An activated phosphate for an efficient amide and peptide coupling reagent

Article abstract of DOI:10.1039/b004264l

An activated phosphate for an efficient amide and peptide coupling reagent was discussed. Activation of diethyl phosphates was realized by attaching trifluoromethanesulfonanilide as an efficient leaving group and the phosphate proved to be a promising amide and peptide coupling reagent. Results showed that reactions of a primary amine with α-branched carboxylic acids and benzoic acid gave within 1 h the amides in quite high yield.

Full text of DOI:10.1039/b004264l

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An activated phosphate for an efficient amide and peptide coupling
reagent
Tomohisa Yasuhara, Yasuo Nagaoka and Kiyoshi Tomioka*
1
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501,
Japan
Received (in Cambridge, UK) 30th May 2000, Accepted 2nd August 2000
Published on the Web 15th August 2000
Activation of diethyl phosphate was realized by attaching
trifluoromethanesulfonanilide as an efficient leaving group
and the phosphate 1 proved to be a promising amide and
peptide coupling reagent.
saturated sodium bicarbonate and then concentrated to afford
a mixture of products, which were purified by recrystallization
or column chromatography to afford the corresponding acet-
amide 3 in 95% yield along with phosphoramide 416 in 5% yield
(Table 1, entry 1). The leaving group of 1, trifluoromethane-
sulfonanilide, was recovered quantitatively for recycling simply
by extracting from an acidified aqueous solution. Formation of
4 could be suppressed by increasing the amount of acetic acid
to 2 equiv., and 3 was the only isolable product in 99% yield
(entry 2). The reaction in DMF proceeded faster than that in
dichloromethane, however, product distribution was not satis-
factory, affording 3 in 93% yield along with 4 in 7% yield (entry
3). Exhaustive examination of organic bases to replace triethyl-
amine, such as Hünigs base, dimethylaniline, 2,6-lutidine, and
1,8-bis(dimethylamino)naphthalene (proton sponge),17 revealed
that proton sponge was a good choice of base to provide 3 in a
satisfactory yield without formation of a detectable amount of
4 (entry 6, 7). It is noteworthy that the coupling reaction pro-
ceeded in methanol to afford 3 quantitatively (entry 9).
Coupling of α-branched primary and secondary amines with
acetic acid proceeded smoothly within 8 h to give the corre-
sponding amides in high yield (Table 2, entries 1–5). Reactions
of a primary amine with α-branched carboxylic acids and benz-
oic acid gave within 1 h the amides in quite high yield (entries
6–8). tert-Butylamine was coupled with α-branched carboxylic
acids and benzoic acid to give the amides in satisfactory yield
(entries 9–11).
Formation of amide and peptide bonds through a coupling
reaction of carboxylic acids with amines is a fundamental
synthetic operation. Although some coupling reagents are
commercially available, coupling reactions of bulky acids with
bulky amines still prove to be challenging. Therefore, continu-
ing efforts are being made to develop more efficient coupling
reagents such as aminium salts,1 phosphonium salts,2 halo-
uronium or halophosphonium salts,3 reagents forming mixed
anhydrides,4 hydroxamic acid-type reagents,5 additives6 and so
on.7 Utilization of a phosphate derivative as a component of a
mixed anhydride has been a promising methodology for an effi-
cient coupling reagent, in which an appropriate leaving group
such as chloro,8 azide,9 cyano,10 heterocyclic,11 and phosphate12
is attached. A more powerful but less nucleophilic leaving
group should provide much more efficient phosphate coupling
reagents. We examined trifluoromethanesulfonanilide13 as the
leaving group, since this group has proven its ability as a chemo-
selective and rapid alkoxycarbonylation reagent.14 We describe
herein that diethyl phosphate 1 bearing trifluoromethanesulfon-
anilide as a leaving group is a new rapid and efficient amide
and peptide coupling reagent.
Successive treatment of trifluoromethanesulfonanilide with
sodium hydride in THF at room temperature for 1 h and then
with diethyl chlorophosphate at room temperature for 2 days
and purification by silica gel column chromatography gave 115
in 90% yield.
The coupling reaction of 2-phenylethylamine 2 with 1.5
equiv. of acetic acid proceeded smoothly using 1.2 equiv. of 1 in
the presence of 2 equiv. of triethylamine in dichloromethane
at room temperature for 0.5 h. The mixture was washed with
As a touchstone for coupling of sterically hindered amines
and carboxylic acids, Z-Aib-OH 8 (Aib = 2-aminoisobutyric
acid) and H-Aib-OMe hydrochloride 9 were treated with 1 in the
presence of 4 equiv. of diisopropylethylamine and 1 equiv. of
1-hydroxy-7-azabenzotriazole (HOAt)18 in DMF for 24 h to
afford Z-Aib-Aib-OMe 10 in satisfactory 70% yield (Scheme 1).
These satisfactory results indicate versatility of 1 as a coupling
reagent.
Table 1 Effects of base and solvent on coupling of AcOH and 2 using 1
Entry
Base
Et3N
Solvent
AcOH (equiv.)
Time/min
3 (%)
4 (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
DMF
CH2Cl2
DMF
CH2Cl2
DMF
MeCN
MeOH
1.5
2.0
2.0
1.5
2.0
1.5
2.0
1.5
2.0
30
30
10
30
10
30
10
30
720
95
99
93
96
88
97
98
97
99
5
0
7
0
12
0
0
0
0
2,6-lutidine
DOI: 10.1039/b004264l
J. Chem. Soc., Perkin Trans. 1, 2000, 2901–2902
This journal is © The Royal Society of Chemistry 2000
2901

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Table 2 Coupling reaction of amine 5 with carboxylic acid 6 using 1
Synthesis, 1984, 572; (b) R. Knorr, A. Trzeciak, W. Bannwarth and
D. Gillessen, Tetrahedron Lett., 1989, 30, 1927; (c) S. Chen and
J.-C. Xu, Tetrahedron Lett., 1992, 33, 647; (d) Z. J. Kaminski,
P. Paneth and J. Rudzinski, J. Org. Chem., 1998, 63, 4248;
(e) M. Kunishima, C. Kawachi, F. Iwasaki, K. Terao and S. Tani,
Tetrahedron Lett., 1999, 40, 5327; ( f ) P. Li and J.-C. Xu, Tetrahedron
Lett., 2000, 41, 721.
2 (a) B. Castro and J. R. Dormoy, Tetrahedron Lett., 1973, 3243;
(b) J. Cost, D. Le-Nguyen and B. Castro, Tetrahedron Lett., 1990, 31,
205.
Entry
R1
R2
R3
Time/h
7 (%)
3 (a) J. Coste, M.-N. Dufour, A. Pantaloni and B. Castro, Tetrahedron
Lett., 1990, 31, 669; (b) J. Coste, E. Frérot and P. Jouin, Tetrahedron
Lett., 1991, 32, 1967; (c) K. Akaji, N. Kuriyama and Y. Kiso, Tetra-
hedron Lett., 1994, 35, 3315; (d) A. El-Faham, Chem. Lett., 1998,
671.
4 (a) J. R. Vaughan and R. L. Osato, J. Am. Chem. Soc., 1951, 73,
5553; (b) R. D. Tung, M. K. Dhaon and D. H. Rich, J. Org. Chem.,
1986, 51, 3350; (c) I. J. Galpin, A. K. A. Mohommed and A. Patel,
Tetrahedron, 1988, 44, 1685.
5 (a) G. H. L. Nefkens and G. F. Tesser; J. Am. Chem. Soc., 1961, 83,
1263; (b) G. W. Anderson, J. E. Zimmerman and F. H. Callahan,
J. Am. Chem. Soc., 1963, 85, 3039; (c) W. König and R. Geiger,
Chem. Ber., 1970, 103, 2024; (d) M. Fujino, S. Kobayashi,
M. Obayashi, T. Fukuda, S. Shinagawa and O. Nishimura, Chem.
Pharm. Bull., 1974, 22, 1857; (e) W. König and R. Geiger, Chem.
Ber., 1973, 106, 3626.
1
2
3
4
5
6
7
8
9
Ph(Me)CH
t-Bu
PhCH2
Ph
H
H
Me
H
Me
H
H
H
H
H
Me
Me
Me
Me
Me
i-Pr
t-Bu
Ph
0.5
8.0
1.0
4.0
6.0
0.5
0.5
1.0
8.0
8.0
24.0
93
89
96
92
99
97
93
95
77
80
92
Ph
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
t-Bu
t-Bu
t-Bu
i-Pr
t-Bu
Ph
10
11
H
6 W. König and R. Geiger, Chem. Ber., 1970, 103, 788.
7 (a) J. M. Humphrey and A. R. Chamberlin, Chem. Rev., 1997, 97,
2243; (b) F. Albericio, J. M. Bofill, A. El-Fahan and S. A. Kates,
J. Org. Chem., 1998, 63, 9678.
8 A. G. Jackson, G. W. Kenner, G. A. Moore, R. Ramage and
W. D. Thorpe, Tetrahedron Lett., 1976, 3627.
9 (a) T. Shioiri, N. Ninomiya and S. Yamada, J. Am. Chem. Soc., 1972,
86, 6203; (b) S. Yamada and N. Ikota and T. Shioiri, J. Am. Chem.
Soc., 1975, 89, 7174.
10 S. Yamada, Y. Kasai and T. Shioiri, Tetrahedron Lett., 1973,
1595.
Scheme 1 Coupling reaction of 2-aminoisobutyric acid using 1.
Phosphate 1 was also applicable for a peptide coupling reac-
tion. Treatment of Bz-Leu-OH and H-Gly-OEt hydrochloride
with 1 in the presence of proton sponge in DMF at room
temperature for 30 min gave Bz-Leu-Gly-OEt in 85% yield
(Young’s test).19 The extent of racemization of the peptide was
determined to be 2%.20
In summary, based on excellent performance in coupling of
bulky amines and carboxylic acids as well as low racemization
in peptide coupling, the new phosphate 1 activated by trifluoro-
methanesulfonanilide was shown to be a promising reagent for
coupling reactions.
11 T. Kunieda, T. Higuchi, Y. Abe and M. Hirobe, Tetrahedron, 1983,
39, 3253.
12 H. Wissmann and H.-J. Kleiner, Angew. Chem., Int. Ed. Engl., 1980,
19, 133.
13 R. D. Trepka, J. K. Harrington and J. W. Belise, J. Org. Chem., 1974,
39, 1094.
14 T. Yasuhara, Y. Nagaoka and K. Tomioka, J. Chem. Soc., Perkin
Trans. 1, 1999, 2233.
15 The compound
1 is a storable colorless oil which is stable
under atmospheric conditions at room temperature. On the other
hand, our attempt to convert N-4-trifluoromethylphenyltrifluoro-
methanesulfonamide with diethyl phosphorochloridate to the corre-
sponding phosphate failed probably because of its instability.
16 A. Heymes and I. Chekron, Synthesis, 1987, 245.
17 R. W. Alder, P. S. Bowman, W. R. S. Steele and D. R. Winterman,
J. Chem. Soc., Chem. Commun., 1968, 723.
Acknowledgements
We gratefully acknowledge financial support from the Ministry
of Education, Science, Sports, and Culture, Japan.
18 L. A. Carpino, J. Am. Chem. Soc., 1993, 115, 4397.
19 M. W. Williams and G. T. Young, J. Chem. Soc., 1963, 881.
Specific rotation of reported Bz-Leu-Gly-OEt: [α]D20 Ϫ34.0 (c 3.1,
EtOH).
Notes and references
20 Specific rotation of synthesized Bz-Leu-Gly-OEt: [α]D20 Ϫ33.3 (c 2.00,
EtOH).
1 (a) V. Dourtoglou, B. Gross, V. Lambropoulou and C. Zioudrou,
2902
J. Chem. Soc., Perkin Trans. 1, 2000, 2901–2902