Ynamide-Mediated Thiopeptide Synthesis

Article abstract of DOI:10.1002/anie.201811586

Exploration of the full potential of thioamide substitution as a tool in the chemical biology of peptides and proteins has been hampered by insufficient synthetic strategies for the site-specific introduction of a thioamide bond into a peptide backbone. A novel ynamide-mediated two-step strategy for thiopeptide bond formation with readily available monothiocarboxylic acids as thioacyl donors is described. The α-thioacyloxyenamide intermediates formed from the ynamides and monothiocarboxylic acids can be purified, characterized, and stored. The balance between their activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Amino acid functional groups such as OH, CONH₂, and indole NH groups need not be protected during thiopeptide synthesis. The modular nature of this strategy enables the site-specific incorporation of a thioamide bond into peptide backbones in both solution and the solid phase.

Full text of DOI:10.1002/anie.201811586

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Accepted Article
Title: Ynamide-Mediated Thiopeptide Synthesis
Authors: Junfeng Zhao, Jinhua Yang, Changliu Wang, and Silin Xu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811586
Angew. Chem. 10.1002/ange.201811586
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http://dx.doi.org/10.1002/ange.201811586

10.1002/anie.201811586
Angewandte Chemie International Edition
COMMUNICATION
Ynamide-Mediated Thiopeptide Synthesis
Jinhua Yang†, Changliu Wang†, Silin Xu, and Junfeng Zhao*
Abstract: Thioamide substitution has evolved into an important tool
for the chemical biology of peptides and proteins. However,
exploration of its full potential has been hampered by insufficient
synthetic strategies for site-specific introduction of a thioamide bond
to
a peptide backbone. A novel ynamide-mediated two-step
thiopeptide bond formation strategy with easily available
monothiocarboxylic acids as the thioacyl donors is described. The α-
thioacyloxyenamide intermediates formed from the addition reactions
of ynamides and monothiocarboxylic acids are stable and can be
purified, characterized and stored. Their appropriate balance between
activity and stability enables them to act as effective thioacylating
reagents to afford thiopeptide bonds under mild reaction conditions.
Notorious issues such as racemization/epimerization and the use of
toxic and noxious thionating reagents, which have long plagued
thiopeptide synthesis, have been addressed. Some side chain
functional groups of amino acids such as –OH, –CONH2, and the NH
of indole are tolerated, rendering their protection during thiopeptide
synthesis unnecessary. Importantly, the modular nature of this
strategy guarantees the site-specific incorporation of a thioamide
bond to peptide backbone in both the solution and solid phase.
Figure 1. Thioamide-containing natural products
folding, stability, function, and dynamics. Recently, Petersson[11]
and Hecht[12] demonstrated that the thioamide bond could also be
incorporated into proteins, thus opening a new era for studying
thioamide substitution at the protein level. Although thioamide
substitution is compatible with the secondary structures of
proteins, the enhanced n→π* electronic delocalization[13] and
altered hydrogen bonding ability of thioamides impose
remarkable position-dependent stabilizing[14] or destabilizing[15]
effects on proteins. Furthermore, the biological behaviors of the
resulting thioproteins are unpredictable. As a consequence,
extensive exploration of the full potential of thioamide substitution
effects is in great demand. However, this study has been
hampered by a lack of synthetic strategies.
Originally, thioamide substitution was accomplished by
converting the carbonyl oxygen atom to an sp2 sulfur atom using
thionating reagents such as P4S10,[16] Lawesson’s reagent,[17] or
other sulfur reagents.[18] However, most of these thionating
reagents are noxious. In addition, it’s hard for them to control the
site-selectivity when more than one amide bond is involved,
especially for peptide and protein substrates. To overcome such
disadvantages, pre-prepared thioacylating reagents such as
thioacylnitrobenzotriazole,[19] thioacyl-N-phthalimides,[20] thio-
benzimidazolones,[21] and thioesters[22] have been developed.
The modular nature of the thioacylating reagents enables them to
install thioamide bonds in a site-specific manner. However, only
few of these thioacylating reagents are amenable for thiopeptide
synthesis, because most of them are highly prone to
epimerization/racemization. Additionally, the preparation of
these thioacylating reagents involves tedious multiple-step
syntheses and the use of thionating reagents, which render
amino acids containing amide side chains incompatible. In this
context, novel thioacylating reagents that can address the
disadvantages of site-specificity, racemization/epimerization and
the use of thionating reagent are urgently demanded. Herein, we
report an unprecedented ynamide-mediated thioamide bond
formation strategy with α-thioacyloxyenamides as the
thioacylating reagents. This two-step synthetic strategy with
monothiocarboxylic acids as the thioacyl donors enabled us to
introduce a thioamide bond into a peptide backbone in a site-
specific and racemization/ epimerization-free manner.
The precise modification and functionalization of peptides and
proteins have evolved into indispensable tools for chemical
biology, particularly for peptide synthesis, drug discovery, and
protein structure-function studies.[1] Among the numerous
synthetic modification strategies, thioamide substitution,[2] the
site-specific introduction of a thioamide bond Ψ[CS-NH] to a
peptide backbone by simple replacement of a carbonyl oxygen
atom with an sp2 sulfur atom, constitutes one that causes minimal
perturbation. Thioamide-containing natural products such as
methanobactin[3] and closthioamide[4] (Figure 1), and thioamide-
substituted peptides[5] and proteins[6] have been identified.
Thioamide substitution does not change the geometry of that
particular amide bond, but confers different chemical and physical
properties.[7] For example, the resistance of a peptide to
enzymatic degradation can be dramatically enhanced by
replacing the canonical peptide bond with a thioamide linkage.[8]
The unique spectroscopic features of thioamides enable them to
serve as cis/trans photoswitches[9] and fluorescence
quenchers.[10] Owing to these features, thioamide bond has
become a multifunctional probe for studying protein structure,
†
†
[*]
J. Yang, [ ] C. Wang,[ ] S. Xu, Prof. Dr. J. Zhao
College of Chemistry & Chemical Engineering, Jiangxi Normal
University
Nanchang 330022 (China)
E-mail: Zhaojf@jxnu.edu.cn
Homepage: http://zhao.jxnu.edu.cn
Prof. Dr. J. Zhao
State Key Laboratory of Elemento-Organic Chemistry, Nankai
University
Tianjin 300071 (China)
Jiangxi Province Key Laboratory of Chemical Biology
[†] These authors contributed equally.
[**]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201811586
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Addition of monothiocarboxylic acids to MYTsA[a]
yield (%)[b]
ratio
Entry
monothioacid 1
(3:4)
3
4
1
Cbz-Ala-SH (1a)
3a (69)
3b (68)
3c (67)
3d (65)
3e (65)
3f (66)
3g (68)
3h (65)
3i (66)
3j (66)
3k (66)
3l (69)
3m (32)
3n (60)
3o (68)
3p (63)
3q (75)
3r (66)
3s (69)
3t (42)
3u (40)
3v (48)
3w (48)
3x (51)
3y (55)
4a (30)
4b (31)
4c (32)
4d (31)
4e (30)
4f (33)
4g (30)
4h (32)
4i (32)
4j (32)
4k (23)
4l (30)
4m (34)
4n (38)
4o (28)
4p (32)
4q (20)
4r (34)
4s (27)
4t (32)
4u (54)
4v (45)
4w (42)
4x (42)
4y (43)
2.3:1.0
2.2:1.0
2.1:1.0
2.1:1.0
2.2:1.0
1.9:1.0
2.3:1.0
2.0:1.0
2.1:1.0
2.1:1.0
2.9:1.0
2.3:1.0
1.0:1.0
1.6:1.0
2.4:1.0
1.9:1.0
3.8:1.0
1.9:1.0
2.6:1.0
1.4:1.0
0.8:1.0
1.1:1.0
1.1:1.0
1.2:1.0
1.3:1.0
Scheme 1. Ynamide-mediated thiopeptide synthesis
2
Boc-Ala-SH (1b)
3
Fmoc-Ala-SH (1c)
Fmoc-Phe-SH (1d)
Fmoc-β-Ala-SH (1e)
Fmoc-Aib-SH (1f)
4
In addition to the aforementioned thionating and thioacylating
reagents, monothiocarboxylic acids have been used as
thioacylating reagent surrogates with the assistance of
phosphorus coupling reagents.[23] However, the co-formation of
oxoamides complicated the purification and resulted in low yields
of the target thioamides. Our group recently disclosed that α-
acyloxyenamides formed from the hydroacyloxylation of
ynamides with carboxylic acids are effective active esters for
amide and peptide bond formation.[24] Theoretically, both α-
acylsulfuryenamides and α-thioacyloxyenamides would be
produced if monothiocarboxylic acids were treated with ynamides
because of the thiol-thioxo tautomerization of monothiocarboxylic
acids.[25] We thus proposed that an ynamide-mediated thioamide
bond formation strategy would be feasible if the α-
thioacyloxyenamide could serve as an active thiocarbonylester.
To implement this proposal, Cbz-Ala-SH, 1a, was treated with N-
methylynetoluenesulfonamide (MYTsA), 2, in dichloromethane
(DCM) at room temperature (Scheme 1). To our delight, the
addition reaction between 1a and 2 indeed gave a mixture of α-
thioacyloxyenamide 3a and α-acylsulfuryenamide 4a in
quantitative yield with a 1:1 ratio (Scheme 1, eq. 1). Most
importantly, the aminolysis of α-thioacyloxyenamide 3a
proceeded smoothly at room temperature to afford the expected
thiodipeptide 5a quantitatively without any epimerization (Scheme
1, eq. 2). Taking these two steps together, ynamide MYTsA acted
as a coupling reagent to facilitate thiopeptide bond formation with
the easily available N-protected amino monothioacid as the sulfur
source. Extensive optimization of the reaction conditions was
conducted to improve the selectivity between α-thioacyloxy
enamide and α-acylsulfuryenamide (for details, see the
Supporting Information). It was observed that the ynamide,
solvent, and temperature played important roles in control of the
chemoselectivity. Polar solvents and low temperature were
beneficial to furnishing α-acylsulfuryenamides, while non-polar
solvents favored α-thioacyloxyenamides. Finally, m- xylene was
identified as the optimal solvent, producing quantitative yields of
the addition products with a 2.3:1 ratio at −40 °C. With the
optimized reaction conditions in hand, the generality of the
reaction with respect to various amino acids was evaluated. As
shown in Table 1, excluding His, most of the N-protected amino
monothioacids derived from 19 natural amino acids, Aib, and β-
Ala added smoothly to MYTsA 2 to give α-thioacyloxyenamides 3
and α-acylsulfuryenamides 4 in excellent yields with ratios of
approximately 2:1. Different protecting groups, such as Cbz, Boc,
and Fmoc, were all tolerated and had no significant influence on
the reaction efficiency (entries 1–3). Although polar side chain
5
6
7
Fmoc-Gly-SH (1g)
Fmoc-Leu-SH (1h)
Fmoc-Ile-SH (1i)
8
9
10
11
12
13[c]
14
15
16
17
18
19
20
21[c]
22[c]
23
24
25
Fmoc-Val-SH (1j)
Cbz-Pro-SH (1k)
Cbz-Ser(OtBu)-SH (1l)
Cbz-Ser-SH (1m)
Fmoc-Tyr(OBn)-SH (1n)
Boc-Lys(Boc)-SH (1o)
Boc-Met-SH (1p)
Boc-Trp(Boc)-SH (1q)
Boc-Glu(OtBu)-SH (1r)
Boc-Asp(SH)-OtBu (1s)
Boc-Cys(Acm)-SH (1t)
Cbz-Thr-SH (1u)
Cbz-Gln-SH (1v)
Boc-Arg(Cbz)2-SH (1w)
Boc-Asn(Trt)-SH (1x)
Boc-Gly-Leu-SH (1y)
[a] Reaction conditions: monothioacid 1 (0.15 mmol, 1.5 equiv.), MYTsA 2
(0.1 mmol), m-xylene (1 mL). [b] Isolated yield. [c] DCM (1 mL), −20 °C.
functional groups such as –OH and –CONH2 could be tolerated,
protection was necessary to attain good selectivity (entry 12 vs.
13). The poor selectivities for the substrates with non-protected
side chains were attributed to their poor solubilities in m-xylene,
which necessitated the use of polar solvent DCM as the reaction
medium (Table 1, entries 13, 21, and 22). The highest ratio up to
3.8:1 in favor of α-thioacyloxyenamide 3q could be obtained for
Boc-Trp(Boc)-SH (Table 1, entry 17). Good selectivity was also
observed for Boc-Asp(SH)-OtBu (Table 1, entry 19). Polar NH-
containing side chains of Gln, Arg, and Asn resulted in poor
selectivities (Table 1, entries 22–24). Interestingly, moderate
selectivity was obtained for a dipeptidethioacid (Table 1, entry 25).
It should be noted that all of the adducts, α-thioacyloxyenamides
3 and α-acylsulfuryenamides 4, are stable and can be purified and
characterized. No deterioration could be detected after they were
stored in fridge for two months.
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10.1002/anie.201811586
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COMMUNICATION
thiocarbonyl esters of the natural amino acids could provide the
target thiodipeptides in excellent yields without any detectable
epimerization at 25 °C (Scheme 2). Even the sterically bulky Val,
Aib, Pro and Ile residues (5i-l and 5u), could be tolerated, albeit a
longer reaction time was required. For the thiocarbonyl esters
derived from Asp, Asn, Tyr, Phe and Trp (5v–z), which are highly
prone to racemization, the slight racemization at 25 °C could be
completely suppressed by performing the aminolysis reaction at
0 °C. It should be noted that all of the aminolysis reactions finished
within few minutes to hours to give the target thiodipeptides in
excellent yields. Notably, side chain functional groups such as –
OH (5d, 5h, and 5r–t), –CONH2 (5f, 5l, and 5r), and the NH of
indole (5y) are compatible, rendering the protection of these side
chains during thiopeptide synthesis unnecessary. Significant
advantages were also observed for the synthesis of all-
thioamided peptides by using this method iteratively. For example,
dithiotripeptide 5a′, which is difficult to prepare by employing
thionating reagents,[26] could be synthesized in good yield using
this strategy.
To explore the synthetic application of this thiopeptide
synthesis strategy, trithioamide-substituted Leu-enkephalin 12, in
which three of four amide bonds were selectively thiosubstituted,
was synthesized. As shown in Scheme 3, α-thioacyloxyenamides
3d, 3g, and 3n could be prepared easily from Fmoc-Phe-SH,
Fmoc-Gly-SH, and Fmoc-Tyr(OBn)-SH, respectively (Table 1).
Thiodipeptide acid 10 could be obtained in good yield via the
treatment of the H2N-Gly-OtBu ester with α-thioacyloxyenamide
3n, followed by conventional deprotection. Following a coupling
and deprotection protocol, dithioamide-substituted tripeptide 11
was produced in good yield. Subsequent MYTsA-mediated 2+3
segment condensation of thiodipeptide acid 10 and
dithiotripeptide 11 finally afforded the trithioamide-substituted
Leu-enkephalin 12 in excellent yield. The synthesis of the
trithioamide-substituted Leu-enkephalin not only demonstrated
the site-specific advantage of the ynamide- mediated thiopeptide
bond formation strategy, but also its potential applicability in
thiopeptide segment condensation.
Scheme 2. Thiopeptide bond formation.[a] [a] Reaction conditions:
thiocarbonylester 3 (0.3 mmol), amine coupling partner 7 (0.36 mmol), DMF (2
mL), isolated yield. [b] 0 °C.
The aminolysis of an α-thioacyloxyenamide (5 min) was much
faster than that of an α-acyloxyenamide (20 h),[24a] which indicated
that the α-thioacyloxyenamides are much more reactive than their
oxo counterparts (Scheme 1, eq. 2). Dimethylformamide (DMF)
was identified as the optimal solvent to facilitate the aminolysis
free of racemization. The substrate scope of this highly efficient
thioamide bond formation strategy was investigated. Most of the
Scheme 3. Synthesis of trithioamide-substituted Leu-enkephalin
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10.1002/anie.201811586
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COMMUNICATION
This promising result prompted us to attempt the total synthesis
of closthioamide, a natural product that contains six consecutive
thioamide bonds in a symmetric manner and possesses highly
potent antibiotic activity.[4] The total synthesis of closthioamide 17
was accomplished conveniently from three building blocks 3e, 15
and propane-1,3-diamine by iteratively employing the ynamide-
mediated thioamide bond formation strategy (Scheme 4). The
NMR, UV, IR and HRMS spectral data of the synthesized
closthioamide were identical to those previously reported for the
isolated closthioamide.[4] The modular nature of this method offers
the possibility to modulate bioactivity of closthioamide by the
convenient introduction of different substituents.
To further illustrate the robustness of this method in thiopeptide
synthesis, its application in solid phase peptide synthesis was
evaluated. As shown in Table 2, the novel thioacylating reagents
α-thioacyloxyenamides could be used to incorporate thioamide
bonds into peptide backbones on a solid support.The reaction
conditions are notably mild and simple. One coupling with 3 equiv.
of α-thioacyloxyenamides derived from Fmoc amino acids could
achieve up to 100% conversion in the absence of any catalysts or
additives (Table 2, crude HPLC traces are shown in the
Supporting Information). A cocktail (DBU 1%/n-C6H13SH 25%, 2
min × 2) was employed to avoid the epimerization of the thioamide
unit during the de-protection process. Both the monothioamide-
substituted and the dithioamide-substituted peptide could be
synthesized using this method. All these results demonstrated
that this strategy could be used to introduce a thioamide bond to
a peptide backbone in a site-specific manner on the solid support.
In conclusion, we have developed an unprecedented ynamide-
mediated thiopeptide synthesis strategy. The key intermediates,
α-thioacyloxyenamides, a type of reactive thiocarbonyl ester,
could be prepared easily from monothiocarboxylic acids and
ynamides. Importantly, the appropriate balance between the
activity and stability of α-thioacyloxyenamides enables α-
thioacyloxyenamides to act as ideal and effective thioacylating
reagents that can be characterized and stored. The aminolysis of
α-thioacyloxyenamides proceeded smoothly to furnish thioamide
bonds under mild reaction conditions, making the handling of the
entire protocol very convenient. The notorious issues of
Table 2. Site-specific incorporation of thioamides into a peptide
backbone on a solid support[a]
entry
thiopeptide
sequence
Fmoc-ASVGF
conv (%)[b]
1
2
3
4
5
6
7
8
19
20
21
22
23
24
25
26
100
99
99
99
98
97
98
97
Fmoc-MSVGF
Fmoc-C(Trt)SVGF
Fmoc-E(tBu)SVGF
Fmoc-ASASVGF
Fmoc-E(tBu)SASVGF
Fmoc-S(tBu) SLASVGF
Fmoc-ASLASVGF
[a] Reaction conditions: 18 (0.03 mmol), X (3.0 equiv.), rt. [b] % conversion
calculated based on crude HPLC.
epimerization/racemization and the use of noxious thionating
reagents, which have long plagued thiopeptide bond formation,
are avoided. Furthermore, the modular nature of this strategy
enabled us to incorporate thioamide bonds into peptide
backbones in a site-specific manner in both the solution and solid
phase. Undoubtedly, this highly efficient method will find broad
application in thiopeptide and thioprotein synthesis and spur
further studies on the thioamide substitution effect in peptide and
protein chemical biology.
Acknowledgements
This work is supported by the National Natural Science
Foundation of China (21462023, 21778025), and the Education
Department of Jiangxi Province (150297).
Keywords: ynamide
• thioamide • thiopeptide synthesis•
monothiocarboxylic acid• peptide backbone post-translational
modification
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10.1002/anie.201811586
Angewandte Chemie International Edition
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COMMUNICATION
Jinhua Yang, Changliu Wang, Silin Xu,
Junfeng Zhao*
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Ynamide-Mediated Thiopeptide
Synthesis
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