Recyclable hypervalent-iodine-mediated solid-phase peptide synthesis and cyclic peptide synthesis

Article abstract of DOI:10.3762/bjoc.14.97

The system of the hypervalent iodine(III) reagent FPID and (4-MeOC₆H₄)₃P was successfully applied to solid-phase peptide synthesis and cyclic peptide synthesis. Four peptides with biological activities were synthesized through SPPS and the bioactive cyclic heptapeptide pseudostellarin D was obtained via solution-phase peptide synthesis. It is worth noting that FPID can be readily regenerated after the peptide coupling reaction.

Full text of DOI:10.3762/bjoc.14.97

Recyclable hypervalent-iodine-mediated solid-phase peptide
synthesis and cyclic peptide synthesis
Dan Liu, Ya-Li Guo, Jin Qu and Chi Zhang*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1112–1119.
State Key Laboratory of Elemento-Organic Chemistry, Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin),
College of Chemistry, Nankai University, Tianjin 300071, China
doi:10.3762/bjoc.14.97
Received: 14 February 2018
Accepted: 27 April 2018
Published: 22 May 2018
Email:
Chi Zhang* - zhangchi@nankai.edu.cn
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
* Corresponding author
Keywords:
Guest Editor: T. Wirth
cyclic peptide; FPID; hypervalent iodine(III) reagent; recyclable;
solid-phase peptide synthesis (SPPS)
© 2018 Liu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The system of the hypervalent iodine(III) reagent FPID and (4-MeOC6H4)3P was successfully applied to solid-phase peptide syn-
thesis and cyclic peptide synthesis. Four peptides with biological activities were synthesized through SPPS and the bioactive cyclic
heptapeptide pseudostellarin D was obtained via solution-phase peptide synthesis. It is worth noting that FPID can be readily regen-
erated after the peptide coupling reaction.
Introduction
The amide bond is one of the most fundamental functional amounts of chemical wastes are produced during the amide
groups in organic chemistry, and it plays a crucial role in the bond formation reaction using these reagents and the coupling
elaboration and composition of biological systems. Amide reagents cannot be regenerated [10]. Thus, methods for the
bonds are widely present not only in peptides and proteins but peptide synthesis which are efficient and atom-economic are
also in pharmaceuticals and many natural products. Among the still needed.
methods for amide bond formation, the direct condensation of
carboxylic acids and amines in the presence of a coupling Hypervalent iodine reagents have drawn researchers’ consider-
reagent is the most convenient and simplest way [1-6]. The able attentions due to their versatile reactivity, low toxicity,
most commonly used coupling reagents such as carbodiimide ready availability, environmental friendliness, and regenera-
[7], phosphonium [8], and uronium salts [9] are efficient and bility [11-27]. Our group has dedicated to the peptide synthesis
commercially available. In spite of these merits of traditional mediated by hypervalent iodine(III) reagents in recent years. In
coupling reagents, it is still far from ideal because large 2012, for the first time, we reported that the hypervalent
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iodine(III) reagent iodosodilactone (Figure 1) can serve as a reactions within 30 minutes to obtain various dipeptides from
condensing reagent to promote esterification, macrolactoniza- standard amino acids as well as sterically hindered amino acids.
tion, amidation and peptide coupling reactions in the presence Moreover, a pentapeptide Leu-enkephalin is successfully syn-
of PPh3 [28]. In addition, the peptide coupling reaction thesized in its protected form using this coupling system. Simi-
proceeds without racemization in the absence of a racemization lar to iodosodilactone, FPID can be easily regenerated after the
suppressant and iodosodilactone can be readily regenerated reaction. The mechanism for this FPID-mediated amide bond
after the reaction. In order to further enhance the reactivity of formation reaction was proposed with the acyloxyphosphonium
iodosodilactone, we designed and synthesized a new derivative intermediate B being the key intermediate (Scheme 1). Herein,
of iodosodilactone 6-(3,5-bis(trifluoromethyl)phenyl)-1H,4H- as part of our continuing exploration of the application of FPID
2aλ3-ioda-2,3-dioxacyclopenta[hi]indene-1,4-dione (abbrevi- in peptide synthesis, we disclose its successful application in
ated as FPID, Figure 1) [29].
solid-phase peptide synthesis and cyclic peptide synthesis.
Results and Discussion
At the beginning of our study, we tried to utilize the system of
FPID/(4-MeOC6H4)3P in the solid-phase peptide synthesis
(SPPS). SPPS has been widely employed in peptide synthesis
since its first report by Merrifield in 1963 [30,31]. Compared
with classical solution-phase peptide synthesis, the fast develop-
ment of SPPS is mainly due to its short reaction time, high effi-
ciency, low racemization, simple work-up and automation. In
recent decades, various strategies, for example, native chemical
ligation (NCL) [32] and serine/threonine ligation (STL) [33],
have been reported to solve the problems occurred during the
development of SPPS. Peptide synthesis in solution mediated
Figure 1: Iodosodilactone and FPID.
In combination with tris(4-methoxyphenyl)phosphine [(4- by FPID/(4-MeOC6H4)3P is rapid (within 30 min) and efficient,
MeOC6H4)3P], FPID can efficiently mediate peptide coupling at the same time the reactions proceed without racemization.
Scheme 1: Proposed mechanism for FPID-mediated amide bond formation.
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Thus, it is possible and significant to test whether the FPID/(4- The synthesis of two ACE inhibitory peptides proceeded
MeOC6H4)3P system can be used in SPPS.
smoothly in moderate yield (Table 1, entries 3 and 4). Notably,
it is unnecessary to protect the hydroxy group of serine, threo-
We selected the commercially available 2-chlorotrityl chloride nine, or tyrosine in advance in the synthesis of these four
resin (2-Cl-Trt-Cl resin) as the solid support and [(9-fluorenyl- peptides. The presence of an unprotected hydroxy group does
methyl)oxy]carbonyl (Fmoc) as the α-amino protecting group. not affect the coupling efficiency, which is consistent with
The peptides were synthesized following the route as shown in peptide coupling in solution phase [29]. The HRMS spectra of
Scheme 2. The C-terminal amino acid was immobilized onto these peptides are consistent with their molecular formula.
the 2-Cl-Trt-Cl resin in the presence of 3.0 equiv of DIPEA in
DCM/DMF (v:v 1:1). Subsequent peptide chain elongation was
Table 1: Peptides synthesized by SPPS mediated by FPID.
completed via Fmoc-SPPS protocol, which includes deprotec-
entry peptide
yield
tion with 20% piperidine/DMF and peptide coupling with
3.0 equiv of Fmoc-protected amino acids, 3.0 equiv of FPID,
3.0 equiv of (4-MeOC6H4)3P and 3.0 equiv of TEA in DMF.
After chain elongation and deprotection of Fmoc, the resulting
resins were treated with 0.5% TFA/DCM to give the N,C-
unprotected peptides as final products. The peptides were puri-
fied by reversed-phase HPLC (RP-HPLC).
1
2
3
4
H2N-Tyr-Gly-Gly-Phe-Leu-OH (1)
H2N-Gly-Gly-Tyr-Pro-Leu-Ile-Leu-OH (2)
42%
53%
H2N-Lys-Leu-Pro-Ala-Gly-Thr-Leu-Phe-OH (3) 30%
H2N-Trp-Val-Pro-Ser-Val-Tyr-OH (4) 21%
Similar to the solution-phase peptide synthesis, FPID can be
For the target peptides, we aimed at peptides with specific bio- easily regenerated after SPPS (Scheme 3). After completion of
logical activities. Leu-enkephalin, which is isolated from pig peptide elongation, the washing solution of peptide coupling in
brains, acts as an endogenous mediator at central morphine re- each cycle was collected and evaporated. Then the mixture was
ceptor sites and thus possesses potent opiate agonist activity acidified with 3 N HCl and extracted with EtOAc, dried and
[34-36]. Leu-enkephalin 1 (Table 1, entry 1) could be success- concentrated in vacuo. The synthetic precursor of FPID 6 could
fully synthesized following the route mentioned above be purified by flash chromatography in order to remove excess
(Scheme 2). Besides, the precursor 2 of a cyclic heptapeptide Fmoc-protected amino acids during the peptide coupling. Com-
pseudostellarin D [37-39] was also obtained via SPPS in good pound 6 was subsequently oxidized with NaOCl/HCl to obtain
yield (Table 1, entry 2), the cyclization of 2 to give pseudostel- FPID in 90% yield.
larin D using FPID/(4-MeOC6H4)3P will be described in the
following part. Moreover, angiotensin I converting enzyme Cyclic peptides, an important kind of peptides, possess several
(ACE) inhibitory peptides, widely exist in plants and animals, favorable properties such as target selectivity, good binding
can serve as potential antihypertensive pharmaceuticals [40-42]. affinity and low toxicity, which make them attractive candi-
Scheme 2: Solid-phase peptide synthesis mediated by FPID/(4-MeOC6H4)3P. Conditions: The resin loading for 2-Cl-Trt-Cl resin is 0.98 mmol/g. For
each peptide synthesized through SPPS, 200 mg 2-Cl-Trt-Cl resin was used. Fmoc-Ser-OH, Fmoc-Thr-OH, Fmoc-Tyr-OH, Fmoc-Trp-OH were
directly used without any protecting group on OH or NH. During the synthesis of 3, Fmoc-Lys(Boc)-OH was used.
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Beilstein J. Org. Chem. 2018, 14, 1112–1119.
Scheme 3: The regeneration of FPID after SPPS.
dates in the development of therapeutics [43,44]. Due to the peptide-PNP ester, which is known as the p-nitrophenyl ester
particular significance of cyclic peptides, chemists pay consid- method (Scheme 4, method A). The other one was described by
erable attention to the efficient synthesis of cyclic peptides [45]. Agrigento and co-workers, the cyclization was completed via
In the second part of the investigation of the synthetic utility of the p-chlorophenyl thioester method with peptide-thioester
the FPID/(4-MeOC6H4)3P system, we tested this system in the being the precursor (Scheme 4, method B) [39]. Herein, we
cyclic peptide synthesis.
realized the synthesis of pseudostellarin D following the same
cyclization strategy mentioned above by direct coupling of the
The roots of Pseudostellaria heterophylla are well-known tradi- precursor 2 without any protecting group utilizing the system of
tional Chinese medicine, which are often used as a lung and FPID/(4-MeOC6H4)3P (Scheme 4, method C).
spleen tonic. There are more than 10 cyclic peptides isolated
from it, for example, pseudostellarin A–H and heterophyllin
A–D [37,46-49]. Cyclo(Gly-Gly-Tyr-Pro-Leu-Ile-Leu), a cyclic
heptapeptide named pseudostellarin D (Figure 2), is one of
these cyclic peptides. Pseudostellarin D was first isolated
and identified in 1994 by Itokawa and co-workers [37]. In
addition, the authors reported that pseudostellarin D showed po-
tent tyrosinase inhibitory activities. In 1999, Belagali and
co-workers further evaluated the antimicrobial, anti-
inflammatory and anthelmintic activities of pseudostellarin D
[38]. As for the synthesis of pseudostellarin D, the existing
methods utilized the active ester method to complete the cycli-
zation of the linear peptide precursor with the same amino acid
sequence of Gly-Gly-Tyr-Pro-Leu-Ile-Leu as a result of the
amide bond between “Gly-Leu” being the cyclization position.
The first one was reported by Belagali in 1999, pseudostellarin
Figure 2: Structure of pseudostellarin D.
D was obtained by the cyclization of the linear heptapeptide
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Beilstein J. Org. Chem. 2018, 14, 1112–1119.
Scheme 4: Synthetic strategies of pseudostellarin D.
We have obtained the precursor 2 through SPPS mediated by first and FPID/(4-MeOC6H4)3P 5 minutes later performed
FPID/(4-MeOC6H4)3P system (Table 1, entry 2). Firstly, the better than the inverse sequence (Table 2, entries 1 and 2).
C-terminal amino acid Leu was immobilized onto 2-Cl-Trt-Cl When prolonging the reaction time to 24 h, the product was ob-
resin. Then the chain elongation was completed by the depro- tained in a yield of 23% and 25% according to different adding
tection of Fmoc and coupling with Fmoc-protected Ile, Leu, sequence of TEA and FPID/(4-MeOC6H4)3P, and the effect of
Pro, Tyr, Gly, Gly in turn. The successive deprotection of the adding sequence was the same with that mentioned above
Fmoc, cleavage from the resin and purification via RP-HPLC (Table 2, entries 3 and 4). Then the reaction was run under N2
yielded the precursor 2 (see Supporting Information File 1). Al- atmosphere instead of air, the cyclization yield increased to
ternatively, the synthesis of the precursor 2 can be achieved 27% (Table 2, entry 5). Increasing the equivalents of FPID and
through a convergent [3 + 4] segment condensation strategy in (4-MeOC6H4)3P to 2.0 equiv resulted in 33% NMR yield of the
solution phase (Scheme 5). Notably, during the synthesis of product (Table 2, entry 7). Ye’s group disclosed that adding
tetrapeptide segment 10, the stepwise manner was adopted in univalent metal ions such as Na+, K+ and Cs+ to the reaction
order to avoid racemization. In the synthesis of tripeptide seg- system for the synthesis of some cyclic pentapeptides and
ment 13, our condensing system, FPID/(4-MeOC6H4)3P was heptapeptide would not only enhance the cyclization yields but
utilized. Besides, the coupling between 10 and 13 to yield also the cyclization rates [51]. Inspired by this finding, we tried
heptapeptide segment 14 was carried out using 3-(diethoxy- to add some metal chlorides into the reaction, such as LiCl,
phosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) as cou- NaCl, KCl, CsCl (Table 2, entries 8–11). The results indicated
pling reagent, which was developed by Ye’s group in order to that adding NaCl, KCl, CsCl could increase the cyclization
reduce racemization and side reactions [50]. The precursor 2 yield, whereas LiCl decreased the yield. Among the efficient
was obtained via successive deprotection of the C-terminal and metal chlorides, adding 5 equiv of CsCl to the reaction yielded
the N-terminal protecting group of 14. The overall yield of this the product in 44% NMR yield. The isolated yield of pseu-
route is 28%.
dostellarin D under the optimized reaction conditions was 32%.
With the precursor 2 in hand, we then investigated the reaction Consequently, pseudostellarin D can be successfully synthe-
conditions of its cyclization. Considering the solubility of 2 and sized in 32% isolated yield (44% NMR yield) under the opti-
FPID, we chose DMF as the solvent. At the beginning of our in- mized conditions: FPID (2 equiv), (4-MeOC6H4)3P (2 equiv),
vestigation, the reaction was carried out under air within 10 h, TEA (3 equiv), CsCl (5 equiv). The 1H NMR and HRMS spec-
we tested the influence of the adding sequence of TEA, FPID tra of pseudostellarin D are in agreement with data from the lit-
and (4-MeOC6H4)3P, and the results indicated that adding TEA erature [37-39].
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Beilstein J. Org. Chem. 2018, 14, 1112–1119.
Scheme 5: Preparation of the precursor of pseudostellarin D.
Table 2: Optimization of cyclization of linear heptapeptide 2.a
entry
x equiv
additive
atmosphere
time
yield (%)
1
1.2
1.2
1.2
1.2
1.2
–
–
–
–
–
air
air
air
air
N2
10 h
10 h
24 h
24 h
24 h
<18
<15
<23
<20
<27
2b
3
4b
5
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Beilstein J. Org. Chem. 2018, 14, 1112–1119.
Table 2: Optimization of cyclization of linear heptapeptide 2.a (continued)
6c
2.0
2.0
2.0
2.0
2.0
2.0
–
N2
N2
N2
N2
N2
N2
24 h
n.d.
7
–
24 h
24 h
24 h
24 h
24 h
33 (NMR)
44 (NMR)
42 (NMR)
28 (NMR)
40 (NMR)
8d
CsCl (5 equiv)
NaCl (5 equiv)
LiCl (5 equiv)
KCl (5 equiv)
9d
10d
11d
aConditions: performed with 2 (0.05 mmol), TEA (0.15 mmol), DMF (50 mL). Unless otherwise mentioned, the adding sequence of TEA and FPID/(4-
MeOC6H4)3P was adding TEA first and FPID/(4-MeOC6H4)3P 5 minutes later. “x equiv” meant the equivalents of FPID and (4-MeOC6H4)3P. The
NMR yield was calculated by adding CH2ClBr as internal standard substance. bAdding FPID/(4-MeOC6H4)3P first and TEA 5 minutes later. c2 was
dissolved in 2 mL of DMF and added portionwise to the reaction system within 2 h. dMetal chloride was dissolved in 0.33 mL of H2O and then added
to the reaction.
4. Prasad, K. V. S. R. G.; Bharathi, K.; Haseena Banu, B.
Conclusion
Int. J. Pharm. Sci. Rev. Res. 2011, 8, 108–119.
The system of the hypervalent iodine(III) reagent FPID and
5. Dunetz, J. R.; Magano, J.; Weisenburger, G. A.
(4-MeOC6H4)3P can be applied to the solid-phase peptide syn-
Org. Process Res. Dev. 2016, 20, 140–177. doi:10.1021/op500305s
thesis because four bioactive peptides were smoothly obtained
6. Yang, J.; Zhao, J. Sci. China: Chem. 2018, 61, 97–112.
including the precursor 2 of cyclic peptide pseudostellarin D.
Moreover, we have also successfully synthesized the bioactive
cyclic heptapeptide pseudostellarin D using this system.
Notably, FPID can be easily regenerated after peptide coupling
reaction in SPPS. These results, along with the successful use of
the FPID/(4-MeOC6H4)3P system in the solution-phase linear
peptide synthesis [29], show its potential in the practical appli-
cation in peptide synthesis.
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Supporting Information File 1
Experimental procedures and characterization data of all
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compounds.
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Acknowledgements
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This work was financially supported by National Key R&D
Program of China (2017YFD020030202), The National
Natural Science Foundation of China (21472094, 21172110,
21421062) and The Tianjin Natural Science Foundation
(17JCYBJC20300). We are grateful to MS. Bo Sun for the pre-
liminary investigation of this project.
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