Facile and mild synthesis of linear and cyclic peptides via thioesters

Article abstract of DOI:10.1021/ol501669n

Thioester-mediated peptide bond formation has recently garnered a lot of attention, most notably in its relevance to condensation of large peptide fragments. Herein, a simple and general ligation method for the preparation of linear and cyclic peptides, starting from peptide thioester, mainly p-chlorophenyl, precursors is reported. The inherent advantages of this method are the low epimerization, reduced dimerization, use of mild reaction conditions, and elimination of superfluous coupling reagents.

Full text of DOI:10.1021/ol501669n

Letter
pubs.acs.org/OrgLett
Facile and Mild Synthesis of Linear and Cyclic Peptides via Thioesters
Paola Agrigento,*,† Fernando Albericio,‡,§,∥,⊥ Sylvie Chamoin,† Isabelle Dacquignies,† Halil Koc,†
and Martin Eberle†
†Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland
‡Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona, Spain
§CIBER-BBN, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain
∥Department of Organic Chemistry, University of Barcelona, Martí i Franques
́
1-11, 08028 Barcelona, Spain
⊥School of Chemistry & Physics, University of Kwazulu-Natal, Durban 4001, South Africa
S
* Supporting Information
ABSTRACT: Thioester-mediated peptide bond formation has
recently garnered a lot of attention, most notably in its relevance
to condensation of large peptide fragments. Herein, a simple and
general ligation method for the preparation of linear and cyclic
peptides, starting from peptide thioester, mainly p-chlorophenyl,
precursors is reported. The inherent advantages of this method are
the low epimerization, reduced dimerization, use of mild reaction
conditions, and elimination of superfluous coupling reagents.
atural cyclopeptides play an important role in pharma-
ceutical research.1 Owing to their enhanced resistance to
developed to overcome this restriction. In all of these methods,
N
the role of the cysteine side chain is mimicked by a thiol-
proteases2 and their reduced conformational flexibility
compared to their open-chain counterparts, cyclopeptides are
meeting the stability, potency and selectivity criteria of drugs.3
Many natural cyclopeptides such as Vancomycin, Cyclosporin
A and Romidepsin, to mention only a few, have been developed
as drugs. Indeed, natural cyclopeptides have presented
themselves as formidable starting points in drug discovery
and have helped inspire generations of medicinal chemists. It is
within this area of small cyclic peptides, which is seen by many
as a natural progression from traditional small molecule entities,
that there is a need for enlarging the tool arsenal for their
preparation.
containing auxiliary.9
Thioesters can be considered as activated acids. Thus,
Jakubke10 reported the peptide bond formation, with near-
quantitative yields, of the Cbz-Gly-Phe-8-thioquinolyl ester
with glycine ethyl ester by simply stirring the components at
room temperature. More recently, this method was extended by
Tam.11 He found that poorly reactive alkyl thioesters, activated
by silver salts, react selectively in buffered aqueous solutions
with amines. Finally, Houghten12 reported that thioesters react
with amines in the presence of imidazole. The authors propose
a two-step mechanism. The thioester is reacted reversibly with
imidazole to give the putative acyl imidazole. This intermediate
is then trapped immediately by the amine to give the observed
amide. In theory, this process appears to be catalytic with
respect to the imidazole. In practice, however, concentrations of
1.5 M are essential in order to drive the reactions to
completion. As a consequence of using these latter methods,
the products tend to be contaminated by traces of silver or
imidazole, which could lead to artifacts in biological assays. In
this regard, we were, naturally, very keen to develop a method
which avoided the use of such catalysts.
Most common synthetic methods of preparing head-to-tail
cyclopeptides rely on lactamization of the fully protected amino
acid prepared by SPPS.4 The use of the classical carboxylic acid
activation requires the presence of all side-chain protecting
groups, which can jeopardize the cyclization step due to the
intrinsic low solubility of these peptides. Since the pioneering
work of Kemp, chemists have tried to develop amide bond
formation methods which are compatible with most of the
functional groups present in amino acids.5 This type of amide
formation has been called ligation.6 Arguably, the most
important extension of this method into peptide synthesis is
the native chemical ligation (NCL).7 In NCL, the thiolate/thiol
of an N-terminal cysteine is reacted reversibly with a thioester,
leading to an intermediate cysteine thioester. In a second step,
this intermediate rearranges via an intramolecular 5-membered
S,N-acyl shift which then gives rise to a native cysteine amide.8
In practice, the addition of an excess of thiol catalyzes the
transthioesterification. Since the scope of the NCL is restricted
to the preparation of cysteine amides, methods have been
Herein, we describe a set of conditions which allowed the
uncatalyzed reaction of simple phenyl thioesters with amino
acids. This reaction covers a broad scope and allows the
buildup of linear and cyclic peptides from readily available and
shelf-stable thioesters which, in turn, are obtained by simply
mixing the components together at room temperature.
Received: June 10, 2014
Published: July 17, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
Compared to the in situ activation of carboxylic acids, this
method is more selective with a simpler workup and the yields
tend to be higher.
Table 2. Screening of Different Solvents
First, the influence of the leaving group was investigated.
Thus, different aryl and alkyl thioesters were tested in a model
ligation test system, consisting of peptide thioester Boc-Ala-Ala-
COSR and the N-terminal unprotected tripeptide Gly-Leu-Tyr.
The peptide thioalkyl and thioaryl esters have been synthesized
from the carboxylic acids13 with 61−91% overall yield (see the
Supporting Information). The amino thioesters have been
proven to be shelf-stable. In fact, when these compounds were
stored without efforts to exclude moisture, we were surprised to
learn that they were stable for many months without detectable
decomposition. Thioesters can also be replaced by oxoesters.
However, because of their lower reactivity, ligations tend to be
incomplete, even with prolonged reaction times (Table 1,
b
conversion (%)
entry
solvent
DMSO
1.5 h
8 h
100
24 h
48 h
1
2
3
4
49
100
89
100
THF
8
41
100
ACN
traces
81
traces
100
99
traces
100
99
traces
100
DMF
c
5
DMF/CHCl3
CHCl3
NMP
53
100
6
7
8
9
traces
53
traces
84
traces
99
traces
100
MeOH
H2O
traces
traces
18
49
60
traces
traces
traces
a
a
Reaction conditions: peptide thioester Boc-Ala-Ala-COSC6H4-4NO2
Table 1. Screening of Different Esters with Gly-Leu-Tyr
b
(1.2 equiv), Gly-Leu-Tyr (1 equiv), solvent (60 mM), rt. All the
conversions were determined by HPLC of the crude reaction mixture
and checked for 96 h. DMF/CHCl3 (50:50).
c
a
Table 3. Screening of Different Additives
b
entry
peptide
XR
yield (%)
1
1a
1b
1c
1d
1e
1f
SC6H4-4NO2
SPh
81
2
84
3
SC6H4-4OCH3
SC6H4-4Cl
SC6H4-2Cl
SC6H4-3Cl
SC6H4-4F
SBzl
50
4
95
b
entry
R
additive
HOBt
yield (%)
5
64
1
2
SPh
SPh
SPh
SPh
84
73
66
67
70
81
81
59
51
6
74
7
1g
1h
1i
78
c
3
HOOBt
HOAt
HOBt
8
no conversion
no conversion
no conversion
no conversion
4
5
6
7
8
9
9
SC6H11
SC6H4-4NO2
SC6H4-4NO2
SC6H4-4NO2
SC6H4-4NO2
SC6H4-4NO2
10
11
12
13
14
15
1j
SEt
1k
1l
OPh
HOOBt
HOAt
c
OC6H4-4Cl
OC6H4-4NO2
OC6H4-4OCH3
OC6F5
81
d
1m
1n
1o
54
PS-HOOBt
no conversion
46
a
Reaction conditions: peptide 1: thioester Boc-Ala-Ala-COSR (1.2
equiv), Gly-Leu-Tyr (1 equiv), additive (2 equiv) DMSO (60 mM), 25
h, rt. Isolated yield.
a
Reaction conditions: thioester (1.2 equiv), amine (1 equiv), DMSO
b
(60 mM), 25 h, rt. All the reactions were stopped after complete
b
consumption of starting materials shown by LCMS. Isolated yields.
c
d
Reaction was stopped after 8 days. Reaction was stopped after 4
days.
model, no enhancement of the yield was found using these
additives. Even in the case of p-nitrophenyl thioester, yields
were higher in the absence of HOBt or other polar additives,
typically from 70 to 81% yield. This fact alone favors the
development of a simpler ligation method whereby polar
additives are completely eliminated, facilitating the recovery
and purification processes.
In order to investigate the scope of the method, Boc-Phe-
Phe-Gly-SC6H4-p-NO2 was ligated with a representative set of
amino acid esters having reactive side chains (Table 4). In all
cases, including the N-methylamino acid sarcosine (entry 11),
products were obtained in medium/moderate to high yields.17
Even the coupling with the His-OEt derivative (entry 10) gave
a good yield. In the case of the lysine, the presence of side-chain
acylation product in the reaction mixture accounts for the low
yield (entry 9).
entries 12−14). From the leaving groups tested, p-nitrophenyl
and, in some sense surprisingly, p-chloro thioesters (entries 1
and 4) gave the best yields. In the case of the alkyl thioesters,
there was no conversion at all (entries 9 and 10). We also
found oxoesters to be far less reactive.14 In general, the results
observed could be explained by the reactivity of the leaving
group. Interestingly, a relatively high reactivity of the p-chloro
thioester has been shown.
Next, different solvents were screened for the same reaction
(Table 2). As expected, polar aprotic solvents were found to be
the best suited. In the case of less polar solvents such as THF,
CHCl3, and MeCN, solubility of the reagents was problematic
leading to lower conversions.
As described in the literature, the addition of N-OH additives
could accelerate the ligation reaction.15 Thus, it was reported
that peptide bond formation via 1-hydroxy-1H-benzotriazole
(HOBt) esters resulted in high yields.16 Accordingly, different
additives were investigated (Table 3). However, with our
In this context, a number of tri- and pentapeptides were
acylated by different p-nitrophenyl thioesters (Table 5). In all
cases, fair to good coupling yields could be obtained by varying
the reaction times between 1 and 4 days.
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Organic Letters
Letter
a
a
Table 4. Screening of Amino Esters
Table 6. Cyclization Condition Screening
b
entry
product
peptide 5
yield (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
Gln-O-t-Bu
Tyr-OBz
Asp-OBz
Ser-OBz
70
71
60
72
89
83
53
51
50
75
70
c
d
peptide
temp
yield
(%)
dimer
(%)
b
entry
10
XR
base
(°C)
1
2
3
4
10a
10a
10a
10b
SC6H4-4Cl
SC6H4-4Cl
SC6H4-4Cl
DIPEA
25
25
60
25
82
65
58
47
<1
16
16
4
NaHCO3
NaHCO3
DIPEA
Arg-OBz
Trp-OMe
Asn-OMe
Thr-OMe
Lys-OMe
His-OEt
SC6H4-
4NO2
6g
6h
6i
5
6
10c
10d
10e
OC6H4-
4NO2
DIPEA
DIPEA
DIPEA
25
25
25
37
40
46
11
7
c
9
10
6j
SC6H4-
4OCH3
d
11
6k
Sar-OBz
e
a
7
OH
15
Reaction conditions: peptide 1: thioester (1.2 equiv), amine (1
equiv), DMSO (10 mM), DIPEA (5 equiv), 25 h, rt. Isolated yields.
Isolated yield as a 1:1 mixture of regioisomers. Reaction time 96 h.
b
a
Reaction conditions: thioester (1 equiv), base (2 equiv) DMF/
CHCl3(5 mM), 20 h. The thioester was prepared from the
corresponding Boc derivative, which was removed before the
cyclization. Isolated yields. Isolated yields. HATU, DIPEA, DMF
(1 mM), 30 min, rt. Reaction was stopped after complete consumption
of starting material as shown by LCMS.
c
d
b
a
c
d
e
Table 5. Scope of Thioester Reaction in Ligation Test
Finally, the efficiency of this approach was further
demonstrated by cyclization tests with different sequences
(Table 7). All peptides 12 were obtained without any
optimization efforts with high yields and, for the case of p-
chloro thioesters, with no (12c,e) or very low epimerization
(12a,d). In the case of p-nitro thioester (12b), the result was
not satisfactory. Importantly, all final cyclic peptides were
b
time
(h)
yield
(%)
entry product
peptide 7, peptide 8
1
2
3
4
5
6
9a
9b
9c
9d
9e
9f
Boc-Ala-Ala- COSC6H4-4NO2
Ala-Tyr-Tyr-Ala-Gly-OH
96
48
48
25
48
48
67
75
70
72
59
76
Boc-Ala-Ala- COSC6H4-4NO2
Val-Gly-Phe-Thr-Ser-OH
Boc-Ala-Ala- COSC6H4-4NO2
Glu-Gly-Phe-Thr-Ser-OH
Boc-Ala-Ala- COSC6H4-4NO2
Gly-Arg(NO2)-Gln-Phe-Thr-Ser-OH
Boc-Gly-Val-Pro- COSC6H4-4NO2
Val-Trp-Ala-OH
Table 7. Study of Cyclization of Thioester for Different
a
Sequences
Boc-Val-Ala-Gly- COSC6H4-4NO2
Val-Pro-Val-OH
a
Reaction conditions: thioester (1.2 equiv), amine (1 equiv), DMSO
b
(60 mM), 25 h, rt. Isolated yields.
b
c
time yield dimer
d
entry
1
peptide 12 SR
product (h)
(%)
(%)
dr
Next, the applicability of this method for the preparation of
cyclopeptides was explored using the hexapeptide H-Val-
MeAla-MeLeu-MeVal-MeLeu-Ala-OH as a core sequence.
First of all, different phenyl (thio)esters were investigated.
The cyclizations were performed at 5 mM concentration (Table
6).
The best results were obtained for the p-chloro thioester
(entry 1), clearly superior to the p-nitro thioester in terms of
yield (82% vs 47%) and less dimer formation (<1% vs 4%).
Furthermore, it was also superior to the classical coupling
reaction conditions using HATU, which is considered the
reagent of choice (46%) (entry 7). In addition, we examined
the analogous oxo-ester (entry 5) that gave a lower yield
compared to the thioesters derivatives. This result is in
accordance with the previous observation for the ligation
tests (Table 2, entries 11−14).
12a, Ala-Ala-Gly-Leu-Tyr
SC6H4-4Cl
13a
13a
13b
20
18
24
43
9
95:5
99:1
99:1
2
3
12b, Ala-Ala-Gly-Leu-Tyr
SC6H4-4NO2
49
51
22
<1
12c, Gly-Ile-Thr-Pro-Val-
Ile-Phe
SC6H4-4Cl
4
12d, Gly-Gly-Tyr-Pro-Ile-
Leu-Ile
13c
13d
24
24
45
75
<1
2
99:1
98:2
SC6H4-4Cl
e
5
12e, Ala-Ile-Pro-Phe-Asn-
Ser-Leu
SC6H4-4Cl
a
Reaction conditions: thioester (1 equiv), DIPEA (2 equiv) DMSO (5
b
c
d
mM). Isolated yields. Isolated cyclized dimer. dr determinated by
e
RP-UPLC-MS or chiral-HPLC analysis. Solvent DMF/CHCl3.
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Organic Letters
Letter
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obtained with high diastereomeric ratio, as monitored by chiral
HPLC analysis (Table 7, entries 1−5).
Again, the p-Cl-thioester gave excellent and better results
than the p-NO2 in terms of dimerization (Table 7).
Heterophyllin A, a natural cyclopeptide isolated from the
roots of Pseudostellaria heterophylla18 (entry 3) was synthesized
for the first time using our methodology based on p-Cl
thioester with 51% of isolated yield. In addition pseudostellarin
D (entry 4), a natural heptapeptide, was synthesized in 45%
isolated yield.19 This clearly demonstrated the convenience and
robustness (very low epimerization and dimer formation) of
our methodology based on the p-Cl-thioester for the synthesis
of cyclic peptides such as pseudostellarin D.
In conclusion, we have demonstrated that the uncatalyzed
reaction of aryl thioesters, preferably p-Cl derivatives, with
peptides provides a far superior ligation method than many
currently existing procedures. Interestingly, the p-Cl gave
superior results compared to the p-NO2 in terms of
epimerization during the preparation of the linear thioester
and cyclization and reduced dimerization. By utilization of this
method, peptide synthesis is reduced to simple mixing of two
shelf-stable components. The mild reaction conditions and
stability of the activated acid is compatible with a broad range
of amino acids. Because of the high selectivity and simple
workup, coupling yields are good to excellent and exceed
reported yields in several cases. We believe that this method
can be particularly interesting for the preparation of cyclic
peptides as it has been demonstrated for heterophyllin A and
pseudostellarin D.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Complete experimental procedures and compound character-
ization. This material is available free of charge via the Internet
at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paola.agrigento@novartis.com.
Notes
The authors declare no competing financial interest.
(14) (a) Connors, K. A.; Bender, M. L. J. Org. Chem. 1961, 26, 2498.
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ACKNOWLEDGMENTS
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17045. (b) Wang, P.; Li, X.; Zhu, J.; Chen, J.; Yuan, Y.; Wu, X.;
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■
We thank Thommen Felix and Urs Rindisbacher for the RP-
purification (Global Discovery Chemistry, NIBR, Novartis,
Basel). We are also grateful to Dr. Eric Francotte, Monique
Kessler, and Dan Huynh (Global Discovery Chemistry, NIBR,
Novartis, Basel) for the chiral analysis and purification. We
thank the Novartis Institutes for BioMedical Research
Education Office for a presidential postdoctoral fellowship.
(18) Ning-Hua, T.; Jun, Z.; Chang-Xiang, C.; Shou-Xun, Z.
Phytochemistry 1993, 32, 1327.
(19) These results are clearly better that those reported, which
required more than three solution-phase synthesis steps, all involving
long workups: Himajaa, M.; Harish Kumarb, K.; Ramanaa, M. V.;
Belagalib, S. L. Eur. J. Med. Chem. 1999, 34, 525.
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