown).
Demethylation (TMSCl/NaI)13 and activation as the
trifluoromethanesulfonate ester (triflate)14 gave 6, which
was cyclized under Heck conditions to the bicyclic olefin
7.15
The Heck approach allows for the installation of addi-
tional functionality to generate substituted pyridines and
pyridone derivatives (Scheme 3).20 3-Lithio-2-fluoro-4-
N
O
O
O
O
a
b
2
N
N
b
e
N
N
c
O
N
O
O
OEt
N
O
O
OEt
OR
a
3
1
11
4
12
13a R = OCH2OEt
13b R = H
d
N
e
c
d
N
OTf
N
O
N
N
H
OTf
5
6
7
14
15
Bn
H
HO
OH
Bn
N
H
N
N
HO
OH
N
g
h
f
2HCl
N
2HCl
g
f
N
N
N
N
N
9
8
18
16
10
17
Scheme 1. 3,11-Diaza-tricyclo[7.3.1.02,7]trideca-2,4,6-triene. Reagents and
conditions: (a) Mesityl lithium, THF, À78 °C, 2, 75%; (b) NH2NH2,
KOH, ethylene glycol, 180 °C, 18 h, 51%; (c) TMSCl, NaI, CH3CN, 100%;
(d) Tf2O, lutidine, CH2Cl2, 93%; (e) Pd(OAc)2, DPPP, TEA, DMF 77%;
(f) NMO, OsO4, acetone/H2O, 100%; (g) (1) NaIO4, (2) BnNH2, (3)
NaBH(OAc)3, 50%; (h) (1) NH4HCO2, Pd(OH)2, MeOH, (2) t-Boc2O,
32%; (i) HCl, EtOAc, 43%.
Scheme 2. 4,11-Diaza-tricyclo[7.3.1.02,7]trideca-2,4,6-triene. Reagents and
conditions: (a) t-BuLi, Et2O, À78 °C, 2; (b) NH2NH2, KOH, ethylene
glycol, 180 °C, 18 h, 51%; (c), Tf2O, py, CH2Cl2, 96%; (d) Pd(OAc)2,
DPPP, TEA, DMF, 80%; (e) NMO, OsO4, acetone/H2O, 68%; (f) (1)
NaIO4, 2-propanol/H2O, (2) BnNH2; (3) NaBH(OAc)3, 50%; (g) (1) HCl,
piperidine, HCOOH, Pd(OH)2, MeOH, (2) t-Boc2O, Na2CO3, H2O,
CH2Cl2, 32%; (i) HCl, EtOAc 43%.

3370
S. Demers et al. / Tetrahedron Letters 49 (2008) 3368–3371
I
I
Li
I
a
b
I
Cl
b
c
a
F
N
F
N
F
N
N
Cl
N
19
20
21
Cl
N
OTf
31
33
30
32
Bn
N
I
HO
OH
H
N
c
d
O
O
d
e
R
N
O
N
F
N
22
2HCl
25
23, R = F
Cl
N
Cl
N
24, R = OMe
N
34
35
36
H
OH
HO
N
Scheme 4. 5,11-Diaza-tricyclo[7.3.1.02,7]trideca-2,4,6-triene. Reagents and
condition: (a) LDA, À78 °C, THF, 31, 89%; (b) Pd(OAc)2, P(o-tolyl)3,
TEA, DMF 76%; (c) NMO, OsO4, acetone/H2O, 7d, 89%; (d) (1) NaIO4,
DCE/H2O; (2) BnNH2, NaBH(OAc)3, 45%; (e) Pd(OH)2, MeOH, HCl,
100%.
e
f
O
N
O
N
27
26
ropyridine), which was quenched with triflate-activated
cyclopentene-3-carbinol 31.24 The resulting alkylated prod-
uct 32 was cyclized in 76% yield to give olefin 33 and con-
verted as before to piperidine 35. Hydrogenation affords
target 36 in 45% yield from 34.
g, h, i
g, j, i
H
H
N
N
HCl
HCl
The final [3.3.1]-bicyclic 6,11-diaza-pyridine derivative
was prepared from 3-methoxy pyridine 37 by regioselective
metalation at 2-position by mesityl lithium12 and addition
to Weinreb amide 2 (Scheme 5). Reduction under Wolff–
Kishner conditions again simultaneously demethylated 38
to give phenol 39 directly. The resulting ketone was con-
verted to target 44 as described above.
O
N
O
N
H
28
29
Scheme 3. 5,11-Diaza-pyridines and pyridones. Reagents and conditions:
(a) LDA, THF, À78 °C, I2, 78%; (b) LDA, THF, À78 °C, 2 h, 2, 48%; (c)
Pd(OAc)2, PPh3, KOAc, n-Bu4NBr, DMF, 0.3 h; MeONa, MeOH, 60%;
(d) TsNHNH2, EtOH, 80%; (PhCOO)2BH, CHCl3, 0 °C, 2 h, 48%; (e)
(CH3)3NO, OsO4, CH2Cl2, 96%; (f) NaIO4, EtOH/H2O; NH4OH,
Pd(OH)2, H2, 16 h, 54%. (g) t-Boc2O, Na2CO3, H2O, CH2Cl2, 95%; (h)
TMSCl, NaI, CH3CN, 50%; (i) HCl, EtOAc, 100%; (j) MeI, 130 °C, 4 h,
then HCl, EtOAc, 40%.
OH
O
O
O
a
b
iodopyridine 21 was prepared via ‘halogen dance’ metala-
tion as described by Queguiner21 and reacted with 2 at
low temperature to generate iodo-Heck precursor 22.
Conversion under the conditions of Jeffery22 spared the
fluoro group and afforded the bicyclic ring system 23. This
reactive material was directly converted to the methoxyl
derivative 24 in high overall yield upon exposure to alkox-
ide. Ketone reduction in this case via the tosylhydrazone
avoided both methoxyl group dealkylation and heterocycle
formation under reducing conditions.23 The piperidine was
exposed as described before11a to give the target methoxy
pyridine 27. The conversion of 27 to the NH-pyridone 28
was accomplished on the t-Boc derivative with TMSI,
while the methylated derivative 29 was accessed from the
t-Boc derivative via pyridine N-methylation (MeI, sealed
tube) and subsequent pyridone formation (HCl).
N
e
N
N
37
38
39
OTf
c
d
N
N
40
41
Bn
H
N
HO
OH
N
g
2HCl
f
N
N
N
42
43
44
Scheme 5. 6,11-Diaza-tricyclo[7.3.1.02,7]trideca-2,4,6-triene. Reagents and
conditions: (a) Mesityl lithium, À78 °C, THF, 2; (b) NH2NH2, KOH,
ethylene glycol, 180 °C, 18 h, 50%; (c) Tf2O, pyridine, CH2Cl2, 86%; (d)
Pd(OAc)2, DPPP, TEA, DMF 80%; (e) NMO, OsO4, acetone/H2O, 72%;
(f) (1) NaIO4, 2-propanol/H2O; (2) BnNH2; (3) NaBH(OAc)3, 50%; (g)
HCl, piperidine, HCOOH, Pd(OH)2, MeOH; (2) t-Boc2O, Na2CO3, H2O,
DCM, 32%; (i) HCl, EtOAc 43%.
This sequence was further streamlined to afford pyridine
36 in 5 steps from 3-iodo-2-chloropyridine 30 (Scheme 4).
Metalation (LDA) and aging provided the thermodynamic
lithium species via ‘halogen dance’ (3-lithio-4-iodo-2-chlo-

S. Demers et al. / Tetrahedron Letters 49 (2008) 3368–3371
3371
P. J. Med. Chem. 2005, 48, 4705–4745; (c) Bunnelle, W. H.; Dart, M.
J.; Schrimpf, M. R. Curr. Med. Chem. 2004, 4, 299–334; (d) Holladay,
M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem. 1997, 40, 4169–
4194; (e) Glennon, R. A.; Dukat, M. Med. Chem. Res. 1996, 6, 465–
486.
Bn
N
HO
OH
b,c
a
2. Wei, Z.-L.; Petukhov, P. A.; Xiao, Y.; Tuckmantel, W.; George, C.;
Kellar, K. J.; Kozikowski, A. P. J. Med. Chem. 2003, 46, 921–924.
3. Sarkar, T. K.; Basak, S.; Slanina, Z.; Chow, T. J. J. Org. Chem. 2003,
68, 4206–4214.
45
46
47
Bn
N
Bn
N
H
N
4. Kanne, D.B.; Ashworth, D.J.; T., C. M.; Mutter, L.C.; Abood, L. G.
J. Am. Chem. Soc. 1986, 108, 7864–7865; Ullrich, T.; Binder, D.;
Pyerin, M. Tetrahedron Lett. 2002, 43, 177–179; Vernier, J.-M.;
Holsenback, H.; Cosford, N. D. P.; Whitten, J. P.; Menzaghi, F.;
Reid, R.; Rao, T. S.; Sacaan, A. I.; Lloyd, G. K.; Suto, C. M.;
Chavez-Noriega, L. E.; Washburn, M. S.; Urrutia, A.; McDonald, I.
A. Bioorg. Med. Chem. Lett. 1998, 8, 2173–2178.
d
2HCl
e,f
g,h
OH
N
O
N
OH
49 N
48
50
O
5. (a) Partheil, A. Arch. Pharm. 1894, 232, 161; (b) Partheil, A.; Ing, H.
R. J. Chem. Soc. 1932, 2778.
6. Hogg, R. C.; Bertrand, D. Curr. Drug Targets CNS Neurol. Disord.
2004, 3, 123–130.
Scheme
6. 4,10-Diaza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene.
(a)
NMO, OsO4, acetone, 20%; (b) NaIO4 dioxane, H2O; (c) BnNH2,
NaBH(OAc)3, DCE, 76%; (d) NMO, OsO4, acetone, 80%; (e) NaIO4,
dioxane, H2O; (f) NH2OCH3ÁHCl, NaOAc, MeOH/H2O; (g) 9/1 DCE/
TFA; (h) NH4HCO2/Pd(OH)2, MeOH, 35%.
7. Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold, E.
P.; Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox, C. B.; Shrikhande, A.;
Schaeffer, E.; Rollema, H.; Lu, Y.; Mansbach, R. S.; Chambers, L.
K.; Rovetti, C. C.; Schulz, D. W.; Tingley, F. D., III; O’Neill, B. T. J.
Med. Chem. 2005, 48, 3474–3477.
8. Beers, W. H.; Reich, E. Nature 1970, 228, 917–922.
9. Brejc, K.; van Dijk, W. J.; Klaassen, R. V.; Schuurmans, M.; van der
Oost, J.; Smit, A. B.; Sixma, T. K. Nature 2001, 411, 269–276.
10. Celie, P. H. N.; Kasheverov, I. E.; Mordvintsev, D. Y.; Hogg, R. C.;
van Nierop, P.; van Elk, R.; van Rossum-Fikkert, S. E.; Zhmak, M.
N.; Bertrand, D.; Tsetlin, V.; Sixma, T. K.; Smit, A. B. Nature Struct.
Mol. Biol. 2005, 12, 582–588.
11. (a) Coe, J. W. Org. Lett. 2000, 2, 4205–4208; (b) O’Neill, Brian T.;
Yohannes, D.; Bundesmann, M. W.; Arnold, E. P. Org. Lett. 2000, 2,
4201–4204.
12. Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1988, 29, 773–
776; Comins, D. L.; Killpack, M. O. J. Org. Chem. 1990, 55, 69–73.
13. Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225–2277.
14. Su, T. M.; Sliwinski, W. F.; Schleyer, P. v. R. J. Am. Chem. Soc. 1969,
91, 5386–5388.
15. Heck, R. F. In Organic Reactions; Dauben, W. G., Ed.; Wiley: New
York, 1982; Vol. 27, p 345.
16. VanRheenen, V.; Cha, D.Y.; Hartley, W.M. Org. Synth. 1988. Coll.,
Vol. 6, 342–348.
17. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862.
18. Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 46, 2101–2108.
19. Shiao, M.-J.; Ku, W.-S.; Hwu, J. R. Heterocycles 1993, 36, 323–328.
20. Allen, M.P.; Coe, J.W.; Liras, S.; O’Donnell, C.J.; O’Neill, B.T.PCT
Int. Appl. WO 2005 007655 A1.
Finally, the [3.2.1]-bicyclic derivative 50 was prepared
from dicyclopentadiene diol 46 (Scheme 6). This was con-
verted to the N-benzyl piperidine 47 by the oxidative cleav-
age/reductive amination procedure. Diol 48 was generated
(NMO, OsO4) and cleaved (NaIO4) to provide an inter-
mediate dialdehyde, which was condensed directly with
O-methyl hydroxylamine to provide the bis-O-methyl-
oxime 49. This crude mixture of geometric isomers was
warmed in 9/1 DCE/TFA to provide the corresponding
pyridine.4 Debenzylation by methods described above pro-
vides target [3.2.1]-bicyclic pyridine 50.
These syntheses demonstrate additional applications of
the Heck strategy and cyclopentene/piperidine synthesis
to the preparation of heterocycle containing bicyclic alka-
loids. The pyridine derivatives described herein are con-
formationally constrained tools designed to explore
specific interactions at nicotinic receptor subtypes. The
results of these interaction studies will be reported sepa-
rately where this unique set of valuable probes will hope-
fully contribute to a better of understanding nicotinic
receptor–ligand interactions.
21. Queguiner, G.; Snieckus, V.; Epsztajn, J. Adv. Heterocycl. Chem.
1991, 52, 189–304; Bunnett, J. F. Acc. Chem. Res. 1972, 5, 139–147.
22. (a) Jeffery, T. Tetrahedron 1996, 52, 10113–10130; (b) LaRock, R. C.
J. Org. Chem. 1989, 54, 2047–2050.
23. Majerski, Z.; Zuanic, M.; Metelko, B. J. Am. Chem. Soc. 1985, 107,
1721–1726; Caglioti, L. Tetrahedron 1966, 22, 487–493; (b) Kabalka,
G. W.; Summers, S. T. J. Org. Chem. 1981, 46, 1217–1218.
24. Bashore, C. G.; Vetelino, M. G.; Wirtz, M. C.; Brooks, P. R.; Frost,
H. N.; McDermott, R. E.; Whritenour, D. C.; Ragan, J. A.;
Rutherford, J. L.; Makowski, T. W.; Brenek, S. J.; Coe, J. W. Org.
Lett. 2006, 8, 5947–5950.
Acknowledgement
J. W. Coe acknowledges the generous support of
S. Demers, H. Stephenson, and J. Candler through Pfizer
Summer Research Fellowships.
References and notes
1. For reviews see: (a) Daly, J. W. Cell. Mol. Neurobiol. 2005, 25, 513–
552; (b) Jensen, A. A.; Frlund, B.; Liljefors, T.; Krogsgaard-Larsen,