A novel route to dipeptides via noncondensation of amino acids: 2-Aminoperfluoropropene as a synthon for trifluoroalanine dipeptides

Article abstract of DOI:10.1021/ol0526726

2-Aminoperfluoropropene has been prepared by the Mg-promoted defluorinative N-silylation of N-p-methoxyphenyl hexafluoroacetone imine and has been employed as a synthon of trifluoroalanine for the preparation of trifluoroalanine dipeptides.

Full text of DOI:10.1021/ol0526726

ORGANIC
LETTERS
2006
Vol. 8, No. 5
827-829
A Novel Route to Dipeptides via
Noncondensation of Amino Acids:
2-Aminoperfluoropropene as a Synthon
for Trifluoroalanine Dipeptides
Yong Guo, Kana Fujiwara, and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama UniVersity,
Okayama 700-8530, Japan
uneyamak@cc.okayama-u.ac.jp
Received November 3, 2005
ABSTRACT
2-Aminoperfluoropropene has been prepared by the Mg-promoted defluorinative N-silylation of N-p-methoxyphenyl hexafluoroacetone imine
and has been employed as a synthon of trifluoroalanine for the preparation of trifluoroalanine dipeptides.
The chemistry and science of peptides and their related
molecules have been increasingly developed over several
decades due to their potential biological activities, and thus,
a number of non-natural peptides and peptidomimetics have
been designed and synthesized to gain the advantages of
increased bioactivity, biostability, and bioselectivity over
those of natural peptides.1 On this basis, highly efficient
peptide-bond formations have been increasingly needed to
enable the synthesis of more complex, newly functionalized,
and/or structurally new peptides. So far, peptide bonds have
been prepared mostly by condensation of amino acids. The
rational activation of the carboxyl group of one amino acid
followed by condensation with another amino ester2 or ring
opening of â-lactams with amino esters3 has been used. Both
enzymatic4 and chemical5 activations have been commonly
employed for the condensation. But, very few methods for
the noncondensation-type peptide synthesis have been known.6
A novel peptide synthesis method, in which C-N bond
formation mechanism is totally different from the conven-
tional condensation of two kinds of amino acids, would open
a door into the field of structurally unique and highly
functionalized peptides, which would create unique biological
activities yet unknown.
Here, we propose â,â-difluoroenamines 1 as general syn-
thons for dipeptides 2 (Scheme 1) and describe, in particular,
Scheme 1
(1) (a) Barrett, G. C., Eds. Amino Acid DeriVatiVes; Oxford University
Press: Oxford, 1999. (b) Abell, A., Eds. AdVances in Amino Acid Mimetics
and Peptidomimetics; JAI Press, Inc.: Greenwich, 1997.
(2) (a) Jones, J. Amino Acid and Peptide Synthesis; Oxford University
Press: Oxford, 1992. (b) Kusumoto, S., Eds. Experimental Chemistry, 4th
ed.; Maruzen: Tokyo, 1990; No. 22. (c) Hodgson, D. R. W.; Sanderson, J.
M. Chem. Soc. ReV. 2004, 33, 422-430.
(3) Ojima, I.; Delaloge, F. Chem. Soc. ReV. 1997, 26, 377-380.
(4) (a) Schellenberger, V.; Jakubke, H. D.; Fachbereich, B. Angew. Chem.
1991, 103, 1440-1452. (b) Murakami, Y.; Hirata, A. J. Biol. Chem. (in
Japanese, Seibutsu Kogaku Kaishi) 1998, 76, 238-254.
10.1021/ol0526726 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/02/2006

a preparation of 2-aminoperfluoropropene 7 and its trans-
formation to trifluoroalanine dipeptides 8 (Scheme 2).
Scheme 3
Scheme 2
The enamine 7 is stable enough to be easily handled and
can be stored at -5 °C, but it is very reactive even with the
less nucleophilic amino group of amino esters due to the
strong electron-withdrawing effect of gem-difluoromethylene
and trifluoromethyl groups. Thus, 7 reacted very smoothly
with amino esters in DMF at room temperature within 1.5
h, affording the desired trifluoroalanine dipeptides 11 as a
diastereomeric mixture16 after the subsequent acid-catalyzed
hydrolysis of the intermediate imidoyl fluoride (Scheme 4).17
Oligopeptides and peptidomimetics of fluorinated amino
acids7 show interesting biological activities as potent enzyme
inhibitors, but very limited numbers of these peptides8 and
related mimetics9 have been prepared due to the lack of a
general synthetic method.
Difluoromethylene group 3 is a potential carbonyl equiva-
lent 4, and 1,1-difluoroalkenes 5 are synthons for carboester11
and carboamide12 groups since they provide the correspond-
ing ketones, carboxylic acids, esters, and amides, respec-
tively, on treating them under hydrolytic conditions.
On this basis, 2-amino-1,1-difluoroalkenes 1, if available,
should react with the amino group of amino esters at the
highly activated difluoromethylene site and give, in principle,
dipeptides 2 on treating them with amino esters under the
addition and the subsequent hydrolytic conditions.
We communicate here a preparation of 7 (Ar ) p-
MeOC6H4) and its one-pot transformation to trifluoroalanine
dipeptides by the reaction with amino esters to demonstrate
the enamine 7 as a synthon of trifluoroalanine. The present
route, which is totally different from the conventional
condensation of two kinds of amino acids, enables the C-N
bond formation for peptide synthesis under very mild
conditions (Scheme 3 and 4).
Scheme 4
The key compound 7 was prepared in an excellent yield
(95%, 100 mmol scale) by the magnesium-promoted deflu-
orinative N-silylation13 of imine 914 in an Mg-TMSCl-THF
system at 0 °C.15
Table 1 summarizes the results of dipeptide synthesis.
Most of the amino esters 10 reacted with 7 smoothly,
affording dipeptides 11 in good to excellent yields.
Interestingly, serine 10e and tyrosine 10f esters reacted
exclusively at the amino site rather than the hydroxyl site
even when the amino esters were employed without protect-
ing the hydroxyl group. The preferred reactivity of the amino
(5) Bordusa, F.; Dahl, C.; Jakubke, D.-D.; Burger, K.; Koksch, B.
Tetrahedron: Asymmetry 1999, 10, 307-313.
(6) Synthesis of phenylalanine-trifluoroalanine dipeptide via N-H inser-
tion of ketocarbene from methyl 2-azo-3,3,3-trifluoropropionate: Osipov,
S. N.; Sewald, N.; Kolomiets, A. F.; Fokin, A. V.; Burger, K. Tetrahedron
Lett. 1996, 37, 615-618.
(7) Welch, J. T.; Gyenes, A.; Jung, M. J. In Fluorine-containing Amino
Acids; Kukhar, V. P., Soloshonok, V. A., Eds.; John Wiley & Sons:
Chichester, 1995; Chapter 9. Sham, H. L. In Fluorine-containing Amino
Acids; Kukhar, V. P., Soloshonok, V. A., Eds.; John Wiley & Sons:
Chichester, 1995; Chapter 10. Kirk, K. L. In Fluorine-containing Amino
Acids; Kukhar, V. P., Soloshonok, V. A., Eds.; John Wiley & Sons:
Chichester, 1995; Chapter 11.
(8) Hoss, E.; Rudolph, M.; Seymour, L.; Schierlinger, C.; Burger, K. J.
Fluorine Chem. 1993, 61, 163-170.
(9) Sani, M.; Bruche, L.; Chiva, G.; Fustero, S.; Piera, J.; Volonterio,
A.; Zanda,M. Angew. Chem., Int. Ed. 2003, 42, 2060-2063.
(10) Ferraris, D.; Cox, C.; Anand, R.; Leckea, T. J. Am. Chem. Soc.
1997, 119, 4319-4325.
(13) (a) Mae, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2000, 41,
7893-7896. (b) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem.
Commun. 1999, 1323-1324.
(14) Middleton, W, J.; Krespan, C. G. J. Org. Chem. 1965, 30, 1398-
1402.
(15) 2-N-Phenylaminoperfluoropropene was prepared in 43-83% yields
by reduction of N-phenylacetoneimine with either zinc or alkyl Grignard
reagents. (a) Zeifman, Y. V.; Vol’pin, I. M.; Postovoi, S. A.; German, L.
S. Y. V. IzV. Akad. Nauk SSSR, Ser. Khim. 1987, 2396-2397; Chem Abstr.
1988, 109, 54292. (b) Zeifman, Y. V. IzV. Akad. Nauk SSSR, Ser. Khim.
1990, 202-205, Chem Abstr. 1990, 113, 40035
(16) The absolute stereochemistry (R) or (S) of the trifluoroalanine site
of both major and minor diastereomers has not been determined except for
11c.
(17) Imidoyl fluoride (R-CFdNAr) was isolated as an intermediate which
was easily hydrolyzed to the corresponding amide under the hydrolysis
conditions. The trifluoroalanine dipeptides were stable under the acidic
conditions employed in the hydrolysis except phenylalanine dipeptide which
showed 6% epimerization at the phenyalanine side.
(11) Ishikawa, N.; Takaoka, A.; Iwakiri, H.; Kubota, S.; Kagaruki, S.
R. F. Chem. Lett. 1980, 1107-1110.
(12) (a) Bailey, P. D.; Boa, A. N.; Crofts, G. A.; Vandiepen, M.;
Helliwell, M.; Gamman, R. E.; Harrison, M. J. Tetrahedron Lett. 1989, 30,
7457-7460. (b) England, D. C.; Melby, L. R.; Dietrich, M. A.; Lindsey,
R. V., Jr. J. Am. Chem. Soc. 1960, 82, 5116-5122.
828
Org. Lett., Vol. 8, No. 5, 2006

nitrate in MeCN-H2O at room temperature18 to give the
deprotected dipeptides 16 (16a; R1 ) H, R2 ) Bn, 83%,
16c; R1 ) PhCH2, R2 ) Et, 80%). The diastereoisomers of
dipeptides 16c (R1 ) PhCH2, R2 ) Et) could be easily
separated and isolated as an enantiomerically pure form by
column chromatography. The absolute stereochemistry of the
major diastereomer 16c was clarified by X-ray crystal-
lographic analysis of the single crystal of its hydrochloric
acid salt. This is the first example of preparation of the
enantiomerically pure (R,S) and (S,S) trifluoroalanine-
phenylalanine dipeptides (Scheme 6).
Table 1. Synthesis of Trifluoroalanine Dipeptides by the
Reaction of 7 with Amino Esters 10a
Scheme 6
It is suggested the present protocol would be promising
for the construction of peptide skeletons and applicable for
the preparation of a variety of trifluoroalanine dipeptides in
an enantiomerically pure form, although 1,4-asymmetric
induction of the chiral center of amine esters to the R-carbon
atom in trifluoroalanine moiety has remained unsolved at
this moment. Study on the generality for the syntheses of
di- and oligopeptides by the present method and 1,4-
asymmetric induction are under active investigation.
a Diastereomeric ratios were analyzed by HPLC.
group to 7 over the hydroxyl group is also revealed by the
fact that the competitive reaction of 7 with a mixture of
equimolar amounts of both benzylamine and benzyl alcohol
provided exclusively benzyl amide 14 of trifluoroalanine in
98% isolated yield and none of the corresponding benzyl
ester (Scheme 5).
Acknowledgment. This work has been supported by the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan (Grant-in-Aid for Scientific Research(C), No.
17550104). We also thank Dr. Toshimasa Katagiri (Okayama
University) and Dr. Masahiko Bandou (Otsuka Pharmaceuti-
cal Co. Ltd.) and the VBL Laboratory of Okayama University
for the X-ray crystallographic analysis.
Scheme 5
Supporting Information Available: Experimental details
for the syntheses of compounds 7, 9, 11a-i, and 16c and
X-ray crystallographic analysis of compound 16c hydro-
chloride. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0526726
The N-protecting group, p-methoxyphenyl, was readily
removed by the oxidation of 11 with cerium ammonium
(18) Sakai, T.; Yan, F.; Uneyama, K. Synlett 1995, 753-754.
Org. Lett., Vol. 8, No. 5, 2006
829