Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics

Article abstract of DOI:10.1021/acs.orglett.7b01324

A general strategy is introduced for the efficient synthetic access of disulfide linked artificial macrocycles via a Ugi four-component reaction (U4CR) followed by oxidative cyclization. The double-mercapto input is proposed for use in the Ugi reaction, thereby yielding all six topologically possible combinations. The protocol is convergent and short and enables the production of novel disulfide peptidomimetics in a highly general fashion.

Full text of DOI:10.1021/acs.orglett.7b01324

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Letter
pubs.acs.org/OrgLett
Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged
Peptidomimetics
Thimmalapura M. Vishwanatha, Enrico Bergamaschi, and Alexander Domling*
̈
Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
*
S Supporting Information
ABSTRACT: A general strategy is introduced for the efficient synthetic access of disulfide linked artificial macrocycles via a Ugi
four-component reaction (U4CR) followed by oxidative cyclization. The double-mercapto input is proposed for use in the Ugi
reaction, thereby yielding all six topologically possible combinations. The protocol is convergent and short and enables the
production of novel disulfide peptidomimetics in a highly general fashion.
1
5
ysteine is the prevailing site for covalent post-translational
modification (PTM) in peptides and proteins. Among
the variety of PTMs, the disulfide bond has gained considerable
(U-MCR) stands out among all the other methods when it
1
,2
16
C
comes to convergent synthesis of peptides, peptidomimet-
ics, and macrocycles in one or a few simple steps.
17
18
momentum in biological chemistry as it occurs instantaneously
Yudin, for example, used protected cysteine peptides as
bifunctional starting material in the Ugi MCR to afford peptide
macrocycle which were subsequently transformed to disulfide-
bridged bicyclic peptide macrocycles. Surprisingly, however,
the isocyanide derived from enantiopure cysteine and its utility
remains largely unexplored. Hence, we herein describe the
synthesis of the chiral cysteine isocyanide and its application in
the Ugi MCR followed by oxidative cyclization to deliver
disulfide-bridged cyclic peptidomimetics. Overall, the strategy
relays on the possible variations in the acid, amine and aldehyde
components, having trityl protected thiol as a side chain in
order to obtain disulfide-containing cyclic peptidomimetics of
variable ring size (Figure 1).
At the outset of the project, stable enantiopure isocyanide 2
was synthesized. Classical formylation with methyl formate was
employed to synthesize formyl-protected Cys(Trt)-OMe 1
starting from cysteine. Nonracemizable dehydrating con-
ditions viz., triphosgene (0.35 equiv) and N-methyl morpholine
NMM) (2.0 equiv) at −78 °C, were employed to synthesize
isocyanide 2, and its enantiopurity was checked by chiral SFC
Supporting Information (SI)]. The quantitative yield of the
3
4
through oxidative folding in peptides, proteins, hormones,
5
enzymes, growth factors, toxins, and immunoglobulins.
19
Macrocylization via disulfide bond often improves the potency,
rigidity, target selectivity, and stability of proteases and also
6
20
stabilizes the secondary structure of peptides. Disulfides are
also a common structural motif in therapeutically active
7
8,9
compunds and nonribosomal natural products
having
10
interesting biological activities. For example, screening of
disulfide-containing macrocyclic libraries has yielded potent
1
1
inhibitors of the insulin-like growth factor-1 receptor.
Unnatural residues such as D-enantiomers of the amino acid,
N-alkylated, α-disubstituted amino acids can be incorporated to
further enhance the biophysical properties of such peptide-
1
2
based therapeutics. Chemical synthesis is a common
bottleneck approach for producing disulfide-rich peptides.
Only a handful of approaches have been developed for a
convenient and straightforward preparation of peptides with
21
13
site-specific disulfide connectivity. For example, classical
peptide synthesis (solution phase, solid phase, or native
chemical ligation) followed by intramolecular oxidation has
been routinely used to synthesize disulfide-containing pep-
(
22
[
1
4
isocyanide was obtained as a pale yellow, odor-free solid by
simple recrystallization from diethyl ether (88%). The
isocyanide is bench-stable at room temperature for several
tides. Importantly, orthogonal protection for Cys has to be
employed, and then the peptides are sequentially transformed
to site-specific disulfides. Alternative methods are still
demanding for industrial-scale synthesis. In particular, produc-
tion of Cys-rich small peptide sequences in solution or solid
phase can be cumbersome. In order to improve yields and
reduce overall production time, Ugi multicomponent reaction
23
months without any decomposition or racemization. The
Received: May 2, 2017
Published: June 5, 2017
©
2017 American Chemical Society
3195
DOI: 10.1021/acs.orglett.7b01324
Org. Lett. 2017, 19, 3195−3198

Organic Letters
Letter
Scheme 2. U-4CR Involving Isocyanide 2 and Disulfide
a
Formation
Figure 1. Topologically possible Ugi-4CR oxidative disulfide backbone
cyclizations resulting in six different cyclic scaffolds.
isocyanide synthesis was also conducted on a ∼30 g scale
without loss of yield (Scheme 1).
Scheme 1. Synthesis of Methyl (R)-2-Isocyano-3-
(
tritylthio)propanoate 2
a
Isolated yields and diastereomeric ratios of Ugi products 3 and
disulfides 4 are provided.
To test the synthetic utility of this novel isocyanide 2, we
peptide synthesis. Tritylamine as ammonia synthon was also
carried out a simple Ugi reaction (U-4CR) to prepare peptide-
like adducts. Thus, the commercially available acid component
Fmoc-Cys(Trt)-OH was reacted in the U-4CR, which we
imagined could well be further used for head-to-tail disulfide
formation. To probe optimal reaction conditions in a classical
U-4CR, Fmoc-Cys(Trt)-OH, paraformaldehyde, benzylamine,
and isocyanide 2 were reacted in different solvents such as
MeOH, trifluorethanol (TFE), and hexafluoroisopropanol
employed to produce N-trityl-protected Ugi adduct 3h, which
24
further can be deprotected easily. A dipeptide acid was also
employed in the Ugi reaction to yield the tetrapeptide adduct 3i
in 52% yield. Moreover 2-(tritylthio)ethan-1-amine was
employed for the first time in U-4CR to afford products such
as 3j in 66% yield. This amine is an interesting building block to
generate unprecedented classes of peptidomimetic artificial
macrocycles through MCR. The trityl-protected mercapto
acetaldehyde was also employed in U-4CR to afford Ugi
adduct 3k in 32% yield, which could serve as promising
synthon for the synthesis of glutathione mimetics through U-
(
HFIP) under different concentrations and temperatures (SI).
Increasing the temperature did not affect the reaction efficiency
and yield. Other solvents such as THF, CH Cl , and DMF also
2
2
25
decreased the reaction efficiency, suggesting that the poor
solubility of the components in either of the solvents may have
compromised the formation of the Ugi product 3a. Thus, we
investigated the use of mixed solvents. Further optimization
resulted in the MeOH/THF/DMF (1:1:0.1, 0.2 M) solvent
mixture which afforded the Ugi product 3a in good 61% yield.
Since our aim was the diverse synthesis of disulfide-bridged
peptides via Ugi cyclization (which is called sulfur-switch Ugi
reaction here), any of the components could carry the
protected thiol moiety. Therefore, with functionalized iso-
cyanide 2 in hand, any other mercapto side-chain component
4CR.
Overall, the U-4CR turned out to be quite general, affording
the Ugi products in moderate to good yield. Simple column
purification was employed to isolate the products. When
paraformaldehyde was used, the Ugi product was obtained as a
single diastereomer. Stereochemical retention of the isocyanide
under the reaction conditions was unambiguously shown by
chiral SFC (SI). Other aldehydes afforded the Ugi products as a
mixture of diastereomers.
Having diverse Ugi adducts in hand, we focused on the
peptide cyclization through disulfide bond formation. Various
oxidative methods have been previously employed such as air,
DMSO, iodine, thallium salts, mercury salts, and carbon
(
acid, amine, or aldehyde) should be useful. The scope of the
optimized U-4CR was first investigated by changing the amine
and aldehyde components but keeping the acid and isocyanide
constant. Not surprisingly, the used amines and aldehydes
displayed good reactivity in the Ugi reaction (Scheme 2, 3a−i).
For example, the use of methylamine affords N-methylated
peptide adduct 3f in 42% yield upon stirring the reaction
mixture for 30 h at room temperature. Notably, such N-
methylated peptides are difficult to synthesize by classical
26
tetrachloride. Recently, NCS was also employed as mild
reagent for peptide disulfide cyclization. However, NCS is not
27
useful when the cysteine is trityl protected. Testing different
variations, we finally employed I as oxidant for the present
2
28
study. All of the Ugi products undergo smooth oxidative
cyclization at room temperature (4 h) in a mixture of
dichloromethane and methanol to yield disulfide-bridged
3
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DOI: 10.1021/acs.orglett.7b01324
Org. Lett. 2017, 19, 3195−3198

Organic Letters
Letter
peptidomimetics in good to excellent yields (Scheme 2, 4a−k).
Interestingly, trityl-protected tertiary amide as well as Boc-
protected amine used are well tolerated under the iodine-
mediated oxidative cyclization, pointing to the possibility of
further orthogonal chemistries.
Scheme 4. Synthesis of Double Disulfide Bridges and
a
Possible Disulfide Isomers
Since methanol is the common solvent for Ugi and oxidative
cyclization, we also tested the one-pot synthesis of disulfide 4a
without isolating the Ugi adduct 3a. However, it resulted in
complex reaction products that resulted in a more difficult
isolation procedure. Therefore, the two-step procedure with
isolation of the intermediate Ugi adduct is advisable.
The obvious advantage of the present method is the reliable
formation of macrocycles through possible variations in the
components. In this context, examples of other cyclizations of
types A, B, and E as shown in Figure 1 were also synthesized in
29
good yield through our present strategy (Figure 2).
a
Conditions: (1) (a) TFE/THF (1:0.5, 0.2 M), rt, 24 h, (b) single
diastereomeric Ugi product 3q was isolated and used for cyclization;
(
2) I , CH Cl /MeOH (10:1), rt, 4 h.
2 2 2
Figure 2. Representative examples of other topologically possible
disulfides synthesized. Isolated yields and diastereomeric ratios are
given.
As an application of our method, we synthesized glutathione
derivative 4p in just two steps (Scheme 3). This tripeptide
glutathione (GSH) is the prevalent nonprotein thiol maintain-
Figure 3. RP-HPLC analysis of the regiosimers from the crude
reaction mixture after random cyclization with I2.
30,31
ing the redox status in eukaryotic cells.
a
Scheme 3. Synthesis of GSH Mimetic 4p
constructed. Examples of all six topologically possible structures
are described. The enantiopure isocyanide derived from L-
cysteine was synthesized for the first time as a configurationally
stable solid and was employed as a bifunctional component in
the Ugi MCR along with the other three components that can
all contain the protected sulfhydryl. The resulting Ugi adducts
were expose to mild oxidative cyclization conditions to deliver
the disulfide peptidomimetics. The method described herein is
very versatile and allows synthesis of novel peptidomimetics not
accessible by other methods. The method is operationally
simple, and overall good yields are obtained in just two steps.
Thus, libraries of these compounds will be valuable additions to
a
Isolated yield is given for major diastereomer isolated from column
chromatography.
Finally, we tested a reaction wherein all four Ugi components
comprise the S(Trt) group to investigate the random formation
of disulfide bridges (Scheme 4). One-pot regioselective
formation of two disulfide bonds in cysteine-rich peptides has
34
screening libraries such as the European Lead Factory. Our
work uncovers the interesting opportunities for the efficient
production of novel class of disulfide peptides for biophysical
and therapeutic applications. The Ugi products presented
herein offer wide applications for the synthesis peptide
thioester, which is a key intermediate for protein chemical
3
2
been reported. Several shape isomers such as globular (1−3,
2
−4), ribbon (1−4, 2−3), and beads (1−2, 3−4) can be
33
expected. On this basis, a random disulfide formation was
carried out under high dilution (Scheme 3). RP-HPLC analysis
of the crude reaction mixture showed three regioisomers
35
synthesis.
(
Figure 3) at distinct peaks at 8.9, 9.6, and 10.7 min, and all the
+
ASSOCIATED CONTENT
Supporting Information
three regioisomers showed the expected m/z at 634 (M + H) .
MS/MS fragmentation analysis suggests that the major isomer
formed corresponds to 5a (SI).
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01324.
In conclusion, we have introduced the concept of “sulfur
switch” in the Ugi reaction, which can lead to a diverse array of
artificial disulfide bridged macrocycles. Ugi reaction followed by
oxidative cyclization (sulfur-switch Ugi reaction) was demon-
strated as an efficient and short synthesis of disulfide tethered
peptidic macrocycles. Depending on the choice of the Ugi
components, medium 8-membered macrocycle and larger 16-
membered cycles involving disulfide rings can be conveniently
Full experimental details and copies of spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: a.s.s.domling@rug.nl.
3
197
DOI: 10.1021/acs.orglett.7b01324
Org. Lett. 2017, 19, 3195−3198

Organic Letters
ORCID
Letter
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Alexander Domling: 0000-0002-9923-8873
Notes
1
(
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
(
2
2
(
The work was financially supported from the NIH
1R01GM097082-01) and by Innovative Medicines Initiative
Grant Agreement No. 115489). Funding has also been
received from the European Union’s Horizon 2020 research
and innovation programme under MSC ITN “Accelerated Early
stage drug dIScovery” (AEGIS), Grant Agreement No. 675555
(
(
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E.; Domling, A. Org. Lett. 2003, 5, 1047. (e) Dietrich, S. A.; Banfi, L.;
Basso, A.; Damonte, G.; Guanti, G.; Riva, R. Org. Biomol. Chem. 2005,
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