Synthesis of Biaryl-Bridged Cyclic Peptides via Catalytic Oxidative Cross-Coupling Reactions

Article abstract of DOI:10.1002/anie.201913305

Biaryl-bridged cyclic peptides comprise an intriguing class of structurally diverse natural products with significant biological activity. Especially noteworthy are the antibiotics arylomycin and its synthetic analogue G0775, which exhibits potent activity against Gram-negative bacteria. Herein, we present a simple, flexible, and reliable strategy based on activating-group-assisted catalytic oxidative coupling for assembling biaryl-bridged cyclic peptides from natural amino acids. The synthetic approach was utilized for preparing a number of natural and unnatural biaryl-bridged cyclic peptides, including arylomycin/G0775 and RP 66453 cyclic cores.

Full text of DOI:10.1002/anie.201913305

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Accepted Article
Title: Synthesis of Biaryl-Bridged Cyclic Peptides via Catalytic
Oxidative Cross-Coupling Reactions
Authors: Mor Ben-Lulu, Eden Gaster, Anna Libman, and Doron Pappo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913305
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10.1002/anie.201913305
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Synthesis of Biaryl-Bridged Cyclic Peptides via Catalytic
Oxidative Cross-Coupling Reactions
Mor Ben-Lulu,‡ Eden Gaster,‡ Anna Libman and Doron Pappo*[a]
group reported an improved synthesis based on approach B.[4c, 7]
Abstract: Biaryl-bridged cyclic peptides comprise an intriguing class
of structurally diverse natural products with significant biological
activity. Especially noteworthy are the antibiotics arylomycin and its
synthetic analog G0775, which exhibits potent activity against Gram-
negative bacteria. Here, we present a simple, flexible, and reliable
strategy based on activating group-assisted catalytic oxidative
coupling for assembling biaryl-bridged cyclic peptides from natural
amino acids. The synthetic approach was utilized for preparing a
number of natural and unnatural biaryl-bridged cyclic peptides,
including arylomycin/G0775 and RP 66453 cyclic cores.
The total synthesis of other bioactive di-tyrosine-containing
macrocyclic peptides, such as RP 66453 (3, Figure 1A) has also
been achieved using various palladium-catalyzed cross-coupling
8]
strategies.[2a,
Nevertheless, a series of functional group
interconversion steps were needed before and after the key
cross-coupling step to ensure selectivity, thus making these
processes lengthy and less favorable in-terms of sustainability. In
order to provide an alternative direct synthesis of the arylomycin
cyclic core 4, the groups of Romesberg and Baran developed
conditions for the oxidative macrocyclization of N-Boc-N-Me-L-
Hpg-L-Ala-L-Tyr-OMe tripeptide 5 according to approach A
(Figure 1B).[4b] In their synthesis, a stoichiometric amount of
copper amine oxidant, which had been prepared from two
equivalents of a freshly crystallized Cu[MeCN]4[PF6] complex and
N,N,N,N-tetramethylethylenediamine (TMEDA) under an O2
atmosphere, afforded the arylomycin cyclic core 4 in an
approximately 60% yield. However, in spite of their success in
identifying the coupling conditions, the generality of the method
was not proven. With the aim to establish a novel platform for the
rapid and general assembly of biaryl-bridged cyclic peptides, we
turned to metal-catalyzed oxidative cross-coupling methods that
are under development in our group[9], employing approach B.
In the past decade, a number of biaryl-bridged cyclic peptides
showing good binding affinity, target selectivity, and low toxicity
have successfully entered the market for the treatment of bacterial
and fungal infections.[1] These biaryl-bridged cyclic peptides
belong to an important class of structurally diverse[2] biologically
active natural products including arylomycin A (1, Figure 1A),
which exhibits only limited activity against pathogens, and its
chemically-optimized analog, G0775 (2, Figure 1A),[3] a potent
antibacterial drug candidate.[4] The conservation of the arylomycin
macrocyclic core in G0775 during the structure-activity-
relationship studies emphasizes the importance of the rigid biaryl-
bridged cyclic core for preserving the mode of activity.[1] However,
the preparation of such cyclic peptides for future therapeutics still
remains challenging. In nature, metalloenzymes are involved in
catalyzing the oxidative coupling of two phenolic units, such as
tyrosine (Tyr) and 4-hydroxyphenyl glycine (Hpg).[5] However,
mimicking this reactivity in the laboratory is not straightforward,
due to the relatively high oxidation potentials of these residues
and the difficulty in enforcing spatial proximity of the reactive ends
in the linear peptide precursor.[6] Herein we propose using
removable activating groups that facilitate the oxidative cross-
coupling of phenolic-based amino acids as a method for the rapid
and efficient assembly of biaryl-bridged cyclic peptides.
Retrosynthetically, two main approaches for synthesizing
biaryl-bridged cyclic peptides have been proposed (Figure 1B).
These approaches (designated here as A and B) differ in the order
in which the biaryl coupling and the amide bond formation steps
are performed. Whereas approach A relies on the macrocyclic
coupling of phenol-based linear peptides, approach B requires
chemoselective cross-coupling between two discrete phenol-
based amino acids, followed by a macrolactamization step. For
example, the Romesberg group prepared the arylomycin cyclic
core 4 in 14 synthetic steps via palladium-catalyzed cross-
coupling strategy according to approach A, whereas the Lim
The first part of the study was devoted to exploring the
conditions needed for synthesizing the simplest biaryl-bridged
linear peptide, di-tyrosine 13, by oxidative dimerization of N-Cbz-
L-Tyr-OMe 10. Previous attempts to dimerize two tyrosine
residues
by
chemoenzymatic,[10]-[11]
photochemical,[12]
electrochemical,[13] or metal oxidation reactions[11a, 14] have met
with only limited success. A number of reasons may account for
this lack of success: (i) the relatively high oxidation potential of
tyrosine precludes selective oxidation under mild conditions;[14b]
(ii) the di-tyrosine coupling product is more reactive than the
parent tyrosine amino acid and is therefore prone to
overoxidation;[15] and (iii) the tyrosyl radical can react through the
ortho- and para-positions as well as the hydroxyl group,[11a, 16]
leading to a mixture of coupling and dehydrogenation products.
For example, the oxidative coupling of tyrosine 10 using
5,10,15,20-tetraphenyl-21H,23H-porphine
iron(III)
chloride
(Fe[TPP]Cl) [0.5 mol %] and urea hydrogen peroxide (UHP, 1
equiv) in HFIP (rt, 24 h, Table 1, entry 1), catalytic conditions that
were developed in our group,[9c, 9f] afforded a complex mixture of
dehydrogenative products (Figure 2A) from which trace amounts
of di-tyrosine 13 were isolated. In
[a]
Ben-Lulu, M.; Gaster, E.; Libman, A.; Prof. Dr. Pappo, D.
Department of Chemistry, Ben-Gurion University of the Negev
Beer Sheva, 84105 (Israel)
E-mail: pappod@bgu.ac.il
‡These authors contributed equally
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201913305
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COMMUNICATION
Figure 1. A] Natural and unnatural bioactive biaryl-bridged cyclic peptides; B] Synthetic strategies for preparing the arylomycin cyclic core via oxidative coupling
methods.
Table 1. Metal-catalyzed oxidative coupling of activated and non-activated
tyrosines 10 and 11, respectively.
removable activating group (AG). We postulated that a tert-butyl
group at the ortho position of tyrosine would comply with the
electronic and steric requirements of tyrosine as a coupling
partner and therefore enhance its reactivity.[9a, 9c, 9e, 9f, 17] This idea
derives from the evidence that bulky alkyl groups at the ortho
position of phenols reduce the bond dissociation energy (BDE) of
the ArO−H bond.[18] For example, the theoretical BDE of 2-tert-
butyl-4-methylphenol is about 2-3 kcal/mol lower than the value
calculated for para-cresol,[19] which shares the same electronic
structure as tyrosine. To date, only a few studies have used
removable substituents with the intention of inducing
regioselectivity in the oxidative coupling of phenols.[20] Hey, for
example, synthesized 4,4'-biphenol by blocking the ortho
positions of phenol with tert-butyl groups,[20a] whereas the
Stephenson group prepared tert-butylated resveratrol by multi-
step synthesis in order to control the regioselectivity in oxidative
dimerization reactions.[20b, 20c]
60
Tyr 10
Non-
activated
Tyr 10
13 [%]a,b
50
40
30
20
10
0
10
(10)3
Activated
Tyr 11
14 [%]a,b
13
10
#
1
catalyst (X mol %)
Fe[TPP]Cl (0.5)
Fe[TPP]Cl (0.5)
FeCl3 (2.5)
oxidant
UHP
(2-t-Bu)Tyr 11
11
14
[10]
<1
23
18
5
[97]
2c
3
mCPBA
DTBP
81d
11
-10
70e
-1
0
1
2
3
0
2
4
6
8
10
12
14
Time [min]
Potential [V]
f
4
[Cu(OH)(tmeda)]2Cl2 (2)
Co[salen] (1)
O2
80
Figure 2. [A] HPLC chromatograms for the oxidative coupling of compounds 10
and 11 by Fe[TPP]Cl (Table 1, entry 1). [B] Cyclic voltammetry of non-activated
Tyr 10 (red curve) and activated Tyr 11 (black curve). E(V) vs. Ag/ 0.01 M
AgNO3.
5
airf
[95]
[a] HPLC yield using mesitylene as internal standard; [b] In square
parenthesis: isolated yields; [c] 1,2-dichloroethane instead of HFIP; [d] 5h;
[e] 2h; [f] 1 atm.
In exploiting the activating group strategy, we prepared Cbz-L-
(2-t-Bu)Tyr-OMe 11 from tyrosine methyl ester [tert-butyl chloride
in methanesulfonic acid, then CbzCl, Na2CO3, THF-H2O] on a 50
g scale in 70% yield. The oxidation potential of activated tyrosine
11 was found to be lower by about 160 mV (vs Ag/AgNO3,
CH3CN) than that of non-activated tyrosine 10 (Figure 2B).
order to address the above difficulties, we examined the idea of
facilitating the oxidative coupling of tyrosine by introducing a
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10.1002/anie.201913305
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Consequently, under the above oxidative coupling conditions
(Fe[TPP]Cl (0.5 mol %), UHP (1 equiv), HFIP, rt) activated
tyrosine 11 underwent chemoselective dimerization (Figure 2A)
within 15 min, affording the desired 2,2'-(di-t-Bu)di-tyrosine
product 14 in 97% yield (Table 1, entry 1). The significant
improvement in the coupling efficiency and selectivity of activated
tyrosine 11 in comparison with non-activated tyrosine 10 may be
attributed to the ability of the tert-butyl group to (i) facilitate the
oxidation step, thereby increasing the lifespan of the phenoxyl
radical intermediate significantly, (ii) prevent the sequential
oligomerization of di-tyrosine, and (iii) ensure selective coupling
promote the oxidative cross-coupling led to a rapid dimerization
of activated tyrosine residue
8
under most conditions
(Supplementary Table S4). Satisfactory results were obtained
when compound 8 (1 equiv) and meta-chloroperbenzoic acid
(mCPBA, 2 equiv) were added portion-wise to a solution of 7 (3
equiv) and Fe[TPP]Cl (1 mol%) in 1,2,-dichloroethane. Under
these conditions, the desired biaryl-bridged linear peptide 6 was
isolated in 48% yield (multigram-scale).
In general, macrolactamization of linear biaryl-bridged cyclic
peptides is a challenging step that relies heavily on the peptide
sequence, the ring size, and the coupling reagents.[6, 22] In this
study (Supplementary Table S5), adequate results were obtained
when a solution of the debenzylated biaryl-bridged linear peptide
6 (Pd-C/H2, EtOH) was added slowly to a highly diluted mixture of
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluoropho-
sphate (PyBOP) and 4-(N,N-dimethylamino)pyridine (DMAP) in
acetonitrile (modified Boger’s conditions).[8f] Under these
conditions, cyclic peptide (SA)-15 was isolated, in 70% yield, as a
mixture of two atropoisomers with limited rotation around the
Boc(Me)N moiety of the 4-hydroxyphenylglycine residue
(Supplementary Figure S5-S7) .[23] The synthesis was completed
by removal of the tert-butyl and Boc groups from 15 (TfOH in
HFIP), affording the desired arylomycin cyclic core 4 in 86% yield.
Compound 4 exists as a single atropoisomer with an SA-axial
configuration, which is in agreement with the arylomycin absolute
configuration.[23] This short and reliable three-step synthesis was
performed on a multi-millimole scale, affording over 0.5 g of pure
macrocycle 4 in a single synthetic effort.
at the ortho position. Other catalytic conditions, based on first-row
transition metals that failed to mediate the oxidative coupling of
tyrosine residue 10, were found to be efficient after installing the
activating group (entries 3-5). For example, activated tyrosine 11
underwent effective dimerization under air atmosphere in the
presence of redox Co[salen] catalyst (HFIP, rt, entry 5),[9b]
affording 14 in 95% yield, whilst almost no reaction took place
when tyrosine 10 was subjected to the same conditions. The
removal of the tert-butyl groups from di-tyrosine 14 turned out to
be a challenging task, since the reported procedures for Friedel-
Crafts dealkylation failed to afford di-tyrosine 12 (Supplementary
Table S3). Finally, we realized that removal of the N-Cbz
protecting groups [Pd-C/H2 in methanol] prior to the Friedel-Crafts
dealkylation [triflic acid (TfOH) in HFIP] is necessary to prevent
undesired side reactions. Under these conditions, di-tyrosine 12
was prepared on a multi-gram scale from 14 in 92% yield.
Scheme 1. Synthesis of the arylomycin cyclic core 4 using the
AG-assisted oxidative coupling according to approach B.
Scheme 3. Synthesis of the biaryl-bridged cyclic peptides using
the AG-assisted oxidative coupling approach.
Conditions: (a) compound
7 (3 equiv), Fe[TPP]Cl (1 mol%) in 1,2-
dichloroethane at rt, then 8 (1 equiv) and meta-chloroperbenzoic acid (2 equiv)
in 4 portions every 20 min, 48% yield; (b) Pd-C (10 mol%), H2 (1 atm), EtOH, rt,
2 h, then PyBOP (2 equiv), DMAP (3 equiv), MeCN (0.9 mM), rt, 16 h, 70%
yield; (c) TfOH (6 equiv), HFIP, rt, 16 h, 86% yield
Having established the AG methodology for combining two
tyrosine residues under mild catalytic conditions with extremely
high efficiency, we turned our attention to synthesizing biaryl-
bridged cyclic peptides via approach B.[21] To further develop the
strategy, we focused first on the synthesis of macrocyclic peptide
4, which is the cyclic core of both arylomycin (1) and G0775 (2).
Conditions: (a) 16, 18 or 21 (1 equiv) and 11 or 19 (3 equiv), Fe[TPP]Cl (1
mol%), UHP (4 equiv), HFIP, rt, 1 h; (b) Pd-C (10 mol %), H2 (1 atm), EtOH or
HFIP, 2-3 h, then PyBOP (2 equiv), DMAP (3 equiv), MeCN (0.9 mM), rt, 16 h;
and (c) TfOH (6 equiv), HFIP, rt, 16 h.
For this aim, N-Boc-N-Me-L-(2-t-Bu)Hpg-OBn (7) and N-Cbz-L-
Ala-L-(2-t-Bu)Tyr-OMe (8), which constitute the units comprising
the arylomycin cyclic core were prepared. Initial attempts to
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L-Pro-OBn (16) and N-Cbz-L-(2-t-Bu)Tyr-OMe (11). The
synthesis was accomplished in only three steps and in a 56%
overall yield (68% yield for the cross-coupling, 88% yield for the
macrolactamization, and 93% yield for the t-Bu removal step). The
ability to discriminate between different phenol-based amino acid
residues constitutes an important synthetic advantage that could
be applied for synthesizing biaryl-bridged polycyclic peptides,
such as RP 66453 (3), which is assembled from a series of
phenolic-based amino acid units. To examine the potential ability
of the t-butyl groups to 'turn-on' the reactivity of specific phenolic
residues, we set out to prepare tri-tyrosine-bridged cyclic peptide
20. For that purpose, we reacted N-Boc-L-(2-t-Bu)Tyr-L-Tyr-OBn
18 (1 equiv), which has both activated and non-activated tyrosine
groups, and N-Cbz-L-(2-t-Bu)Tyr 11 (3 equiv) using our general
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conditions. This reaction exhibited
a
high degree of
chemoselectivity, leaving the non-activated tyrosine residue in 18
untouched, affording a cross-coupling product in 63% yield that
readily converts to macrocycle 20 in only two more synthetic steps
(66% yield for the macrolactamization and 88% yield for the t-Bu
removal step) and with an overall yield of 37%. Finally, the RP
66453 biaryl-bridged cyclic core 22 was prepared in only three
steps from compounds 19 and 21 in an excellent 46% yield.[8g]
In summary, we report that phenol-based amino acids with a
tert-butyl substituent at the ortho position undergo highly selective
and efficient oxidative coupling reactions under mild catalytic
conditions. On the basis of this finding, we developed an
activating group-assisted oxidative cross-coupling methodology
that enables the efficient assembly of biaryl-bridged cyclic
peptides for the first time via approach B. Arylomycin/G0775 and
RP 66453 cyclic cores as well as other structurally related cyclic
peptides were prepared in just a few synthetic steps via an iron-
catalyzed oxidative cross-coupling reaction. We hope that this
work will support the effort to ensure a continuous supply of
candidate lead compounds to be tested in the ongoing battle
against multiple antibiotic-resistant pathogens.
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Bu)Hpg-L-Ala-L-(2-t-Bu)Tyr-OMe, which is the precursor of the arylomycin
cyclic core, afforded only dimmeric products under catalytic conditions
(Supplementary Table S6).
Acknowledgements
We thank Dr. Amira Rudi for NMR assistance. This research was
supported by the Israel Science Foundation (grant number
164/16).
Keywords: Iron catalysis • Oxidative cross-coupling • Biaryl-
bridged cyclic peptides • Arylomycin • Dityrosine
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10.1002/anie.201913305
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Mor Ben-Lulu,‡ Eden Gaster,‡ Anna
Libman and Prof. Doron Pappo*
Page No. – Page No.
Synthesis of Biaryl-Bridged Cyclic
Peptides via Catalytic Oxidative
Cross-Coupling Reactions
Activating group assisted oxidative cross-coupling strategy for the assembly of
biaryl-bridged cyclic peptides from natural amino acids was developed for the
synthesis of arylomycin/G0775 and RP 66453 cyclic cores.
This article is protected by copyright. All rights reserved.