Thionation of di and tripeptides employing thiourea as a sulphur transfer reagent

Article abstract of DOI:10.1039/c6ra18639d

A simple and efficient method for the synthesis of thiopeptides by the treatment of N^α-protected peptide esters employing DMF/PCl₅ and thiourea as a sulphur transfer reagent is described. The conversion is carried out at room tempera

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Thionation of di and tripeptides employing thiourea as a sulfur
transfer reagent
Received 00th January 20xx,
Accepted 00th January 20xx
Veladi Panduranga, Girish Prabhu, Roopesh Kumar L, Muniyappa Krishnamurthy, and Vommina V.
Sureshbabu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple and efficient method for the synthesis of thiopeptides by reduced amide isosteres10 as well. Replacing the oxygen of a
the treatment of Nα-protected peptide esters employing DMF/PCl5 peptide bond with sulfur has several consequences.11 The larger
and thiourea as a sulphur transfer reagent is described. The radius of sulfur and the larger charge transfer from nitrogen to
conversion is carried out at room temperature within short sulfur make thioamide a higher barrier of the rotation about the C-
duration of reaction time. The method is high yielding and free N bond. The thioamide has a higher rotational barrier than does an
from racemization. Multiple thionation is demonstrated by oxoamide, owing to greater C–N double bond character. The
conversion of two peptide bonds of tripeptides into thioamides. In thiocarbonyl bond is 37% longer than that of a carbonyl group, and
addition, amino acid derived arylamides are also converted into sulfur has 32% larger van der Walls radius than oxygen, which could
aryl thioamides.
disturb close atomic packing within the triple helix.12-15 Thioamides
are weaker hydrogen bond acceptors as well as stronger hydrogen
bond donors than is an oxoamide16 and are known to perturb
backbone n-ꢀ* interactions.17,18 Thioamides therefore provide a
strategy for subtly modulating a variety of effects on protein
stability. Recently thioamide was employed as fluorescence
quenching probe in the monitoring of the unfolding of small
proteins.19,20
Introduction
Peptide backbone modification by replacement of an amide bond
by a thioamide moiety has attracted considerable attention in
recent years for several reasons. The receptor interactions of sulfur
analogues of biologically active peptides may be more selective or
more potent than their parent compounds. In addition, the
enhanced stability against enzymatic action can be expected
towards various proteolytic enzymes. It is also possible to obtain
backbone-conformations compatible with the three major types of
regular secondary structures (α-helix, β-sheet, and β-turn) through
thioxylated peptides.1 Thioxopeptides, popularly known as
thiopeptides, can be employed for the synthesis of a wide range of
peptidomimetics including triazole,2,3 tetrazole,4 thiazole,5-9 and
Methods for the preparation of thiopeptides mainly involve the
conversion of amide to thioamide using thionating agents and the
use of thioacyalting agents which involve multistep protocols.
Thionation of N- and C-protected peptides to thiopeptides have
been reported using P4S10/triethylamine (TEA)21 or Lawesson
reagent (LR) under reflux conditions.22,23 Belleau group employed
Yakoyama’s reagent which is structurally similar to that of LR. It can
be used for the selective thionation of amides even in the presence
of other susceptible groups such as ester, urethane, or keto
carbonyls. Recently our group reported an improvement for the
synthesis of thiopeptides from dipeptide esters utilizing ultrasound
assisted P2S5.24 This route was later demonstrated to be useful in
the preparation of all thioamidated tri- and tetrapeptides including
# Room No.109, Peptide Research Laboratory, Department of Studies in Chemistry,
Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore
560 001, India. E-mail: sureshbabuvommina@rediffmail.com, hariccb@gmail.com,
hariccb@hotmail.com
†
Electronic Supplementary Information (ESI) available: Details of mass
spectrometry, 1H and 13C NMR spectra of synthesized compounds and chiral HPLC
chromatograms. See DOI: 10.1039/x0xx00000x
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the ones containing norleucine (Nle) as well. Multiple thionation of into imidoyl chloride intermediate prior to thionation. None of the
oxygenated peptides was accomplished by treatment with P2S5 in reagents proved beneficial than PCl5. Further investigations
anhydrous THF under ultrasound irradiation in about 3-5 hr with revealed that PCl5 in the presence of catalytic amount of DMF (0.3
addition of 9-10 equiv of P2S5 in several portions. On the other equiv) in acetonitrile as solvent drastically increased the yield to
hand, the synthesis of Ala bis and tristhioamidation involved use of 95%. After the initial reaction had subsided, stirring at 25 oC was
excess of LR and longer reaction duration (upto nine days).25 Aparna continued for another 15 min. A simple work up followed by the
et al. employed thiourea as thionating agent but the reaction was column purification of the crude product led to the isolation of the
carried out under solvothermal conditions in an autoclave for about thioxopeptide 1.2a in good yields (IR absorption: strong peak at
4 hours.26 Ley et al. reported the synthesis of thioamides using 1538 cm−1 for C=S stretching frequency; 13C NMR δ 205 ppm for C=S
aminothiophosphate resin as
a polymer supported thionating carbon).
agent.27 Most of these procedures often require excess of reagents
and elevated temperatures for longer durations.
Several groups developed thioacylating agents as monomeric
building blocks for selective thionation in an oligopeptide. Rapoport
and co-workers described the thioacyl benzotriazolides of amino
acid derivatives as efficient thioacylating agents to obtain
endothiopeptides.28 The thioacyl benzotriazole precursors were
made in three steps involving preparation of anilides, thionation
and cyclization through TFA treatment resulting in the Boc
protected amino acid derived benzotriazoles which were used as
building blocks. Later the same group employed thioacyl
nitrobenzotriazole as thioacylating agent based on requirement of
good leaving group adjacent to thiocarbonyl group.29 In addition,
Scheme 1 One pot synthesis of thioxopeptides from peptides using thiourea
Table 1. Optimization of thionation of peptides.
Entry
1
Chlorinating reagent
PCl5
Solvent
C6H6
Yield
52
2
PCl5
CH2Cl2
C6H6
48
3
triphosgene
oxalyl chloride
SOCl2
NR[a]
NR
40
4
C6H6
thioacyl
benzimidazolinones,
thioacylfluorobenzimidazolones,
5
C6H6
thioacyl-N-phthalimides30 have been employed as thioacylating
agents for the preparation of thiopeptides.31
6
POCl3
C6H6
34
7
DMF/PCl5
DMF/PCl5
C6H6
93
Alternatively the formation of thiocarbonyl function (C=S) makes
use of Nα-protected amino thioacids mediated by phosphorous
8
CH2Cl2
CH3CN
Toluene
THF
78
[b]
9
DMF/PCl5
95
based
reagents
such
as
benzotriazol-1-yl-
10
11
DMF/PCl5
DMF/PCl5
85
oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)32 and
bis(2-oxo-3-oxazolidinyl) phosphonic chloride (BOP-Cl).33
55
[a] NR = no reaction. [b] 0.3 equiv with respect to quantity of PCl5
Results and discussion
The above optimized protocol was then utilized for the conversion of a
series of dipeptides into thioxopeptides. Different peptide esters with
Cbz- and Fmoc- as N-protectors as well as benzoyl and acetyl protected
amino acid esters were converted into respective thioamides. As
delineated in Table 2 it was found that all the thioxopeptides were
obtained in good to excellent yields after purification by column
chromatography.
In the initial part of the study, model substrate Cbz-Phg-Phe-OMe
was treated with PCl5 for 20 min at room temperature followed by
the addition of thiourea (1.5 equiv) in ethanol (5 mL). After 15 min
of the reaction, the expected thioxopeptide was obtained in 52%
yield along with significant amount of unreacted peptide. To
improve the yield, different solvents and chlorinating agents
including triphosgene, oxalyl chloride, thionyl chloride, and
phosphorous oxychloride were tried for the conversion of peptide
2 | J. Name., 2012, 00, 1-3
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Based on the results of our study and previous reports, a plausible
mechanism for the formation of thiopeptide has been presented in
scheme 3. The first step involves the reaction of DMF with PCl5 to
give a Vilsmeier type reagent (A) (for ESI-MS of the intermediate 1.4
generated from Fmoc-Phe-Ala-OMe 1.3). In the next step, the
iminium chloride A reacts with peptide leading to the formation of
imidoyl chloride tethered intermediate B with the release of DMF.
The intermediate B then reacts with thiourea to produce an
intermediate species, which rearranges into the desired product.
The catalytic amount of DMF is crucial for the generation of imidoyl
chloride intermediate as recorded in earlier reports.35
Table 2 List of thioxo dipeptide/aryl/alkyl thioamide esters synthesized
Entry
Compound
Yield[a] (%)
1.2a
95
1.2b
1.2c
92
90
1.2d
1.2e
88
86
1.2f
1.2g
91
87
Scheme 2 Postulated mechanism for the DMF/PCl5 mediated thionation of
the peptide bond.
[a] Isolated yields after silica gel (100-200 mesh) column chromatography.
Peptide-thioxo peptide hybrids: N-Terminal extension of thioxo
dipeptides
The generation of imidoyl chloride from dipeptide employing
PCl5/DMF has been confirmed to be free from racemization.34 The
thiopeptides were analyzed by RP-HPLC for possibility of
epimerization under the present conditions. The thiopeptdes Cbz-L-
Phg-ψ[CSNH]-Phe-COOMe 1.2a and Cbz-D-Phg-ψ[CSNH]-Phe-
COOMe 1.2a* showed retention times of 16.44 min and 12.67 min
respectively. And their 1:1 mixture showed distinct retention times
of 17.29 and 13.63, thereby confirming the absence of
epimerization during their synthesis from respective peptides.
The chain extension from the N-terminus of Fmoc protected
thioxopeptides leading to tripeptide bearing one thioxo peptide
bond and the peptide bond/s in the backbone was undertaken. In a
typical example, thioxodipeptide was treated with diethylamine in
dry dichloromethane (DCM, 40%) and the free amino
thioxodipeptide ester 1.6 (not isolated) was coupled to Boc-Gly-OH
under standard peptide coupling conditions using 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC)/ 1-hydroxybenzotriazole
(HOBt) method. The resulting hybrid peptide 1.7 was isolated after
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column purification in good yield (Scheme 3).
Scheme 3 Synthesis of thioxo peptide-peptide hybrids
to the isolation of the product 1.9 in about 45−60% yield. Later, on
careful optimization, it was found that three equiv of PCl5, 0.9 equiv
of DMF, and 4.5 equiv of thiourea was necessary to obtain the
acceptable yield of products 1.9 (Scheme 4).
Dithioxo Tripeptides: Tripeptides possessing two thioxo bonds
The scope of the present protocol is then extended to thionation of
two peptide bonds of tripeptide esters. For this, initial experiments
were carried out using three equiv of each reagent; however, it led
Scheme 4 Synthesis dithioxo tripeptide esters.
scheme 5. The products were obtained in moderate to good yields
Thionation of amino acid arylamides
(Table 3).
Amino acid arylamides are widely used in preparation of polymers,
peptidomimetics, and pharmaceuticals. The present study also
encompassed the conversion of amino acid arylamides to
thioamides. The arylamides were then treated with PCl5 mediated
by DMF and thiourea by using the optimized conditions shown in
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acetonitrile 30–100% in 30 min. Melting points were determined in
an open capillary and are uncorrected. TLC experiments were
performed using MERCK TLC aluminum sheets (silica gel 60 F254)
and chromatograms were visualized by exposing in an iodine
chamber or to a UV-lamp. Column chromatography was performed
on silica gel (100–200 mesh) using ethyl acetate and hexane
mixtures as the eluent.
Scheme 5 Synthesis of amino acid derived arylthioamides.
General procedure for the synthesis of thioxodipeptide/aryl/alkyl
thioamide esters 1.2a-1.2g, 1.11a-1.11e.
Table 3. List of amino acid arylthioamides
Entry
1.11a
1.11b
1.11c
1.11d
1.11e
Pg
R
R1
Yield (%)
To a stirred suspension of protected dipeptide ester (1.0 mmol) in
acetonitrile (5 mL) was added PCl5 (205 mg, 1.0 mmol) and DMF
(0.025−0.03 mL) at room temperature under nitrogen atmosphere.
A clear yellow solution was formed after 10 min. The stirring was
continued for another 10 min. Then, a prepared ethanolic solution
of thiourea (360 mg, 1.5 mmol, 0.947 M) was added. The reaction
was found to be complete in 15 min (TLC analysis). The solvent was
evaporated under vacuum and diluted with EtOAc (10 mL). Organic
phase was washed with 1 N NaHCO3 (3 × 10 mL), 1 N citric acid (2 ×
10 mL), H2O (2 × 10 mL), and saturated NaCl (10 mL) solution and
dried over Na2SO4. The solvent was filtered and evaporated under
reduced pressure. The crude reaction mixture was purified under
column chromatography using hexane/ethyl acetate (8:2) as the
eluent to afford the desired product.
Fmoc
Fmoc
Fmoc
Cbz
CH2CH(CH3)2
CH3
4-CH3
H
87
86
84
83
79
4-CH3
H
CH2COOBn
CH2C6H5
H
H
Cbz
Conclusions
In summary thioxopeptides and oligothioxopeptides can be
prepared in good yields from corresponding peptides
employing thiourea as a thionating reagent. The method offers
a high-yielding, racemization-free, and cost effective way to
access the title compounds. The versatility of the method is
demonstrated by its application to peptides containing
differential Nα- and carboxyl protection. Further, peptide-
thioxopeptide hybrids can be prepared by coupling to Nα-free
amino thioxopeptides in good yields.
General procedure for the preparation of thioxo peptide-peptide
hybrids 1.7a-1.7c
Step 1. To a solution of Fmoc protected thioxo dipeptide ester 1.5
(1.0 mmol) in CH2Cl2 (10.0 mL), 18 mL of 40% DEA in CH2Cl2 was
added, and the solution was stirred for 20 min at rt under nitrogen
atmosphere. After complete deprotection of the Fmoc group
(observed by TLC analysis), the solvent and excess DEA were
removed completely under reduced pressure with repeated co-
evaporation with CH2Cl2. The resulting amino free thioxo dipeptide
ester was dissolved in anhydrous THF (5.0 mL) and maintained at 0
°C.
Experimental Section
General
All chemicals were used as obtained from Sigma Aldrich Company,
USA. All the solvents were dried and purified using recommended
procedures in the literature whenever necessary. High resolution
mass spectra were recorded on a Micromass Q-TOF micromass
spectrometer and ESMS on a LCQ Deca XP MAX using an electron
spray ionization mode. 1H NMR and 13C NMR spectra were recorded
on Bruker NMR AV 400 MHz and 100 MHz spectrometers,
respectively, at the Indian Institute of Science, Bangalore. RP-HPLC
analysis of epimers was carried out by using a LCQ Deca XP MAX
Step 2. Activation of Fmoc/Z-amino/dipeptide acid (1.1 mmol) was
carried out separately by dissolving with dry THF (5 mL) and cooled
to 0 °C. EDC (1.0 mmol) and HOBt (1.2 mmol) were added to the
above solution and stirred for 10 min. While maintaining the
temperature at 0 °C, the above amino free thioxo peptide ester (1.1
VWD at
λ = 254 nm; flow rate: 1.0 mL min−1; column:
Thermoscientific C18 syncronis, pore size-5 μm, diameter × length =
4.6 × 250 nm; method: gradient 0.1% TFA water–acetonitrile;
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mmol) was added, and the resulting mixture was stirred for 1−2 h,
during which the coupling was complete. The solvent was
evaporated under a vacuum and diluted with EtOAc (10 mL).
Organic phase was washed with 1 N NaHCO3 (3 × 10 mL), 1 N citric
acid (2 × 10 mL), H2O (2 × 10 mL), and brine (10 mL) solution and
dried over Na2SO4. The solvent was filtered and evaporated under
reduced pressure. The crude reaction mixture was purified under
column chromatography using hexane/ethyl acetate (8:2) as the
eluent.
7
8
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General procedure for the synthesis of dithioxo tripeptide esters
1.9a-1.9c
To a stirred suspension of protected tripeptide ester (1.0 mmol) in
acetonitrile (10 mL) was added crystalline PCl5 (615 mg, 3.0 mmol)
and DMF (0.062 mL). A clear solution was formed within 20 min at
rt under nitrogen atmosphere. Then, a prepared ethanolic solution
of thiourea (1.082 g, 4.5 mmol, 2.847 M) was added. The reaction
was completed in 15 min (TLC analysis), solvent was evaporated
under vacuum and diluted with EtOAc (10 mL). Organic phase was
washed with 1 N NaHCO3 (3 × 10 mL), 1 N citric acid (2 × 10 mL),
H2O (2 × 10 mL), and brine (10 mL) solution followed by drying over
Na2SO4. The solvent was filtered and evaporated under reduced
pressure. The crude reaction mixture was purified under column
chromatography using hexane/ethyl acetate (8:2) as the eluent.
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34 V. V. Sureshbabu, T. M. Vishwanatha, N. Narendra, B.
PAPER
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Thionation of di and tripeptides employing thiourea as a sulphur transfer
reagent
Veladi Panduranga, Girish Prabhu, Roopesh Kumar, Muniyappa Krishnamurthy, and
Vommina V. Sureshbabu*
Keywords: Peptides • peptidomimetics • thiourea • thionation • thiopeptides
Thiopeptides has been introduced into peptide backbones by thionation employing
DMF/PCl5 and thiourea as a sulphur transfer reagent. The protocol was also successfully
used for the thionation of two peptide bonds, tripeptide bearing thioxopeptide-peptide
hybrids, amino acid derived arylamides to aryl thioamides in good yields.