Epimerization-free synthesis of cyclic peptide by use of the O-acyl isopeptide method

Article abstract of DOI:10.1002/psc.1261

A head-to-tail cyclization of a protected linear hexapeptide with a C-terminal O-acyl isopeptide proceeded to give a cyclic O-acyl isopeptide without epimerization. The cyclic O-acyl isopeptide possessed different secondary structures compared with the native cyclic peptide. The isopeptide was then efficiently converted to the desired cyclic peptide via an O-to-N acyl migration reaction using a silica gel-anchored base. Copyright

Full text of DOI:10.1002/psc.1261

Research Article
Received: 28 April 2010
Revised: 17 May 2010
Accepted: 17 May 2010
Published online in Wiley Interscience: 6 July 2010
(www.interscience.com) DOI 10.1002/psc.1261
Epimerization-free synthesis of cyclic
peptide by use of the O-acyl isopeptide
method
Taku Yoshiya,‡ Hiroyuki Kawashima,‡ Yuka Hasegawa, Kazuhiro Okamoto,
Tooru Kimura, Youhei Sohma and Yoshiaki Kiso∗
A head-to-tail cyclization of a protected linear hexapeptide with a C-terminal O-acyl isopeptide proceeded to give a cyclic O-acyl
isopeptide without epimerization. The cyclic O-acyl isopeptide possessed different secondary structures compared with the
native cyclic peptide. The isopeptide was then efficiently converted to the desired cyclic peptide via an O-to-N acyl migration
c
reaction using a silica gel-anchored base. Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article
Keywords: racemization; cyclic peptide; isopeptide; epimerization; O-to-N acyl migration
Introduction
cyclic O-acyl isopeptide, would give the target cyclic peptide
(Figure 1C). Martinez and Amblard’s group reported a proof-of-
principle by constructing cyclic peptides via O-acyl isopeptides
[25]. In the communication, the O-acyl isoforms of cyclic tetra,
penta, hexa and heptapeptides were successfully synthesized.
They also showed that the subsequent O-to-N acyl migration
reaction effectively proceeded to afford cyclic penta, hexa and
heptapeptides, while the formation of cyclic tetrapeptide was
difficult probably due to the constraint of the final structure.
We herein report (i) a comparative study on epimerization extent
in head-to-tail cyclization reactions of the native peptide and
O-acylisopeptide,(ii) optimalreactionconditionstoformthecyclic
O-acyl isopeptide, (iii) a concise O-to-N intramolecular acyl
migration using a silica gel-anchored base and (iv) the secondary
structure of the cyclic O-acyl isopeptide.
Cyclic peptides often possess higher biological activity than their
corresponding linear peptides due to conformational constraints
and less entropic penalty [1–4]. Additionally, the rigid structure
of the cyclic peptides generally increases metabolic resistance
against biodegradations [5]. Despite the promises of cyclic
peptides in drug development, a head-to-tail cyclization reaction
of a corresponding linear peptide is often accompanied by
incomplete coupling and/or epimerization (Figure 1A) [6,7]. The
epimerization occurs because, in contrast to urethane-protected
amino acids, peptides easily form chirally labile oxazolones upon
C-terminal carboxyl activation.
We discovered that the presence of an O-acyl instead of N acyl
residue within the peptide backbone significantly changed the
secondary structure of the native peptide. In addition, the target
peptide was subsequently generated by an O-to-N intramolecular
acyl migration reaction. These findings led to the development
of a novel method, called ‘O-acyl isopeptide method’, for peptide
synthesis[8,9].Todate,theO-acylisopeptidemethodhasalsobeen
usedinvariousresearchfields[10–21].Alongtheselines,we[22,23]
andCoinet al.[24]previouslyreportedanovelconvergentmethod
of peptide synthesis: racemization-free segment condensation
based on the O-acyl isopeptide method (Figure 1B). The idea was
that an N-segment with a C-terminal O-acyl isopeptide structure
at Ser or Thr residue could be coupled to an amino group of the
C-segmentwithoutepimerization,becausetheaminogroupofthe
C-terminal isopeptide is protected by a urethane-type protective
group. Thus, formation of the epimerization-inducible oxazolone
would be suppressed upon carboxyl group activation. Finally, the
deprotected O-acyl isopeptide released the native peptide via the
O-to-N acyl migration reaction.
Results and Discussion
Cyclization Reaction of a Hexapeptide by a Conventional
Solution Phase Method
The cyclization of protected linear hexapeptide 1 (H-Arg(Pmc)-
Ala-Gly-Asn(Trt)-Ala-Ser(tBu)-OH, for synthesis: see Section on
Experimental) was performed under three conditions (Table 1):
HATU–collidine method [26–28] in DMF (Entry 1), HATU–collidine
method in CH2Cl2 (1% DMF contained, Entry 2) and DPPA
(diphenylphosphoryl azide)–NaHCO3 [29,30] method in DMF
∗
Correspondence to: Yoshiaki Kiso, Department of Medicinal Chemistry, Center
for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University,
Yamashina-ku, Kyoto 607-8412, Japan. E-mail: kiso@mb.kyoto-phu.ac.jp
If the racemization-free segment condensation strategy is
applied to an intramolecular system, a linear peptide with a
C-terminal O-acyl isopeptide could undergo epimerization-free
cyclization due to the urethane-type protective group at the
Ser/Thr residue, and following the O-to-N acyl migration of the
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal
Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412,
Japan
‡
These authors contributed equally to this work.
c
J. Pept. Sci. 2010; 16: 437–442
Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd.

YOSHIYA ET AL.
(A)
O
R3
H
N
R4
R2
R1
O
R3
O
R5
O
N
H
N
H
H
H
cyclization
deprotection
N
N
NH
O
O
H2N
N
N
OH
O
O
HN
H
H
O
R2
O
R4
O
H
N
R5
∗
R1
N
O
H
O
linear protected peptide
OH
cyclic peptide (epimerized mixture)
O
(B)
O
H
H
N
Boc
Boc
N
OH
segment
peptide B
N
H
condensation
R1
+
peptide B
H2N
R1
O
H
O
H
H
N
H
N
peptide A
peptide A
C-segment
O
O
R2
R2
N-segment
O
R2
TFA•H2N
O
peptide B
N
H
H
N
deprotection/
cleavage
O-to-N intramolecular
acyl migration
R1
N
H
peptide A
peptide B
N
H
O
H
O
R1
H
peptide A
N
HO
O
H
R2
peptide
O-acyl isopeptide
R3
(C)
O
R3
H
N
O
O
H
R4
R2
H
R4
R2
N
N
O-to-N
intramolecular
acyl migration
Boc
R5
N
H
N
OH
NH
O
O
H
O
O
NH
R1
O
R3
O
O
HN
cyclization
deprotection
O
O
O
HN
H
H
R5
H
O
N
N
R1
NH
N
R5
H2N
N
N
N
H
H
H
R1
O
R2
O
R4
O
O
O
O
OH
native cyclic peptide
NH2·TFA
cyclic O-acyl isopeptide
linear protected O-acyl isopeptide
Figure 1. (A) A conventional synthesis of cyclic peptide via a head-to-tail cyclization of a linear peptide; (B) segment condensation methodology based
on the O-acyl isopeptide method; (C) synthesis of cyclic peptide by use of the O-acyl isopeptide method.
(Entry 3). In Entry 1 condition, 39% (HPLC yield) of the cyclic
[D-Ser] derivative was observed in addition to the desired 2
(60%) after 12 h reaction (Figure S1, Supporting Information),
indicating that a large amount of epimerization occurred during
the cyclization reaction. When CH2Cl2 was used (Entry 2), the
[D-Ser] derivative was 2%. In Entry 3, 21% of the starting material
1 remained even after 5 days and the [D-Ser] derivative (15%)
was also observed. The epimers observed in Entries 1–3 were
probably due to the formation of the chirally labile oxazolones
upon C-terminal carboxyl activation.
CH2Cl2 (1% DMF contained), 94% of 4 was formed after 1 h reac-
tionwithoutepimerization(Figure 2B).InthecyclizationwithDPPA
(Entry 3), the des-Ser by-product (36%) was detected in addition to
the desired 4, and a few percent of a peak derived from the D-Ser
derivativewasdetected(Figure 2C). Thedes-Serby-productwould
be derived from the formation of an intramolecular mixed anhy-
dride with Boc-ꢀAla-OH upon activation of the carboxyl group
(Scheme S1, Supporting Information), as proposed in our previous
study with the O-acyl isodipeptide unit [31]. Finally, the isolated
yield of cyclic O-acyl isopeptide 5·TFA after two steps from 3 (i.e.
cyclization of 3 by Entry 2 + deprotection of 4 with TFA-cocktail
followed by HPLC purification) was 53% (Scheme 1, Figure 3A).
Cyclization Reaction in the O-Acyl Isopeptide
O-to-N IntramolecularAcylMigrationReactionofCyclicO-Acyl
Isopeptide to Afford Cyclic Hexapeptide
As shown in Table 2, a protected O-acyl isopeptide (3, Boc-Ser(H-
Arg(Pmc)-Ala-Gly-Asn(Trt)-Ala)-OH), for synthesis: see Section on
Experimental; crude HPLC: Figure S2, Supporting Information)
was cyclized under Entries 1–3 conditions. In the HATU–collidine
method in DMF (Entry 1), the desired 4 (94%, HPLC yield) was
obtained after 12 h reaction and the D-Ser derivative derived from
epimerization was not detected (detection limit: 0.5%) in the crude
sample (Figure 2A). This result indicates that the [D-Ser] formation
(39% in the cyclization of the corresponding native peptide by the
conventionalmethod)couldbesuppressedinthecyclizationatthe
Boc-protected O-acyl isopeptide, suggesting that the ring-closing
reaction did notinvolve the formation of oxazolone. In Entry 2 with
In neutral phosphate buffer (pH 7.6), the isopeptide 5·TFA
was converted to the native cyclic peptide 6 via the O-to-N
intramolecular acyl migration reaction (Figure S3, Supporting
Information). The reaction was completed within 1 min. The result
suggests that the O-to-N acyl migration reaction could rapidly
proceed in conformationally constrained cyclic isopeptide as well
as linear peptides, which agrees with the results from Martinez and
Amblard’s group [25] and a tendency for the O-to-N acyl shift to
takeplaceduring thesynthesisof cyclicdepsipeptide[32]. Wenext
attempted the rearrangement reaction in the presence of a silica
c
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EPIMERIZATION-FREE SYNTHESIS OF CYCLIC O-ACYL ISOPEPTIDE
Table 1. Cyclization of protected linear peptide 1 TFAa
Entry
Reagents
Solvent
DMF
Time
Yieldb (%) 1 : 2:[D-Ser]-2c
1
2
3
HATU (2 eq)-collidine (4 eq)
HATU (2 eq)-collidine (4 eq)
DPPA (3 eq)-NaHCO3 (3 eq)
12 h
1 h
1 : 60 : 39
3 : 95 : 2
d
CH2Cl2
DMF
5 days
21 : 64 : 15
a Peptide concentration = 1 mM; temp = rt.
b Yields were estimated by the peak area in analytical HPLC.
c Authentic D-Ser derivative was synthesized independently and used to determine the ratio of epimerization by HPLC.
d Containing 1% DMF.
Table 2. Cyclization of protected O-acyl isopeptide 3 TFAa
Entry
Reagents
Solvent
DMF
Time
12 h
Yieldb (%) 3 : 4:[D-Ser]-4c:des-Ser-4d
1
2
3
HATU (2 eq)-collidine (4 eq)
HATU (2 eq)-collidine (4 eq)
DPPA (3 eq)-NaHCO3 (3 eq)
6 : 94 : N.D.e : N.D.
6 : 94 : N.D. : N.D.
1 : 61 : 2 : 36
f
CH2Cl2
1 h
DMF
5 days
a Peptide concentration = 1 mM; temp = rt.
b Yields were estimated by the peak area in analytical HPLC.
c Authentic D-Ser derivative was synthesized independently and used to determine the ratio of epimerization by RP-HPLC.
d Cyclo(RAGNA) + the [D-Ala] derivative.
e N.D., not detected (detection limit: 0.5%).
f Containing 1% DMF.
Figure 2. HPLC charts of crude 4 from3 in Entry 1 (A), Entry 2 (B) and Entry 3 (C). ∗No detectable peak derived from [D-Ser]-4 (detection limit: 0.5%). ∗∗∼2%
of a peak derived from the D-Ser derivative was detected. Analytical HPLC was performed using a C18 reverse phase column (4.6 mm × 150 mm; YMC
Pack ODS AM302) with binary solvent system: a linear gradient of CH3CN (45–100% CH3CN, 55 min) in 0.1% aqueous TFA at a flow rate of 0.9 ml min−1
(40 ◦C), detected at 230 nm.
c
J. Pept. Sci. 2010; 16: 437–442 Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd. www.interscience.com/journal/psc

YOSHIYA ET AL.
Scheme 1. Reagents and conditions: (i) HATU (2 eq), 2,4,6-collidine (4 eq), CH2Cl2 (containing 6% DMF), final peptide conc: 1 mM, 3 h, rt; (ii) TFA (92.5%)-
m-cresol (2.5%)-thioanisole (2.5%)-H2O (2.5%), 60 min, rt; (iii) 3-(trimethylammonium)propyl-functionalized silica gel carbonate (2 eq), CH3CN/H2O (1 : 1),
3 h, rt, then treated with 0.1% aqueous TFA.
Figure 3. (A) Purified cyclic O-acyl isopeptide 5; (B) O-to-N acyl migration of 5 to give 6 in water/CH3CN (1 : 1) in the presence of silica gel-anchored
base (2× excess mole), T = 1 min; (C) pure cyclic peptide 6, synthesized via the isopeptide 5. Analytical HPLC was performed using a C18 reverse phase
column (4.6 mm × 150 mm; YMC Pack ODS AM302) with binary solvent system: a linear gradient of CH3CN [2–22% CH3CN, 40 min for (A, B); 0–100%
CH3CN, 40 min for (C)] in 0.1% aqueous TFA at a flow rate of 0.9 ml min−1 (40 ◦C), detected at 220 nm for (A, B) and 230 nm for (C).
gel-anchored base, 3-(trimethylammonium)propyl-functionalized
silica gel carbonate. With the silica gel-anchored base, the desired
peptide can readily be separated by a simple filtration. When
the isopeptide 5·TFA was dissolved in water/CH3CN (1 : 1) in the
presence of two molar excess of silica gel-base, approximately
25% of 6 was formed within 1 min (Figure 3B) and a quantitative
O-to-N acyl migration was observed after 3 h reaction without any
side reaction. The pure target peptide 6 was isolated after filtration
followed by lyophilization of the filtrate (Figure 3C). When the
same reaction was performed in water (without acetonitrile), ∼2%
of hydrolyzed product was observed at the ester of 5, although
the O-to-N migration was completed within 1 h. The obtained 6
had identical elution time on the HPLC analysis as the authentic
sample prepared by the conventional synthetic method.
CD spectrometry (Figure 4). In the CD spectrum of 5, a negative
maximum at 190 nm and positive ellipticity around 200 nm were
observed. In the case of the corresponding native peptide 6, a
positive ellipticity around 190 nm and negative maximum around
203 nm were observed. These results indicated that the O-acyl
isopeptide 5 and cyclic peptide 6 adopted different secondary
structures, suggesting that a well-known secondary structure
disrupting effect by the introduced O-acyl isopeptide observed in
many linear peptides [8–21] is also exerted in cyclic peptides.
Experimental
H-Arg(Pmc)-Ala-Gly-Asn(Trt)-Ala-Ser(tBu)-OH (1)
Secondary Structure of Cyclic O-Acyl Isopeptide
Protectedlinearpeptide1·TFAwassynthesizedinasimilarmanner
to that described in Ref. 23 (0.088 mmol scale). Yield: 42.3 mg,
0.034 mmol,38%(basedontheresin-bound-Ser).MALDI-MS(TOF):
Secondary structures of 5 and 6 in pH 2.6 phosphate buffer
containing 38 mM NaCl at room temperature were examined by
c
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EPIMERIZATION-FREE SYNTHESIS OF CYCLIC O-ACYL ISOPEPTIDE
Cyclo(Arg-Ala-Gly-Asn-Ala-Ser) (6)
Toasolutionof5·TFA(6.1 mg,7.8 µmol)inwater–acetonitrile(1 : 1,
0.2 ml), was added 3-(trimethylammonium)propyl-functionalized
silica gel carbonate (21.7 mg, 15.6 µmol) (final pH 7). After the
solution was shaken for 3 h at room temperature, the silica gel was
filtered off and the desired peptide was washed out with 4.8 ml
of water containing 0.1% v/v TFA. The filtrate was lyophilized to
give 6·TFA as a white amorphous powder. Yield: 5.2 mg, 7.8 µmol,
>99%; MALDI-MS (TOF): Mcalc: 556.6; M + Hfound: 557.6; HPLC
analysis at 230 nm: purity was 96%.
Conclusions
We herein showed that a cyclic hexapeptide was synthesized
in an epimerization-free fashion using the O-acyl isopeptide
method. The head-to-tail cyclization of the linear peptide with
a C-terminal O-acyl isopeptide proceeded to give the cyclic
O-acyl isopeptide without epimerization. Interestingly, the cyclic
O-acyl isopeptide possessed a different secondary structure when
compared with the native cyclic peptide. Finally, the isopeptide
was efficiently converted to the desired cyclic peptide via the
O-to-N acyl migration reaction.
Figure 4. Circular dichroism (CD) spectroscopy of the O-acyl isopeptide 5
and the corresponding native peptide 6 (0.1 mM each) in pH 2.6 phosphate
buffer containing 38 mM NaCl, measured at room temperature. The
samples were measured right after dissolving in the buffer. The molar
ellipticity [θ] values have been normalized for the number of backbone
amide groups.
Acknowledgements
Mcalc: 1139.4; M + Nafound: 1162.3; HPLC analysis at 230 nm: purity
TY is grateful for Research Fellowships of JSPS for Young Scientists.
We are grateful to Dr H. Mukai for fruitful discussions. We thank
Mr W. Yamanashi for technical assistance and Mr H.O. Kumada
for mass spectra measurements. We thank Dr J.-T. Nguyen for his
English correction.
was 93%.
Boc-Ser(H-Arg(Pmc)-Ala-Gly-Asn(Trt)-Ala)-OH (3)
Protected O-acyl isopeptide 3·TFA was synthesized in a similar
manner to that described in Ref. 23 (0.046 mmol scale). Yield:
27.2 mg,0.021 mmol,46%(basedontheresin-bound-isodipeptide
unit). MALDI-MS (TOF): Mcalc: 1183.4; M + Nafound: 1206.0. HPLC
analysis at 230 nm: purity was 97%.
Supporting information
Supporting information may be found in the online version of this
article.
O-acyl isopeptide of cyclo(Arg-Ala-Gly-Asn-Ala-Ser) (5)
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+ Hfound: 557.6; HPLC analysis at 230 nm: purity was 95%.
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