Sequence control in polymer chemistry through the Passerini three-component reaction

Article abstract of DOI:10.1002/anie.201308960

A new strategy to achieve sequence control in polymer chemistry based on the iterative application of the versatile Passerini three-component reaction (P-3CR) in combination with efficient thiol-ene addition reactions is introduced. First, stearic acid was used as a starting substrate to build up a sequence-defined tetramer with a molecular weight of 1.6 kDa. Using an acid-functionalized PEG allowed for an easier isolation of the sequence-defined macromolecules by simple precipitation and led to a sequence-defined pentamer in a block-copolymer architecture. Importantly, this new strategy completely avoids protecting group chemistry. By following this strategy, a different side chain can be introduced to the polymer/oligomer backbone in a simple way and at a defined position within the macromolecule. The iterative application of the Passerini three-component reaction and the thiol-ene addition reaction provides sequence-defined macromolecules without the utilization of any protecting group. Copyright

Full text of DOI:10.1002/anie.201308960

Angewandte
Chemie
DOI: 10.1002/anie.201308960
Sequence-Controlled Polymers
Sequence Control in Polymer Chemistry through the Passerini
Three-Component Reaction**
Susanne C. Solleder and Michael A. R. Meier*
Abstract: A new strategy to achieve sequence control in
polymer chemistry based on the iterative application of the
versatile Passerini three-component reaction (P-3CR) in
combination with efficient thiol–ene addition reactions is
introduced. First, stearic acid was used as a starting substrate
to build up a sequence-defined tetramer with a molecular
weight of 1.6 kDa. Using an acid-functionalized PEG allowed
for an easier isolation of the sequence-defined macromolecules
by simple precipitation and led to a sequence-defined pentamer
in a block-copolymer architecture. Importantly, this new
strategy completely avoids protecting group chemistry. By
following this strategy, a different side chain can be introduced
to the polymer/oligomer backbone in a simple way and at
a defined position within the macromolecule.
sequence-defined synthetic polymers.[11] Leigh and co-work-
ers reported on the synthesis of sequence-specific peptides by
a rotaxane-based small-molecule machine; here the peptide
chain was elongated by successive native ligation reactions in
a non-DNA-templated approach.[12]
In addition, other non-DNA-templated approaches[12,13]
and step-growth polycondensation[14] approaches can be
employed to achieve sequence control. In contrast, chain-
growth-based approaches mainly rely on the high cross-
propagation reactivity of styrene with maleic anhydrides[15] or
maleimides in radical polymerizations.[16] By application of
living polymerization techniques, the maleimides can be
incorporated in certain regions (within the first monomer
units, the middle of the chain, or within the last monomer
units) of the polymer chains.[16b,17] Due to the N-substitution
of the maleimides, the introduction of specific moieties into
the polymer chain can be realized. Furthermore, it is possible
to sequentially add different maleimides to the polymeri-
zation system, leading to a polymer with diversely substituted
maleimides in the polymer chain.[16d] It should be noted that
these polymers are formed in a radical process, which implies
that the maleimides cannot be introduced at an absolutely
defined position in each chain. Additionally, due to statistic
processes and the simultaneous growth of many chains, it is
unavoidable that some chains will remain nonfunctionalized
and others will carry more than one functional group.
Therefore, in order to obtain highly defined sequence-
controlled materials, the above-mentioned sequential
approaches are inevitable.
Nowadays, several methods are known for the precise
synthesis of macromolecular architectures with defined
molecular weights and end groups. Of these, the controlled
radical polymerization methods, such as RAFT,[1] ATRP,[2]
and NMP,[3] enable the synthesis of defined and complex
architectures. In contrast, the synthesis of polymers bearing
well-defined monomer sequences only recently gained more
interest.[4] The development of solid-phase peptide synthesis
by Merrifield in 1963 can be considered the most important
milestone in the synthesis of sequence-defined macromole-
cules.[5] In addition, the solid-phase oligonucleotide synthesis
is well established.[6] Inspired by the natural synthesis of DNA
strands, several approaches making use of DNA-templated
reactions, for instance nucleotide coupling,[7] Wittig olefina-
tions,[8] reductive aminations,[8a] and Huisgen cycloadditions
have been described.[9] The DNA-templated Wittig olefina-
tion was also utilized for the synthesis of sequence-defined
oligomers by stepwise addition of different monomers.[8b]
Moreover, the DNA-templated synthesis was used for the
synthesis of polymers. Saito et al. oligomerized five DNA
pentamers by photoinduced cyclobutane formation[10] and Liu
et al. introduced a DNA-templated translation system ena-
bling the enzyme-free translation of DNA templates into
Our novel approach is based on the efficient P-3CR. Such
multicomponent reactions (MCR) have been known since
1850, when Strecker discovered the formation of a-amino-
nitriles from aldehydes, ammonia, and hydrogen cyanide.[18]
One important subclass of MCRs are the isocyanide-based
multicomponent reactions (IMCR), of which the P-3CR[19]
and the Ugi 4CR are most famous.[20] The P-3CR, first
described in 1921, is a three-component reaction of an oxo
component with a carboxylic acid and an isocyanide (isoni-
trile), forming an a-acyloxy carboxamide.[19] Although MCRs
are widely used in organic chemistry,[21] they were only
recently introduced to polymer chemistry. In 2011, our group
developed a novel Passerini polymerization method; the use
of a bifunctional carboxylic acid and a bifunctional aldehyde
in combination with structurally diverse isocyanides led to the
formation of high-molecular-weight polymers.[22] Recently,
our group reported on the preparation of acrylate monomers
by the P-3CR. After polymerization, the resulting materials
showed tunable thermoresponsive properties.[23] Within this
contribution, we describe the synthesis of a sequence-defined
tetramer as well as the synthesis of a block copolymer bearing
[*] S. C. Solleder, Prof. Dr. M. A. R. Meier
Institute of Organic Chemistry
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
E-mail: m.a.r.meier@kit.edu
Homepage: http://www.meier-michael.com
[**] We thank Prof. Barner-Kowollik (KIT) and his group for access to his
SEC-ESI-MS equipment and Prof. Luy (KIT) and his group for fruitful
discussions on NMR spectroscopy. S.C.S. is grateful for a scholar-
ship from the Verband der Chemischen Industrie (VCI).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308960.
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a sequence-defined pentamer block. In order to
achieve sequence control, we applied orthogonal
reactions iteratively to synthesize the sequence-
defined macromolecules in a stepwise manner with-
out the utilization of protecting groups. In this aspect,
the versatile P-3CR and the efficient thiol–ene
addition reaction proved to be a powerful combina-
tion. Applying this approach, the introduction of
different side chains to each monomer unit was
Figure 1. Structure of the obtained sequence-defined tetramer having four
different side chains.
(Figure 1) with a molecular weight of 1.6 kDa was
prepared in seven steps in an overall yield of 26%.
The results obtained after each synthesis step of
the sequence-defined tetramer (Table S2) as well as
all analytical data and further details can be found in
the Supporting Information. The NMR data of the
obtained products show the success of each exper-
imental step by the appearance of characteristic
signals and appropriate integrals for the introduced
amide protons after the P-3CR and the absence of
signals for olefin protons after the thiol–ene addition
reaction, respectively. Furthermore, mass spectrom-
etry of the obtained products proves the existence of
the desired products. GPC analysis (Figure 2) further
indicates the successful formation of the desired
products and verifies the high purity of the products
by the shifting towards higher molecular weights after
each step and the absence of low-molecular-weight
by-products.
The successful synthesis of 12 provided valuable
details about the synthesis procedures and also about
the behavior and stability of the oligomers. In order
Scheme 1. Synthesis of a sequence-defined tetramer (starting from 1a) or
a sequence-defined block copolymer (starting from 1b) by iterative application of
the P-3CR and the thiol–ene addition reaction.
achieved by simply employing different isocyanides in each
step of the P-3CR (Scheme 1).
to improve the yields and to significantly simplify the workup,
we changed the initial acid substrate. As also reported
earlier,[24] the use of a soluble polymer support significantly
facilitates the purification of the sequence-defined products
by straightforward precipitation and also speeds up the
overall synthesis. Therefore, a PEG acid was synthesized
from a commercially available PEG. Starting from the PEG
acid 1b, the sequence-defined block was synthesized accord-
ing to the aforementioned procedure. As anticipated, com-
plicated purification steps were not required in this case: the
This strategy has several advantages over other sequential
approaches (i.e. polypeptide synthesis). The use of coupling/
activating reagents is avoided and protecting groups are not
necessary for the backbone synthesis. As a result our
approach is more versatile (easy choice of side groups) and
scaleable, as well as more efficient and sustainable since less
waste is produced. Furthermore, the chemical diversity in the
field of sequence-defined macromolecules is enlarged by this
novel approach.
First, the P-3CR of stearic acid (1a), 2, and 3a was
investigated. THF and dichloromethane were tested as
solvents in different molarities (see Table S1 in the Support-
ing Information). The results revealed that high concentra-
tions of the reactants resulted in higher conversions, shorter
reaction times, and higher yields. However, when an equi-
molar ratio of the reactants was used, traces of 1a were
observed in the obtained product. Therefore, in order to
ensure full conversion of the carboxyl groups, we used 2 and
3a in a 1.5-fold excess. After this brief optimization, we
examined the conditions for the thiol–ene addition reaction
and found that the highest yields can be obtained by using
a tenfold excess of the thiol 4, 5.0 mol% DMPA 5 as an
initiator, and irradiation with UV light for two hours.
These optimized conditions were used in the further
synthesis steps of the oligomer and in the synthesis of the
Figure 2. GPC traces obtained after P-3CR and thiol–ene addition
block copolymer. Thus,
a
sequence-defined tetramer
reactions in the synthesis of the sequence-defined tetramer.
712
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products were isolated by simple precipitation. For the block
copolymer synthesis, the GPC results (Figure 3) also revealed
a shift of the complete molecular weight distribution towards
higher molecular weights, which is in agreement with the
material to the desired products in each reaction step.
Moreover, the integration of the 1H NMR signals of the
modified polymer endgroups are in good agreement with
those of the desired products and confirm the success of the
synthetic steps. Table S3 summarizes the results obtained for
each polymer after precipitation.
The synthesis of the block copolymer was much easier
than the oligomer synthesis thanks to the time-saving
purification by precipitation. Moreover, higher yields can be
obtained in the synthesis of 21, which has a sequence-defined
pentamer structural motif. An overall yield of 34% was
obtained after nine reaction steps.
All in all, the synthesis of the sequence-defined block
utilizing the PEG acid is more efficient with regard to ease of
purification and reaction efficiency, and also the overall
preparation procedure is significantly accelerated. Moreover,
it represents a more desirable polymeric architecture, since
the combination of defined polymers obtained by controlled/
living polymerizations with sequence-defined oligomeric
blocks might ultimately lead to the development of polymers
that can mimic proteins and other biopolymers.
Figure 3. GPC traces of the PEG copolymer after each P-3CR.
In conclusion,
a novel synthesis approach towards
sequence-defined polymers was successfully applied to the
synthesis of a tetramer as well as a block copolymer
containing a sequence-defined block of five units and bearing
five different side chains. The products were obtained in high
yields and purity. Thereby, the iterative utilization of the P-
3CR and the thiol–ene addition reaction proved to be
a powerful combination for the preparation of sequence-
defined materials and enabled an easy and versatile intro-
duction of different side chains. Moreover, the use of a PEG
acid allowed for a straightforward isolation of the sequence-
defined products by precipitation. It should be emphasized
that this novel synthesis protocol does not require any
protecting groups or activating reagents due to the orthogonal
reactions.
successful formation of the desired sequence-defined prod-
ucts. In all GPC traces a small shoulder is observed, which was
already present in the initially used PEG and probably arises
from bis-OH-functionalized PEG chains. Additional GPC/
ESI-MS measurements confirm the success of each reaction
step.
Figure 4 shows the mass spectra of 13 and 15 obtained
after the first and the second P-3CR, respectively. It is obvious
that all polymer chains are functionalized, owing to the shift
of the whole molecular weight distribution by 357.3 Da
[D(m/z) 119.1], which corresponds to the mass of 4, 2, and 3b.
Furthermore, the introduction of the desired functional
groups can be followed by NMR spectroscopy. The presence
or absence of the terminal double bond and the presence of
amide signals also verify full conversion of the starting
Received: October 14, 2013
Published online: December 4, 2013
Keywords: block copolymers · defined polymers ·
.
multicomponent reactions · Passerini reactions ·
sequence control
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