Organic Letters
Letter
Crystallographic data for 5a (CIF)
Experimental details and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
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Author Contributions
†I.Y. and S.-E.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by funding from the University of
Pennsylvania. We thank Pat Carroll (University of Pennsylva-
nia) for X-ray crystallographic assistance. The instruments were
supported by the National Science Foundation and the
National Institutes of Health including HRMS (Grant No.
NIH RR-023444) and the X-ray diffractometer (Grant No.
CHE-0840438). I.Y. is grateful for support from a fellowship
from the Kwanjeong Educational Foundation.
REFERENCES
Figure 1. (a) Graphical representation of the fluorescence-quenching
3WJ assay. (b) Dissociation constants of triptycenes 17−20. Note:
Synthesis of triptycene 20 lacking a bridgehead substituent has been
previously reported.5
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(1) (a) Duckett, D. R.; Lilley, D. M. J. EMBO J. 1990, 9, 1659−1664.
(b) Shlyakhtenko, L. S.; Potaman, V. N.; Sinden, R. R.; Gall, A. A.;
Lyubchenko, Y. L. Nucleic Acids Res. 2000, 28, 3472−3477. (c) Lilley,
D. M. J. Q. Rev. Biophys. 2000, 33, 109−159.
(2) (a) Tor, Y. ChemBioChem 2003, 4, 998−1007. (b) Thomas, J. R.;
Hergenrother, P. J. Chem. Rev. 2008, 108, 1171−1224. (c) Blond, A.;
that of 20 with Kd values of 0.27 and 0.46 μM, respectively
(Figure 1b). The presence of lysine appears to play an
important role in binding to the junction and will be
investigated in future studies.
Ennifar, E.; Tisne,
1996.
́
C.; Micouin, L. ChemMedChem 2014, 9, 1982−
(3) Guan, L.; Disney, M. D. ACS Chem. Biol. 2012, 7, 73−86.
(4) Barros, S. A.; Chenoweth, D. M. Angew. Chem., Int. Ed. 2014, 53,
13746−13750.
(5) Barros, S. a; Chenoweth, D. M. Chem. Sci. 2015, 6, 4752−4755.
(6) (a) Boas, U.; Brask, J.; Jensen, K. J. Chem. Rev. 2009, 109, 2092−
2118. (b) Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100,
2091−2158.
(7) (a) Bartlett, P. D.; Cohen, S. G.; Cotman, J. D.; Kornblum, N.;
Landry, J. R.; Lewis, E. S. J. Am. Chem. Soc. 1950, 72, 1003−1004.
(b) Bartlett, P. D.; Lewis, E. S. J. Am. Chem. Soc. 1950, 72, 1005−1009.
(8) (a) Swager, T. M. Acc. Chem. Res. 2008, 41, 1181−1189.
(b) Chong, J. H.; MacLachlan, M. J. Chem. Soc. Rev. 2009, 38, 3301−
3315.
(9) Ng, K.-K. D.; Hart, H. Tetrahedron 1995, 51, 7883−7906.
(10) (a) Wang, D.; Mei, T.; Yu, J. J. Am. Chem. Soc. 2008, 130,
17676−17677. (b) Zhang, Y.; Zhao, H.; Zhang, M.; Su, W. Angew.
Chem., Int. Ed. 2015, 54, 3817−3821. (c) Wang, D.-H.; Engle, K. M.;
Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315−320.
(11) Harsanyi, M. C.; Norris, R. K.; Sze, G.; Witting, P. K. Aust. J.
Chem. 1995, 48, 1949−1967.
(12) (a) Klanderman, B. H.; Perkins, W. C. J. Org. Chem. 1969, 34,
630−633. (b) Chong, J. H.; MacLachlan, M. J. J. Org. Chem. 2007, 72,
8683−8690. (c) Chong, J. H.; MacLachlan, M. J. Inorg. Chem. 2006,
45, 1442−1444. (d) Zhang, C.; Chen, C.-F. J. Org. Chem. 2006, 71,
6626−6629. (e) Ma, Y.-X.; Meng, Z.; Chen, C.-F. Synlett 2014, 26, 6−
30.
(13) Xu, M.-L.; Huang, W. Synth. Commun. 2014, 44, 3435−3440.
(14) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.; Yoon,
W. H.; He, Y.; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669−
1675.
In summary, we have developed a synthetic approach for
preparing new 9-substituted triptycene building blocks. This
approach enables solid-phase diversification of triptycene.
During the synthesis, O-directed nitration was observed from
the MOM protected primary alcohol (4), primary alcohol (7),
and carboxylic acid (8) at the C9 position of triptycene. These
results indicated that the carboxylic group increased the ratio of
nitration on β-carbons toward the linker position, pointing to a
possible carboxylic acid directing effect. In addition, a key
amide bond formation was achieved on a sterically hindered
and geometrically fixed tertiary carboxylic acid using a unique
MsCl activation strategy. This may be regarded as a general
strategy toward functionalization of extremely sterically
encumbered tertiary carboxylic acids. For diversification of
the new triptycene building block, three amino acids were
utilized including histidine, lysine, and asparagine to produce
trisubstituted triptycenes 17−19. The binding ability of the
synthesized triptycene derivatives toward a d(CAG)·(CTG)
trinucleotide repeat junction was evaluated, and triptycenes 18
and 19 exhibited better binding affinity to the junction
compared to that of a previously reported triptycene with no
linker (20). This new synthetic strategy provides rapid and
efficient access to triptycene building blocks, enabling high-
throughput diversification for rapid evaluation of potential
junction binders and other medicinal chemistry targets.
ASSOCIATED CONTENT
* Supporting Information
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(15) (a) Friede, M.; Denery, S.; Neimark, J.; Kieffer, S.; Gausepohl,
H.; Briand, J. P. Pept. Res. 1992, 5, 145−147. (b) Quesnel, A.; Briand,
J. P. J. Pept. Res. 1998, 52, 107−111.
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The Supporting Information is available free of charge on the
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