A Simple Post-Polymerization Modification Method for Controlling Side-Chain Information in Digital Polymers

Article abstract of DOI:10.1002/anie.201702384

A three-step post-polymerization modification method was developed for the design of digitally encoded poly(phosphodiester)s with controllable side groups. Sequence-defined precursors were synthesized, either manually on polystyrene resins or automaticall

Full text of DOI:10.1002/anie.201702384

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702384
German Edition: DOI: 10.1002/ange.201702384
Digital Polymers
A Simple Post-Polymerization Modification Method for Controlling
Side-Chain Information in Digital Polymers
Niklas Felix Kçnig, Abdelaziz Al Ouahabi, Salomꢀ Poyer, Laurence Charles,* and
Jean-FranÅois Lutz*
[
1c]
Abstract:
A
three-step post-polymerization modification
intentionally tuned to facilitate sequencing. For instance,
the presence of repeated alkoxyamine and carbamate link-
ages facilitates MS/MS sequencing of information-containing
method was developed for the design of digitally encoded
poly(phosphodiester)s with controllable side groups.
Sequence-defined precursors were synthesized, either man-
ually on polystyrene resins or automatically on controlled pore
glass supports, using two phosphoramidite monomers contain-
ing either terminal alkynes or triisopropylsilyl (TIPS) pro-
tected alkyne side groups. Afterwards, these polymers were
modified by stepwise copper-catalyzed azide–alkyne cyclo-
addition (CuAAC). The terminal alkynes were first reacted
with a model azide compound, and after removal of the TIPS
groups, the remaining alkynes were reacted with another
organic azide. This simple method allows for quantitative side-
chain modification, thus opening up interesting avenues for the
preparation of a wide variety of digital polymers.
[
5–7]
macromolecules.
However, polymers that are tailor-made
for one particular sequencing technique are not necessarily
optimal for another one. For instance, nanopore sequenc-
[
12]
ing, which is a non-destructive analytical technique, may
require specific readable side-chain motifs rather than break-
able main-chain motifs. In this approach, sequence-defined
polyelectrolytes are subjected to an ionic current and thread
through nanopores of defined diameter. The interactions of
the monomers with the pore lead to current variations that
can be monitored and related to a sequence. Yet, this
technique is not trivial, and DNA pore sequencing required
about twenty years of optimization. This is, in part, due to
the fact that DNA nucleobases have closely related structures
(i.e., purine and pyrimidine heterocycles) that are difficult to
distinguish from one another. In comparison, the molecular
bits of non-natural sequence-coded polymers could be
engineered to interact with a pore to a larger or smaller
extent, thus rendering the analytes more “readable” than
DNA. More generally speaking, the molecular structure of
monomer bits may greatly influence the storage density and
[
12]
D
igital polymers are natural or non-natural information-
containing macromolecules that store binary information in
[1]
their monomer sequences. For instance, DNA, which is the
natural storage medium of genetic information, can be
engineered to store digital data. Alternatively, digital
information can be stored in a wide variety of synthetic
[
2]
[3]
polymers, including poly(triazole amide)s, poly(phospho-
[4]
[5]
[1c]
diester)s, poly(alkoxyamine phosphodiester)s, poly(al-
readability of digital polymers. In this context, it seems
[6]
[7]
koxyamine amide)s, and polyurethanes. Digital polymers
are currently studied for different applications in data
crucial to develop synthetic methods that can be used to
readily tune the side-chain information in digital polymers.
Herein, we describe a universal approach for side-chain
modification in digitally encoded poly(phosphodiester)s.
Scheme 1 shows the strategy studied in this work. Several
interesting routes have been described during the last few
years for the synthesis of sequence-defined polymers.
Among them, iterative phosphoramidite chemistry, which
was initially introduced for the synthesis of oligonucleotides,
[
8]
[9]
storage,
tags.
long-term storage,
In all cases, information is usually written in the
polymer chains using a step-by-step iterative process and is
and anti-counterfeiting
[
10]
[
1c]
read using a sequencing technology. Numerous sequencing
methods are available for deciphering the sequences of
information-containing macromolecules.
binary information stored on non-natural polymer backbones
may be deciphered by tandem mass spectrometry (MS/MS),
protein nanopore sequencing, solid-state nanopore sequenc-
ing, or controlled depolymerization. It was pointed out that
the molecular structure of non-natural polymers can be
[13]
[
11]
For instance,
[*] M. Sc. N. F. Kçnig, Dr. A. Al Ouahabi, Dr. J.-F. Lutz
Universitꢀ de Strasbourg, CNRS
Institut Charles Sadron UPR22
23 rue du Loess, 67034 Strasbourg Cedex 2 (France)
E-mail: jflutz@unistra.fr
Dr. S. Poyer, Prof. L. Charles
Aix Marseille Univ, CNRS, ICR UMR7273
13397 Marseille (France)
E-mail: laurence.charles@univ-amu.fr
Scheme 1. General concept for the selective functionalization of
sequence-defined poly(phosphodiester)s: 1) CuAAC modification of
the 0 bit units, 2) deprotection of the 1 bit units, and 3) CuAAC
modification of the 1 bit units.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702384.
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has been shown to also be a robust method for the
preparation of non-natural sequence-defined poly(phospho-
pendant terminal alkynes, and 5b, which contains two TIPS-
protected alkynes (Figure 1a). The synthesis of 5a begins with
the reaction of diethyl malonate and propargyl bromide (i)
followed by a reduction to the corresponding diol 3a (ii). For
5b, the corresponding TIPS-functionalized propargyl bro-
mide was employed in step i. For both monomers, one alcohol
function of the diols is then monoprotected with a 4,4’-
dimethoxytrityl (DMT) group (iii), and the remaining alcohol
is converted into a reactive phosphoramidite (iv). Both 5a
and 5b were obtained in excellent yields. The monoprotected
intermediates 4a and 4b were also used to prepare the
polystyrene supports 7a and 7b for manual iterative synthesis
(Figure 1b). They were first transformed into the base-labile
succinidyl ester linkers 6a and 6b (v) and then coupled to an
aminomethylated polystyrene resin (vi). Aside from modified
polystyrene resins, the commercial controlled pore glass
(CPG) support 8 was also used for the automated synthesis
(Figure 1c).
[4a,14]
diester)s.
an automated fashion, thus enabling the preparation of long
This method can be performed manually or in
[
4b]
coded chains.
Phosphoramidite chemistry was therefore
selected herein for the synthesis of digitally encoded polymers
of different lengths. These precursors contained two reactive
bits 0 and 1 as shown in Scheme 1; one of them bears terminal
alkynes and the other one TIPS-protected alkynes. Although
a variety of reactions can be performed on acetylenes, the
copper-catalyzed azide–alkyne cycloaddition (CuAAC) was
chosen for the modification of these precursors. Indeed, this
reaction has been shown to be a versatile process for the
[
15]
stepwise modification of DNA and synthetic polymers. The
terminal alkynes in the 0 bits were first reacted with an
1
organic azide R N to afford substituted triazoles. Afterwards,
3
the TIPS protecting groups in the 1 bits were removed, and
the obtained terminal alkynes were reacted with another
2
azide R N in a second CuAAC reaction.
The sequence-coded precursors were synthesized by
iterative phosphoramidite chemistry. Classical cycles involv-
ing DMT deprotection (vii), alcohol–phosphoramidite cou-
3
Two phosphoramidite monomers were used to build the
information-containing polymers, namely 5a, which bears two
Figure 1. a) Monomer synthesis: i) NaH, (protected) propargyl bromide; ii) LiAlH ; iii) DMT chloride; iv) 2-cyanoethyl-N,N-diisopropylchlorophos-
4
phoramidite. b) Functionalization of the polystyrene resin: v) succinic anhydride, DMAP; vi) aminomethylated polystyrene, DMAP, DCC.
c) Commercial dT-CPG support modified with deoxythymidine. d) Example of an iterative synthesis on polystyrene support: vii) DMT deprotection
with TCA; viii) coupling: 5a or 5b, 1H-tetrazole; ix) oxidation: I ; x) phosphate deprotection with piperidine; xi) iodine reduction with sodium
2
1
thiosulfate; xii) cleavage from the resin with aqueous methylamine/ammonia. e) Example of a post-polymerization modification: xiii) R N (10),
CuBr, TBTA, sodium ascorbate; xiv) TBAF; xv) R N (11), CuBr, TBTA, sodium ascorbate.
3
2
3
2
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pling (viii), and oxidation of the formed phosphites into
phosphates (ix) were used. To illustrate the versatility of our
approach, some polymers were prepared manually on the
polystyrene supports 7a and 7b (Figure 1d) whereas some
others were prepared on 8 using an automated DNA
synthesizer. In all cases, readable binary sequences were
implemented through the use of 5a and 5b. However, robot-
made sequences contain a thymine residue that comes from
the use of thymine-loaded support 8. Once the desired
sequence and length had been reached, the 2-cyanoethyl
phosphate protecting groups (x) and the ester linker were
cleaved (xii; Figure 1d). All digital polymers were charac-
terized by negative-mode high-resolution electrospray mass
spectrometry (ESI-HRMS; Table 1; see also the Supporting
Figure 2. ESI-HRMS spectrum (the m/z 950–1200 range) recorded for
the precursor P1 with the sequence 01100110, which was detected as
a triply deprotonated molecule (m/z 966.2) together with iodinated
species.
[
a]
Table 1: ESI-HRMS characterization of the sequence-coded precursors.
Support Sequence
Yield m/zth
m/zexp
[
b,c]
[d]
[e]
[e]
[e]
P1 7a
P2 7a
P3 7b
P4 7b
01100110
53% 966.1367
73% 708.8620
68% 708.8620
69% 708.8620
966.1375
708.8626
708.8638
708.8628
1288.9659
880.4030
prepared on 8, a logical explanation would be that traces of
iodine used in step ix remain entrapped in the resins despite
extensive washing. These traces may accumulate and react
[
b,c]
b,c]
b]
0110
[
1001
[
1001
[16]
with terminal alkynes when ammonia is used in step xii.
[
e]
f]
P5
P6
8
8
T 01000001
T 01001110
54% 1288.9641
[
Even if acetylene iodination does not prevent post-modifica-
70% 880.4022
[
17]
tion by alkyne–azide cycloaddition, the concomitant use of
both terminal alkynes and iodinated alkynes may lead to
heterogeneously modified, and thus unreadable, polymers. To
avoid this side reaction, a sodium thiosulfate wash (xi) was
conducted to reduce residual iodine before step xii (Fig-
ure 1d). Sample P4, which was prepared according to that
procedure, did not exhibit any iodinated species in ESI mass
spectra (Figure S4) whereas a comparable sample P3, which
was cleaved in the presence of iodine, contained iodinated
alkyne units (Figure S3). Altogether, the results in Table 1
suggest that any binary sequence can be synthesized using 5a
and 5b.
0
1001011
T 01000001 01000001 49% 945.2324
1000011
T 01001000 01000001
1010000 01010000
1011001 01000000
1010000 01001000
1000100
[
g]
h]
P7
P8
8
8
945.2326
0
[
[i]
1079.0947
1079.0873
0
0
0
0
[
[
[
[
a] The numbers 0 and 1 denote monomers 5a and 5b, respectively.
b] Contains missed steps. [c] Contains iodinated terminal alkyne units.
3
À
2À
7À
8À
d] [MÀ3H] . [e] [MÀ2H] . [f] [MÀ7H] . [g] [MÀ8H]
.
2
0À
h] [MÀ20H] . [i] The lack of standards at the appropriate charge state
accounts for the larger error (À7 ppm) associated with the measurement
of this highly charged oligomer. All ions were measured at the isotopic
maximum.
Sequential CuAAC modification was then performed on
some non-iodinated sequence-defined precursors. Although
the modification steps xiii, xiv, and xv could be directly
performed on the solid support, step xiv may interfere with
the base-labile linkers used in the present work. Therefore,
sequential modification of the cleaved polymers was inves-
tigated in solution. Figure 3 shows the characterization of
species obtained within the post-polymerization modification
process of resin-made polymer P4 as an example. As
displayed in Figure 1e, the terminal alkynes of the resin-
made precursors were first reacted with a model azide,
namely 1-azido-2-(2-(2-methoxyethoxy)ethoxy)ethane (10),
in a CuAAC reaction (xiii). This reaction was performed in
Information, Figures S1–S8). In all cases, the targeted struc-
tures were detected as deprotonated molecules in different
charge states. However, it should be noted that the polymers
prepared manually on 7a and 7b (P1–P4 in Table 1) exhibited
impurities and slight polydispersity owing to missed coupling
steps, whereas those prepared on 8 using the automated
synthesizer (P5–P8 in Table 1) were monodisperse. This is
probably due to the fact that the automated procedure
employs two capping steps per cycle that were not performed
during the manual synthesis of short oligomers. Moreover, it
should be noted that these sequence-coded precursors cannot
be purified by conventional reverse-phase chromatography
because of the apolar character of the TIPS protecting groups.
For some samples prepared on polystyrene resins, ESI-HRMS
also confirmed the presence of several species with masses
that were higher by increments of 126 Da than the expected
mass of the desired poly(phosphodiester)s (Figures 2 and S1–
S3). These signals are most probably due to the fact that some
terminal alkynes are randomly iodinated during the iterative
synthesis. As this side reaction does not occur for polymers
I
a mixture of DMSO and tert-butanol using Cu Br as the
copper source and tris(benzyltriazolylmethyl)amine (TBTA)
as the ligand following conditions previously optimized by
[
15b]
Carrell and co-workers for DNA modification.
The
resulting singly modified polymer P4’ was purified by dialysis
in methanol and characterized by ESI-HRMS (Figure S9) and
1
H NMR spectroscopy (Figure 3c). Both methods confirmed
successful CuAAC modification. In particular, quantitative
modification was supported by the complete disappearance of
the peaks corresponding to terminal alkyne protons at
1
2.3 ppm in the H NMR spectrum and the appearance of
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Figure 3. Characterization of the binary-coded poly(phosphodiester) P4 at different stages of its modification: after solid-phase synthesis (light
gray), after CuAAC transformation of the 0 units (P4’, blue), after TIPS removal on the 1 units (P4’’, dark gray), and after CuAAC modification of
1
9
the 1 units (P4’’’, red). a) ESI-HRMS spectrum of the fully modified polymer P4’’’. b) F NMR spectrum of the fully modified polymer P4’’’.
1
c) H NMR spectra for P4, P4’, P4’’, and P4’’’ recorded in [D ]MeOH. The displayed regions are 8.5–7.5 ppm and 4.7–0.5 ppm. The omitted region
4
(
7.5–4.7 ppm) contains the water peak of the deuterated solvent.
1
new peaks that are due to the triazole proton (8.1 ppm),
methylene protons adjacent to the triazole rings (4.5 ppm and
HRMS and H NMR spectra of the intermediates P7’ and P7’’
1
while Figure S13 shows the H NMR spectrum of the final
2
.8 ppm), and methylenoxy protons (3.75–3.4 ppm). After-
polymer P7’’’. The complete disappearance of resonances
corresponding to terminal alkyne protons in this spectrum
confirmed the successful stepwise CuAAC modification of
the digital polymer.
wards, the TIPS protecting groups of the 1 units in P4’ were
cleaved with TBAF in THF solution (xiv) to obtain P4’’
(
Figure S10). Quantitative deprotection was confirmed by the
complete disappearance of the peaks for the triisopropylsilyl
protons at 1 ppm in the H NMR spectrum and the reappear-
In summary, we have shown that stepwise CuAAC
modification is an efficient strategy for the side-chain
modification of digitally encoded polymers. Importantly, all
modification steps studied herein appeared to be quantitative,
enabling the synthesis of defect-free readable sequences.
Consequently, this work opens up interesting avenues for the
design of “universally” readable non-natural information-
containing macromolecules.
1
ance of terminal alkyne protons at 2.3 ppm (Figure 3c). The
second CuAAC modification (xv) was then achieved under
the same conditions as in step xiii using N-[2-{2-[2-(2-azidoe-
thoxy)ethoxy]ethoxy}ethyl]-2,2,2-trifluoroacetamide (11) as
the model azide. After methanol dialysis, the fully modified
digitally encoded polymer P4’’’ was characterized by ESI-
1
9
HRMS (Figure 3a) as well as F NMR (Figure 3b) and
1
H NMR (Figure 3c) spectroscopy. The latter technique
confirmed the quantitative disappearance of the terminal Acknowledgements
alkyne protons and a significant increase in the intensity of
the broad peak of the methylenoxy protons. Successful
modification was also confirmed by the appearance of
a resonance that is due to trifluoroacetamide moieties at
À77 ppm in the F NMR spectrum. Perhaps more impor-
tantly, ESI-HRMS corroborated the formation of polymer
P4’’’ in which all 0 and 1 units had been quantitatively
modified in steps xiii and xv, respectively. In addition,
incompletely modified sequences could not be detected,
thus suggesting that the stepwise CuAAC method is suitable
J.F.L. thanks the H2020 program of the European Union
(project Euro-Sequences, H2020-MSCA-ITN-2014, Grant
Agreement 642083), the European Research Council (ERC
Proofs-of-Concept project Sequence Barcodes, Grant Agree-
ment 680097), and the CNRS for financial support. The PhD
position of N.F.K. is supported by the ITN Euro-Sequences.
The manager position of A.A.O. is supported by the ERC.
1
9
for the modification of information-containing macromole- Conflict of interest
cules.
A slightly modified procedure was used for the modifica-
tion of polymers prepared on 8; these were typically obtained
in smaller quantities than those prepared on 7a and 7b. The
first CuAAC step was not performed in solution but directly
on the controlled pore glass cartridge. Subsequently, the
singly modified polymer was cleaved from the support, and
TIPS deprotection and the second CuAAC step were then
performed in solution. Following this method, sample P7 with
the sequence T 01000001 01000001 01000011 was modified
with azides 10 and 11. Figures S11 and S12 show the ESI-
The authors declare no conflict of interest.
Keywords: digitally encoded polymers ·
information-containing macromolecules ·
polymer modification · sequence-controlled polymers ·
solid-phase synthesis
4
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Manuscript received: March 6, 2017
2013, 52, 13154 – 13161; Angew. Chem. 2013, 125, 13392 – 13399.
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Digital Polymers
N. F. Kçnig, A. Al Ouahabi, S. Poyer,
L. Charles,* J.-F. Lutz*
&&&& — &&&&
A Simple Post-Polymerization
Modification Method for Controlling
Side-Chain Information in Digital
Polymers
0-1-1-0-1…: In digital polymers, binary
information is written using two como-
nomers that have slightly different
molecular structures and are defined as 0
and 1 bits, respectively. A simple stepwise
modification method is described that
can be used to tune the molecular
structures of the bits after polymeri-
zation.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!