Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomycin through ruthenium-based cyclization chemistries

Article abstract of DOI:10.1016/j.tetlet.2017.10.046

The synthesis of a bicyclic tripeptide that mimics the ABC ring system of vancomycin is described by using a ring closing metathesis (RCM) – peptide coupling – ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) strategy.

Full text of DOI:10.1016/j.tetlet.2017.10.046

Accepted Manuscript
Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomy-
cin through ruthenium-based cyclization chemistries
Xin Yang, Lucas P. Beroske, Johan Kemmink, Dirk T.S. Rijkers, Rob M.J.
Liskamp
PII:
S0040-4039(17)31338-2
https://doi.org/10.1016/j.tetlet.2017.10.046
TETL 49408
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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14 October 2017
17 October 2017
Please cite this article as: Yang, X., Beroske, L.P., Kemmink, J., Rijkers, D.T.S., Liskamp, R.M.J., Synthesis of
bicyclic tripeptides inspired by the ABC-ring system of vancomycin through ruthenium-based cyclization
chemistries, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.046
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Synthesis of bicyclic tripeptides inspired by
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Xin Yang, Lucas P. Beroske, Johan Kemmink, Dirk T. S. Rijkers, and Rob M. J. Liskamp
OSugar
N
OMe
Cl
E
N
O
O
H
O
N
D
C
HO
Cl
OH
Mimicry
O
O
O
H
N
H
N
O
NH2Me
N
H
O
N
H
O
O
N
H
N
H
O
NH
NH
A
O
O
CONH2
N
H
O
HN
B
O
Vancomycin
ABC ring mimic 10
OH
OH
HO

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomycin
through ruthenium-based cyclization chemistries
Xin Yanga , Lucas P. Beroskea , Johan Kemminka, † , Dirk T.S. Rijkersa, ∗ and Rob M. J. Liskampb, ∗
aDivision of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science,
Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
bSchool of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow, G12 8QQ, United Kingdom
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of a bicyclic tripeptide that mimics the ABC ring system of vancomycin is
described by using a ring closing metathesis (RCM) – peptide coupling – ruthenium-catalyzed
azide-alkyne cycloaddition (RuAAC) strategy.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Macrocycles
Peptides
Peptidomimetics
Ring-Closing Metathesis
Ru-based Azide-Alkyne Cycloaddition
1. Introduction
highly constrained side-chain to side-chain knotted peptides.
Previously, we have shown that alkyne-, alkene- and triazole-
Cyclic peptides are increasingly important and serve as
relevant lead structures and bioactive molecules in medicinal
chemistry and drug design since they offer a plethora of
biological activities and are especially interesting for the
modulation of protein-protein interactions.1 Their (total)
synthesis, however, is still a highly challenging task and the
development of novel and efficient cyclization approaches is an
active field of research.1f Within this class, multicyclic as well as
side-chain knotted cyclic peptides, including the conotoxins and
cyclotides,2 lantibiotics,3 and glycopeptide antibiotics,4 are of
special interest since they combine extreme potency with shape
persistent folding of the peptide backbone. The most classical
and outstanding example of the effects of macrocyclization and
side-chain knotting is found in the heptapeptide vancomycin.5
These lead to an almost absolute control of shape and folding of
this glycopeptide antibiotic and allows for a very strong binding
of the rather flexible natural target ~Lys-D-Ala-D-Ala-OH.6
tethered cyclic tri-, hexa- and heptapeptides could be synthesized
that mimic vancomycin by binding ~Lys-D-Ala-D-Ala-OH and
~Lys-D-Ala-D-Lac-OH. To further increase the rigidity of these
mimics, we were looking for complementary cyclization
approaches for introducing an additional cyclic constraint to
control the sequence of cyclization and thereby the folding
topology of the peptide backbone. So far, most vancomycin
mimics, including our own, have focused mainly on the CDE-
ring system.10 However, the ABC-ring system probably provides
the additional needed rigidity in the form of a lid, making
vancomycin more of a clam to hold ~Lys-D-Ala-D-Ala-OH more
permanently by reducing the off-rate. Herein, we describe our
efforts towards effective mimicry of the ABC-ring system,10h, 11, 12
which ultimately combined with DE-mimicry should lead to
potent vancomycin mimics.
Over the years we have been inspired by cyclized peptides
such as vancomycin as well as nisin and have explored
alternative approaches for peptide cyclization, among others,
Sonogashira cross-coupling,7 ring closing metathesis,8 and Cu+ as
2. Results and Discussion
Previously, we have reported the synthesis of triazole-
containing vancomycin mimics like 14 (Fig. 1).9b Despite their
bicyclic framework these structures are still relatively flexible,
since mimics such as 14 do bind Ac-Lys(Ac)-D-Ala-D-Ala-OH
well as Ru2+ catalyzed azide-alkyne cycloadditions,9 to obtain
———
∗ Corresponding author. Tel.: +31 (0)6 2026 0572; fax: +31 (0)30 253 6655; e-mail: D.T.S.Rijkers@uu.nl
∗ Corresponding author. Tel.: +44 (0)141 330 5168; fax: +44 (0)141 330 6867; e-mail: Robert.Liskamp@glasgow.ac.uk
† Present address: University of Groningen, Faculty of Mathematics and Natural Sciences, Stratingh Institute, Nijenborgh 4, 9747 AG
Groningen, The Netherlands

2
Tetrahedron
albeit with a lower affinity than vancomycin as judged by
azide into an amine via a Staudinger reduction.22 Therefore, the
second generation Hoveyda-Grubbs catalyst23 was used in
refluxing CH2Cl2 and macrocyclic peptide 8 was isolated in 55%
yield as a mixture of the E/Z diastereoisomers, as shown in
Scheme 3 (8a (Z):8b (E) = 1:2.3). After Boc removal both
diastereoisomers 8a, b could be separated by preparative HPLC
and were characterized by NMR and LC-(HR)MS.
isothermal microcalorimetry (ITC). In order to include the AB-
ring system,11 we wished to apply RCM, which we and others
have successfully reported on several occassions.13 This led to the
target bicyclic tripeptide 10. Retrosynthesis showed that bicycle
10 might be accessible through two consecutive macrocyclization
steps starting from 12 (Fig. 1). Since the preferred order of the
macrocyclization steps, by RCM or RuAAC,14 was not known
(vide infra), precursor dipeptide 7 was proposed, in order to
optimize the RCM in the presence of an azide moiety (Fig. 1).
N3
N3
HO
H
N
H
N
NHBoc
OSugar
Cl
O
NH2
O
5
NHBoc
O
Ref. 16
N
OMe
N
D
N
E
C
N
HO
Cl
O
OH
N
DCC, pyridine
(54%)
N
Mimicry
O
O
O
H
N
H
N
NH2Me
O
O
O
N
H
H
H
N
N
H
N
H
H
O
N
N
NH2Me
4
6
NH
A
O
O
CONH2
N
H
N
H
N
O
H
B
O
O
O
O
N3
1) TFA/CH2Cl2
2) BOP/DIPEA
OH
Vancomycin CDE-Ring Mimic 14
Vancomycin
HO
OH
Mimicry
O
H
N
Boc-
D-Alg-OH
N
N
OMe
NHBoc
N
H
O
CH2Cl2 (92%)
TMS
OMe
N
H
N3
H
N3
retro
synthesis
O
O
H
N
O
O
NHBoc
H
H
N
O
N
H
O
O
N
H
7
N
NH
N
H
NHBoc
O
N
H
HN
O
O
12
7
ABC ring mimic 10
Scheme 2. Synthesis of RCM precursor dipeptide 7.
Figure 1. Design of vancomycin mimics.
TMS
N3
OMe
HG2 (10 mol%)
CH2Cl2
1) TFA/CH2Cl2
2) 3/BOP/DIPEA
CH2Cl2
N3
reflux
O
TMS-protected alkyne 3 was conveniently accessible from
commercially available 4-hydroxy-D-phenylglycine (Scheme 1).
After protection of the amine group, conversion of the phenolic
hydroxy group to a methyl ether and preparation of the methyl
ester, amino acid derivative 1 was subjected to iodination,
according to Nicolaou and co-workers,15 to give mono-iodo
compound 2 in high yield (90%). After saponification of the
methyl ester, the alkyne was installed by a Pd-catalyzed
Sonogashira cross-coupling reaction to give protected
phenylglycine building block 3 in an acceptable yield of 57%.16
(55%)
(54%)
O
O
NHBoc
7
O
NH HN
O
NH
N
H
HN
NHR
8 R = Boc
9
TFA/CH2Cl2
1) TBAF in
THF (95%)
8a R = H.TFA (Z)
8b R = H.TFA (E)
2) [Cp*RuCl]4 (10 mol%)
THF/MeOH
80 oC, MW, 2 h (22%)
N
N
N
OMe
OMe
N
4
5
N
N
O
1
1) TFA/CH2Cl2
2) HPLC
O
O
O
O
NHBoc
NH2
O
NH
NH
2
N
3
7
N
H
HN
H
HN
6
11a (Z) (20%)
11b (E) (37%)
OH
OMe
1) Boc2O/NaHCO3
H2O/acetone (quant.)
2) CH3I/K2CO3
10
I2/CF3CO2Ag
CHCl3 (90%)
O
Scheme 3. RCM–coupling–RuAAC strategy for the synthesis of bicyclic
tripeptide 10.
DMF (86%)
HO
MeO
NH2
N
H
O
1
O
O
OMe
TMS
OMe
In its protected form, both diastereoisomers (Rt 32.97 and
33.36 min) of macrocycle 8 could not be separated (see, ESI Fig.
SI-18). However, when an aliquot of 8 was treated with TFA to
remove the Boc functionality, this resulted in a base line
separation of both diastereoisomers 8a, b (Rt 22.24 and 22.98
I
1) LiOH, H2O/THF (quant.)
2) TMS-acetylene
10 mol% [Pd(PPh3)4]/CuI/DIPEA
THF (57%)
O
O
MeO
HO
N
H
O
N
H
O
2
3
O
O
1
Scheme 1. Synthesis of phenylglycine building block 3.
min, Fig. SI-19). The H NMR spectrum of diastereoisomer 8a
gave broad peaks at 25 ˚C; fortunately at higher temperature,
peak splitting was observed and at 80 ˚C a well-defined J
coupling of the olefinic protons could be derived (Fig. SI-11).
This value, ~8 Hz, corresponded to the Z-configuration of the
double bond. The proton spectrum of diastereoisomer 8b had
resulted already at 25 ˚C in a well-defined J coupling of ~13 Hz
for the alkene bond indicating an E-geometry of 8b (Fig. SI-
12).24
The synthesis of the required RCM-precursor 7 is shown in
Scheme 2. To this end 2-allylaniline 4 was obtained by a Claisen
rearrangement according to Brucelle and Renaud.17 In a first
attempt to couple aniline 4 to azido acid 5,18 BOP/DIPEA as a
coupling reagent did not afford anilide 6. Therefore, DCC in
pyridine was used to form the anilide 6 in 54% yield since this
combination of coupling reagent/solvent was effective in the
coupling of the poor nucleophile 4-nitroaniline with amino
acids.19 After deprotection of anilide 6 by treatment with TFA,
Boc-D-Alg-OH was coupled using BOP/DIPEA, and bisalkene
dipeptide 7 was obtained in 92% yield over two steps.
Thus, macrocycle 8 was treated with TFA and the resulting
free α-amine coupled to alkyne derivative 3 in the presence of
BOP/DIPEA to afford the protected click precursor 9 in 54%
overall yield (Scheme 3). Then, tripeptide 9 was treated with
TBAF to remove the TMS functionality, and the unprotected
alkyne which was isolated in 95% yield after column
chromatography, subjected to RuAAC in THF/MeOH at 80 ˚C
As RCM precursor peptide 7 contained an azide moiety, the
first20 and second21 generation Grubbs catalysts could not be used
since the tricyclohexylphosphine ligands would likely reduce the

3
under microwave irradiation in the presence of 10 mol%
reactivity to yield 2-silyl-substituted 1,3-dienes, which,
[Cp*RuCl]4. Bicyclic tripeptide 10 was isolated in 22% yield
however, were not identified.26 Alternatively, TMS-protected
precursor peptide 12 was treated with TBAF and subsequently
subjected to RuAAC to install the triazole moiety as the cyclic
constraint. Via this route, macrocycle 13 was obtained in an
improved 41% yield compared to the above preparation of 10
(Scheme 3). Unfortunately, RCM of 13 did not result in the
successful isolation of bicyclic tripeptide 10. TLC analysis
indicated that conversion of the starting compound was
incomplete and some baseline material was present, additionally
the formation of bicyclic tripeptide 10 could not be observed by
LCMS.
after column chromatography as
a
mixture of E/Z
diastereoisomers. Heating at 80 ˚C under microwave irradiation
in the absence of [Cp*RuCl]4 did not lead to any conversion. To
improve the yield of cyclization, lower and higher catalyst
loadings (5 and 15 mol%, respectively) were used which turned
out to be ineffective since incomplete conversion of the starting
material (at 5 mol%) or extensive formation of baseline
compounds (at 15 mol%) were observed. As
a control
experiment, the unprotected alkyne was also subjected to regular
CuAAC25 in the presence of either CuI or [Cu(CH3CN)4]PF6 as
the Cu+ species; these reaction conditions did not lead to the
formation of bicyclic tripeptide 10. This experiment showed that
a 1,5-triazole moiety with a curved geometry was essential for
ring closure since the more linear geometry of the 1,4-triazole
was clearly incompatible with the topology of the bicyclic
framework of tripeptide 10. Similar to macrocycle 8, the
individual diastereoisomers of bicyclic tripeptide 11 (Z-11a and
E-11b, respectively) could be obtained after Boc removal of 10
and purification by preparative HPLC. It is interesting to note
that the Z:E ratio during the conversion of 8a, b into 11a, b
shifted from 1:2.3 to 2:1, an indication that the Z-geometry of the
alkene was favored in the bicyclic tripeptide topology.
Figure 2. Superimposition of balhimycin (in red) with bicyclic tripeptide
11a (left) and 11b (right), respectively. The carbon atoms αC1, αC2, αC3,
arom-C4, triazole-C5, N6, benzylic-C7 have been used as fixed coordinates for
superimposition.
Since bicyclic tripeptide 11 can be used as a versatile building
block in the synthesis of tricyclic heptapeptides to mimic the
side-chain to side-chain connectivity pattern of vancomycin,
hydrogenation of the double bond to an alkane bridge would be
desirable to obtain a single isomer instead of an E/Z mixture of
diastereoisomers. Therefore, several hydrogenation conditions in
the presence of Pd/C, Raney Ni, and Pd(OH)2 were investigated,
unfortunately all were unsuccessful.
Table 1. The binding affinity as measured using ITC.
compound
VM
ligand
Ka (M-1)a
Ac-Lys(Ac)-D-Ala-D-Ala-OH (3.95 0.41)×105
Ac-Lys(Ac)-D-Ala-D-Lac-OH (2.38 0.23)×103
Ac-Lys(Ac)-D-Ala-D-Ala-OH (2.35 0.36)×103
Ac-Lys(Ac)-D-Ala-D-Lac-OH (2.17 0.30)×103
Ac-Lys(Ac)-D-Ala-D-Ala-OH (4.06 0.84)×103
Ac-Lys(Ac)-D-Ala-D-Lac-OH (1.21 0.86)×103
VM
11a
11a
1) TBAF, THF (94%)
TMS
N3
OMe
1) TFA/CH2Cl2
2) 3/BOP/DIPEA
CH2Cl2
2) [Cp*RuCl]4 (10 mol%)
11b
THF/MeOH
80 oC, MW, 2 h (41%)
11b
(69%)
O
H
N
H
N
7
aMeasured in a Na-citrate/citric acid buffer (0.02 M, pH 5.1), VM:
vancomycin.
N
H
NHBoc
O
O
12
HG2 (10 mol%)
CH2Cl2
reflux
N
OMe
N
The structures of bicyclic tripeptides 11a (as the Z-
diastereoisomer) and 11b (as the E- diastereoisomer) were energy
minimized using the simulated annealing protocol employing the
AMBER99 force field using the YASARA Structure 10.5.2.1
software package.27 The peptides were superimposed with the left
half of the vancomycin-related balhimycin antibiotic comprising
the ABC-ring system.28 An RMSD of 0.76 and 0.58 Å over seven
atoms was calculated (see Scheme 3 for atom numbering) of the
superimpositions of 11a and 11b, respectively. To evaluate if this
structural resemblance correlates with binding affinity toward
Ac-Lys(Ac)-D-Ala-D-Ala-OH and Ac-Lys(Ac)-D-Ala-D-Lac-OH,
isothermal microcalorimetry (ITC) was performed, as shown in
Table 1.29, 30 Based on these data, mimics 11a and 11b still bind
Ac-Lys(Ac)-D-Ala-D-Ala-OH appreciably, considering that a
large part of the 'clam' is missing, albeit at least 100-fold less
compared to vancomycin. Bicycle 11b is somewhat more active
than 11a, while binding toward Ac-Lys(Ac)-D-Ala-D-Lac-OH
was comparable for all three receptor molecules. This was in line
with the MIC-values obtained from a growth inhibition assay31 of
the Staphylococcus aureus ATCC 49320 strain, where values of
300 µg/mL (11b), >300 µg/mL (11a) and 2 µg/mL (VM) were
HG2 (10 mol%)
CH2Cl2
9
N
reflux
O
10
O
NHBoc
H
N
NH
13
N
H
O
Scheme 4. Alternative RCM–coupling–RuAAC strategies for the
synthesis of bicyclic tripeptide 10.
Two reverse reaction sequences to arrive at the desired
bicyclic tripeptide 10 were also investigated, both starting from
linear dipeptide 7 (Scheme 4). As the first step, Boc-protected 7
was treated with TFA and the resulting amine coupled to alkyne
derivative 3 in the presence of BOP/DIPEA to afford tripeptide
12 in 69% yield after purification by column chromatography.
RCM of precursor peptide 12 in the presence of second
generation Hoveyda-Grubbs catalyst in CH2Cl2 or 1,2-
dichloroethane did not result in the formation of alkene-bridged
macrocycle 9. The progress of the reaction was monitored by
LCMS, and although starting material had disappeared, the
desired bicyclic peptide 9 could not be observed. In hindsight, it
was assumed that the desired ene-ene RCM pathway was
possibly overrun by the thermodynamically favored ene-yne
found, respectively. Although
a
reasonable structural
resemblance was found, not unexpectedly, for efficient binding
(and activity) some extra factors need to be addressed such as the

4
Tetrahedron
Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am.
Chem. Soc. 1999, 121, 10004–10011. (i) Arnusch, C. J.; Pieters,
R. J. Eur. J. Org. Chem. 2003, 3131–3138. (j) Pearson, A. J.;
Ciurea D. V. J. Org. Chem. 2008, 73, 760–763.
proper alignment of hydrogen bonding and further
rigidification, possibly in attempts to combine the ABC and
CDE-ring systems.9b
11. Although bicycle 10 represents the ACD-ring system of
vancomycin we call this fragment an ABC-ring mimic to stress the
fact that 10 represents the C-terminal part of vancomycin.
12. (a) Evans, D. A.; Dinsmore, C. J. Tetrahedron Lett. 1993, 34,
6029–6032. (b) Evans, D. A.; Dinsmore, C. J.; Evrard, D. A.;
DeVries, K. M. J. Am. Chem. Soc. 1993, 115, 6426–6427.
13. (a) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem.
Soc. 1996, 118, 9606–9614. (b) Gradillas, A.; Pérez-Castells, J.
Angew. Chem., Int. Ed. 2006, 45, 6086–6101. (c) Brik, A. Adv.
Synth. Catal. 2008, 350, 1161–1675. (d) Gleeson, E. C.; Jackson,
W. R.; Robinson, A. J. Tetrahedron Lett. 2016, 57, 4325–4333. (e)
Rijkers, D. T. S. Top. Heterocycl. Chem. 2017, 47, 191–244.
14. (a) Barlow, T. M. A.; Tourwé, D.; Ballet, S. Eur. J. Org. Chem.
2017, 4678– 4694. (b) Johansson, J. R.; Beke-Somfai, T.; Said
Stålsmeden, A.; Kann, N. Chem. Rev. 2016, 116, 14726–14768.
(c) Kelly, A. R.; Wei, J.; Kesavan, S.; Marié, J. C.; Windmon, N.;
Young, D. W.; Marcaurelle, L. A. Org. Lett. 2009, 11, 2257–2260.
(d) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao,
H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130,
8923–8930.
15. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.;
Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bräse, S.;
Solomon, M. E. Chem. Eur. J. 1999, 9, 2602–2621.
16. (a) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084–
5121. (b) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874–
922.
17. Brucelle, F.; Renaud, P. Org. Lett. 2012, 14, 3048–3051.
18. Initially we used imidazole-1-sulfonyl azide·HCl as the diazo-
transfer reagent for the synthesis of azido acid 5, acccording to: (a)
Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–
3800, however, currently the significantly safer to handle
imidazole-1-sulfonyl azide·H2SO4 is preferred, according to: (b)
Potter, G. T.; Jayson, G. C.; Miller, G. J.; Gardiner, J. M. J. Org.
Chem. 2016, 81, 3443–3446.
3. Conclusion
In conclusion, bicyclic tripeptide 10 as a mimic of the ABC-
ring system was successfully synthesized starting from precursor
dipeptide
7 following an RCM-coupling-RuAAC strategy.
Mimics of this part of the vancomycin structure are less explored
as only a single hydrogen bond contributes to the binding of Ac-
Lys(Ac)-D-Ala-D-Ala-OH via the carbonyl oxygen of the lysine
residue. The mixture of double bond isomers could be separated
by HPLC to give each individual E/Z diastereoisomer as the free
amine as judged by NMR and LC-MS. Bicyclic tripeptide 10
represents an important building block to ultimately arrive at a
series of tricyclic heptapeptides for possible effective mimicry of
vancomycin in which ruthenium-based cyclization approaches
will be used to control the topology and rigidity of the peptide
backbone.
Acknowledgments
This research was supported by the China Scholarship Council
(CSC) awarded to X.Y. We thank Javier Sastre Torano for
performing the HRMS analyses and Hao Zhang for his help with
the modeling experiments.
References and notes
1. (a) Gilon, C.; Halle, D.; Chorev, M.; Selinger, Z.; Byk, G.
Biopolymers 1991, 31, 745–750. (b) Wessjohann, L. A.; Ruijter,
E.; Garcia-Rivera, D.; Brandt, W. Mol. Divers. 2005, 9, 171–186.
(c) Katsara, M.; Tselios, T.; Deraos, S.; Deraos, G.; Matsoukas,
M.-T.; Lazoura, E.; Matsoukas, J.; Apostolopoulos, V. Curr. Med.
Chem. 2006, 13, 2221–2232. (d) Driggers, E. M.; Hale, S. P.; Lee,
J.; Terrett, N. K. Nat. Rev. Drug Discovery 2008, 7, 608–624. (e)
Marsault, E.; Peterson, M. L. J. Med. Chem. 2011, 54, 1961–2004.
(f) White, C. J.; Yudin A. K. Nat. Chem. 2011, 3, 509–524.
2. (a) Janes, R. W. Curr. Opin. Pharmacol. 2005, 5, 280–292. (b) de
Veer, S. J.; Weidmann, J.; Craik, D. J. Acc. Chem. Res. 2017, 50,
1557–1565.
19. Rijkers, D. T. S.; Adams, H. P. H. M.; Hemker, H. C.; Tesser, G.
I. Tetrahedron 1995, 51, 11235–11250.
20. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100–110.
21. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
22. For a comprehensive review, see: Gololobov, Y. G.; Kasukhin, L.
F.; Tetrahedron 1992, 48, 1353–1406.
23. Garber, S. B.; Kingsbury, J. S.; Gray B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179.
24. Karplus M. J. Am. Chem. Soc. 1963, 85, 2870–2871.
25. (a) Meldal, M.; Tornøe C. W. Chem. Rev. 2008, 108, 2952–3015.
(b) Hein, J. E.; Fokin, V. V. Chem Soc Rev. 2010, 39, 1302–1315.
(c) Singh, M. S.; Chowdhury, S.; Koley, S. Tetrahedron 2016, 72,
5257–5283.
3. Chatterjee, C.; Paul, M.; Xie, L.; van der Donk, W. A. Chem. Rev.
2005, 105, 633–684.
4. Binda, E.; Marinelli, F.; Marcone, G. L. Antibiotics 2014, 3, 572–
594.
26. (a) Park, S.; Kim, M.; Lee, D. J. Am. Chem. Soc. 2005, 127, 9410–
9415. (b) Ostrowska, S.; Powala, B.; Jankowska-Wajda, M.; Zak,
P.; Rogalski, s.; Wyrzykiewicz, B.; Pietraszuk, C. J. Organomet.
Chem. 2015, 783, 135–140.
27. Modelling has been performed with using the YASARA software
(www.yasara.org).
28. The crystal structure of balhimycin (a vancomycin-related
glycopeptide antibiotic) in complex with Lys-D-Ala-D-Ala
(Protein Data bank accession code: 1GO6) was used,
see:Lehmann, C.; Bunkóczi, G.; Vértesy, L.; Sheldrick, G. M. J.
Mol. Biol. 2002, 318, 723–732.
29. McPhail, D.; Cooper, A. J. Chem. Soc. Faraday Trans. 1997, 93,
2283–2289.
30. Xie, J.; Okano, A.; Pierce J. G.; James, R. C.; Stamm, S.; Crane C.
M.; Boger, D. L. J. Am. Chem. Soc. 2012, 134, 1284–1297.
31. Wiegand, I.; Hilpert, K.; Hancock, R. E. W. Nature Protocols
2008, 3, 163–175.
5. (a) James, R. C.; Pierce, J. G.; Okano, A.; Boger, D. L. ACS
Chem. Biol. 2012, 7, 797–804. (b) Okano, A.; Isley, N. A.; Boger,
D. L. Chem. Rev. 2017, 117, 11952–11993.
6. (a) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38,
1172–1193. (b) Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.;
Winssinger, N.; Hughes, R.; Bando, T. Angew. Chem., Int. Ed.
1999, 38, 240–244.
7. ten Brink, H. T.; Rijkers, D. T. S.; Liskamp, R. M. J. J. Org.
Chem. 2006, 71, 1817–1824.
8. ten Brink, H. T.; Rijkers, D. T. S.; Kemmink, J.; Hilbers, H. W.;
Liskamp, R. M. J. Org. Biomol. Chem. 2004, 2, 2658–2663.
9. (a) Zhang, J.; Kemmink, J.; Rijkers, D. T. S.; Liskamp, R. M. J.
Org. Lett. 2011, 13, 3438–3441. (b) Zhang, J.; Kemmink, J.;
Rijkers, D. T. S.; Liskamp, R. M. J. Chem. Commun. 2013, 49,
4498–4500.
10. (a) Pant, N.; Hamilton, A. D. J. Am. Chem. Soc. 1988, 110, 2002–
2003. (b) Evans, D. A.; Ellman, J. A.; DeVries K. M. J. Am.
Chem. Soc. 1989, 111, 8912–8914. (c) Boger, D. L.; Borzilleri, R.
M.; Nukui, S. Bioorg. Med. Chem. Lett. 1995, 5, 3091–3096. (d)
Bois-Choussy, M.; Neuville, L.; Beugelmans, R.; Zhu, J. J. Org.
Chem. 1996, 61, 9309–9322. (e) Boger, D. l.; Borzilleri, R. M.;
Nukui, S.; Beresis, R. T. J. Org. Chem. 1997, 62, 4721–4736. (f)
Xu, R.; Greiveldinger, G.; Marenus, L. E.; Cooper, A.; Ellman, J.
A. J. Am. Chem. Soc. 1999, 121, 4898–4899. (g) Boger, D. L.;
Castle, S. L.; Miyazaki, S.; Wu, J. H., Beresis, R. T.; Loiseleur, O.
J. Org. Chem. 1999, 64, 70–80. (h) Boger, D. L.; Miyazaki, S.;
Supplementary Material
Experimental procedures, 1H and 13C NMR spectra, HPLC
profiles, HRMS spectra and ITC binding curves.

5
•An efficient synthesis of highly constrained bicyclic
tripeptides.
•Constraining peptides by two consecutive Ru-catalyzed
macrocyclizations.
•Synthesis of a tripeptide motif to mimic the ABC-ring
system of vancomycin.