Synthesis and applications of propargyl pentafluorophenyl carbonate for peptide synthesis

Article abstract of DOI:10.1016/S0040-4039(02)00287-3

Propargyl pentafluorophenyl carbonate was synthesised in quantitative yield by the reaction of propargyl chloroformate and pentafluorophenol. All the N-propargyloxycarbonyl (N-Poc) amino acids were obtained in good yield. The use of Poc-OPfp in peptide synthesis has been explored.

Full text of DOI:10.1016/S0040-4039(02)00287-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2467–2469
Synthesis and applications of propargyl pentafluorophenyl
carbonate for peptide synthesis
Ramakrishna G. Bhat, Erwan Ke´roure´dan,† Emmanuel Porhiel and Srinivasan Chandrasekaran‡*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 7 January 2002; revised 30 January 2002; accepted 6 February 2002
Abstract—Propargyl pentafluorophenyl carbonate was synthesised in quantitative yield by the reaction of propargyl chlorofor-
mate and pentafluorophenol. All the N-propargyloxycarbonyl (N-Poc) amino acids were obtained in good yield. The use of
Poc-OPfp in peptide synthesis has been explored. © 2002 Elsevier Science Ltd. All rights reserved.
A number of protective groups have been developed for
the amino group for peptide and protein synthesis.
However, the development of more satisfactory protec-
tive groups and more effective methods for protection
and cleavage are still important in organic synthetic
methodology. The tempting possibility to build chains
by linking amino acids or peptides to each other and to
continue the build-up without isolation of intermediates
attracts wide interest. To prevent side reactions like
double acylation, either acidic additives such as 1-
hydroxybenzotriazole1 or else highly reactive penta-
fluorophenyl esters are used.2,3 In the last few years the
N-fluorenylmethoxycarbonyl (Fmoc) protective group
has become a useful tool for peptide chemistry. As the
Fmoc group is sensitive to mild base, premature
deblocking leading to multiple acylations is a major
drawback to its use. Scho¨n and Kisfaludy have intro-
duced and shown the utility of Fmoc-OPfp in peptide
synthesis4 and since then it has been extensively used
for the synthesis of glycopeptides.
Earlier work from our laboratory has shown the
efficiency of the propargyloxycarbonyl (Poc) group as a
new protecting group for alcohols, phenols as well as
amines and amino acids. The protective group was
selectively cleaved by benzyltriethylammonium tetra-
thiomolybdate [(PhCH2NEt3)2MoS4] under mild and
neutral conditions.5,6
O
O
O
a
b
Cl3C
O
Cl
O
Cl
Cl
Cl
OH
1
F
F
F
F
F
F
F
O
c
+
1
HO
F
O
O
F
F
2
Scheme 1. Reagents and conditions: (a) Et2O, C (activated), 0°C, 7 h. (b) Et2O, 0°C, 12 h. (c) NEt3, Et2O, 0°C, 7 h.
Keywords: amino acids; peptide synthesis; protecting groups; propargyl pentafluorophenyl carbonate; tetrathiomolybdate.
* Corresponding author. Fax: 91-80-3600529; e-mail: scn@orgchem.iisc.ernet.in
† Summer project trainee from the University of Rennes, France.
‡ Honorary Professor, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00287-3

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R. G. Bhat et al. / Tetrahedron Letters 43 (2002) 2467–2469
Results of this work led us to explore the use of N-Poc
amino acids for peptide synthesis via the activation of the
carboxylic group using pentafluorophenol. Here, we wish
to report the synthesis of propargyl pentafluorophenyl
carbonate (Poc-OPfp) 2 and its utility in peptide synthe-
sis. Poc amino acids and the synthesis of dipeptides have
been achieved by the use of propargyl pentafluorophenyl
carbonate 2. The reagent, Poc-OPfp, 2 can be easily
synthesised under mild conditions from propargyl chlo-
roformate (Poc-Cl) 1.7 It is a stable crystalline solid8
(Scheme 1) obtained in almost quantitative yield and is
better than Fmoc-OPfp in terms of thermal stability and
reactivity.9
The N-Poc amino acid pentafluorophenyl esters 4 were
prepared in excellent yields by the addition of EDC to
the solution of pentafluorophenol and the corresponding
N-Poc amino acids in acetonitrile at 0°C (Scheme 2)
(Table 1). In the initial studies, reactions were carried out
in two steps so as to characterise the intermediate
products. Subsequently it was demonstrated that liber-
ated pentafluorophenol in the first step can be used for
the synthesis of 4 in one pot so as to have a rapid
continuous process. All the peptides 5–8 were synthesised
by the addition of 4 to the suspension of amino acid in
H2O/acetone/DMF and sodium hydrogen carbonate
(−10°C, 15 min and then at 28°C, 30 min) (Scheme 3) and
were obtained in good yields (Table 1).10 Use of EDC
proved to be better as a coupling reagent than DCC in
our case as the reaction with DCC entailed a troublesome
work-up and low yield. All the peptides were enantiomer-
ically pure by chiral HPLC.11
A number of N-Poc amino acids 3 were synthesised in
very good yields (76–93%) by the addition of the reagent,
Poc-OPfp, 2 to the corresponding amino acids as a
suspension in sodium hydrogen carbonate in H2O/ace-
tone/DMF at −10°C (Table 1). Generally low yields were
obtained if the reactions were carried out at room
temperature (60–66%).
In conclusion, we have introduced propargyl penta-
fluorophenyl carbonate (Poc-OPfp) as a new reagent for
Table 1.
Amino acids
N-Poc-amino acids (3)
N-Poc-amino acid -Pfp esters (4)
N-Poc peptides (5)–(8)
yield (%)
yield (%)
yield (%)
a. Gln
b. Ile
84
83
89
93
84
80
89
93
Poc-Ile-Phe-OH (5)
Poc-Phe-Ala-OH (6)
95
89
90
90
c.
Phe
Poc-dl-Phe-Ala- (7)
OH
Poc-Val-Leu-OH (8)
d. Val
e.
f.
Ala
Leu
86
78
76
77
89
90
–
–
–
90
g. Pro
h. Ser
i.
dl-Phe
F
F
F
HO
F
F
O
R
F
O
b
a
O
F
F
R
+
+
2
O
N
H
OH
O
R
O
NH2
F
OH
O
N
H
F
O
4
3
4a. R = -CH2CH2CONH2
4d. R = -CH(CH3)2
4e. R = -CH3
4b. R = -CH(CH3)CH2CH3
4c. R = -CH2C6H5
Scheme 2. Reagents and conditions: (a) H2O/acetone/DMF, NaHCO3, −10°C, 1 h then rt, 3–16 h. (b) EDC, CH3CN, 0°C, 1 h then
rt, 3 h.

R. G. Bhat et al. / Tetrahedron Letters 43 (2002) 2467–2469
2469
F
F
HO
F
F
F
O
a
R1
4
+
+
OH
O
R
O
NH2
H
N
O
N
H
OH
O
R1
5. R = -CH(CH3)CH2CH3, R1 = -CH2C6H5
6. R = -CH2C6H5, R1 = -CH3
7. R = -CH2C6H5 (rac), R1 = -CH3
8. R = -CH(CH3)2 , R1 = -CH2CH(CH3)2
Scheme 3. Reagents and conditions: (a) H2O/acetone/DMF, NaHCO3, −10°C, 15 min then rt, 30 min.
the preparation of N-Poc amino acids and for the
convenient synthesis of peptides in excellent yield.
6. Sinha, S.; Ilankumaran, P.; Chandrasekaran, S. Tetra-
hedron Lett. 1999, 40, 771.
7. To a solution of propargyl chloroformate (6 g, 4.9 ml,
0.050 mol) and pentafluorophenol (9.2 g, 0.050 mol) in
dry diethyl ether (100 ml), triethylamine (7 ml, 0.050 mol)
was added dropwise at 0°C. The mixture was stirred for
7 h at 0°C, then washed with water and immediately
dried over sodium sulfate. The solvent was removed in
vacuo and the crude product was recrystallised from
n-hexane to give propargyl pentafluorophenyl carbonate
(Poc-OPfp) as a white crystalline solid in quantitative
yield.
Acknowledgements
We thank the Department of Science and Technology,
New Delhi, for financial support to R.G.B., the Brit-
tany Region (France) for financial help to E.K. and the
Foreign Ministry of France for a Lavoisier grant to
E.P.
8. Selected data for (2): Mp 65–67°C; 1H NMR (CDCl3, 300
MHz) l 4.9 (d, 2H, J=2.7 Hz), 2.65 (t, 1H, J=2.3 Hz);
13C NMR (CDCl3, 75.5 MHz) l 57.5, 75.3, 77.2, 136.0,
138.3, 139.5, 142.9, 150.8; 19F NMR (CDCl3, 282.2 MHz)
l −153.54 (2F, o-F), −157.62 (1F, p-F), −162.4 (2F,
m-F).
9. Scho¨n, I.; Kisfaludy, L. Synthesis 1986, 303.
10. In the present work, peptide synthesis has not been
attempted using pentafluorophenyl esters derived from
leucine, proline and serine.
References
1. Bodanszky, A.; Bodanszky, M.; Chandramouli, N.;
Kwei, J. Z.; Martinez, J.; Tolle, J. C. J. Org. Chem. 1980,
45, 72.
2. Kisfaludy, L.; Roberts, J. E.; Johnson, R. H.; Mayers, G.
L.; Kovacs, J. J. Org. Chem. 1970, 35, 3563.
3. Kisfaludy, L.; Scho¨n, I.; Szirtes, T.; Nye´ki, O.; Lo¨w, M.
Tetrahedron Lett. 1974, 1785.
4. Scho¨n, I.; Kisfaludy, L. Synthesis 1983, 325.
5. Swamy, V.; Ilankumaran, P.; Chandrasekaran, S. Synlett
1997, 513.
11. HPLC was carried out using Chiralcel OD CN:0000CE
JH 004, Shimadzu SPD-6A, solvent system 30% iso-
propanol in n-hexane.