Organic Letters
Letter
352, 801−805. (b) Qin, T.; Malins, L. R.; Edwards, J. T.; Merchant, R.
R.; Novak, A. J. E.; Zhong, J. Z.; Mills, R. B.; Yan, M.; Yuan, C.; Eastgate,
M. D.; Baran, P. S. Angew. Chem. 2017, 129, 266−271. (c) Edwards, J.
T.; Merchant, R. R.; McClymont, K. S.; Knouse, K. W.; Qin, T.; Malins,
L. R.; Vokits, B.; Shaw, S. A.; Bao, D.-H.; Wei, F.-L.; Zhou, T.; Eastgate,
M. D.; Baran, P. S. Nature 2017, 545, 213−218. (d) Smith, J. M.; Qin, T.;
Merchant, R. R.; Edwards, J. T.; Malins, L. R.; Liu, Z.; Che, G.; Shen, Z.;
Shaw, S. A.; Eastgate, M. D.; Baran, P. S. Angew. Chem., Int. Ed. 2017, 56,
11906−11910.
(3) (a) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557−6602.
(b) For a graphical guide to amide bond formation, see: Ishihara, Y.;
Montero, A.; Baran, P. S. The Portable Chemist’s Consultant, version
2.7.1; Apple Publishing Group: New York, 2016; pp 835−895.
(4) For discussion of representative tetramethyluronium-containing
reagents, see the following. (a) HBTU, HATU, and TATU: Abdelmoty,
I.; Albericio, F.; Carpino, L. A.; Foxman, B. M.; Kates, S. A. Lett. Pept. Sci.
1994, 1, 57−67. (b) HBTU: Dourtoglou, V.; Ziegler, J.-C.; Gross, B.
Tetrahedron Lett. 1978, 19, 1269−1272. (c) TDTU and HDTU:
Carpino, L. A.; El-Faham, A.; Albericio, F. J. Org. Chem. 1995, 60, 3561−
3564. (d) HOTT: Garner, P.; Anderson, J. T.; Dey, S.; Youngs, W. J.;
Galat, K. J. Org. Chem. 1998, 63, 5732−5733.
(5) (a) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.;
Pan, C.-M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P. S. J.
Am. Chem. Soc. 2016, 138, 2174−2177. (b) Sandfort, F.; O’Neill, M. J.;
Cornella, J.; Wimmer, L.; Baran, P. S. Angew. Chem., Int. Ed. 2017, 56,
3319−3323.
(6) For a representative review, see: Sletten, E. M.; Bertozzi, C. R.
Angew. Chem., Int. Ed. 2009, 48, 6974−6998.
(7) Wang, J.; Qin, T.; Chen, T.-G.; Wimmer, L.; Edwards, J. T.;
Cornella, J.; Vokits, B.; Shaw, S. A.; Baran, P. S. Angew. Chem., Int. Ed.
2016, 55, 9676−9679.
The data revealed no correlation when run through the Yoshida
explosivity prediction model, signifying that the compound is
unlikely to be shock sensitive and/or explosion propagating. For
comparison, TBTUone of the most structurally similar of the
common coupling reagentsis classified as an explosive with an
energy release of 401 kJ/mol, a value nearly 1.5 times higher than
that of CITU (277 kJ/mol).10a Importantly, the reagent has been
prepared in kilogram batches from tetrachlorophthalic anhy-
dride, a factor which all but eliminates both cost and safety
concerns.10c CITU is bench-stable when stored as a solid at
ambient temperature; however, as with many comparable
reagents, stock solutions (including those frequently employed
in automated peptide synthesizers) should be freshly prepared
every 2 days to avoid degradation and hydrolysis.
CITU, now commercially available,11 is an inexpensive, dual-
purpose reagent that enables both solid- and solution-phase
acylation and decarboxylative cross-coupling reactions. It is best
suited for practitioners seeking a safe alternative to the standard
array of coupling reagents, particularly on large scale. While
CITU is not recommended for use in the previously disclosed
decarboxylative Suzuki cross-coupling reaction,7 it can be readily
employed for the analogous Ni-catalyzed Negishi alkylation,
arylation, alkenylation, and alkynylation reactions, as well as for
solution- and solid-phase acylations.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
(8) Katritzky, A. R.; Haase, D. N.; Johnson, J. V.; Chung, A. J. Org.
Chem. 2009, 74, 2028−2032.
(9) Han, Y.; Albericio, F.; Barany, G. J. Org. Chem. 1997, 62, 4307−
4312.
Detailed experimental procedures and analytical data for
linear peptides and small molecules (PDF)
(10) (a) Wehrstedt, K. D.; Wandrey, P. A.; Heitkamp, D. J. Hazard.
́
Mater. 2005, 126, 1−7. (b) Subiros-Funosas, R.; Prohens, R.; Barbas, R.;
AUTHOR INFORMATION
■
El-Faham, A.; Albericio, F. Chem. - Eur. J. 2009, 15, 9394−9403. (c)
Personal communication (poster session, Pfizer, Inc.): Sperry, J. B.;
Minteer, C.; Tao, L.; Johnson, R.; Duzguner, R.; Hawksworth, M.; Oke,
S.; Eisenbeis, H.; Barnhart, R.; Bill, D. R.; Giusto, R.; Weaver, J. Thermal
Stability of Common Peptide Couping Reagents, Oct 2017.
(11) CITU is now available in the MilliporeSigma catalog
(ALD00598).
Corresponding Author
ORCID
Author Contributions
⊥J.N.D. and L.R.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support for this work was provided by Bristol-Myers
Squibb, NSF GRFP (J.N.D.), NIH (F32GM117816 postdoctoral
■
fellowship to L.R.M. and GM-118176), Schrodinger Fellowship
̈
of the Austrian Science Fund (L.W.), Marie Skłodowska-Curie
Fellowship (H2020-MSCA-IF-2014 to J.L.-O.), and Catalan
Government (postdoctoral fellowship to J.C.). We are grateful to
Drs. D.-H. Huang and L. Pasternack (TSRI) for assistance with
nuclear magnetic resonance (NMR) spectroscopy, Dr. M.
Schmidt (BMS) for help with DSC data, Dr. J. Chen (TSRI)
for purification and analysis assistance, and Dr. Y. Shao (TSRI)
for providing Phth-AV-OH.
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