Because the amide and carbamate functional groups were
intact, we next targeted the application of the NaOMe-catalyzed
amidation to peptide-coupling reactions, in which epimerization
of a-amino acid derivatives was a major problem under such
basic conditions. In fact, the reaction of Boc-Phe-OMe (1s, 99% ee)
and 2a under the optimized conditions resulted in epimerization
of the corresponding benzyl amide 3sa (Table 2, entry 1, 2% ee).
This severe epimerization was successfully rectified by the
addition of rather acidic alcohols such as 2,2,2-trifluoroethanol
(entry 2) and various phenols (entries 3–11) to manipulate the
basicity of NaOMe. As expected, both enantiomeric excess
and yield of the product 3sa correlated well with the pKa
values of the added alcohols;12 the increased acidity of the
added alcohol increased the enantiomeric excess of the product
and decreased the yield. Among the tested conditions, a
mixture of 10 mol% of NaOMe and 30 mol% of 4-trifluoro-
methylphenol (4g) was selected as the best catalytic condition
to maintain a good balance between enantiomeric excess and
yield of the product 3sa (entry 11, 81%, 97% ee). With the
optimized catalyst system for a-amino esters in hand, we
conducted catalytic amidation of various N-Boc protected
chiral a-amino esters with benzylamine (2a). The reactions
of a-alkyl substituted amino methyl esters 1t–w afforded the
corresponding amides in high yield without epimerization
(entries 12–15). Furthermore, chiral a-amino esters with func-
tional groups in the side-chain could be used as substrates. A
thioether functionality on the methionine (1x) did not disrupt
the amidation reaction and the desired product 3xa was
obtained in good yield without epimerization (entry 16). The
side-chain carboxyl group on glutamic acid protected by a
standard tertiary butyl ester did not participate in the present
NaOMe-catalyzed reaction, and only the main-chain methyl
ester of Boc-Glu(OtBu)-OMe (1y) was converted to benzyl-
amide (entry 17).
To the best of our knowledge, this is the first example of a
catalytic peptide coupling reaction without the need for enzymatic
methods, and provides a new convenient synthetic protocol for
the synthesis of various peptides with the advantages of being
nontoxic, catalytic, and environmentally benign.
In conclusion, we present a simple, but highly efficient,
NaOMe catalyst for the direct amidation of esters with amines
with a wide variety of functional groups, as the first catalytic
amidation reaction under mild conditions. Notably, the catalyst
is a combination of NaOMe and 4-trifluoromethylphenol that
serves as a unique artificial peptidyl transferase to mediate the
peptide coupling reactions by precluding epimerization.
This work was supported by CREST from JST. We also
appreciate partial financial support from Grant-in-Aid for
Scientific Research (B) from MEXT, Takeda Science Foundation,
and Uehara Memorial Foundation. Y.H. thanks Global COE
Program ‘Global Education and Research Center for Bio-
Environmental Chemistry’ of Osaka University and JSPS
Research Fellowship.
Notes and references
1 For reviews, see: (a) Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon Press, New York, 1992,
vol. 6; (b) R. C. Larock, Comprehensive Organic Transformations,
Wiley-VCH, New York, 2nd edn, 1999; (c) M. B. Smith, Compen-
dium of Organic Synthetic Methods, Wiley, New York, 2001, vol. 9,
pp. 100; (d) C. A. G. N. Montalbetti, V. Falque and M. Park,
Tetrahedron, 2005, 61, 10827.
2 (a) J. L. Hansen, T. M. Schmeing, P. B. Moore and T. Steitz, Proc.
Natl. Acad. Sci. U. S. A., 2002, 99, 11670; (b) M. Beringer and
M. V. Rodnina, Mol. Cell, 2007, 26, 311; (c) K. Watanabe, Y. Toh,
K. Suto, Y. Shimizu, N. Oka, T. Wada and K. Tomita, Nature,
2007, 449, 867.
3 (a) K. Ishihara, Y. Kuroki, N. Hanaki, S. Ohara and H. Yamamoto,
J. Am. Chem. Soc., 1996, 118, 1569; (b) Y. Kuroki, K. Ishihara,
N. Hanaki, S. Ohara and H. Yamamoto, Bull. Chem. Soc. Jpn., 1998,
71, 1221.
4 C. Han, J. P. Lee, E. Lobkovsky and J. A. Porco, Jr., J. Am. Chem.
Soc., 2005, 127, 10039.
5 M. Movassaghi and M. Schmidt, Org. Lett., 2005, 7, 2453.
Furthermore, the NaOMe–4g catalyst system was success-
fully applied to a peptide coupling reaction of Boc-Phe-OMe
(1s) and H-Gly-OtBu (2h) at 70 1C to afford dipeptide 3sh in
79% yield with 96% ee (Scheme 2). Although the reactivity
was lower than that of 2h, this catalysis was also applicable to
the reaction of 1s and H-Ala-OtBu (2i), giving the corres-
ponding coupling product 3si in 53% yield along with the
recovered 1s (39%) and only trace amounts of byproducts
(87% yield of 3si based on recovered starting materials).
6 K. E. Price, C. Larrivee-Aboussafy, B. M. Lillie, R. W.
´
McLaughlin, J. Mustakis, K. W. Hettenbach, J. M. Hawkins
and R. Vaidyanathan, Org. Lett., 2009, 11, 2003.
7 C. Sabot, K. A. Kumar, S. Meunier and C. Mioskowski, Tetra-
hedron Lett., 2007, 48, 3863.
8 X. Yang and V. B. Birman, Org. Lett., 2009, 11, 1499.
9 C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007,
317, 790.
10 B. Gnanaprakasam and D. Milstein, J. Am. Chem. Soc., 2011,
133, 1682.
11 T. Ohshima, T. Iwasaki, Y. Maegawa, A. Yoshiyama and
K. Mashima, J. Am. Chem. Soc., 2008, 130, 2944.
12 For details, see ESIw.
13 (a) R. A. Sheldon, Chem. Ind., 1992, 903; (b) R. A. Sheldon, Chem.
Ind., 1997, 12; (c) R. A. Sheldon, Pure Appl. Chem., 2000, 72, 1233;
(d) M. Poliakoff, J. M. Fitzpatrick, T. R. Farren and P. T. Anastas,
Science, 2002, 297, 807.
14 (a) J. Otera, Chem. Rev., 1993, 93, 1449; (b) H. E. Hoydonckx,
D. E. De Vos, S. A. Chavan and P. A. Jacobs, Top. Catal., 2004, 27, 83.
15 (a) J. Bunnett and G. Davis, J. Am. Chem. Soc., 1960, 82, 665;
(b) R. J. De Feoand and P. D. Strickler, J. Org. Chem., 1963,
28, 2915.
16 (a) R. S. Varma and K. P. Naicker, Tetrahedron Lett., 1999,
40, 6177; (b) L. Perreux, Tetrahedron, 2003, 59, 2185.
Scheme 2 Peptide coupling reactions catalysed by NaOMe–4g.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.