Crystal-to-Crystal Synthesis of Triazole-Linked Pseudo-proteins via Topochemical Azide-Alkyne Cycloaddition Reaction

Article abstract of DOI:10.1021/jacs.6b07538

Isosteric replacement of amide bond(s) of peptides with surrogate groups is an important strategy for the synthesis of peptidomimetics (pseudo-peptides). Triazole is a well-recognized bio-isostere for peptide bonds, and peptides with one or more triazole units are of great interest for different applications. We have used a catalyst-free and solvent-free method, viz., topochemical azide-alkyne cycloaddition (TAAC) reaction, to synthesize pseudo-proteins with repeating sequences. A designed β-sheet-forming l-Ala-l-Val dipeptide containing azide and alkyne at its termini (N₃-Ala-Val-NHCH₂C=CH, 1) was synthesized. Single-crystal XRD analysis of the dipeptide 1 showed parallel β-sheet arrangement along the b-direction and head-to-tail arrangement of such β-sheets along the c-direction. This head-to-tail arrangement along the c-direction places the complementary reacting motifs, viz., azide and alkyne, of adjacent molecules in proximity. The crystals of dipeptide 1, upon heating at 85 °C, underwent crystal-to-crystal polymerization, giving 1,4-triazole-linked pseudo-proteins. This TAAC polymerization was investigated by various time-dependent techniques, such as NMR, IR, DSC, and PXRD. The crystal-to-crystal nature of this transformation was revealed from polarizing microscopy and PXRD experiments, and the regiospecificity of triazole formation was evidenced from various NMR techniques. The MALDI-TOF spectrum showed the presence of pseudo-proteins >7 kDa.

Full text of DOI:10.1021/jacs.6b07538

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Communication
Crystal-to-Crystal Synthesis of Triazole-linked Pseudo-
proteins via Topochemical Azide-Alkyne Cycloaddition Reaction
Baiju P. Krishnan, Rishika Rai, Aromal Asokan, and Kana M. Sureshan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07538 • Publication Date (Web): 28 Oct 2016
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Crystal-to-Crystal Synthesis of Triazole-linked Pseudo-proteins via
Topochemical Azide-Alkyne Cycloaddition Reaction
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Baiju P. Krishnan, Rishika Rai, Aromal Asokan, and Kana M. Sureshan*
School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695016, India
Supporting Information Placeholder
We have developed topochemical azideꢀalkyne cycloaddition
(TAAC) reaction for the synthesis of triazole linked
oilgomers/polymers of carbohydrates and nucleosides.7 We herein
report the synthesis of triazoleꢀlinked pseudoproteins or
pseudopolypeptides.
ABSTRACT: Isosteric replacement of amide bond(s) of peptides
with surrogate groups is an important strategy for the synthesis of
peptidomimetics (pseudopeptides). Triazole is a wellꢀrecognized
bioisostere for peptideꢀbond and peptides with one or more triaꢀ
zole units are of great interest for different applications. We have
used a catalystꢀfree and solventꢀfree method viz. topochemical
azideꢀalkyne cycloaddition (TAAC) reaction to synthesize pseuꢀ
doproteins with repeating sequences. A designed βꢀsheetꢀforming
LꢀAlaꢀLꢀVal dipeptide containing azide and alkyne at its termini
(N3ꢀAlaꢀValꢀNHCH2C≡CH, 1) was synthesized. The single crysꢀ
tal XRD analysis of the dipeptide 1 showed parallel βꢀsheet arꢀ
rangement along ‘b’ direction and headꢀtoꢀtail arrangement of
such βꢀsheets along ‘c’ direction. This headꢀtoꢀtail arrangement
along ‘c’ direction places the complementary reacting motifs viz.
azide and alkyne of adjacent molecules at proximity. The crystals
of dipeptide 1 upon heating at 85 ˚C underwent crystalꢀtoꢀcrystal
polymerization giving 1,4ꢀtriazoleꢀlinked pseudoproteins. This
TAAC polymerization was investigated by various timeꢀ
dependent techniques such as NMR, IR, DSC and PXRD. The
crystalꢀtoꢀcrystal nature of this transformation was revealed from
polarizing microscopy and PXRD experiments and the regiospeciꢀ
ficity of triazole formation was evidenced from various NMR
techniques. MALDIꢀTOF spectrum showed the presence of pseuꢀ
doproteins size more than 7 kDa.
Figure 1. (A) Antiparallel and (B) parallel βꢀsheet arrangement of
peptides. (C) Proposed headꢀtoꢀtail arrangement of βꢀsheet formꢀ
ing dipeptide mimic with CRMs and their topochemical reaction.
Peptides constitute one of the important building block of the
biosphere and many peptide based natural biomaterials such as
silk, wool etc., instilled interests in developement of synthetic
peptideꢀmimics with attractive properties.1 Peptidomimetics,
synthetic mlecules that mimic the structure and often the function
of peptides, attract much attention due to their easy synthesis,
improved stability, attractive properties over traditional peptides
and find use in many fields spanning from medicine to materials.2
Isosteric replacement of amide bond constitute an important
strategy for peptidomimetics synthesis and such peptides with
amideꢀsurrogates are called pseudopeptides.3 Triazole is one of
the widely accepted isostere for peptide bond due to its robust and
biocompatible nature.4 Polytriazolylpeptide are attractive
polymers in the field of material science. However, the traditional
synthesis of such polymers would involve Cu(I) catalyzed click
polymerization of monomers having azide and alkyne
functionalities.5 Apart from the unavoidable use of solvents, the
purification of oligopeptides is cumbersome as the metal catalyst
can bind to the polymer formed. Topochemical reactions,
The essential criterion for topochemical reaction is the proximiꢀ
ty of reacting motifs in the crystal lattice and design of molecules
that upon crystallization place the reacting partners at distances
suitable for their topochemical reaction is one of the major chalꢀ
lenges in this field. It is well known that valine and alanine rich
small peptides (di or tripeptides) adopt βꢀsheet packing in their
crystals (Figure 1A & 1B, Supporting Information). Also, the
adjacent sheets arrange in such a way that peptides form headꢀtoꢀ
tail arrangement in the direction perpendicular to the direction of
the sheet formation. We envisioned that peptides with LꢀAla and
LꢀVal and modified with azide and alkyne, two complementary
reacting motifs (CRMs), at their termini would crystallize in βꢀ
sheet packing and this would bring azide and alkyne motifs of
adjacent molecules in close proximity, which would undergo
TAAC
reaction
between
them
forming
oligo/polyꢀ
triazolylpeptides (Figure 1C).
proximity driven reaction in a crystal lattice,6
plausible alternative that avoid catalysts, solvents and purification.
represent a
Dipeptide 1 was synthesized from Lꢀvaline and Lꢀalanine (see
the Supporting Information) and crystallized from DCM/toluene
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mixture. FTIR spectrum of crystals of the dipeptide 1 showed the
In order to do a systematic study of this reaction, we have kept
CO stretching band at 1630 cmꢀ1 indicating the formation of the βꢀ
parallel assembly.8 Single crystal Xꢀray analysis revealed that
dipeptide 1 crystallizes in the monoclinic C2 space group (Figure
2B). As anticipated, dipeptide 1 adopts parallel βꢀsheet packing
along “b” direction via N5ꢀH5…O4 (2.10 Å) and N4ꢀH4…O2
(2.13 Å) hydrogen bonds (Figure 2C). In addition, two CꢀH…O
hydrogen bonds viz. C1ꢀH1…O2 (2.31 Å; 150.8°) and C3ꢀ
H3…O4 (2.44 Å; 149.8°) also help in stabilization of the βꢀsheet
assembly. The shortest distance between azide and alkyne is 3.7 Å
(N1…C6) and the distances between the termini of azide and
alkyne are 4.1 Å and 4.7 Å. Though these distances satisfy the
proximity criterion, the azide and alkyne motifs are not in parallel
orientation, an arrangement necessary for their cycloaddition, but
at an angle of 72.2°. However, it would be possible to attain the
essential parallel geometry by minor conformational changes of
the flexible propargyl and the azide groups.
crystals of dipeptide 1 at 85 ˚C and withdrawn small fraction of it
at regular intervals for various timeꢀdependent studies. Timeꢀ
dependent FTIR spectroscopy with these crystals revealed that the
azide stretching band at 2103 cmꢀ1 gradually decreased with time
of heating. This suggests that the azide gets consumed gradually
with time, probably by reacting with the alkyne (Figure 3C). As
stated earlier, DSC analysis of peptide showed an exothermic
peak at 153 ˚C ascribable to the sudden, uncontrolled reaction
between azide and alkyne. DSC studies with the crystals kept at
85 ˚C for different durations revealed that the intensity of the
exothermic peak due to uncontrolled thermal reaction at around
150 ˚C decreased with increase in duration of preꢀheating at 85 ˚C
(Figure 3D). This also suggests that some of the azide and alkyne
groups are gradually reacting during the preheating thereby reducꢀ
ing the number of azide and alkyne left for their uncontrolled
reaction at high temperature. Also the extent of reaction depends
on the duration of preꢀheating.
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Figure 2. (A) Chemical structure and (B) ORTEP diagram of the
dipeptide 1. (C) Packing arrangement of dipeptide 1 along the
“bc” plane, showing the proximal placement of azide and alkyne
motifs (highlighted in ballꢀandꢀstick model). The brown dotted
lines represent the hydrogen bonds, N5ꢀH5…O4 and N4ꢀH4…O2
along the “b” direction.
In order to check the feasibility of topochemical reaction of diꢀ
peptide 1, its crystals were heated. The crystals did not melt even
at very high temperature (300 °C) suggesting that the crystals may
be undergoing polymerization upon heating. Differential Scanning
Calorimetric (DSC) analysis of the crystals of 1 also did not show
any endothermic peak that can be ascribed to melting. On the
other hand, DSC profile showed an exothermic peak at around
150 °C, which could be due to the exothermic dipolar cycloaddiꢀ
tion reaction between azide and alkyne (Figure 3A). The IR specꢀ
trum of heated crystals also suggested that the azide and the alꢀ
kyne reacted during heating; while the signals due to azide and
alkynyl group were sharp and strong in the starting crystals, the
intensity and sharpness of these peaks reduced to an insignificant
level after heating, suggestive of their consumption (Figure 3B).
Also the solubility of the heated crystal was very low in common
solvents (Supporting Information), ascribable to the formation of
Figure 3. (A) DSC profile of crystals of dipeptide 1. (B) IR specꢀ
tra of crystals before and after heating at 153 ˚C. (C) Timeꢀ
dependent IR spectra during the course of TAAC reaction of diꢀ
peptide 1. (D) Timeꢀdependent DSC analyses during TAAC reacꢀ
tion of dipeptide 1.
1
1
The kinetics of the reaction was studied by timeꢀdependent H
large polymers. H NMR spectrum of the crystals heated at 153
NMR spectroscopy (Figure 4A). One portion of the preꢀheated
˚C for 1 h, showed a complex mixture of products having both
1,4ꢀ and 1,5ꢀtriazolyl linkages (Figure S2, Supporting Inforꢀ
mation) suggesting uncontrolled and nonꢀselective polymerizaꢀ
tion.
1
crystals withdrawn at each time was analyzed by H NMR specꢀ
troscopy after dissolving in DMSOꢀd6. It was observed that the
reaction started at 7 h of heating as evident from the emergence of
new signals notably the ones due to triazolyl proton at δ 7.93,
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methyne proton connected to triazole at δ 5.56 and methylene
While the reaction under high temperature proceeded nonꢀ
selectively, distinct and clear H NMR signals were observed for
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protons as dd at δ 4.42. The intensities of these signals increased
gradually with time along with concomitant reduction in the inꢀ
tensities of signals due to the dipeptide 1. This trend continued till
the reaction was 89% complete in 6 days after which the reaction
reached a state of stagnancy. A plot of % of the reaction against
time revealed that the reaction followed a sigmoidal kinetics, as
anticipated for a topochemical reaction (Figure S1B, Supporting
Information).
each proton throughout the reaction at 85 ˚C suggesting the regioꢀ
specific formation of only one kind of triazole linkages (linkage
homogeneity) in all the oligomers formed (Figure 4C). In order to
know which of the two possible regiomeric triazoles is formed in
the reaction, we have chromatographically isolated a few oligoꢀ
mers (trimer and tetramer) and characterized extensively using
various spectroscopic techniques (Supporting Information). In
both the cases, it was found that 1,4ꢀtriazole is formed in the reacꢀ
tion. The very similar NMR pattern of trimer, tetramer and even
higher oligomers suggests that in all the oligomers/polymers, the
1,4ꢀtriazolyl linkage is conserved.
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Even after 89% of the reaction was over, the crystals were
morphologically intact. Polarizing microscopic images of dipepꢀ
tide 1 before and after the polymerization reaction show birefrinꢀ
gence, suggesting that the crystallinity is maintained throughout
the course of the reaction (Figure 5A & 5B).6ad This was also
evident from the timeꢀdependent PXRD analysis. A comparison
of the PXRD spectra of the crystals preꢀheated for different duraꢀ
tions suggested that the reaction occurred in a crystalꢀtoꢀcrystal
fashion (Figure 5C). Diffraction pattern of polypeptide (a heated
single crystal of dipeptide 1) also suggested its crystalline nature.
However we failed in solving its crystal structure (Figure S15,
Supporting Information). It is clear that the crystals of the dipepꢀ
tide 1 undergo crystalꢀtoꢀcrystal topochemical azideꢀalkyne cyꢀ
cloaddition upon mild heating giving oligomers/polymers having
only 1,4ꢀtriazolyl linkages. The regiospecificity is very interesting
as the parent crystal did not have any orientation of azide and
alkyne that favor any of the two possible regioisomers. However,
from a close look at the crystal structure, it is clear that the both
propargyl and azide groups can rotate around CꢀN single bond,
without significant steric hindrance, to adopt a conformation,
wherein the azide and the alkyne orient in antiꢀparallel arrangeꢀ
ment and favors 1,4ꢀtriazole formation. Also in this conformation,
the azide and alkyne are at much more favorable distances for
their easy topochemical reaction (Figure 5D).
Figure 4. (A) Kinetics of the TAAC reaction at 85 °C monitored
by 1H NMR. (B) MALDIꢀTOF spectrum of polymerized crystals.
(C) Chemical structure of oligopeptides obtained by TAAC.
The MALDIꢀTOF mass spectrum of the soluble fraction of the
heated crystals showed peaks corresponding to oligomers from
dimer to 28ꢀmers (similar size to a 7 kDa protein) with gradual
decrease in their intensities. This decrease in intensities with size
suggests that the solubility decreases with increase in size of the
polymer (Figure 4B) and this is in line with the trend of other
triazoleꢀbased polymers.7aꢀc Many natural proteins are as small as
7 kDa.9 It is interesting to note that we could make pseudopepꢀ
tides of sizes similar to small functional proteins.
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Design for Biopharmaceutical Applications; Jensen, K. J., Eds.; John
Wiley & Sons, Ltd: Cambridge, 2009, pp 49. (g) Alfonso, I. Chem.
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Figure 5. (A) Polarizing microscopic image of the crystals of
dipeptide 1 (A) before and (B) after TAAC. (C) Timeꢀdependent
PXRD spectra of crystals of dipeptide 1 kept at 85 °C for various
durations. (D) Plausible rotation of alkyne and azide giving TSꢀ
likeꢀarrangement for 1,4ꢀregioisomer.
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In summary, we have designed a dipeptide, decorated with two
complementary reacting motifs viz. azide and alkyne, which can
selfꢀassemble to form βꢀsheet structures in its crystal with proxiꢀ
mally placed azide and alkyne from adjacent sheets. The crystals
of this modified dipeptide underwent smooth topochemical azideꢀ
alkyne cycloaddition reaction upon heating yielding triazoleꢀ
linked polypeptides, which are otherwise difficult to synthesize
using conventional solution phase reactions. Though the azide and
alkyne were not properly oriented, for the topochemical reaction,
in the crystal, the flexibility of the propargyl and azide groups and
the empty space around them allowed their rotation, which lead to
a transition stateꢀlike antiꢀparallel arrangement of azide and alꢀ
kyne at short distance and this lead to the regiospecific formation
of 1,4ꢀtriazolylꢀlinked polypeptide in a crystalꢀtoꢀcrystal fashion.
This is the first synthesis of pseudoprotein or pseudopolypeptide
in the solid state. This proofꢀofꢀconcept would generate interests
in topochemical synthesis of several pseudopolypeptides with
repeating sequences for various applications.
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ASSOCIATED CONTENT
Supporting Information
Details of synthesis and characterization of dipeptide 1 and oliꢀ
gomer (trimer 9 and tetramer 10), DSC, PXRD, SXRD, IR, NMR,
TGA and MALDIꢀTOF. This material is available free of charge
via the internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kms@iisertvm.ac.in
ACKNOWLEDGMENT
K.M.S. thanks Department of Science and Technology (DST,
India) for Swarnajayanti Fellowship.
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