Propargyloxycarbonyl (Poc) amino acid chlorides as efficient coupling
reagents for the synthesis of 100% diastereopure peptides and resin
bound tetrathiomolybdate as an effective deblocking agent for the Poc
group
Ramakrishna G. Bhat, Surajit Sinha and Srinivasan Chandrasekaran†*
Department of Organic Chemistry, Indian Institute of Science, Bangalore- 560 012, India.
E-mail: scn@orgchem.iisc.ernet.in
Received (in Cambridge, UK) 7th January 2002, Accepted 26th February 2002
First published as an Advance Article on the web 13th March 2002
Synthesis of short peptides using propargyloxycarbonyl
amino acid chlorides as effective coupling reagents and
polymer supported tetrathiomolybdate as an efficient de-
blocking agent are reported.
All the N-Poc amino acids were found to be stable for several
days at room temperature (28 °C). Since the reagents seques-
tered on polymers are becoming increasingly popular in organic
synthesis, we decided to use in our studies resin bound
tetrathiomolybdate6 prepared by the reaction of ammonium
tetrathiomolybdate with amberlite IRA-400 resin. The N-Poc
amino acids (2a–2h) when treated with resin bound tetra-
thiomolybdate (MeOH, rt, 1.0–1.5 h) under sonochemical
conditions7 underwent smooth deprotection to give the corre-
sponding free amino acids in quantitative yields. The advan-
tages of this deprotection are simple filtration for work-up, no
by-product to be removed by chromatography, no acidic or
basic reagents used and the reaction conditions are mild and
essentially neutral. Unlike the Fmoc group the danger of
premature deblocking of the Poc group by excess base is not
observed.8
The N-Poc group is stable under the conditions which cleave
the Boc group (HCl, 10 min or CF3CO2H, 1 day) and Bts group
(AcOH). The N-Poc amino acids (2a–2e) on treatment with
SOCl2 in CH2Cl2 afforded the corresponding N-Poc amino acid
chlorides (3a–3e) respectively (Fig. 2). Interestingly all the N-
Poc amino acid chlorides were stable for several days at room
temperature under anhydrous conditions. To demonstrate the
wide utility of the coupling methodology peptides of non-
proteinogenic amino acids were synthesised. Direct reaction of
N-Poc amino acid chlorides (3a–3d) with a variety of amino
acid methyl ester hydrochlorides under Schotten–Baumann
conditions (H2O–Na2CO3–CH2Cl2 25 to 0 °C, 15 min) gave
protected dipeptides in high yield (4a = 83%, 4b = 88%, 4c =
86%, 4d = 88%, 4e = 83%) as crystalline solids indicating
facile coupling over a short time (Scheme 1).
While the most obvious method of activation of a carboxy group
for amide bond formation in peptide synthesis is via simple
amino acid chlorides, they are rarely used since they are
perceived to be ‘over-activated’ leading to numerous side
reactions including the danger of racemisation.1 More im-
portantly the acid chlorides obtained from N-acylamino acids
undergo cyclisation to the readily racemised oxazolones.2
However, in recent years the use of Fmoc amino acid
chlorides,3 Fmoc amino acid fluorides4 and N-Bts protected
amino acid chlorides5 have found use in the racemisation-free
synthesis of peptides in high yield. The limitation of these
methods is the use of basic or harsher acidic conditions that are
used for the N-deprotection which leads to undesired by-
products.
Herein we report the use of a propargyloxycarbonyl (Poc)
group as a novel N-protecting group, propargyloxycarbonyl
(Poc) amino acid chlorides as new coupling reagents for the
completely racemisation free, high yield synthesis of peptides
and selective deprotection of the Poc group under neutral and
non-hydrolytic conditions with resin bound tetrathiomolyb-
date.
A number of N-Poc protected amino acids (2a–2h) were
obtained by treatment of the appropriate amino acid with
propargyl chloroformate (1) in aq. NaOH, while maintaining the
pH in the range of 9.5 to 10.5 (Fig. 1). This method provided the
N-Poc derivatives, to a large extent, as crystalline solids in
90–95% yield in the case of alanine, valine, leucine, phenyl-
alanine, isoleucine, proline, phenylglycine and a-aminoisobu-
tyric acid.
N-Methylated dipeptide (6) was synthesised by treatment of
MeHNAla-OMe (5) with Poc-NMeAla-Cl (3e) under the above
mentioned biphasic system (Scheme 2). The purity of all the
peptides (4a–4e) synthesised was ascertained by use of a chiral
shift reagent in 1H NMR9 and chiral HPLC10 and were found to
be 100% diastereomerically pure.11 The results obtained with
Poc-Phg-Cl are superior in terms of reactivity and simpler
work-up compared to the use of Bts-Phg-Cl.5
Synthesis of peptides containing multiple Aib (a-aminoiso-
butyric acid) units still remains a challenging task. Their
chemical synthesis and homosequences are known to be
difficult under normal conditions.2b,12 The classical reagent
DCC (or DCC–HOBt) gives mediocre yields despite long
reaction times. To the best of our knowledge there are no reports
in the literature for the synthesis of peptides with multiple Aib
residues in the absence of any additives or trapping agents via
Fig. 1
† Honorary Professor, Jawaharlal Nehru Centre for Advanced Scientific
Research, Jakkur, Bangalore.
Fig. 2
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CHEM. COMMUN., 2002, 812–813
This journal is © The Royal Society of Chemistry 2002