Synthesis and Diversification of Macrocyclic Alkynediyl Sulfide Peptides

Article abstract of DOI:10.1002/chem.202003655

The synthesis of rare macrocyclic alkynediyl sulfides by a Cu-catalyzed C_sp?S cross-coupling is presented. The catalytic protocol (Cu(MeCN)₄PF₆/dtbbpy) promotes macrocyclization of peptides, dipeptides and tripeptides at ambient temperature (14 examples, 23→73 % yields) via thiols and bromoalkynes, and is chemoselective with regards to terminal alkynes. Importantly, the underexplored alkynediyl sulfide functionality incorporates a rigidifying structural element and opens new opportunities for diversification of macrocyclic frameworks through S oxidation, halide addition and azide–alkyne cycloaddition chemistries to integrate sulfones, halides or valuable fluorophores (7 examples, 37→92 % yields).

Full text of DOI:10.1002/chem.202003655

Accepted Article
Accepted Article
Title: Synthesis and Diversification of Macrocyclic Alkynediyl Sulfide
Peptides
Authors: Shawn Collins, Éric Godin, Sacha Nguyen Thanh, Javier
Guerrero-Morales, Jeffrey Santandrea, Antoine Caron,
Clémentine Minozzi, Noémie Beaucage, Bastien Rey,
Mathieu Morency, and Xavier Abel-Snape
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202003655
Link to VoR: https://doi.org/10.1002/chem.202003655
01/2020

10.1002/chem.202003655
Chemistry - A European Journal
COMMUNICATION
Synthesis and Diversification of Macrocyclic Alkynediyl Sulfide
Peptides
Éric Godin, Sacha Nguyen Thanh, Javier Guerrero-Morales, Jeffrey Santandrea, Antoine Caron,
Clémentine Minozzi, Noémie Beaucage, Bastien Rey, Mathieu Morency, Xavier Abel-Snape and
Shawn K. Collins*[a]
Dedication ((optional))
[a]
Éric Godin, Sacha Nguyen Thanh, Dr. Jeffrey Santandrea, Javier Guerrero-Morales, Clémentine Minozzi, Antoine Caron, Noémie Beaucage, Bastien Rey,
Mathieu Morency, Xavier Abel-Snape and Prof. Dr. Shawn K. Collins
Department de Chimie, Centre for Green Chemistry and Catalysis, Université de Montréal, Complexe des Sciences, 1375 Avenue Thérèse-Lavoie-Roux,
Montréal, Québec H2V 0B3 Canada
E-mail: shawn.collins@umontreal.ca
Supporting information for this article is given via a link at the end of the document.
Abstract: The synthesis of rare macrocyclic alkynediyl sulfides via a
new Cu-catalyzed Csp-S cross-coupling is presented. The catalytic
protocol (Cu(MeCN)4PF6/dtbbpy) promotes macrocyclization of
peptides, dipeptides and tripeptides at ambient temperature (14
examples, 23→73 % yields) via thiols and bromoalkynes, and is
chemoselective with regards to terminal alkynes. Importantly, the
construction of peptidic macrocycles that help to preclude the
formation of dimers and oligomers continue to be developed.[11]
a
Past Work: Traditional Disconnections
O
O
Macrolactonization
CO2H
HO
• Stoichiometric activation
• No diversification of the ester
underexplored alkynediyl sulfide functionality incorporates
a
rigidifying structural element and opens new opportunities for
diversification of macrocyclic frameworks through S-oxidation, halide
addition and azide-alkyne cycloaddition chemistries to integrate
sulfones, halides or valuable fluorophores (7 examples, 37→92 %
yields).
1
Macrocyclic Olefin
Metathesis
• Catalysis
• Some diversification possible:
installation of E/Z stereochemistry,
epoxidation, hydrogenation (most common)
2
Macrocycles offer a unique topology within chemical space.[ 1]
Despite their large ring structures they can retain remarkable
conformational bias with appropriate functionality present.
Current bioactive macrocyclic drugs are almost exclusively
derived from natural products,[ 2 ] yet synthetic macrocycles
represent a growing class of drug candidates. Retrosynthetically,
a macrocyclic precursor typically contains a core from which
extend appendages with functionality for cyclization. Upon
formation of the macrocycle, the newly formed functionality is
often referred to as the “linker”.[ 3 ] Through the linker and
macrocyclization, a conformation that is preferential for biological
activity can be locked in, or alternatively, conformers exhibiting
unwanted side-effects can be locked out.[4] Consequently, the
“linker” plays a critical role and is often modified systematically to
examine its effects on activity. The most common linkers exploit
well-known functional group manipulations (Figure 1).
Macrolactonization[5] via stoichiometric activation of a seco-acid
can be used to form ester-based linkers. Macrocyclic olefin
metathesis,[6] now a common strategy to form large rings was
investigated by Tsuji in 1980[7] and the reaction was first applied
to stapled peptides by Miller and Grubbs.[8] In addition, copper-
catalyzed azide-alkyne cycloaddition (CuAAC)[ 9 ] reactions are
examples of catalytic processes that have been shown by
N
Macrocyclic
N
N
X
X
Azide/Alkyne
Cycloaddition
N3
• Catalysis
• Diversification only
possible when X=I
3
b This Work: Alkynyl Sulfides as Novel Macrocyclic "Linkers"
Macrocyclic Csp-S
S
Br
Coupling
Cu
HS
• Base metal catalysis, Chemoselectivity versus terminal alkynes
Inclusion of underexplored alkynyl sulfide functional group and
rigidifying structural element within macrocyclic frameworks
• Diversification/labeling possible through sulfur/alkyne functionalities
• Applicable to macrocyclic di- and tripeptides
•
Figure 1. Strategies for the synthesis of macrocycles.
In each of the above processes, the linker serves primarily to
form the macrocycle, and no further diversification of the ring is
10
]
Meldal[
to form macrocycles, and new variants for the
envisioned.
No functionalization
of
the
esters
via
1
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10.1002/chem.202003655
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COMMUNICATION
macrolactonization is usually possible and most olefin metathesis
macrocyclizations terminate with hydrogenolysis of the olefin.
While the CuAAC can be used in tandem and post
functionalization processes in intermolecular cases,[12] it has not
been exploited to add further complexity in the context of
macrocyclization. The lack of utility of the linker is unfortunate, as
it could be exploited to add diverse pharmacophores, or to tag the
dipyridyl) and 2,6-lutidine as the catalytic system.[13] To
investigate whether the method was adaptable for
macrocyclization, the cysteine-derived precursor 4 was prepared
and submitted to the standard conditions, however low
concentrations (5 mM) and slow addition of 4 over a 12 h period,
followed by an additional 6 h of stirring were employed (Table 1).
Gratifyingly, cyclization afforded the 16-membered ring 5 in 56 %.
When the concentration was further decreased to 2.5 mM, or the
catalyst loadings increased, no improvement in the isolated yield
of macrocycle 5 was observed. Eliminating or reducing the time
of the slow addition resulted in reduced yields of 5. Furthermore,
under the optimized conditions, the macrocyclization of 4 could
be easily scaled to 500 mg scale affording an identical 56 % yield.
With optimized conditions in hand, the scope of Csp-S coupling
was first investigated with cysteine-derived macrocycles (Table 2).
As mentioned previously, the macrocycles whereby the alkynyl
bromide was connected via the ester functionality 5 was isolated
in 56 % yield. Switching from Boc to Fmoc-protected cysteines
was also compatible with the reaction conditions (macrocycle 6,
47 % yield). Next, an analogous macrocycle derived from cysteine
in which the amide linkage was incorporated within the
macrocyclic framework (7) was prepared, and could be obtained
in 50 %. Macrocycle 8 derived from propargyl glycine could also
be prepared in 52 % yield. A macrocycle 9 derived from the
angiotensin-converting-enzyme-inhibitor captopril was isolated in
67 % yield. Several dipeptide-derived macrocycles were also
macrocycle with useful appendages.
A rare example of
macrocyclization chemistry that installs new functionality with the
possibility of further diversification was developed by the Yudin
group, who used amphoteric molecules as linchpins in the
synthesis of macrocyclic peptides.[ 13 ] To develop new linker
strategies for macrocyclization, the bond-forming event must
create new functionality that has predictable reactivity patterns,
and multiple avenues for diversification. Heteroatom-substituted
alkynes are virtually unexplored as linkers for macrocyclization,
despite possessing enhanced reactivity and predictable
regioselectivity in their transformations when compared to
common internal alkynes.[14] Alkynyl sulfides[15] are perhaps ideal
for the purpose, as they possess suitable stability and are well
[
known synthons for a variety of transformations. ] In addition, the
16
C
sp-S motif is almost non-existent in macrocyclic scaffolds, and
provides some measure of orthogonality with functionality
typically observed within natural products, heterocyclic chemistry
and peptide science. We have previously reported a Cu-catalyzed
synthesis of alkynyl sulfides, analogous to other Cu-catalyzed
C
sp-N cross-couplings,[17] that is applicable to the coupling of
alkyl-, aryl-, silyl and heteratom-substituted alkynes.[ 18 ] We
envisioned using such method to construct complex
prepared:
a
cysteine-phenylalanine derived macrocyclic
alkynediyl sulfide 10 was obtained in 35 % yield. Similarly,
macrocyclic dipeptides having cysteine/isoleucine (11) or
cysteine/acc (12) (acc = 1-aminocyclopropane-1-carboxylic acid)
were smoothly prepared in 35 and 52 % yields respectively. A
macrocyclic dipeptide having an unprotected terminal alkyne
(cysteine/propargyl glycine) (13) was formed in 23% yield. The
selective Csp-S bond formation in the presence of a terminal
alkyne is noteworthy, as the process provides some orthogonality
with other common macrocyclization processes that utilize
terminal alkynes such as CuAAC,[ 22 ] multicomponent A3 –
a
macrocycles with a unique alkynediyl sulfide functionality. Other
methods such as the use of highly reactive and electrophilic
alkynes based on dibenzothiophenium triflates or hypervalent
iodine[19] might not be tolerant to the multi-step synthesis required
to construct the precursors. Catalytic metallaphotoredox
approaches are also limited to aryl-substituted alkynyl sulfides.[20]
Herein, we report application of a Csp-S coupling toward
macrocyclic peptides.[ 21 ] The macrocyclization exhibits high
chemoselectivity and occurs at ambient temperature. In addition,
we disclose diversification of the alkynediyl sulfide functionality
through oxidations, halide additions or Ir-catalyzed azide-alkyne
cycloadditions (IrAAC).
23
]
24 ]
coupling[
and Glaser coupling.[
Finally, a macrocyclic
alkynediyl sulfide derived from glycine and cysteine (14) was
prepared in 73 % yield. Notably, the macrocycle incorporated an
aromatic alkynediyl sulfide that allowed comparison to other
existing methods for Csp-S bond formation. When the macrocycle
was formed using metallaphotoredox chemistry, the yield of 14
was notably lower (21 %), demonstrating the advantages of using
Table 1. Optimization of a Cu-Catalyzed Coupling to form a Cysteine-Derived
Macrocyclic Alkynediyl Sulfide.[a]
O
O
Cu(MeCN)4PF6
NHBoc
the
newly
developed
chemistry.
Gratifyingly,
X-ray
O
(10 mol%)
( )9
crystallographic analysis also confirmed the connectivity of
macrocycle 14.[25] Next, the synthesis of macrocyclic tripeptides
was targeted due to their interest in medicinal chemistry.[26] As
with dipeptides, tripeptides are appealing for drug discovery and
development as their low molecular weight typically translates to
cost-effective syntheses, the possibility of oral administration, and
simplified structure-activity investigations.[ 27 ] The synthesis of
tripeptides can be challenging due to unfavorable amide
BocHN
dtbbpy (20 mol%)
O
16
S
2,6-lutidine (2 equiv)
MeCN (5 mM)
Br
SH
rt, 18 h
slow addition over 12 h
4
5
Entry
Changes
none
Yield 5 (%)
1
2
3
4
5
56
38
29
41
34
[2.5 mM]
double the catalyst loadings
slow addition over 2 h
no slow addition
28
]
conformations.[
As such, the Cu-catalyzed method for
introduction of the alkynyl sulfide not only facilitates the synthesis
of the macrocycles, but has the potential to create rigidified
peptidomimetics useful in peptide-based drug discovery.[29] To
prepare the macrocycles, an alkynyl bromide was installed on a
serine residue and then used to form a series of cyclic tripeptides
(Table 2c).
[a] Isolated yields. Linear dimer and cyclic dimers are also formed (<10 %). No
starting material recovered. Ring size indicated in red.
Previously reported conditions involved the use of a copper
salt (Cu(MeCN)
4
PF , a ligand dttbpy (4,4′-di-tert-butyl-2,2′-
6
2
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10.1002/chem.202003655
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Scope of the Macrocyclic Cu-Catalyzed Formation of Alkynyl Sulfides and Subsequent Diversification.[a]
Table 2.
Cu(MeCN)4PF6
(10 mol%)
dtbbpy (20 mol%)
S
ring
size
SH
2,6-lutidine (2 equiv)
MeCN (5 mM)
rt, 18 h
Br
slow addition over 12 h
b
Dipeptide Macrocycles
a
Cysteine-Derived Macrocycles
Ph
O
BocHN
O
O
CO2Me
S
H
O
O
O
O
O
H
N
O
O
N
N
O
NHFmoc
NHBoc
Me
NHBoc
O
O
15
16
16
19
19
15
(
)
S
S
( )
S
4
S
4
S
O
O
8, 52 %
10, 35 %
5, 56 %
9, 67 %
6, 47 % (2.5 mM)
7, 25 %
50 % (70 oC)
b
Dipeptide Macrocycles
Me
O
Me
H
O
H
N
H
O
O
O
O
O
O
O
N
N
NHBoc
NHBoc
NHBoc
O
NH
O
)
O
18
17
19
19
(
)
(
(
)
S
S
S
2
4
4
O
NH
S
CO2Me
12, 52 % (2.5 mM)
, 35 %
11
, 73 %
14
metallaphotoredox
13, 23 %
ORTEP drawing of 14
21 %
c
Tripeptide Macrocycles
Me
Ph
Me
H
H
O
O
H
H
O
O
O
O
O
O
N
N
N
N
NHBoc
NHBoc
NHBoc
NHBoc
HN
EtO2C
17
HN
HN
HN
EtO2C
EtO2C
EtO2C
17
17
17
S
S
S
S
O
O
O
O
O
(
)
2
(
)
2
(
)
2
(
)
2
O
O
O
15, 55 %
16, 30 %
17, 30 %
18, 58 %
d
Diversification of the Alkynyl Sulfide Motif
Me
O
O
NHBoc
Me
O
O
O
H
N
O
NHBoc
2
O
S
CO2Et
NH
O
Br
NHBoc
S
HN
17
16
16
EtO2C
S
O
Ph
17
O
(
)
2
(
)
NH
S
N
O
NH
S
O
O
N
N
NH
O
S
O
N
O
N
O
N
BocHN
O
Fluoroscent Tagging
Halide Addition
Oxidation
Fluorescent Tagging
Alkyne Modification
Alkyne Modification
Sulfur Modification
Alkyne Modification
NMe2
NMe2
20, 53 %
21, 70 %
22, 82 %
19, 59 %
e
Orthogonal Diversification via Azide-Alkyne "Click" Chemistry
N
N
N
O
O
Farnesylation
NHBoc
H
O
O
H
O
O
CuAAC
then
Fluorophorylation
N
N
NHBoc
NHBoc
O
HN
5
HN
16
(
)
S
EtO2C
EtO2C
IrAAC
24, 36 %
unoptimized over
two steps
17
O
N
17
S
N
N
S
O
2
N
O
N
(
)
N
NH
S
(
)
2
O
(
)
2
(85 % purity)
Fluorophorylation
O
O
N
O
N
Alkyne Modification
, 81 %
23
Me2N
[a] Yields following chromatography
NMe2
3
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The macrocycles incorporated other amino acids such as leucine,
phenylalanine, acc and propargylglycine and were isolated in 55,
30, 30 and 58 % yields (15, 16, 17 and 18 respectively).
of functionality for further cross-coupling and cycloaddition
chemistry, there is
a growing number of regioselective
transformations of alkynyl sulfides[16] that could be exploited to
create structurally unique peptidic macrocycles. In addition, given
that AAC approaches for the modification of drug and peptide
candidates is a powerful approach in pharmaceutical science, the
facile cycloaddition to incorporate fluorescence quenchers
provides proof-of-principle that there is significantly more potential
to exploit the alkynediyl sulfide linker to attach other labels such
as PEG sidechains, biotin affinity tags or even bioconjugates.[40]
In summary, the macrocyclization protocol described herein
highlights:
To demonstrate the value of the alkynediyl sulfide linker,
modification and diversification of the functional group when
incorporated within the macrocyclic skeleton was performed
(Table 2d). First, the sulfur atom of macrocycle 16 was oxidized
smoothly to the corresponding sulfone 19 in 59 % yield. The
resulting α,β-unsaturated sulfone is an advantageous
functionality for diversification via cycloaddition chemistry,[30] and
possibilities for annulation to form heterocycles.[31] Halide addition
(LiBr (10 equiv., HOAc (1 equiv), rt, 18 h) using reported
conditions that exclusively add to the α-position due to the
electronic bias of the thioalkyne afforded the macrocycle 20
(53 %), where the bromide handle opens avenues to generate
complexity via cross-coupling.[ 32 ] Azide-alkyne cycloadditions
have already demonstrated significant potential for peptide
modification and conjugation,[ 33 ] but these strategies normally
involved the popular Cu-catalyzed variant (CuAAC). An
underexplored version involves Ir-catalyzed AAC on alkynyl
sulfides which has been shown experimentally to exclusively form
the 5-sulfenyl-1,2,3-triazole.[ 34 ] Computational studies have
suggested the regioselectivity is due to the strong π-donating
properties of the alkynyl sulfide that stabilize Ir−carbene
intermediates.[ 35 ] The IrACC could be used to incorporate
fluorescence quenchers onto the novel alkynediyl sulfide
macrocycles. Importantly, the late stage modification of peptides
and peptidomimetics with fluorescent dyes continues to be of
interest.[36] The macrocycles 5 and 15 underwent cycloaddition to
1) Incorporation of underexplored and rare macrocyclic
alkynediyl sulfides. Their incorporation in macrocyclic
peptides, dipeptides and tripeptides is notable given their
importance in medicinal chemistry. The incorporation of an
alkynyl sulfide adds an element of structural rigidity to the
macrocycle skeletons pertinent to medicinal chemistry.[41]
2) There are ample avenues for diversification through
oxidation to incorporate sulfones, halide addition, or via
cycloaddition to add valuable fluorescence quenchers,
amino acid or farnesylated appendages. Functionalization
of other terminal alkynes is possible in an orthogonal
manner to the alkynediyl sulfides, again provide a variety
of options to modify cyclic peptide frameworks.
The Cu-catalyzed
Csp-S cross-coupling demonstrates the
potential for metal catalysis to prepare peptidic macrocycles[42]
with new topologies for application in medicinal chemistry.
37
]
afford dansyl-derived[
macrocycles appended with the
corresponding fluorescence quenchers (21 and 22, 70 and 82 %
yields, respectively).[38] The macrocycles could also be appended
with a methyl red-derived fluorescence quencher.[39] Following
IrACC, macrocycle 23 was isolated in 81 % yield from the
corresponding alkynyl sulfide peptide. Importantly, the alkynyl
sulfides’ reactivity patterns provide some orthogonality with the
common CuAAC for terminal alkynes.[6a] The tripeptide 17 could
first undergo cycloaddition on the terminal alkyne of the propargyl
glycine residue to install a farnesyl moiety without affecting the
alkynediyl sulfide “linker”; a subsequent IrAAC then modified the
macrocycle to include a dansyl-derived fluorophore (24 36 %
unoptimized over two steps). Although the above examples of
diversification focused on modification of oxidation state, addition
Acknowledgements
The authors acknowledge the Natural Sciences and Engineering
Research Council of Canada (NSERC, Discovery 1043344),
Université de Montréal and the Fonds de recherche Nature et
technologie via the Centre in Green Chemistry and Catalysis
(FRQNT-2020-RS4-265155-CCVC) for generous funding. EG
and MM thank NSERC and the FRQNT for graduate scholarships.
Keywords: macrocycles • copper catalysis • alkynyl sulfides •
peptides • cycloaddition
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Macrocyclic Csp-S
S
Br
Coupling
Cu
HS
• Copper-catalyzed : simple setup, mild conditions & orthogonal reactivity
• Chemoselectivity versus terminal alkynes
• Underexplored alkynyl sulfide functional group acts as rigidifying element
and enables diversification/labeling through sulfur/alkyne functionalities
• Applicable to macrocyclic di- and tripeptides
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