Journal of the American Chemical Society
Page 4 of 5
Magano, J.; Weisenburger, G. A. Org. Process Res. Dev. 2016, 20, 140ꢀ
177.
four of which were MYMsAꢀmediated peptide bond formation.
1
2
3
4
5
6
7
8
No detectable evidence of racemization was observed in the entire
synthesis. The synthesis of Leuꢀenkephalin 20 clearly demonstratꢀ
ed that the ynamide not only can be used as a coupling reagent for
amides and dipeptides but is also effective for peptide segment
condensation.
2. Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067ꢀ1068.
3. Gawne, G.; Kenner, G. W.; Sheppard, R. C. J. Am. Chem. Soc. 1969, 91,
5669ꢀ5671.
4. Carpino, L. A.; Henklein, P.; Foxman, B. M.; Abdelmoty, I.; Costisella,
B.; Wray, V.; Domke, T.; ElꢀFaham, A.; Mügge, C. J. Org. Chem. 2001, 66,
5245ꢀ5247.
In conclusion, we have successfully developed a twoꢀstep, oneꢀ
pot strategy for amide and peptide bond formation by employing
ynamides as novel coupling reagents. It was established on the
basis of an extremely efficient hydroacyloxylation of ynamides
5. For selected examples, see: (a) Gunanathan, C.; BenꢀDavid, Y.; Milstein,
D. Science 2007, 317, 790ꢀ792. (b) Bode, J. W.; Fox, R. M.; Baucom, K.
D. Angew. Chem. Int. Ed. 2006, 45, 1248ꢀ1252. (c) Shen, B.; Makley, D.;
Johnston, J. Nature 2010, 465, 1027ꢀ1033. (d) Wu, W.; Zhang, Z.;
Liebeskind, L. S. J. Am. Chem. Soc. 2011, 133, 14256ꢀ14259. (e) Dumas,
A. M.; Molander, G. A.; Bode, J. W. Angew. Chem. Int. Ed. 2012, 51,
5683ꢀ5686. (f) Soulé, J.ꢀF.; Miyamura, H.; Kobayashi, S. J. Am. Chem.
Soc. 2011, 133, 18550ꢀ18553. (g) Liu, J.; Liu, Q.; Yi, H.; Qin, C.; Bai, R.;
Qi, X.; Lan, Y.; Lei, A. Angew. Chem. Int. Ed. 2014, 53, 502ꢀ506. (h) Li, J.;
Lear, M. J.; Kawamoto, Y.; Umemiya, S.; Wong, A. R.; Kwon, E.; Sato, I.;
Hayashi, Y. Angew. Chem. Int. Ed. 2015, 54, 12986ꢀ12990.
9
with carboxylic acids and an unprecedented aminolysis of
αꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
acyloxyenamides. Both the hydroacyloxylation and the aminolyꢀ
sis proceeded under very mild reaction conditions in a“click”
manner, making ynamides as efficient coupling reagents. The
ynamide coupling reagents have several advantages: 1) ynamides
MYTsA and MYMsA can be prepared easily from readily availaꢀ
ble chemicals and are stable to air and moisture; 2) the ynamide
coupling reagents can be used alone without the assistance of any
additive or catalyst; 3) MYMsA (mol. wt.: 133.02) is the smallest
racemizationꢀfree peptide coupling reagent, highlighting its atomꢀ
economic advantage; 4) excellent amidation selectivity toward
amino group in the presence of ꢀOH, ꢀSH, ꢀCONH2, ArNH2, and
the NH of indole renders the protection of these functional groups
unnecessary in amide and peptide synthesis; and 5) ynamide couꢀ
pling reagents can also be used for peptide segment condensation
as well as largerꢀscale reactions. All of these features make ynaꢀ
mides practical coupling reagents for amide and peptide synthesis
in both academia and industry. Further studies toward more effecꢀ
tive ynamides, more efficient coupling reaction systems and their
application in solid phase peptide synthesis are underway in our
laboratory.
6. Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer,
J. J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells,
A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411ꢀ420.
7. For recent contributions, see: (a) Kamiński, Z. J.; Kolesińska, B.;
Kolesińska, J.; Sabatino, G.; Chelli, M.; Rovero, P.; Błaszczyk, M.;
Główka, M. L.; Papini, A. M. J. Am. Chem. Soc. 2005, 127, 16912ꢀ16920.
(b) Krause, T.; Baader, S.; Erb, B.; Gooszen, L. J. Nat. Commun. 2016, 7,
11732. (c) Li, H.; Jiang, X.; Ye, Y.ꢀh.; Fan, C.; Romoff, T.; Goodman, M.
Org. Lett. 1999, 1, 91ꢀ94. (d) Tian, J.; Gao, W.ꢀC.; Zhou, D.ꢀM.; Zhang, C.
Org. Lett. 2012, 14, 3020ꢀ3023. (e) Orliac, A.; Gomez Pardo, D.;
Bombrun, A.; Cossy, J. Org. Lett. 2013, 15, 902ꢀ905. (f) SubirósꢀFunosas,
R.; Prohens, R.; Barbas, R.; ElꢀFaham, A.; Albericio, F. Chem. Eur. J.
2009, 15, 9394ꢀ9403.
8. (a) Wang, T.; Yuan, L.; Zhao, Z.; Shao, A.; Gao, M.; Huang, Y.; Xiong,
F.; Zhang, H.; Zhao, J. Green Chem. 2015, 17, 2741ꢀ2744. (b) Zhao, Z.;
Wang, T.; Yuan, L.; Hu, X.; Xiong, F.; Zhao, J. Adv. Synth. Catal. 2015,
357, 2566ꢀ2570. (c) Zhao, Z.; Wang, T.; Yuan, L.; Jia, X.; Zhao, J. RSC
Adv. 2015, 5, 75386ꢀ75389.
ASSOCIATED CONTENT
Supporting Information
9. Smith, D. L.; Goundry, W. R. F.; Lam, H. W. Chem. Commun. 2012, 48,
1505ꢀ1507.
Experimental procedures and characterization data for all reacꢀ
tions and products, including 1H and 13C NMR spectra and HPLC
chromatograms. This material is available free of charge via the
10. Xu, S.; Liu, J.; Hu, D.; Bi, X. Green Chemistry 2015, 17, 184ꢀ187.
11. (a) Neuenschwander, M. Helv. Chim. Acta 2015, 98, 881ꢀ898. (b) van
Mourik, A. S.; Harryvan, E.; Arens, J. F. Recl. Trav. Chim. Pays-Bas 1965,
84, 1344ꢀ1347. (c) Hafner, K.; Neuenschwander, M. Angew. Chem. Int. Ed.
1968, 7, 459ꢀ460. (d) Gais, H.ꢀJ. Angew. Chem. Int. Ed. 1978, 17, 597ꢀ598.
(e) Neuenschwander, M.; Fahrni, H.ꢀP.; Lienhard, U. Helv. Chim. Acta
1978, 61, 2437ꢀ2451. (f) Neuenschwander, M.; Lienhard, U.; Fahrni, H.ꢀP.;
Hurni, B. Helv. Chim. Acta 1978, 61, 2428ꢀ2436. (g) Buijle, R.; Viehe, H.
G. Angew. Chem. Int. Ed. 1964, 3, 582ꢀ582.
AUTHOR INFORMATION
Corresponding Author
12. (a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064ꢀ5106. (b) Evano, G.; Coste,
A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49, 2840ꢀ2859. (c) Cook, A.
M.; Wolf, C. Tetrahedron Lett. 2015, 56, 2377ꢀ2392. (d) Wang, X.ꢀN.;
Yeom, H.ꢀS.; Fang, L.ꢀC.; He, S.; Ma, Z.ꢀX.; Kedrowski, B. L.; Hsung, R.
P. Acc. Chem. Res. 2014, 47, 560ꢀ578.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interests.
13. A comparative study of epimerization/racemization of nonꢀnatural
amino acid FmocꢀLꢀphenylglycine, which is extremely prone to
epimerization/ racemization, was also performed (see the Supporting
Information).
ACKNOWLEDGMENT
This work was supported by the National Natural Science Founꢀ
dation of China (21462023) and the Natural Science Foundation
of Jiangxi Province (20143ACB20007).
14. Although the first step had to be performed in DCM, the subsequent
aminolysis of
solvents such as DMF with a significantly shorter reaction time (see the
Supporting Information).
αꢀacyloxyenamide could also be performed in other
REFERENCES
1. For reviews, see: (a) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480,
471ꢀ479. (b) White, C. J.; Yudin, A. K. Nat. Chem. 2011, 3, 509ꢀ524. (c)
Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem. Int. Ed. 2008, 47,
10030ꢀ10074. (d) Han, S. Y.; Kim, Y. A. Tetrahedron 2004, 60, 2447ꢀ2467.
(e) ElꢀFaham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557ꢀ6602. (f)
Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606ꢀ631. (g)
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827ꢀ10852.
(h) Coltart, D. M. Tetrahedron 2000, 56, 3449–3491. (i) Dunetz, J. R.;
ACS Paragon Plus Environment