C. W. Gray, Jr. et al. / Tetrahedron Letters 48 (2007) 2683–2686
2685
ing functionality in the pairs of amides and amines. As
Supplementary data
the nitrogen atoms closest to the aromatic ring of the
receptor will be nearer the membrane interface if the
proposed binding model is correct, neutral groups
may interact with the phosphates as effectively as
charged species. This system seemed a useful synthetic
precursor to the fully cationic azacrowns; however,
attempts to selectively (to furnish 4) or globally reduce
this macrocycle to the target structures met with only
limited success. Unfortunately, 3 decomposed slowly
in air to brown biproducts that were not identified
and this severely compromised its usefulness as a syn-
thetic intermediate.
Supplementary data associated with this article can be
References and notes
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first of our desired core structures contain a nitrogen
functionality that harbors no hydrogens capable of
hydrogen bonding anions such as phosphates, but the
strong dipole of the sulfonamides may still bind PIP2
at membrane interfaces. It will be interesting to com-
pare binding of this neutral compound in relation to
the free amine structures described below. Deprotec-
tion of this compound under a variety of conditions
(e.g., HBr/HOAc,18 sodium napthalide19) and tempera-
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Reaction of 9 with a,a0-dibromo-m-xylene furnished 10
and the deprotection now proceeded smoothly with
HCl/dioxane to generate the second target core struc-
ture 11 (33% for two steps).20 Thus, the framework is
in place to generate families of neutral and cationic
receptors for membrane-sequestered phosphoinositides.
Whether any of these azacrowns alone have apprecia-
ble affinity for inositol phosphates remains to be deter-
mined. At present there are still no de novo synthetic
receptors capable of selective recognition of PIP2 at
membrane interfaces, but the work described here is
being applied to this end. Such a compound will be
useful in dissecting the intricacies of complex cell-sig-
naling pathways where PIP2 occupies a crucial message
branch point. It will provide complementary informa-
tion to signal disruption by polycations, such as neo-
mycin, whose affinity for PIP2 and IP3 is less
discretionary.
Acknowledgments
We wish to thank Virginia Commonwealth University
for support through the Mary Kapp Fund and Grant-
in-Aid Program. Funding from the Jeffress Memorial
Trust is also gratefully acknowledged. K.B. was a partic-
ipant in the NSF REU program at VCU.
13. Vandenburg, Y. R.; Zhang, Z.-Y.; Fishkind, D. J.; Smith,
B. D. Chem. Commun. 2000, 149.