Solvent-free peptide synthesis assisted by microwave irradiation: Environmentally benign synthesis of bioactive peptides

Article abstract of DOI:10.1039/c3ra46643d

An efficient and facile, solvent-free peptide synthesis assisted by microwave irradiation, using DIC/HONB as the coupling reagent combination is reported. Key features of this original protocol are solvent-free synthesis, very short reaction time and scal

Full text of DOI:10.1039/c3ra46643d

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Solvent-free peptide synthesis assisted by
microwave irradiation: environmentally benign
Cite this: RSC Adv., 2014, 4, 3065
synthesis of bioactive peptides†
Received 13th November 2013
Accepted 25th November 2013
*
Amit Mahindra, Neha Patel, Nitin Bagra and Rahul Jain
DOI: 10.1039/c3ra46643d
www.rsc.org/advances
An efficient and facile, solvent-free peptide synthesis assisted by a reaction under solvent-free conditions in the presence of MW
microwave irradiation, using DIC/HONB as the coupling reagent irradiation provides an ideal eco-friendly process in terms of
combination is reported. Key features of this original protocol are reducing solvent cost and enhancement of the rate of reaction.
solvent-free synthesis, very short reaction time and scalability without
Amide bond formation is one of the most important reac-
affecting yield and purity. The versatility of the method was success- tions in organic synthesis due to its presence in a large number
fully demonstrated by synthesizing several biologically active peptides of natural and synthetic scaffolds having biological signi-
in high purity, yield and without racemization.
cance.14 Among them, peptides represent an important class of
compounds that are used as drugs in the treatment and
prevention of several diseases.15 Lately, apart from their bio-
logical importance, peptides have been used as catalyst in
asymmetric synthesis,16 biosensors,17 molecular hydro-
gelators,18 and biological markers in diagnostic tests.19 Over the
years, peptides have been synthesized by two strategies of
solution phase and solid phase peptide synthesis (SPPS).20
These procedures generate huge amount of toxic solvents like
N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidone (NMP),
N,N-dimethylacetamide (DMA) and dichloromethane (CH2Cl2).
Therefore, reducing and/or eliminating these solvents from the
synthesis has been an ever-growing concern of the chemists.21
In quest for eco-friendly peptide synthesis, several research
groups have reported SPPS in water (H2O) as a solvent medium.
The rst SPPS in H2O was reported by Kawasaki et al.22 followed
by Grøtli et al.23 and Collins in 2012.24 All these methods have
limitations either in terms of coupling reagent, solid support or
requirement of special protection on amino acids. Our efforts in
the development of benign peptide synthesis have resulted in
the disclosure of methods in neat water and under MW irradi-
ation.25,26 The important highlights of the “in-water” method
were the use of commercially available amino acids, short
reaction time, and elimination of hazardous solvents in the
synthetic cycle. In continuation of our efforts to establish
environmentally benign peptide synthesis, we now describe the
rst report on the solvent-free peptide synthesis assisted by MW
irradiation. The scope of this eco-friendly synthetic trans-
formation was established by illustrating its application in the
synthesis of bioactive peptides.
In recent years, the search for environmentally benign chemical
processes and transformations has received much attention
from chemists, as they are essential for the conservation of
global ecosystems.1 Solvent-free synthesis is probably the most
efficient way to create eco-friendly complex organic syntheses,
because organic solvents are generally the main source of toxic
waste.2 The omission of solvents from the synthetic cycle can
address the increasing concern of the effect of harmful chem-
icals on the environment and human body.3 In organic
synthesis, several reactions have been performed under solvent-
free conditions. Examples include, Mukaiyama-Aldol conden-
sation,4 Claisen and Cannizzaro reaction,5 Wittig reaction,6
Mannich reaction,7 Suzuki-Miyara coupling reaction,8 Passerini
reaction,9 and Prins cyclization.10 The viability of solvent-free
synthesis has become particularly very effective, when used in
combination with microwave (MW) irradiation.11 MW heating
makes it convenient to perform reactions very effectively in neat
conditions, and follow the twelve principles of green chemistry
postulated by Anastas and co-workers.12 In 1992, Sheldon et al.13
coined the term “E factor” and dened it as the ratio of the
weight of waste to the weight of product. In organic reactions,
solvent contributes the most waste, and their elimination from
the synthetic procedure reduces the E factor of the chemical
reaction and enhances the sustainability of the chemistry. Thus,
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India. E-mail: rahuljain@
niper.ac.in; Fax: +91 (172) 2214692; Tel: +91 (172) 2292024
Pursuing our interest in establishing solvent-free peptide
synthesis, we found few interesting articles on the construction
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra46643d
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of amide bond in the presence of 1,10-carbonyldiimidazole
(CDI).27 These reports use high temperature (250 ꢀC) to form
amide bonds; however could not be extended to peptide
synthesis. More recently, Lamaty et al.28,29 have reported a
solvent-free construction of amide bond, and a liquid-assisted
synthesis of peptide; both performed under ball milling
conditions. The peptide synthesis method used pre-activated
Boc-protected a-amino acid N-carboxy anhydrides or N-hydrox-
ysuccinimide esters in the presence of ethyl acetate as the liquid
grinding assistant.29 To the best of our knowledge, till date no
report exists on the synthesis of peptides under solvent-free
conditions.
Fig. 2 HPLC chromatogram of 2a. Method: C-18, 300 A˚, 5 mm, 250 ꢁ
4.6 mm column, run for 60 min with a flow of 1 mL minꢂ1, using a
gradient of 95–5%, where buffer A was 0.1% CF3CO2H (TFA) in H2O
and buffer B was 0.1% TFA in CH3CN and detection at 220 nm.
We initiated study by optimizing the microwave parameters
under solvent-free conditions. For the model study, we took
Boc–Phe–OH (1a) and Ile–OMe$HCl (1b) as the coupling amino
acids, while DIC was used as the coupling reagent and HONB as
an auxiliary nucleophile (Scheme 1).
Table 1 Various solvent-free reaction conditionsa
Entry
Various solvent-free conditions
Yield (%)
Purity (%)
1
2
3
4
5
6.
AA1 + AA2
AA1 + AA2 + DIEA
AA1 + AA2 + DIC
AA1 + AA2 + DIC + HONB
AA1 + AA2 + DIC + DIEA
AA1 + AA2 + DIC + HONB + DIEA
No reaction
No reaction
70
47
90
97
—
—
94%
96%
95%
97%
The criterion for the selection of the coupling reagent and
auxiliary nucleophile was based upon their low cost and wide
application in peptide synthesis. A number of experiments were
conducted under variable sets of temperature and time, keeping
pressure and power constant, under MW. From the bar graph
(Fig. 1), we envisaged that the temperature of 60 ꢀC and reaction
time of 15 min provide the best coupling conditions, and gave
97% isolated yield of Boc–Phe–Ile–OMe (2a).
a
Reaction conditions: AA1 (1.2 equiv.), AA2 (1 equiv.), HONB (1.2 equiv.),
DIEA (3 equiv.), DIC (1.2 equiv.), MW (60 ꢀC, 15 min, 40 W); AA1
represent 1a and AA2 represent 1b.
The HPLC analysis (Fig. 2) indicated a purity of 97% of 2a,
conrming the effectiveness of the protocol. It is important to
note that, when reaction was conducted at a temperature higher
than 60 ꢀC, some racemization was observed with reduced yield proceed in the absence of coupling reagent and auxiliary
of the peptide.
nucleophile (entries 1 and 2). The reaction of the HCl salt of 1b
Aer establishing MW parameters, the role of DIEA, DIC and with 1a using DIC gave 70% of 2a (Table 1, entry 3), while in situ
HONB was investigated by their sequentially addition in the neutralization of the HCl salt with DIEA, and subsequent
reaction. From Table 1, it was evident that reaction does not coupling with DIC enhanced the product yield to 90% (Table 1,
entry 5). The coupling reaction with DIC and HONB gave only
47% yield (Table 1, entry 4). The best coupling combination was
established by addition of DIEA to DIC and HONB, resulting in
the synthesis of 2a in highest yield and purity (entry 6).
To conrm the importance of MW irradiation, the peptide
coupling using the same reactants and coupling combination
was performed under conventional heating condition. The
ꢀ
reaction was performed in a pre-heated oil bath at 60 C for a
Scheme 1 Generalized scheme for coupling.
duration between 15 and 45 min. We observed much lower yield
of the peptide (14%), clearly demonstrating the importance of
MW irradiation in the solvent-free synthesis of peptides.
We also explored the various sets of coupling combinations
under the optimized conditions. It was interesting to note that
all tested coupling combinations provide peptide under solvent-
free conditions. The coupling combinations of PyBOP/HOBt,
HATU/HOAt and TBTU/HOBt gave 63–81% yield of 2a (Fig. 3). As
observed from the chart graph, DIC/HONB gave the best result
among all screened coupling combinations. As seen from the
Fig. 2, DCC provides comparable yield of 91%, while the use of
CDI as the coupling reagent furnished 2a in 19% yield.
To explore the substrate scope of the reaction, a series of
peptides were synthesized under solvent-free conditions. The
results of this study are summarized in Table 2. The dipeptides
Fig. 1 Optimization of microwave parameters.
3066 | RSC Adv., 2014, 4, 3065–3069
(Table 2, entries 1–13) were synthesized in 75–97% yield. The
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electronic nature of the substituents present on the side-chain
of the amino acid governed the yield of peptides. As observed
from Table 2, the reaction proceeds smoothly even in cases
where His, Pro, Trp and Arg were used without protection on the
side-chain group (Table 2, entries 2, 4, 6, 7, 11, 19 and 23),
conrming the reactive functional group tolerance of the
process and racemization-free synthesis. The reaction is versa-
tile to accommodate smooth coupling of bulky side-chain
containing amino acids such as Leu, Ile, and Val.
Both hydrophobic (Table 2, entries 1, 4, 7, and 12) and
hydrophlilic peptides (Table 2, entry 6), beside peptides con-
taining both hydrophobic and hydrophilic residues were
successfully synthesized. The removal of the a-Boc group was
achieved by the reaction with aqueous 6N HCl for 15 min at
ambient temperature. A set of tripeptides (Table 2, entries 14–19)
was synthesized in 70–78%. The scope of the reaction was
further extended with the successful synthesis of tetrapeptides
Fig. 3 Screening of coupling reagents under optimized parame-
ters [AA1 (1.2 equiv.), AA2 (1 equiv.), DIEA (3 equiv.), MW (60 ꢀC,
15 min, 40 W)].
Table 2 Solvent-free peptide synthesis assisted by MWa
Entry
AA1
AA2
Product code
Sequence
Yield (%)
Purityb (%)
Dipeptides (n ¼ 1)
1
Phe
Ile
His
Ile
His
Ile
His
Ile
Lys(Z)
Ile
Ile
Pro
Ile
Tyr(Bzl)
2a
2b
2c
2d
2e
2f
2g
2h
2i
Phe–Ile
Phe–His
Ser(Bzl)–Ile
Trp–His
Val–Ile
His(1-Bzl)–His
Trp–Ile
Asp(Bzl)–Lys(Z)
Met–Ile
Abu–Ile
Lys(Z)–Pro
Phg–Ile
97
75
99
75
75
76
98
78
96
86
76
86
87
97
93
96
92
92
99
95
91
98
91
93
95
99
2
Phe
3
4
Ser(Bzl)
Trp
5
Val
6
7
His(1-Bzl)
Trp
8
9
Asp(Bzl)
Met
10
11
12
13
Abu
Lys(Z)
Phg
2j
2k
2l
Val
2m
Val–Tyr(Bzl)
Tripeptides (n ¼ 2)
14
15
16
17
18
19
Ile
Phe–Ile
Phe–Ile
Val–Tyr(Bzl)
Phe–Ile
Phe–Ile
3a
3b
3c
3d
3e
3f
Ile–Phe–Ile
77
78
73
71
78
70
94
92
93
95
94
98
Thr(Bzl)
Asp(Bzl)
His(Bom)
Ala(2-naphthyl)
Pro
Thr(Bzl)–Phe–Ile
Asp(Bzl)–Val–Tyr(Bzl)
His(Bom)–Phe–Ile
Ala(2-naphthyl)–Phe–Ile
Pro–Met–Ile
Met–Ile
Tetrapeptides (n ¼ 3)
20
21
22
Ala
Thr(Bzl)-Phe-Ile
Asp(Bzl)-Val-Tyr(Bzl)
Ala(2-naphthyl)-Phe-Ile
4a
4b
4c
Ala–Thr(Bzl)–Phe–Ile
Lys(Z)–Asp (Bzl)–Val–Tyr(Bzl)
Met–Ala(2-naphthyl)–Phe–Ile
60
65
62
97
95
93
Lys(Z)
Met
Pentapeptide (n ¼ 4)
23
Arg
Lys(Z)–Asp(Bzl)–Val–Tyr(Bzl)
5a
Arg–Lys(Z)–Asp(Bzl)–Val–Tyr(Bzl)
55
94
a
b
Reaction Conditions: AA1 (1.2 mmol), AA2 (1.0 mmol), DIEA (3 mmol), DIC(1.2 mmol), HONB (1.2 mmol). Purity was determined by HPLC
analysis.
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(Table 2, entries 20–22, yield: 60–65%) and a pentapeptide
(Table 2, entry 23, 55% yield). In all cases, cleaner reaction and
high yield were obtained irrespective of the orthogonality of
the a-amino and side-chain protecting groups. It is important
to mention that peptides in general were synthesized in higher
yield compared to earlier reported MW-assisted approaches of
peptide synthesis.25,26
To establish the application of the solvent-free synthesis in
peptide-based drug discovery, we synthesized a number of
peptides of pharmaceutical importance. The peptides selected
for the solvent-free synthesis were carnosine (6, used in
complications of diabetes),30 aspartame (7, a commercially used
articial sweetener),31 thyrotropin-releasing hormone (8, a
regulatory neuropeptide),32 thymopentin (9),33 and Leu-
enkephalin (10, an opioid neurotransmitter peptide)34 (Fig. 4).
The synthesis of thymopentin is discussed herein, while the
synthetic schemes and discussion on the remaining four
peptides is provided in the ESI.†
Scheme 2 Synthesis of thymopentin (9).
Thymopentin (TP-5), a pentapeptide derived from the thy-
mopoietin hormone, possess a broad range of therapeutic
activities and elicits all biological responses of hormone.33 In
vitro treatment of cells homologous to human T cells with thy-
mopentin increases level of cGMP.35 Whereas, in vivo activities
of thymopentin nds it as immunomodulating agent in primary
and secondary immune deciencies like metastatic colorectal
cancer (CC), generalized lymphadenopathy, atopic dermatitis,
and rheumatoid arthritis adjuvant in vaccination against
hepatitis B.36
The ten steps synthesis of thymopentin assisted by MW is
illustrated in Scheme 2. The peptide was obtained in an overall
yield of 53%, starting from Tyr(Bzl)–OMe$HCl. The key high-
light of the synthesis was the successful coupling of Boc–Arg–
OH (bearing a side-chain reactive group), in the penultimate
step of the synthesis. Protected thymopentin 5a upon depro-
tection (aqueous acidolysis to remove Boc group, base-catalyzed
removal of ester group, and nally Pd-catalyzed removal of side-
chain protective groups) afforded thymopentin 9 in the purity of
97% (Fig. 5).
Fig. 5 HPLC chromatogram of 9. Method: C-18, 300 A˚, 5 mm, 250 ꢁ
4.6 mm column, run for 60 min with a flow of 1 mL minꢂ1, using a
gradient of 95–5%, where buffer A was 0.1% TFA in H2O and buffer B
was 0.1% TFA in CH3CN and detection at 220 nm.
Conclusion
We have developed an original and environmentally benign
process for the synthesis of peptides under solvent-free condi-
tions. This solvent-free synthesis was assisted by MW irradia-
tion and requires about 1.2 fold excess of reactants to provide
peptides in 15 min at 60 ꢀC. The reaction is easily applicable to
hydrophobic/hydrophilic amino acids containing a variety of
orthogonal protective groups. The reaction also allows
successful coupling of amino acids bearing side-chain reactive
groups. The applicability and scope of this synthetic process
was realized by synthesizing a varied number of bioactive
peptides having signicance in pharmaceutical industry. In
summary, the synthesis of peptides under solvent-free condi-
tions in reduced reaction time, high yield and purity, and
without racemization, ably assisted by MW irradiation offers a
new paradigm to sustainable chemistry.
Finally, we attempted to establish the versatility of the
reaction by synthesizing peptides on a higher scale. The ques-
tion of reaction scale was successfully answered by solvent-free
synthesis of peptides in #1g, while maintaining the ratio of
reactants and conditions intact, in an overall identical yield and
purity.
Acknowledgements
Amit Mahindra thank the Council of Scientic and Industrial
Research (CSIR), New Delhi for the award of Senior Research
Fellowship.
Fig. 4 Chemical structure of the bioactive peptides synthesized using
solvent-free conditions (overall yield in parentheses).
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