Synthesis of triazole-linked homonucleoside polymers through topochemical azide-alkyne cycloaddition

Article abstract of DOI:10.1002/anie.201404797

There is a great deal of interest in developing stable modified nucleic acids for application in diverse fields. Phosphate-modified DNA analogues, in which the phosphodiester group is replaced with a surrogate group, are attractive because of their high stability and resistance to nucleases. However, the scope of conventional solution or solid-phase DNA synthesis is limited for making DNA analogues with unnatural linkages. Other limitations associated with conventional synthesis include difficulty in making larger polymers, poor yield, incomplete reaction, and difficult purification. To circumvent these problems, a single-crystal-to-single-crystal (SCSC) synthesis of a 1,5-triazole-linked polymeric ssDNA analogue from a modified nucleoside through topochemical azide-alkyne cycloaddition (TAAC) is reported. This is the first solvent-free, catalyst-free synthesis of a DNA analogue that proceeds in quantitative yield and does not require any purification. Crystals go click: Modified DNA analogues are attractive materials for applications in many fields, however, the synthesis of DNA analogues by conventional methods is difficult owing to poor yield and efficiency and tedious purification. A highly homogeneous, enzyme-stable, crystalline ssDNA analogue was synthesized regiospecifically in quantitative yield through single-crystal-to-single-crystal azide-alkyne cycloaddition polymerization of a modified nucleoside.

Full text of DOI:10.1002/anie.201404797

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DOI: 10.1002/anie.201404797
DNA Analogues
Synthesis of Triazole-linked Homonucleoside Polymers through
Topochemical Azide–Alkyne Cycloaddition**
Atchutarao Pathigoolla and Kana M. Sureshan*
Abstract: There is a great deal of interest in developing stable
modified nucleic acids for application in diverse fields.
Phosphate-modified DNA analogues, in which the phospho-
diester group is replaced with a surrogate group, are attractive
because of their high stability and resistance to nucleases.
However, the scope of conventional solution or solid-phase
DNA synthesis is limited for making DNA analogues with
unnatural linkages. Other limitations associated with conven-
tional synthesis include difficulty in making larger polymers,
poor yield, incomplete reaction, and difficult purification. To
circumvent these problems, a single-crystal-to-single-crystal
(SCSC) synthesis of a 1,5-triazole-linked polymeric ssDNA
analogue from a modified nucleoside through topochemical
azide–alkyne cycloaddition (TAAC) is reported. This is the
first solvent-free, catalyst-free synthesis of a DNA analogue
that proceeds in quantitative yield and does not require any
purification.
Figure 1. The structures of natural DNA (A), PNA (B), and triazolyl
DNA (C). Base=nucleobase.
N
ucleic acids constitute a major class of biopolymers that
form the basis of life.[1] Nucleic acids find application in
therapeutics,[2a] drug delivery,[2b] biotechnology,[2c] chemical
biology,[2d] biosensing,[2e] templated syntheses,[2f] supramolec-
ular chemisty,[2g] charge transport,[2h] materials science,[2i–k]
and nanotechnology.[2l, m] There is a great deal of interest in
developing stable modified nucleic acids[3] with improved
properties for application in various fields. Among the
possible modifications, phosphate-modified analogues are
attractive because of their high stability and resistance to
nulceases.[4a] Peptide nucleic acids (PNA),[4b] in which the
phosphodiester linkage is replaced by an amide linkage
(Figure 1), are known to be functionally similar or even
superior to DNA. The 1,2,3-triazole motif, which has similar
polarity and topology to an amide linkage, is more stable
under acidic, basic, and enzymatic conditions and is consid-
ered a stable functional mimic (bioisostere) of the amide
linkage.[5a] Accordingly, there have been attempts to replace
one or more phosphodiester linkages with 1,4-triazole units in
synthetic DNA oligomers, and this linkage has been found to
be a promising functional surrogate for the phosphodiester
linkage in nucleic acids (Figure 1).[5b,c] However, the scope of
solution or solid-phase synthesis of triazole-linked oligomers
is limited owing to the difficulty in making larger polymers,
poor yield,[5d] incomplete reaction, difficult purification, and
degradation of oligonucleotides in presence of CuI cata-
lysts.[5b] Herein, we report the first single-crystal-to-single-
crystal (SCSC) synthesis of a triazole-linked polymeric DNA
analogue through topochemical azide–alkyne cycloaddition
(TAAC).
Topochemical reactions—reactions controlled by the
geometry and proximity of the reactive partners in the crystal
lattice—are attractive because they involve solvent-free and
catalyst-free conditions, high yields, and stereo/regiospecifi-
city.[6] Topochemical polymerization[7] enables the synthesis of
highly ordered, stereoregular and homogeneous polymers.[8]
However, owing to the inconvenience of designing crystals
that fulfill the strict geometrical prerequisites, topochemical
polymerization is limited to a small set of compounds.[6–9]
Because of the possible attractive noncovalent forces such as
dipole···p and p···p interactions between azide and alkyne
motifs, they prefer to a adopt parallel orientation in close
proximity in crystals.[10] They can then undergo topochemical
azide–alkyne cycloaddition (TAAC) to form either 1,4-
substituted or 1,5-substituted triazoles regiospecifically,
depending on their orientation in the crystal lattice. We
have recently introduced this strategy for the synthesis of
[*] A. Pathigoolla, Prof. Dr. K. M. Sureshan
School of Chemistry, Indian Institute of Science Education and
Research Thiruvananthapuram, CET-Campus
Thiruvananthapuram-695016 (India)
E-mail: kms@iisertvm.ac.in
Homepage: http://www.iisertvm.ac.in/scientists/kana-m-sure-
shan/personal-information.html
[**] A.P. thanks CSIR-India for Senior Research Fellowship assistance.
K.M.S. thanks the Department of Science and Technology (DST,
India) for a Ramanujan Fellowship and SwarnaJayanti Fellowships.
This work was made possible by financial support from DST and
CSIR.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404797.
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1
triazole-linked polysaccharides.[10a,11] Following these lines,
we envisioned that triazole-linked DNA analogues could be
made through TAAC reaction of a nucleoside modified with
azide and alkyne functional groups at the 3’ and 5’ positions.
Nucleoside 1 (Figure 2A,B) was synthesized in six steps
from the commercially available 3,5-anhydro-2-deoxy-b-d-
threo-pentofuranosyl-1-thymine (see the Supporting Infor-
mation) and crystallized from a 1:1 mixture of ethyl acetate
and benzene. Single crystal X-ray analysis revealed that
monomer 1 crystallizes in the orthorhombic P212121 space
group. The pentose ring adopts C3’-exo puckering (3E). As
expected, the azide and alkyne motifs of adjacent molecules
are positioned at close proximity as a result of p···p
interactions between them and the molecules are arranged
linearly in a head-to-tail fashion in the a direction (Fig-
ure 2C,D). This linear arrangement is further supported by
the p···p interaction and p···dipole interaction between the
phenyl ring and the cytosine ring of adjacent molecules (d =
3.3 ꢀ) along the a direction. The close proximity between the
alkyne and azide motifs (dmean = 3.33 ꢀ) and their parallel
alignment suggests that they could undergo a topochemical
1,3-dipolar cycloaddition reaction to form 1,5-substituted
triazoles.
heating above 808C, as evidenced from the H NMR spec-
trum of a solution of the heated crystal dissolved in
[D6]DMSO. As expected, the solubility of the heated crystals
decreased in common organic solvents. Crystals kept at 1008C
for 3 days were completely insoluble in any solvent, thus
suggesting that the monomer underwent complete polymer-
ization. However, a sample of crystals kept at 908C took 60 h
for complete consumption of the monomer. The polymer
obtained after keeping 1 at 908C for 60 h was partially soluble
in DMSO and could be analyzed by NMR spectroscopy
(Figure 3).
The polymerization reaction was also confirmed by using
IR spectroscopy, differential scanning calorimetry (DSC),
powder X-ray diffraction (PXRD) and NMR spectroscopy. In
the IR spectrum, 1 showed sharp signals at 2097 cmÀ1 and
2128 cmÀ1 corresponding to the azide and terminal alkyne
functionalities, respectively, whereas these signals were
almost absent in the IR spectrum of a sample kept at 908C
for 60 h (Figure 3A). DSC analysis of 1 showed a melting
point of 1478C and further heating gave a broad exothermic
peak as a result of uncontrolled polymerization in the molten
state. Uncontrolled random polymerization in the molten
stage was further confirmed by recording the 1H NMR
spectrum of a molten sample, which showed the presence of
both 1,4- and 1,5-triazolyl linkages (see the Supporting
Information). DSC analyses of crystals kept at 908C for
different durations revealed the gradual polymerization of the
monomer. Samples kept for longer duration showed lower
melting points. A gradual depression in the melting point
The crystals of the monomer (1; M.P = 1478C) were stable
under ambient conditions for several months. This suggests
that despite the geometrical criteria for reaction being met,
the crystals of 1 cannot undergo spontaneous topochemical
polymerization reaction. However, compound 1 underwent
azide–alkyne cycloaddition in its crystalline state upon
Figure 2. A) The structure of the monomer (1). B) An ORTEP diagram
of 1. C) Packing along the ac plane with p···p interaction between the
azide and alkyne groups in the a direction. The pink dotted lines
represent p···p interactions between aromatic rings in the a direction
and the gray dashed lines represent interactions between the azide
and alkyne groups. D) A close-up view of the interactions between the
azide and alkyne groups.
Figure 3. A) A comparison of IR spectra of the monomer (1) and
polymer (2), showing the absence of azide signal for the polymer. The
1H NMR spectra (B) and 13C NMR spectra (C) of 1 and 2 show clear
and well resolved signals for all of the carbon and hydrogen atoms of
the repeating unit.
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proportionate to the exposure time was observed, as antici-
pated based on the formation of small amounts of oligomers
observed. While a (7.0231 ꢀ in 1, 5.810 ꢀ in 2) decreased
considerably, b (11.402 ꢀ in 1, 11.566 ꢀ in 2) and c (22.047 ꢀ
in 1, 24.503 ꢀ in 2) increased slightly, thereby leading to an
overall reduction in cell volume (ca. 6.7%) and a concomitant
7.22% increase in density. The pentose sugar ring slightly
changed its conformation to 43T from 3E. The monomer units
are connected through a 1,5-triazolyl moiety in the a direction
to form an infinite polymer chain. The polymer is isotactic
with the shape of a comb (Figure 4C).
A comparison of the crystal structures of the monomer (1)
and the polymer (2) revealed that major positional changes
after polymerization are in the a direction (see the Supporting
Information) owing to the formation of covalent linkages at
the expense of noncovalent interactions in this direction.
Interestingly, the p···p stacking between N-benzoylcytosine
moieties is conserved even after polymerization. Also the
hydrogen bond between the amide and O2 is intact even after
polymerization. The adjacent polymeric chains are connected
through CH···O hydrogen bonds (C5–H5···O7, C6–H6···O7)
in the b direction to form a zig-zag arrangement. Such
noncovalent zig-zag chains are packed in the c direction
through interdigitated N-benzoylcytosine units of adjacent
chains.
Although solid-state structures of protein-complexed
ssDNA oligomers are known, to our knowledge, crystal
structures of isolated ssDNA or its analogues are not known.
The present report is the first crystal structure of an ssDNA
analogue. While natural polynucleotides have six-bond perio-
dicity in their backbone, our 1,5-triazole-linked DNA ana-
logue has only five-bond periodicity. This restricts the degrees
of freedom. Moreover, the flexible phosphodiester linkage in
natural nucleic acids is replaced by a rigid triazole ring. As
a result of these conformational constraints, the nucleobases
are stacked on one side of the polymer. The stacking between
adjacent bases is interesting and is partially responsible for
the isotactic conformation of the polymer. Small isosequential
ssDNA oligomers are known to adopt base stacked con-
formations in solution.[12]
1
in the crystals of monomer with time. The H and 13C NMR
spectra (in [D6]DMSO) of a solution of the crystals of
monomer 1 kept at 908C for 60 h suggested its smooth
polymerization under these conditions. The signals were clear
with distinct peaks for each proton and carbon atom of the
repeating unit, thus suggesting that the polymer (2) is highly
homogeneous, pure, and stereoregular in nature (Figure 3).
Furthermore, the polymeric product showed high thermal
stability as shown by thermogravimetric analysis (see the
Supporting Information).
The fact that the polymerization occurs at a temperature
much below the melting point and the morphology of the
crystals remains the same and provides a regiospecific
polymer suggests that the polymerization is a topochemical
reaction. The topochemical nature of the polymerization was
also substantiated by recording the PXRD spectra at regular
intervals of a sample of 1 kept at 908C. The sample
maintained its crystalline nature throughout the reaction as
evidenced from PXRD (see the Supporting Information). As
the morphology of the crystals was intact even after poly-
merization, we solved the single-crystal X-ray structure of the
polymer (Figure 4). It should be noted that the reliability of
the data was very good with an R-factor of 4.34, thus
suggesting that the polymers formed are homogeneous and
monodisperse. To our knowledge, such high resolution
structures are not known for DNA or its analogues. While
the space group of the polymer (P212121) was same as that of
the monomer, slight changes in the unit-cell parameters were
Conventional solid-phase synthesis is not suitable for the
synthesis of large nucleic acid polymers[13] or polymers with
unnatural linkages. By adopting topochemical polymerization
of an appropriately substituted nucleoside with complemen-
tary reacting motifs, namely alkyne and azide groups, we were
able to synthesize a highly homogeneous, enzyme stable,
crystalline DNA analogue regiospecifically in a crystalline
state in quantitative yield without using solvents and catalysts.
This is the first successful synthesis of a DNA analogue (1,5-
triazolyl DNA) by topochemical polymerization. While the
head-to-tail arrangement of monomers in the crystal lattice
facilitates polymer formation, the parallel orientation of the
alkyne and azide motifs in the crystal lattice dictates that the
reaction is regiospecific to give the 1,5-triazole-linked poly-
mer. Although DNA is proposed to have important applica-
tions in various fields, its anionic nature and the presence of
coordinated (H-bonded) water molecules and counterions
pose difficulties for some of these applications. Given that the
triazole ring is an uncharged phosphate surrogate, triazolyl
DNA analogues would be ideal substitutes for natural DNA
for such applications. The p-stacked ssDNA analogues with
Figure 4. A) The structure of the polymer (2). B) An ORTEP diagram of
2. C) The conformation of a single polymer chain. D) Packing along
the ac plane. The triazole-linked polymer aligned in the a direction.
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Keywords: click chemistry · cycloaddition · DNA ·
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SCSC transformations · topochemical polymerization
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