Synthesis of a 2,3′;6′,3″-terpyridine scaffold as an α-helix mimetic

Article abstract of DOI:10.1021/ol0521228

(Chemical Equation Presented) A terpyridine scaffold has been designed as an α-helix mimetic. A facile synthesis of the ortho-functionalized 2,3′-oligopyridine has been accomplished using sequential Bohlmann-Rahtz heteroannulation reactions.

Full text of DOI:10.1021/ol0521228

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5405-5408
Synthesis of a 2,3
′;6′,3′′-Terpyridine
Scaffold as an -Helix Mimetic
r
Jessica M. Davis, Anh Truong, and Andrew D. Hamilton*
Department of Chemistry, Yale UniVersity, P.O. Box 20810,
New HaVen, Connecticut 06511
andrew.hamilton@yale.edu
Received September 2, 2005
ABSTRACT
A terpyridine scaffold has been designed as an
r-helix mimetic. A facile synthesis of the ortho-functionalized 2,3′-oligopyridine has been
accomplished using sequential Bohlmann Rahtz heteroannulation reactions.
−
R-Helices on protein surfaces function as recognition regions
for protein-protein, protein-DNA, and protein-RNA in-
teractions. Mimicking these domains with small molecules
has proven to be an effective means to disrupt protein
function.1
arrangement of substituents to mimic the i, i + 3 or i + 4,
and i + 7 residues of an R-helix.3 In this study, we sought
to expand the strategy to include scaffolds based on other
aryl derivatives, such as pyridine.
Pyridines play important roles in pharmaceuticals, agro-
chemicals, and preparative organic chemistry. As a result,
many methods of pyridine synthesis have been developed.4
In the case of oligopyridines, several examples of 2,2′-
bipyridine synthesis can be found in the literature, primarily
because of their application in metal chelation.5 Fewer
examples of other substitution patterns can be found,
although such systems are desirable for use as pharmaco-
phores in drug design and in situations where metal chelation
may interfere with the desired effect.
In many cases, residues in the i, i + 4, i + 7, and i + 11
positions on the helix play a key role in mediating protein
contact. For example, the interaction of Bcl-xL with Bak
involves the residues Val74, Leu78, Ile81, and Ile85 on the
R-helical BH3 domain of Bak, making contacts with a
shallow hydrophobic cleft on the surface of Bcl-xL.2
We have previously established that a trisfunctionalized
3,2′,2′′-terphenyl (Figure 1) has the appropriate spacial
* Corresponding author. Tel: + 1-203-432-5570. Fax: + 1-203-432-
3221.
(1) For recent reviews, see: (a) Jain, R.; Ernst, J. T.; Kutzki, O.; Park,
H. S.; Hamilton, A. D. Mol. DiVers. 2004, 8, 89. (b) Cochran, A. G. Curr.
Opin. Chem. Biol. 2001, 5, 654. (c) Zutshi, R,; Brickner, M.; Chmielewski,
J. Curr. Opin. Chem. Biol. 1998, 2, 62. (d) Toogood, P. L. J. Med. Chem.
2002, 45, 1543.
(2) (a) Adams, J. M.; Cory, S. Science 1998, 281, 1322. (b) Reed, J. C.
Nature 1997, 387, 773. (c) Sattler, M.; Liang, H.; Nettesheim, D.; Meadows,
R. P.; Harlan, J. E.; Eberstadt, M.; Yoon, H. S.; Shuker, S. B.; Chang, B.
S.; Minn, A. J.; Thompson, C. B.; Fesik, S. W. Science 1997, 275, 983.
(3) (a) Kutzki, O.; Park, H. S.; Ernst, J. T.; Orner, B. P.; Yin, H.;
Hamilton, A. D. J. Am. Chem. Soc. 2002, 124, 11838. (b) Ernst, J. T.;
Kutzki, O.; Debnath, A. K.; Jiang, S.; Lu, H.; Hamilton, A. D. Angew.
Chem., Int. Ed. 2002, 41, 278. (c) Orner, B. P.; Ernst, J. T.; Hamilton, A.
D. J. Am. Chem. Soc. 2001, 123, 5382.
(4) For recent reviews, see: (a) Murugan, R.; Scriven, E. F. V. J.
Heterocycl. Chem. 2000, 37, 451. (b) Henry, G. D. Tetrahedron 2004, 60,
6043.
(5) For a review, see: Kaes, C.; Katz, A.; Hosseini, M. W. Chem. ReV.
2000, 100, 3553.
10.1021/ol0521228 CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/02/2005

Figure 1. Evolution of R-helix mimetic design: (a) R-helix with i, i + 3, and i + 7 residues highlighted in red; (b) energy-minimized
trimethyl-substituted terphenyl; (c) energy-minimized trimethyl-substitued terpyridine; (d) superimposed terpyridine on the R-helix (root-
mean-square deviation of 1.14 Å). (Image produced using InsightII.)
The 2,3′-substitution pattern desirable for an R-helix
mimetic can be synthesized through heteroannulation condi-
tions first reported by Bohlmann and Rahtz6 and further
developed by Bagley et al.7 The reaction provides a handle
for subsequent heteroannulations in the form of an ester. An
efficient conversion of the ester to the ketoalkyne annulation
precursor can be used for rapid oligopyridine synthesis.
Ketoalkyne 6 was synthesized from 1,4-butanediol (Scheme
1).8 The diol was monoprotected using standard methods,
ethynylmagnesium bromide, followed by Jones oxidation,
yielded compound 6.
Ethyl 5-methyl-3-oxohexanoate (8) was obtained by reac-
tion of Meldrum’s acid with pyridine and isovaleryl chloride
in methylene chloride. The resulting intermediate was then
refluxed in ethanol to obtain the â-keto ester 8, as shown in
Scheme 2.9
Scheme 2. Synthesis of â-Keto Ester 8
Scheme 1. Synthesis of 6
The pyridine was synthesized through adaptation of the
conditions reported by Bagley et al.,7 who found that
refluxing 1 equiv of â-keto ester with up to 2 equiv of the
alkynone with ammonium acetate and a Lewis acid catalyst
allows for a one-pot condensation to form a 2,3,4,6-
tetrasubstituted pyridine. For our terpyridine scaffold, the
easily obtained â-keto ester was used in excess and first
refluxed in toluene with dry ammonium acetate for 1 h to
generate the enamine. The alkynone was then added with
the Lewis acid, and the reaction was refluxed for an
additional 48 h. Similarly to Bagley et al., we found that
ytterbium(III) triflate gave slightly better yields than zinc-
(II) bromide, as seen in Table 1.
H. M.; Taylor, P. H.; Xiong, X. Synlett 2003, 10, 1443. (f) Xiong, X.;
Bagley, M. C.; Chapaneri, K. Tetrahedron Lett. 2004, 45, 6121. (g) Bagley,
M. C.; Chapaneri, K.; Dale, J. W.; Xiong, X.; Bower, J. J. Org. Chem.
2005, 70, 1389.
with subsequent oxidation of the free alcohol, via Swern
conditions, to afford the aldehyde 4. The addition of
(8) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3,
2721.
(6) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265.
(7) (a) Bagley, M. C.; Dale, J. W.; Bower, J. Synlett 2001, 7, 1149. (b)
Bagley, M. C.; Dale, J. W. Hughes, D. D.; Ohnesorge, M.; Phillips, N. G.;
Bower, J. Synlett 2001, 10, 1523. (c) Bagley, M. C.; Brace, C.; Dale, J.
W.; Ohnesorge, M.; Phillips, N. G.; Xiong, X.; Bower, J. J. Chem. Soc.,
Perkin Trans. 1 2002, 1663. (d) Bagley, M. C.; Dale, J. W.; Bower, J.
Chem. Commun. 2002, 1, 1682. (e) Bagley, M. C.; Hughes, D. D.; Sabo,
(9) Selwood, D. L.; Brummell, D. G.; Budworth, J.; Burtin, G. E.;
Campbell, R. O.; Chana, S. S.; Charles, I. G.; Fernandez, P. A.; Glen, R.
C.; Goggin, M. C.; Hobbs, A. J.; Kling, M. R.; Liu, Q.; Madge, D. J.;
Meillerais, S.; Powell, K. L.; Reynolds, K.; Spacey, G. D.; Stables, J. N.;
Tatlock, M. A.; Wheeler, K. A.; Wishart, G.; Woo, C. K. J. Med. Chem.
2001, 44, 78.
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Org. Lett., Vol. 7, No. 24, 2005

The desire for a facile route to oligopyridine scaffolds led
to a thorough investigation of an efficient conversion of the
pyridine ester to the pyridine alkynones (10a,b). Our route
to compounds 10a,b orginally involved a four-step sequence
using well-established chemistry, as shown in Scheme 3. The
Table 1. Bohlmann-Rahtz Heteroannulation
Scheme 3. Original Extended Synthesis of Pyridine Alkynones
alkynone
Lewis acid
product
yield (%)
6
6
10a
10a
10b
10b
ZnBr2
Yb(OTf)3
ZnBr2
Yb(OTf)3
ZnBr2
Yb(OTf)3
9a
9a
9b
9b
9c
9c
61
65
47
78
45
57
ester. The pyridine alkynone was synthesized in reasonable
yield with in situ generation of the Weinreb amide from the
ester, as shown in Scheme 4.
As shown in Scheme 5, the final product, terpyridine 1,
was obtained in three steps from 10b. The benzyl ether was
Scheme 5. Completion of Terpyridine 1
ester was first reduced to the alcohol with DIBAL-H and
then oxidized to the aldehyde under Swern conditions.
Addition of ethynylmagnesium bromide followed by oxida-
tion with manganese(II) oxide gave the alkynones 10a,b.
This route was deemed unsuitable for an efficient oli-
gopyridine synthesis because of the length of the sequence
and the overall low yields. Therefore, various conditions were
explored to synthesize the alkynone in one or two steps. We
found that conditions similar to those reported by Williams
et al. gave the best results.10 They reported that with excess
Grignard, the ketone can be obtained in one step from the
Scheme 4. One-Step Pyridine Alkynone Synthesis
Org. Lett., Vol. 7, No. 24, 2005
5407

deprotected with palladium hydroxide as a catalyst under a
hydrogen atmosphere. Jones oxidation was used to obtain
the monoacid, and the ester of the crude oxidation product
was saponified with lithium hydroxide in water and THF.
other analogues will be tested against the Bcl-xL/Bak peptide
interation, the results of which will be reported in a
subsequent report.
Acknowledgment. We thank the National Institutes of
Health (GM69850) for financial support of this work.
Terpyridine 1 was synthesized in 15 steps from 1,4-
butadiol. The key repetitive sequence of the synthesis,
seqential condensation followed by ketoalkyne generation,
provides a route to 2,3′-oligopyridines. The terpyridine 1 and
Supporting Information Available: Experimental pro-
cedures and characterizations of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
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