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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%.
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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.
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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,