Simultaneous protection and activation of amino acids using propargyl pentafluorophenyl carbonate

Article abstract of DOI:10.1021/ol060494q

A very efficient method for the simultaneous protection of the amino group and activation of the carboxyl group of amino acids is reported using propargyl pentafluorophenyl carbonate (PocOPfp). The amino group is protected as a propargyloxycarbonyl (Poc) derivative, and the carboxyl group is activated as a pentafluorophenyl ester. The yields obtained are good to excellent ranging from 60 to 87%.

Full text of DOI:10.1021/ol060494q

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1933-1936
Simultaneous Protection and Activation
of Amino Acids Using Propargyl
Pentafluorophenyl Carbonate
Ramapanicker Ramesh, Sakthidevi Rajasekaran, Rohit Gupta, and
Srinivasan Chandrasekaran*,†
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
scn@orgchem.iisc.ernet.in
Received February 28, 2006
ABSTRACT
A very efficient method for the simultaneous protection of the amino group and activation of the carboxyl group of amino acids is reported
using propargyl pentafluorophenyl carbonate (PocOPfp). The amino group is protected as a propargyloxycarbonyl (Poc) derivative, and the
carboxyl group is activated as a pentafluorophenyl ester. The yields obtained are good to excellent ranging from 60 to 87%.
The most important steps involved in peptide synthesis are
protection of the R-amino group and activation of the
R-carboxylic acid group. The efficiency and simplicity of
peptide synthesis relies on the strategies employed in
achieving these two steps. The most commonly used strate-
gies in peptide synthesis involve protection of the R-amino
group in an early step, activation of the carboxylic acid
group, and coupling with the amino group of the subsequent
amino acid in a later step. Protection of the amino acids is
usually done by converting them to carbamates, and the
carboxylic acid groups are activated either during the
coupling step using various coupling reagents or in a different
step as an active ester. Pentafluorophenyl esters, prepared
from the carboxylic acids and pentafluorophenol using DCC
or EDC, are the most common active esters used in this
regard.1 It is a definite advantage over existing strategies, if
protection and activation of amino acids can be achieved in
the same step. Suto and Gayo2 have studied the possibilities
of simultaneous protection and activation of amino and thiol
carboxylic acids using trifluoroacetyl pentafluorophenolate
(TFAOPfp). They could achieve good yields in the protection
of amino group as a trifluoroacetamide and the activation
of carboxylic acid group as a pentafluorophenyl ester. Their
efforts to use 9-fluorenylmethylpentafluorophenyl carbonate
(FmocOPfp) for simultaneous protection and activation was
limited to just one substrate, o-aminobenzoic acid, and was
not advantageous, requiring 6 equiv of the reagent. Rao and
co-workers3 have studied the use of N-trifluoroacetoxysuc-
cinimide (TFAOSu) for simultaneous protection and activa-
tion of amino acids. Though they have reported good yields,
their study is limited to unnatural amino acids, which are
soluble in a mixture of dichloromethane and pyridine and
required 6 equiv of the reagent. Thus, the two available
reports on simultaneous protection and activation of amino
acids are limited to a few unnatural amino acids, and the
protection of the amino group is achieved by converting it
to a trifluoroacetamide, which is seldom used in standard
peptide synthesis protocols.
An earlier report from our laboratory has shown that
propargyl pentafluorophenyl carbonate (PocOPfp, 1) can be
† Honorary Professor, Jawaharlal Nehru Centre for Advanced Scientific
Research, Bangalore, India.
(1) Bodanszky, M. Principles of Peptide Synthesis, 2nd ed.; Springer-
Verlag: Berlin, 1993.
(2) Gayo, L. M.; Suto, M. J. Tetrahedron Lett. 1996, 37, 4915.
(3) Rao, T. S.; Nampalli, S.; Sekher, P.; Kumar, S. Tetrahedron Lett.
2002, 43, 7793.
10.1021/ol060494q CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/04/2006

used as an efficient reagent for the protection of amino acids
as their propargyl carbamates (Scheme 1).4
Table 1. Preparation of Pentafluorophenyl Esters Using
PocOPfp
Scheme 1. Poc Protection of Amino Acids Using PocOPfp
The propargyloxycarbonyl group (Poc), which can be
cleaved using benzyltriethylammonium tetrathiomolybdate
2, has been shown to be an excellent protecting group for
amines, and its application in solution-phase peptide synthesis
is documented.5 The application of N-Poc-protected pen-
tafluorophenyl esters of amino acids in peptide coupling has
also been addressed.4 We report here the results of our studies
to use 2 equiv of PocOPfp for the simultaneous protection
and activation of amino acids yielding a Poc-protected amino
group and an activated pentafluorophenyl ester of the
carboxylic acid (Scheme 2).
a Pyridine (1.1 equiv) was added to a solution of the N-protected amino
acid dissolved in CH2Cl2, PocOPfp (1.2 equiv) was added at 0 °C, the
temperature was raised to rt, and the mixture was stirred for 3 h.
(Table 1). Preparation of pentafluorophenyl esters of N-
protected amino acids using trifluoroacetyl pentafluorophe-
nolate has been reported,6 and we find that the method using
PocOPfp is equally efficient.
Having established that PocOPfp (1) can activate car-
boxylic acids as pentafluorophenyl esters and that 1 is an
excellent reagent for the protection of amino groups as Poc
derivatives,4 the simultaneous protection and activation of
amino acids with PocOPfp looked feasible.
Scheme 2. Simultaneous Protection and Activation of Amino
Acids Using PocOPfp
We initiated our studies with m-aminobenzoic acid (5a),
which on treatment with 1 (2.1 equiv, DMF/pyridine, 3 h, 0
°C to rt) yielded the protected and activated compound 6a
in 92% yield (Scheme 4). o-Aminobenzoic acid 5b under
Scheme 4. Simultaneous Protection and Activation of
m-Aminobenzoic Acid with PocOPfp
Before attempting simultaneous protection and activation
of amino acids, we tried to prepare pentafluorophenyl esters
of N-protected amino acids using PocOPfp to ensure that
PocOPfp can activate carboxylic acids by forming the
corresponding pentafluorophenyl esters.
Treating Boc-Pro-OH, 3a, with PocOPfp (1.1 equiv, 3 h,
CH2Cl2, pyridine, 0 °C to rt) yielded the corresponding
pentafluorophenyl ester 4a in 88% yield (Scheme 3). We
Scheme 3. Activation of Carboxylic Acid Using PocOPfp
the same reaction conditions afforded the N-protected and
C-activated compound 6b in 90% yield (Table 2). Encour-
aged by this success, this methodology was extended to a
number of natural R-amino acids. Accordingly, when L-leu-
cine 5c was treated with PocOPfp in the presence of pyridine
in DMF, 6c was isolated in 82% yield (Scheme 5).
The results of N-protection and C-activation of a number
of amino acids with 1 are summarized in Table 2. The yields
were very good, ranging from 60% to 87% (Table 2).
It was interesting to note that R-amino acids having alkyl
side chains yielded the N-protected active esters in better
carried out the activation of two other N-protected amino
acids (3b,c) using PocOPfp and the corresponding pentafluo-
rophenyl esters (4b,c) could be obtained in excellent yields
(4) Bhat, R. G.; Kerouredan, E.; Porheil, E.; Chandrasekaran, S.
Tetrahedron Lett. 2002, 43, 2467.
(5) Bhat, R. G.; Sinha, S.; Chandrasekaran, S. Chem. Commun. 2002,
812.
(6) Green, M.; Berman, J. Tetrahedron Lett. 1990, 31, 5851.
Org. Lett., Vol. 8, No. 9, 2006
1934

Scheme 5. Simultaneous Protection and Activation of
Table 2. Simultaneous Protection and Activation of Amino
Acids Using PocOPfp
L-Leucine with PocOPfp
yield than other amino acids (entries 3-6, 9, 10). Surpris-
ingly, the yield of Poc-Ala-OPfp (6d) was lower than that
of Poc-Leu-OPfp (6c), Poc-Val-OPfp (6e), and Poc-Ile-OPfp
(6f). Most interestingly and quite surprisingly, the more
hindered aminoisobutyric acid (5j) yielded Poc-Aib-OPfp (6j)
in 76% yield. The reaction of unnatural amino acids
3-aminopropanoic (5k) and 4-aminobutyric acid (5l) and
L-phenylglycine (5m) under these conditions with 1 yielded
the corresponding N-protected active esters in 60%, 68%,
and 75% yields, respectively. When R-amino-protected lysine
(5n) was used for the reaction, the fully protected active ester
Cbz-Lys(Poc)-OPfp (6n) was obtained in 76% yield. Reac-
tion of lysine (5o) with 3.1 equiv of 1 afforded the fully
protected active ester Poc-Lys(Poc)-OPfp (6o) in 57% yield.
Similarly, when glutamic acid (5p) was treated with 3.1 equiv
of 1, the N-protected active diester Poc-Glu(Pfp)-OPfp (6p)
was obtained in 62% yield. The optical rotation values of
the pentafluorophenyl esters were found to match with the
values for those prepared previously4 in two steps, suggesting
that there is no racemization during the simultaneous
protection and activation.
The success with PocOPfp on the simultaneous protection
and activation of amino acids prompted us to study a similar
application of N-propargyloxycarbonyloxysuccinimide,
PocOSu (7). PocOSu was prepared by treating N-hydroxy-
succinimide with PocCl in the presence of triethylamine
(Scheme 6).
Scheme 6. Preparation of PocOSu
As with PocOPfp, we initially attempted to prepare
N-succinimidyl active esters of N-protected amino acids using
PocOSu (7). Treating Boc-Leu-OH (3b) with 1.1 equiv of 7
did not give the expected active ester; instead, the corre-
sponding propargyl ester 8 was isolated in 15% yield after
24 h (Scheme 7). Though the formation of 8 was unexpected,
it was not surprising as the esterification of carboxylic acids
using chloroformates in the presence of a base is well
documented.7 We believe that, in this case, PocOSu acts more
like propargyl chloroformate and results in the formation of
the propargyl ester of 3b rather than the expected active ester.
a Except where otherwise noted, PocOPfp (2.1 equiv) was added to a
suspension of the amino acid and pyridine (2.1 equiv) in DMF at 0 °C and
the reaction mixture was allowed to attain room temperature and stirred
for 3-5 h. b 3.1 equiv of PocOPfp and pyridine were used.
(7) Kim, S.; Lee, J. I.; Kim, Y. C. J. Org. Chem. 1985, 50, 560.
Org. Lett., Vol. 8, No. 9, 2006
1935

activation of amino acids, PocOSu (7) is not useful to achieve
the same goal.
Scheme 7. Reaction of PocOSu with Boc-Leu-OH
In conclusion, we have developed a very effective
methodology for the simultaneous protection and activation
of R-amino acids using PocOPfp (1). The method described
here is better than all the previously reported methods as it
allows the protection of amino group as a propargyloxycar-
bonyl (Poc) derivative, which can be deprotected using 2,
and has found its place as an amino protecting group in
peptide synthesis. The products are obtained in good to
excellent yields. The protection and activation of amino acids
containing more than one amino or carboxylic acid groups
are also possible. However, efforts toward extending this
methodology using PocOSu (7) were unsuccessful.
Reaction of m-aminobenzoic acid 5a with 2.1 equiv of
PocOSu in the presence of pyridine yielded only the
N-protected carboxylic acid 9 and the propargyl ester 10
instead of the expected N-protected active ester after 24 h
(Scheme 8). These observations suggest that while PocOPfp
can be used successfully for simultaneous protection and
Acknowledgment. R.R. thanks CSIR, New Delhi, for a
Senior Research Fellowship.
Scheme 8. Reaction of PocOSu with m-Aminobenzoic Acid
Supporting Information Available: Full experimental
1
details, characterization data, and H, 13C, and 19F NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL060494Q
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Org. Lett., Vol. 8, No. 9, 2006