Synthesis of two conformationally constrained analogues of the minor tobacco alkaloid anabasine.

Article abstract of DOI:10.1021/ol006056f

The anabasine analogues spiro[4-azaindan-1,2'-piperidine] (7) and spiro[6-azaindan-1,2'-piperidine] (8) have been prepared. A series of palladium-catalyzed reactions, where an intramolecular cyclization constituted a key reaction, were utilized for the pr

Full text of DOI:10.1021/ol006056f

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2291-2293
Synthesis of Two Conformationally
Constrained Analogues of the Minor
Tobacco Alkaloid Anabasine
Stefan Lindstro1m,† Lena Ripa, and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, BMC, Uppsala UniVersity,
Box 574, SE-751 23 Uppsala, Sweden
anders.hallberg@bmc.uu.se
Received May 13, 2000
ABSTRACT
The anabasine analogues spiro[4-azaindan-1,2′-piperidine] (7) and spiro[6-azaindan-1,2′-piperidine] (8) have been prepared. A series of palladium-
catalyzed reactions, where an intramolecular cyclization constituted a key reaction, were utilized for the preparation of the two target compounds.
Selective nicotine receptor ligands have potential as thera-
peutic agents for CNS diseases and other disorders.1 The
(S)-(-)-enantiomer of nicotine 1 (Figure 1) displays higher
affinity than the (R)-(+)-enantiomer at nicotine receptors.
However, there are observations in functional assays that (S)-
(-)-nicotine is not always more potent, suggesting that the
enantiomers of nicotine may interact differently with different
types of nicotine receptors.2 Molecular modeling studies
suggest that the pyridine and pyrrolidine rings of nicotine
are skewed and nearly perpendicular3 in low-energy con-
formations, but the exact bioactive conformation(s) is not
† Present address Medivir AB, Lunastigen 7, SE-141 44 Huddinge,
Sweden.
(1) (a) Arneric, S. P.; Sullivan, J. P.; Williams, M. Psychopharmacol-
ogy: The Fourth Generation of Progress; Raven Press: Ltd.: New York,
1995; pp 95-110. (b) Bannon, A. W.; Decker, M. W.; Holladay, M. W.;
Curzon, P.; Donnelly-Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz,
A.; Dickenson, A. H.; Porsolt, R. D.; Williams, M.; Arneric, S. P. Science
1998, 279, 77-81. (c) Gopalakrishnan, M.; Sullivan, J. P. Drug News
Perspect. 1994, 7, 444-448. (d) Holladay, M. W.; Dart, M. J.; Lynch, J.
Figure 1.
K. J. Med. Chem. 1997, 40, 4169-4194. (e) Rosencrans, J. A. Chem. Ind.
1998, 525-529. (f) Williams, M.; Sullivan, J. P.; Arneric´, S. P. Drug News
Perspect. 1994, 7, 205-223.
known. The synthesis and evaluation of conformationally
restricted analogues4 of nicotine should help to determine
(2) Nordberg, A. Med. Chem. Res. 1993, 2, 522-529.
(3) Glennon, R. A.; Dukat, M. Med. Chem. Res. 1996, 6, 465-486.
10.1021/ol006056f CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/06/2000

the conformation(s) that induce ion channel opening. A
limited number of restricted analogues have been synthe-
sized5 and among these the fused (+) and (-) isomers of 2
bind with low affinities,5c,g compounds 35a and 45b exhibited
no appreciable activity, while the bridged nicotinoid 55d was
very potent in binding and functional assays.5e A recent study
that describes the effect of the minor tobacco alkaloids, (S)-
(-)-anabasine 6 and its N-methyl analogue on dopamine
release from superfused rat stratial slices, suggests that these
compounds produce comparative and in some cases more
pronounced effects than (S)-(-)-nicotine (1) and (S)-(-)-
nornicotine.6
We herein present the syntheses of two rigid anabasine
analogues, the spiro compounds 7 and 8, where we have
used an intramolecular Heck arylation7 onto an enamide, as
a key step.
The synthesis of 7 commenced with acylation of com-
mercially available 2-bromo-3-hydroxypyridine to give 9
(Scheme 1). Compound 9 was reacted with trimethylsily-
fluoride in THF-water to give 11. Subsequent palladium-
catalyzed coupling with the triflate 12,9 where CuI was used
as cocatalyst, delivered the enyne 13 in 70% yield. A
selective hydrogenation of the triple bond was conducted
with Pd/C-quinoline to give 14 in modest yield (36%).10 Ester
hydrolysis to give 15, followed by a reaction with triflic
anhydride afforded the triflate 16, the precursor for the
palladium-catalyzed intramolecular reactions.
In the initial cyclization experiments, we employed pal-
ladium acetate with tri-2-furylphosphine11 as the catalytic
system and triethylamine as the base using acetonitrile as
solvent. Only traces of spiro compounds were formed under
these conditions. Neither an increase of reaction temperature
nor the addition of lithium chloride12 improved the outcome.
We previously employed (S)-(-)-4-tert-butyl-2-[2-(diphe-
nylphosphino)phenyl]-4,5-dihydrooxazole,13 as a chiral ni-
trogen-phosphorus bidentate ligand14 with diisopropylethyl-
amine as base in related intramolecular coupling reactions
where we obtained very high enantiomeric excesses.15 No
conversion of 16 proceeded under these reaction conditions,
neither with THF nor with toluene as solvents, and substitu-
tion of diisopropylethylamine for triethylamine and use of
DPPF16 as ligand led to no significant improvement. How-
ever, the intramolecular cyclization could be accomplished
in reasonable yield with BINAP,17 a ligand that has been
successfully utilized for control of double-bond migration
Scheme 1a
(4) (a) Woodruff, G. N. Trends Pharmacol. Sci. 1982, 3, 59-61. (b)
Law, S.-J.; Morgan, J. M.; Masten, L. W.; Borne, R. F.; Arana, G. W.;
Kula, N. S.; Baldessarini, R. J. J. Med. Chem. 1982, 25, 213-216. (c)
Cannon, J. G.; Rege, A. B.; Gruen, T. L. J. Med. Chem. 1972, 15, 71-75.
(5) (a) Catka, T. E.; Leete, E. J. Org. Chem. 1978, 43, 2125-2127. (b)
Chavdarian, C. G.; Seeman, J.; I.; Wooten, J. B. J. Org. Chem. 1983, 48,
492-494. (c) Glassco, W.; Suchocki, J.; George, C.; Martin, B. R.; May,
E. L. J. Med. Chem. 1993, 36, 3381-3385. (d) Kanne, D. B.; Ashworth,
D. J.; T.; C. M.; Mutter, L. C. J. Am. Chem. Soc. 1986, 108, 7864-7865.
(e) Kanne, D. B.; Abood, L. G. J. Med. Chem. 1988, 31, 506-509. (f)
Sarkar, T. K.; Basak, S.; Ghosh, S. K. Tetrahedron Lett. 2000, 41, 759-
762. (g) 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. (h) Xu, Y.-z.; Choi, J.;
Calaza, M. I.; Turner, S.; Rapoport, H. J. Org. Chem. 1999, 64, 4069-
4078.
(6) Dwoskin, L. P.; Teng, L.; Buxton, S. T.; Ravard, A.; Deo, N.; Crooks,
P. A. Eur. J. Pharmacol. 1995, 276, 195-199.
(7) For the preparation of anabasine by an intermolecular Heck reaction
see: Nilsson, K.; Hallberg A. J. Org. Chem. 1990, 55, 2464-2470.
(8) Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1987, 53, 386-390.
(9) Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656-2657.
(10) The reaction was stopped when 14 was formed in highest amount
relative to the yields of the partially and fully reduced products. 14 was
obtained after chromatography and recrystallization.
(11) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-
9595. (b) Sonesson, C.; Larhed, M.; Nyqvist, C.; Hallberg, A. J. Org. Chem.
1996, 61, 4756-4763.
(12) Lithium chloride has been reported to promote the oxidative addition
of aryl triflates, see for example: Amatore, C.; Jutand, A.; Suarez, A. J.
Am. Chem. Soc. 1993, 115, 9531-9541.
(13) (a) Peer, M.; de Jong, J. C.; Kiefer, M.; Langer, T.; Rieck, H.; Schell,
H.; Sennhenn, P.; Sprintz, J.; Steinhagen, H.; Wiese, B.; Helmchen, G.
Tetrahedron 1996, 52, 7547-7583. (b) Koch, G.; Lloyd-Jones, G. C.;
Loiseleur, O.; Pfalts, A.; Pre´toˆt, R.; Schaffner, S.; Schnider, P.; von Matt,
P. Recl. TraV. Chim. Pays-Bas 1995, 114, 206-210.
(14) The ligand was introduced by Pfaltz as ligand in an intermolecular
Heck reaction. (a) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int.
Ed. Engl. 1996, 35, 200-202. (b) Pfaltz, A. Acta Chem. Scand. 1996, 50,
189-194.
a (a) Ac2O, ∆; (b) PdCl2(PPh3)2, CuI, Et3N, HCCSiMe3, THF,
RT; (c) TBAF, THF/H2O, 0 °C; (d) PdCl2(PPh3)2, CuI, Et3N, THF,
RT; (e) H2, Pd/C, quinoline, EtOAc, RT; (f) NaHCO3, MeOH/H2O,
RT; (g) (Tf)2O, Et3N, CH2Cl2, -78 °C; (h) Pd(OAc)2, (R)-BINAP,
Et3N, CH3CN; (i) H2, Pd/C; (j) KOH, H2NNH2‚H2O, H2O/ethylene
glycol.
(15) Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595-602.
(16) DPPF ) 1,1′-bis(diphenylphosphino)ferrocene
(17) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Noyori, R.;
Takaya, H. Acc. Chem. Res. 1990, 23, 345-350.
lacetylene under palladium catalysis in the presence of a
catalytic amount CuI.8 The coupled product 10, isolated in
83% yield was thereafter desilylated by tetrabutylammonium
2292
Org. Lett., Vol. 2, No. 15, 2000

in related cyclizations.18 A mixture of the three double-bond
isomers was afforded.19 Reduction of this mixture and
subsequent determination of the enantiomeric excess20
revealed that a moderate enantioselectivity had been obtained
in THF (THF, 41% ee; acetonitrile, 10% ee; DMAA, 9%
ee; DMF, 2% ee). No product attributed to the undesired
endo cyclization was traced under these conditions but the
reductive elimination of the triflate group constituted a major
side reaction, which frequently became the predominant
reaction. In a preparative experiment we employed aceto-
nitrile since the highest yield was achieved in this solvent.
A 41% yield of the mixture of spiro compounds was isolated.
Hydrogenation on Pd/C gave 17, which was hydrolyzed,
employing KOH and hydrazine in water/ethylene glycol,
furnishing 7 in 77% yield.
Scheme 2a
The synthesis of 8 was executed essentially according to
the strategy used for the synthesis of 7. The iodopyridine
derivative 18 was prepared from 3-hydroxypyridine by
transformation to its diethylaminocarbamate,21 followed by
directed lithiation, subsequent iodination, and hydrolysis of
the carbamate function.22 The reaction sequence as depicted
in Scheme 2 was thereafter followed. For the preparation of
triflate 25, N-(5-chloro-2-pyridyl)triflimide23 was found to
be superior as compared to triflic anhydride in promoting
the reaction. The palladium-catalyzed intramolecular cy-
clization of 25 was sluggish under the same conditions as
those used for the cyclization of 16 and a longer reaction
time was required for complete conversion of 25. Reduction
of the triflate group was the predominant reaction. Hydro-
genation of the double-bond isomers and hydrolysis of the
carbamate delivered the rigid anabasine analogue 8.
a (a) Ac2O, 70 °C; (b) PdCl2(PPh3)2, CuI, Et3N, HCCSiMe3, THF,
RT; (c) TBAF, THF/H2O, 0 °C; (d) 12, PdCl2(PPh3)2, CuI, Et3N,
THF, RT; (e) H2, Pd/C, quinoline, EtOAc, RT; (f) NaHCO3, MeOH/
H2O, RT; (g) N-(5-chloro-2-pyridyl)triflimide, Et3N, CH2Cl2; (h)
Pd(OAc)2, (R)-BINAP, Et3N, CH3CN; (i) H2, Pd/C; (j) KOH,
H2NNH2‚H2O, H2O/ethylene glycol.
In conclusion we have described the synthesis of two
conformationally restricted anabasine analogues where we
have employed a series of palladium-catalyzed reactions to
achieve our goal. These potential nicotine receptor ligands
comprise a piperidine that is nearly perpendicular to the plane
of the pyridine ring. The biological testing will be reported
elsewhere.
(18) Ripa, L.; Hallberg, A. J. Org. Chem. 1996, 61, 7147-7155.
(19) Reaction in the presence of ammonium formate lead to a sluggish
reaction and a complex reaction mixture.
(20) Analytical separations of the enantiomers were achieved by gas
chromatography, on a chiral capillary column (10 m × 0.32 mm) coated
with 20% octakis(2,6-di-O-methyl-3-O-pentyl)-γ-cyclodextrin in OV 1701,
with H2 as carrier gas and a flame ionization detector. The column was
prepared and developed by Professor W. A. Ko¨nig, Institut fu¨r Organische
Chemie, Universita¨t Hamburg, D-201 46 Hamburg, Germany.
(21) Millner, O. E., Jr.; Stanley, J. W.; Purcell, W. P. J. J. Med. Chem.
1974, 17, 13-18.
(22) Miah, M. A. J.; Snieckus, V. J. J. Org. Chem. 1985, 50, 5436-
5438.
(23) (a) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org.
Synth. 1997, 74, 77-81. (b) Comins, D. L.; Dehghani, A. Tetrahedon Lett.
1992, 33, 6299-6302.
Acknowledgment. The authors are grateful to the Swed-
ish Natural Science Research Council for financial support.
Supporting Information Available: Experimental pro-
cedures and full characterization data for compounds 7-26.
This material is available free of charge via the Internet at
http:/pubs.acs.org.
OL006056F
Org. Lett., Vol. 2, No. 15, 2000
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