Sequence-Defined Dithiocarbamate Oligomers via a Scalable, Support-free, Iterative Strategy

Article abstract of DOI:10.1021/acs.macromol.0c00412

Precise control over the monomeric sequence on natural sequence-defined polymers (SDPs) leads to their structural diversity and functions. However, absolute control over the monomeric sequence on a synthetic polymer remains a challenging process. Herein, we describe a support-free, protection-deprotection-free, cost-effective, and fast iterative strategy for multigram production of a new class of SDP with a unique functional group, dithiocarbamate, a potential group for material and biomedical applications. The strategy is based on a unique monomer, named as amine-hydroxyl monomer, and a three-component reaction between the monomer, CS2, and terminal chloro group of the growing chain. The fast strategy allows us to synthesize a 5-mer sequence-defined oligomer in 6 h. For a proof of concept, a range of aliphatic and aromatic groups have been incorporated at different sequences in the sequence-defined oligomer. This SDP platform has further been advanced by two ways: (i) multiple approaches for postsynthetic modification of SDP and (ii) increasing the chain length in a single step.

Full text of DOI:10.1021/acs.macromol.0c00412

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Article
Sequence-Defined Dithiocarbamate Oligomers via a Scalable,
Support-free, Iterative Strategy
Pandurangan Nanjan, Anna Jose, Liya Thurakkal, and Mintu Porel*
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ABSTRACT: Precise control over the monomeric sequence on natural
sequence-defined polymers (SDPs) leads to their structural diversity and
functions. However, absolute control over the monomeric sequence on a
synthetic polymer remains a challenging process. Herein, we describe a support-
free, protection−deprotection-free, cost-effective, and fast iterative strategy for
multigram production of a new class of SDP with a unique functional group,
dithiocarbamate, a potential group for material and biomedical applications. The
strategy is based on a unique monomer, named as amine-hydroxyl monomer,
and a three-component reaction between the monomer, CS2, and terminal
chloro group of the growing chain. The fast strategy allows us to synthesize a 5-
mer sequence-defined oligomer in 6 h. For a proof of concept, a range of
aliphatic and aromatic groups have been incorporated at different sequences in
the sequence-defined oligomer. This SDP platform has further been advanced
by two ways: (i) multiple approaches for postsynthetic modification of SDP and
(ii) increasing the chain length in a single step.
highly efficient, support-free, and iterative strategy to yield
multigram scale of a new class of monodispersed SDPs. The
unique feature of this class of SDP is that its backbone harbors
an important functional groupdithiocarbamate (DTC)
which is reported as an excellent candidate for both material
(e.g., heavy metal sensors27 and vulcanizing accelerators in
rubber industries28) and biomedical applications (e.g., anti-
leishmanial,29 antiacute myelogenous leukaemia,30 antitrypa-
nosomatids,31 and anticancer agents32). To our knowledge,
this is the first report on a DTC-based SDP. Our strategy
possesses multiple advantages including (i) a support-free and
protection−deprotection-free synthesis with readily available
starting materials under mild reaction conditions; (ii) yielding
multigram-scale product; and (iii) modular postsynthetic
modification of the SDP via versatile paths. The strategy is
based on (a) the design and synthesis of a unique monomer
and strategic incorporation of commercially available como-
nomer and (b) two key reactions yielding fast quantitative
conversion. Employing this strategy, more than 5 g of a 5-mer
was synthesized in 6 h, indicating the high-scalability, fast, and
efficient production of sequence-defined DTC oligomers (SD-
INTRODUCTION
■
Natural sequence-defined polymers (SDPs) including nucleic
acids and proteins are crucial for a living system because of
their structural and functional diversity. The monomeric
sequence is the key parameter that tunes their structure and
properties, which eventually leads to their unique functions.
However, precise control over the monomeric sequence on
nonnatural synthetic polymer backbones is challenging. A
nonnatural SDP possesses a wider scope of unlimited
functional groups at the side chain and backbone, leading to
extensive structural diversity and tunable properties. In the last
few decades, chemists have made great efforts for developing
nonnatural SDPs.1−8 An iterative strategy is an efficient
strategy to precisely control monomer sequences. Solid-
supported iterative synthesis9−13 is the pioneer and efficient
strategy to build SDPs for its ease of purification and
automation. However, kinetics of the solid-supported coupling
reaction is limited for poor diffusion into a solid support.
Soluble-supported strategies have been developed to overcome
this via solution-phase homogenous kinetics.14−19 Another
notable strategy is the support-free strategy20−26 which has
added advantages including fast solution-phase kinetics and
avoiding attaching and removal steps of the polymer from the
support. However, precise control over the monomeric
sequence via a support-free iterative process is difficult.
Hence, a limited number of support-free iterative strategies
have been developed so far. Motivated by the promises of
synthetic SDPs and the pressing need for developing an
efficient strategy for synthesizing the same, we report here a
Received: February 24, 2020
Revised: November 12, 2020
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DTCO). This methodology can be considered eco-friendly
because no hazardous waste is liberated except HCl gas which
can be neutralized by sodium bicarbonate base. A wide range
of functional groups has been incorporated in the SD-DTCO
through the custom synthesis of a monomer.
DTCO. A primary amine with the desired functional group
was reacted with chloroacetyl chloride to form a chloro-
terminal amide (1, Scheme 1b), which was further reacted with
ethanolamine to yield the amine-hydroxyl monomer (2,
Scheme 1b). The reaction mixture was extracted with 1:1
ethyl acetate/water, and >95% pure product was isolated from
the ethyl acetate layer. The monomers were directly used for
polymerization reaction without further purification. The
monomers were characterized by 1H NMR and liquid
chromatography−mass spectrometry (LC−MS) (Figures S2−
S7). Monomers with six different functional groups (Scheme
1b, 2a−f) were synthesized for the proof of concept of
incorporation of different groups in SD-DTCO.
Synthesis of SD-DTCO via a Three-Component
Reaction Strategy. SD-DTCO synthesis starts with a
secondary amine reacting with chloroacetyl chloride (como-
nomer) to yield chloroacetyl amide with the desired functional
group (3, Scheme 2). The next monomer was reacted with 3 in
the presence of CS2 to yield a 2-mer with two (or three when
R1 ≠ R1′) different functional groups (4, Scheme 2).
Thereafter, the hydroxyl functionality of 4 was reacted with
chloroacetyl chloride to yield 5 (Scheme 2). Subsequently,
repetition of steps 2 and 3 will produce a desired n-mer of SD-
DTCO (6, Scheme 2). For a proof of concept, N,N-diphenyl
amine was reacted with chloroacetyl chloride in dimethylfor-
mamide (DMF) at room temperature to form 7 (Figure 1).
The quantitative conversion occurred in 20 min. The reaction
mixture was washed with water, and the pure product was
extracted in ethylacetate. This compound was utilized for the
next step without any further purification. The next reaction
between 7 and the cyclohexyl amine-hydroxyl monomer (2a,
Scheme 1) in the presence of CS2 yielded the 2-mer (8, Figure
1). According to the three-component reaction strategy, the
first reaction generates active thiol by the reaction of secondary
amine of 2a and CS2 (Figure 1). The second reaction involves
nucleophilic substitution of the terminal chloride of 7 by the
active thiol generated in the first reaction to yield the 2-mer (8,
Figure 1) at quantitative conversion in 30 min with >95%
purity without silica gel column chromatography purification.
RESULTS AND DISCUSSION
■
Design and Synthesis of a Unique Monomer. In the
present study, an effort was made to synthesize SD-DTCO via
strategic design of a unique bifunctional monomer, named as
amine-hydroxyl monomer (Scheme 1a). This monomer
Scheme 1. (a) Structure of the Amine-Hydroxyl Monomer
and the Comonomer and (b) Synthesis of the Amine-
a
Hydroxyl Monomer
a
Reaction conditions: i = DMF, rt, 15 min; ii = ACN, 85 °C, 30 min.
framework consists of two reactive groups: a secondary
amine (blue) and a hydroxyl group (red) to provide reactive
sites for two key reactions. Chloroacetyl chloride was selected
as a comonomer to couple two amine-hydroxyl monomers
together to build the SD-DTCO (Scheme 1a). The amino
group of the monomer was utilized to generate in-situ active
thiol by the addition of CS2 and this active thiol was reacted
with the alkyl-chloro group of the comonomer to yield a DTC.
At room temperature, this three-component reaction was
selective towards the amine group of the monomer, keeping
the hydroxyl group inert. The hydroxyl group was reacted with
the acyl-chloro group of the comonomer to assemble the SD-
a
Scheme 2. Synthetic Strategy for Sequence-Defined DTC Polymers; Inset: Merits of the Strategy
a
Purification procedure: for step 1 and step 2, the reaction mixture was extracted in 1:1 ethyl acetate/water and the product was obtained in the
ethyl acetate layer. For step 3, the reaction mixture was extracted in 1:1 dichloromethane/water and the product was obtained in the
dichloromethane layer.
B
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Figure 1. Assembly of a 5-mer; left-structure, middleHPLC, and right(M + H)+ in LC−MS.
Kinetic study has been performed for the two above-
mentioned key reactions to establish the time required for
the quantitative conversion of each reaction (Figures S8 and
S9).
3-mer (9, Figure 1). The 3-mer showed the expected (M +
H)+ at 776.25 Da in LC−MS (Figure 1) and the proton signal
corresponding to butyl group in the 1H NMR spectrum
(Figure S10). Similarly, the reaction strategy was continued
until 5-mer (11, Figure 1) with the benzyl and diethyl
monomers respectively (2c and 2d, Scheme 1) under identical
conditions. 4-mer and 5-mer SD-DTCOs were characterized
by their (M + H)+ at 1100.10 and 1391.45 Da, respectively, in
LC−MS spectra (Figure 1). Retention time of the HPLC
traces of 7-11 (Figure 1-middle) indicates that the hydro-
phobicity of SD-DTCOs increases with the increase in chain
length as retention time is proportional to hydrophobicity.
The sequence was validated via a tandem-MS (MS/MS)
experiment on (M + H)+ ion of the 5-mer (Figure 2). From
the fragmentation analysis, it was identified that cleavage
occurs between β-carbon of DTC nitrogen and oxygen of ester,
High-performance liquid chromatography (HPLC) trace of
the corresponding 7 and 8 (Figure 1) shows high purity
without silica gel column chromatography purification. 7 and 8
showed the expected (M + H)+ peaks at 246.15 and 486.20
Da, respectively, in the LC−MS spectrum (Figure 1). Both the
cyclohexyl (δ = 1−1.8 ppm) and aromatic (δ = 7.3−7.6 ppm)
protons in the 1H NMR spectrum of 8 (Figure S10) confirmed
the presence of these groups in the 2-mer. Thereafter, the 2-
mer was reacted with chloroacetyl chloride to make a chloro
derivative of the 2-mer which was further reacted with butyl
amine-hydroxyl monomer (2b, Scheme 1) and CS2 via the
above-mentioned three-component reaction strategy to yield a
C
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Figure 2. (a) LC−MS (inset: structure) and (b) tandem-MS spectrum of a 5-mer.
and this pattern was consistent for all SD-DTCOs. The
expected mass of all the sequence-specific fragmentation ions
of 5-mer was identified in the MS/MS spectrum, confirming
the precisely arranged sequence of diphenyl−cyclohexyl−
butyl−benzyl−diethyl groups on the 5-mer (Figure 2).
analysis (TGA) and differential scanning calorimetry (DSC)
experiments. The results indicate that the SD-DTCO is stable
up to 180 °C (Figures S30 and S31). It was also observed that
SD-DTCO is stable under a free-radical atmosphere (Figure
S32) and under acidic and basic pH conditions (at least in the
range of pH 4−9, Figure S33).
Four more 5-mer SD-DTCOs were synthesized by changing
the functional groups and their sequence to prove that the
strategy is robust and consistent. The sequence of all the
synthesized SD-DTCO, their characterization (MS, MS/MS
Postsynthetic Modifications. Postsynthetic modification
is an important strategy for many applications in biomedical
and material sciences.33,34 Keeping this in mind, we made our
synthetic strategy versatile for postsynthetic modification of
SD-DTCO via three different paths (Figure 4). Multiple paths
for postsynthetic modification are important when availability
of the functional group of the secondary system is limited. In
path 1, an alkyne-terminal 3-mer and an azide terminal
molecule were synthesized (Figures 4a left, S34 and S35).
Reaction between them via Cu(I)-catalyzed azide−alkyne click
reaction yielded the expected product 12 (Figure 4a), which
was characterized by its (M + H)+ peak in the LC−MS
spectrum (Figures 4a-right and S36). In path 2, a naphthalene
moiety was attached with a 3-mer SD-DTCO via reaction of
the chloro-terminal 3-mer SD-DTCO and N-methyl-1-
naphthylmethylamine (Figure 4b). The product 13 was
characterized by its (M + H)+ peak in the LC−MS spectrum
(Figures 4b-right and S37). The fluorophore (naphthalene)-
conjugated SD-DTCO can be a potential candidate for
photophysical studies. In path 3, a 4-mer hydroxy terminal
SD-DTCO was reacted with adipoyl chloride to demonstrate
that postsynthetic modification is possible via any functional
group that can react with the hydroxy group (Figure 4c). The
product was confirmed by LC−MS (Figures 4c-right and S38).
As the reaction mixture was worked up in aqueous solution,
the second acyl-chloride (after postsynthetic modification) was
transformed into an acid group. The versatile postsynthetic
modification paths will make SD-DTCO potential for various
applications.
1
and H NMR), and yield are shown in Figures 3a and S21−
Figure 3. (a) Sequence and mass of the synthesized 5-mer SD-
DTCOs and (b) their HPLC traces.
S29. The overall yield of the synthesis of the 5-mer is 60−75%.
The product conversion at each reaction is quantitative.
However, the loss at each step occurred because of the
extraction process. The retention time of different 5-mer SD-
DTCOs in HPLC spectra (Figure 3b) suggests that by
changing the functional groups and their sequence, the
hydrophobic property of SD-DTCOs was modulated. Thermal
stability of the SD-DTCO was tested by thermogravimetric
Strategy for Increasing the Chain Length of SDOs.
Furthermore, we developed a strategy to increase the chain
length of the SD-DTCO by twofold in a single step via a linker.
D
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Figure 4. Postsynthetic modifications of the SD-DTCO via three approaches: (a) Cu(I)-catalyzed azide−alkyne click reaction between alkyne of
the SD-DTCO and azide of the secondary system, (b) chloro−amine reaction between chloro of the SD-DTCO and amine of the secondary
system, and (c) hydroxyl−acylchloride reaction between hydroxyl of the SD-DTCO and acyl chloro of the secondary system.
Figure 5. Synthesis of (a) 4-mer from a 2-mer (left) and its MS spectrum (right) and (b) 6-mer from a 3-mer (left) and its MS spectrum (right) via
a 1,3-propane-diamine linker.
One equivalent of 1,3-propane di-amine (linker) was reacted
with two equivalents of a chloro-terminal 2-mer and 3-mer to
generate a 4-mer and 6-mer, respectively (Figure 5). The
products were confirmed by the (M + H)+ and (M+2H)2+/2
peaks of the 4-mer (Figures 5a right, S39) and (M + H)2+/2
peak of the 6-mer (Figures 5b right and S40) in the respective
LC−MS spectrum. The 2-mer and 3-mer were selected to
prove this strategy because the masses of the 4-mer and 6-mer
fall in the detection range (50−2000 Da) of the LC−MS
instrument used in this study.
For example, a 5-mer was synthesized at >5 g in about 6 h. Five
SD-DTCOs were synthesized by changing functional groups
and their sequence and were characterized by LC−MS and
MS/MS study. The ease of monomer preparation along with
the efficient strategy facilitates the incorporation of a wide
range of functional groups into the SD-DTCO structure, which
will lead us for developing novel materials in the future.
Additionally, the strategy leads us to generate terminal
hydroxyl/chloro/alkyne reactive groups which can be utilized
for postsynthetic modifications by a secondary system to
extend its potential for various applications. Furthermore, a
strategy was developed to double the chain length of the SD-
DTCO via connecting the SD-DTCO at two terminals of a
linker in a single step. Postsynthetic modifications will enable
the SD-DTCO platform to engineer structural diversity,
tunable properties, and applications in material and biomedical
sciences. We are currently working on developing different
architectures of SD-DTCOs and exploration of their potential
applications.
CONCLUSIONS
■
In conclusion, an efficient strategy has been developed for the
synthesis of a new class of SD-oligomers incorporating DTC in
the backbone via strategic design of a unique bifunctional
monomer. This strategy is support-free, protection−depro-
tection-free, scalable at a multigram level, and consistent for
fast production of SD-oligomers from readily available
inexpensive starting materials under mild reaction conditions.
E
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tetrahydrofuran (6 mL). Sodium ascorbate (0.3 mmol) was
added, followed by the addition of CuSO4·5H2O (0.03 mmol).
The heterogeneous mixture was stirred vigorously for 1h at
room temperature. 1:1 ethyl acetate: water was added in the
reaction mixture and the product was extracted in the ethyl
acetate layer. Then, the solvent was removed under vacuum to
afford 84% of the product (12, Figure 4a). The post
synthetically modified product was further purified using silica
gel column chromatography and characterized by LC−MS
analysis.
Chloro-Amine Reaction. To a solution of a chloro
derivative of the 3-mer (0.5 mmol) in PEG-200 (1 mL), N-
methyl-1-naphthylmethylamine (0.5 mmol) was added and
stirred for 10 min at room temperature. Then, CS2 (2 mmol)
was added and stirred at room temperature for 1 h. 1:1 ethyl
acetate: water was added in the reaction mixture and the
product (13, Figure 4b) was extracted in the ethyl acetate
layer. Removal of solvent under reduced pressure yielded an
oily naphthalene-attached product which was further con-
firmed by LC−MS analysis.
Hydroxy-Acyl Chloro Reaction. Pyridine (0.6 mmol) was
added to a solution of a 4-mer SD-DTCO (0.3 mmol) in
dichloromethane (10 mL) and stirred for 10 min at room
temperature. Then, adipoyl chloride (0.4 mmol in 5 mL
DCM) was added slowly. The reaction mixture was stirred for
2h at room temperature. After completion of the reaction, the
reaction mixture was neutralized with aqueous NaHCO3
solution. Thereafter, the reaction mixture was washed with
water and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure, and the product (14, Figure
4c) was characterized by LC−MS analysis.
Increasing the Chain Length of SD-DTCO by Twofold
via a Single Step. To a chloro derivative of a 2-mer SD-
DTCO (15, Figure 5a, 0.106 mmol) dissolved in acetonitrile
(10 mL), potassium carbonate (0.424 mmol) and 1,3 propane
diamine (0.048 mmol) were added. The reaction mixture was
refluxed at 85 °C for 12 h. Thereafter, the reaction mixture was
cooled and filtered to remove potassium carbonate, and the
filtrate was extracted with ethyl acetate, washed with water, and
dried over anhydrous Na2SO4. After the removal of the solvent,
the product (16, Figure 5a, 4-mer) was obtained and
confirmed by LC−MS analysis. The same procedure was
followed to synthesize a 6-mer from a 3-mer (18, Figure 5b)
HPLC Analysis. The purity of all the synthesized
compounds was analyzed by HPLC analysis, as shown in
Figure 1. A binary solvent system (water with 0.1% formic acid
and acetonitrile with 0.1% formic acid) was used for the HPLC
experiment, and the gradient is detailed in the Supporting
Information. The flow rate of the HPLC experiment was
maintained at 1 mL/min, and the spectrum was monitored at
210 and 254 nm wavelength. Being a reverse-phase chromato-
graphic separation, increasing the retention time of the HPLC
spectrum indicates the increase in hydrophobicity of the
compound. The relative hydrophobicity of all synthesized SD-
DTCOs was analyzed by HPLC experiment (Figure 3b).
LC−MS Analysis. The product of each reaction was
characterized by its mass/charge (m/z) analysis using an LC−
MS instrument monitoring at 210 and 254 nm with a positive
mode for mass detection. The sequence of the synthesized SD-
DTCOs was identified by LC−MS/MS fragmentation. A
binary solvent system (water with 0.1% formic acid and
acetonitrile with 0.1% formic acid) was used for the LC−MS
experiment, and the gradient is detailed in the Supporting
EXPERIMETAL SECTION
■
Synthesis of Amine-Hydroxyl Monomers. Chloro-
terminal amide (1, Scheme 1) was synthesized via the reaction
of a primary amine with the desired functional group (1 mmol)
and chloroacetyl chloride (2 mmol) in DMF (5 mL). The
reaction was completed in 20 min at room temperature. After
completion of the reaction, the excess chloroacetyl chloride
was quenched by the addition of sodium bicarbonate solution.
Thereafter, 1:1 water: ethyl acetate was added in the reaction
mixture and the product (chloro-terminal amide) was
extracted in the ethyl acetate layer with >95% purity. The
chloro-terminal amides (1, Scheme 1) were directly used for
the next reaction without column chromatography purification.
Next, in a solution of chloro-terminal amides (1 mmol) in
acetonitrile (5 mL), ethanolamine (5 mmol) and potassium
carbonate (10 mmol) were added and the reaction mixture was
refluxed at 85 °C for 30 min. Thereafter, the reaction mixture
was cooled at room temperature and 1:1 water: ethyl acetate
was added in the reaction mixture. The product (2, Scheme 1,
amine-hydroxyl monomer) was extracted in the ethyl acetate
layer. The solvent was removed under reduced pressure, and
the amine-hydroxyl monomer (2, Scheme 1) was obtained at
90−95% yield with >95% purity. All the monomers were
characterized by 1H NMR and LC−MS. Monomers (2,
Scheme 1) were directly used for polymerization reaction
without further purification.
Synthesis of SD-DTCOs. A secondary amine (1 mmol)
with the desired functional group and chloroacetyl chloride (2
mmol) were stirred in DMF (5 mL) at room temperature to
yield 3 (Scheme 2). The reaction was completed in 20 min.
After completion of the reaction, excess chloroacetyl chloride
was quenched by the addition of sodium bicarbonate solution.
Thereafter, 1:1 water: ethyl acetate was added in the reaction
mixture and the product was extracted in the ethyl acetate layer
with >95% purity. Thereafter, the respective monomer (2a−2f,
Scheme 1, 2 mmol) and CS2 (4 mmol) were added in a chloro
derivative of 1-mer (3, Scheme 2, 1 mmol) solution in
polyethylene glycol (PEG)-200 (1 mL). The reaction mixture
was stirred at room temperature for 30 min. 1:1 water: ethyl
acetate was added in the reaction mixture, and the 2-mer (4,
Scheme 2, 3-mer) was extracted in the ethyl acetate layer and
was employed for the next step without column chromatog-
raphy purification. Next, the chloro derivative of the 2-mer (5,
Scheme 2) was prepared via the reaction of the 2-mer (1
mmol) and chloroacetyl chloride (2 mmol) in the presence of
triethylamine (2 mmol) in dichloromethane (5 mL) at room
temperature. The reaction was completed in 20 min, and
thereafter, the excess chloroacetyl chloride was quenched with
sodium bicarbonate solution. The dichloromethane was
removed under reduced pressure. This product (5, Scheme
2) was used directly for the next reaction without further
purification. The same cycle of reactions was repeated for the
synthesis of different SD-DTCOs (6, Scheme 2). SD-DTCOs
were characterized by LC−MS and MS/MS study.
Postsynthetic Modifications. Postsynthetic modification
of SD-DTCOs was performed in three different approaches
according to the following procedures.
Cu(I)-Catalyzed Azide−Alkyne Click Reaction. Alkyne-
substituted SD-DTCO (0.5 mmol) and azide terminal diethyl
amide (0.5 mmol) (see section 8 under the Supporting
Information for synthetic procedure for both the starting
materials) were suspended in a 1:1 mixture of water and
F
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.macromol.0c00412.
■
sı
Synthesis and characterizations of different oligomers
including NMR, HPLC−MS, MS/MS, TGA, and DSC
(PDF)
(10) Davidson, E. C.; Rosales, A. M.; Patterson, A. L.; Russ, B.; Yu,
B.; Zuckermann, R. N.; Segalman, R. A. Impact of helical chain shape
in sequence-defined polymers on polypeptoid block copolymer self-
assembly. Macromolecules 2018, 51, 2089−2098.
AUTHOR INFORMATION
Corresponding Author
■
̈
(11) Kos, P.; Lachelt, U.; He, D.; Nie, Y.; Gu, Z.; Wagner, E. Dual-
Mintu Porel − Discipline of Chemistry, Indian Institute of
Technology Palakkad, Palakkad, Kerala 678577, India;
orcid.org/0000-0002-2742-2559; Email: mintu@
iitpkd.ac.in
targeted polyplexes based on sequence-defined peptide-PEG-
oligoamino amides. J. Pharm. Sci. 2015, 104, 464−475.
(12) Trinh, T. T.; Laure, C.; Lutz, J.-F. Synthesis of monodisperse
sequence-defined polymers using protecting-group-free iterative
strategies. Macromol. Chem. Phys. 2015, 216, 1498−1506.
(13) Grate, J. W.; Mo, K. F.; Daily, M. D. Triazine-based sequence-
defined polymers with side-chain diversity and backbone-backbone
interaction motifs. Angew. Chem., Int. Ed. 2016, 55, 3925−3930.
(14) Brown, J. S.; Acevedo, Y. M.; He, G. D.; Freed, J. H.; Clancy,
P.; Alabi, C. A. Synthesis and solution-phase characterization of
sulfonated oligothioetheramides. Macromolecules 2017, 50, 8731−
8738.
Authors
Pandurangan Nanjan − Discipline of Chemistry, Indian
Institute of Technology Palakkad, Palakkad, Kerala 678577,
India
Anna Jose − Discipline of Chemistry, Indian Institute of
Technology Palakkad, Palakkad, Kerala 678577, India
Liya Thurakkal − Discipline of Chemistry, Indian Institute of
Technology Palakkad, Palakkad, Kerala 678577, India
(15) Chan-Seng, D.; Lutz, J.-F. Primary structure control of
oligomers based on natural and synthetic building blocks. ACS
Macro Lett. 2014, 3, 291−294.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.macromol.0c00412
(16) Porel, M.; Alabi, C. A. Sequence-defined polymers via
orthogonal allyl acrylamide building blocks. J. Am. Chem. Soc. 2014,
136, 13162−13165.
Notes
(17) Porel, M.; Thornlow, D. N.; Phan, N. N.; Alabi, C. A.
Sequence-defined bioactive macrocycles via an acid-catalysed cascade
reaction. Nat. Chem. 2016, 8, 590−596.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(18) Kanasty, R. L.; Vegas, A. J.; Ceo, L. M.; Maier, M.; Charisse, K.;
Nair, J. K.; Langer, R.; Anderson, D. G. Sequence-defined oligomers
from hydroxyproline building blocks for parallel synthesis applica-
tions. Angew. Chem., Int. Ed. 2016, 55, 9529−9533.
■
We sincerely acknowledge the Indian Institute of Technology
Palakkad, India, and the Ramanujan Fellowship, Science and
Engineering Research Board, Department of Science and
Technology, India, for the financial support. Central
Instrumentation Facility (CIF) at the Indian Institute of
Technology Palakkad and DST-SAIF Cochin are acknowl-
edged for the support for analytical instruments.
(19) Dong, R.; Liu, R.; Gaffney, P. R. J.; Schaepertoens, M.;
Marchetti, P.; Williams, C. M.; Chen, R.; Livingston, A. G. Sequence-
defined multifunctional polyethers via liquid-phase synthesis with
molecular sieving. Nat. Chem. 2019, 11, 136−145.
(20) Wang, S.; Tao, Y.; Wang, J.; Tao, Y.; Wang, X. A versatile
strategy for the synthesis of sequence-defined peptoids with side-chain
and backbone diversity via amino acid building blocks. Chem. Sci.
2019, 10, 1531−1538.
(21) Solleder, J.-F.; Meier, M. A. R. Sequence control in polymer
chemistry through the Passerini three-component reaction. Angew.
Chem., Int. Ed. 2014, 53, 711−714.
ABBREVIATIONS
SDP sequence-defined polymers
DTC dithiocarbamate
■
PEG polyethylene glycol
THF tetrahydrofuran
(22) Leibfarth, F. A.; Johnson, J. A.; Jamison, T. F. Scalable synthesis
of sequence-defined, unimolecular macromolecules by Flow-IEG.
Proc. Natl. Acad. Sci. U.S.A. 2015, 112, 10617−10622.
(23) Barnes, J. C.; Ehrlich, D. J. C.; Gao, A. X.; Leibfarth, F. A.;
Jiang, Y.; Zhou, E.; Jamison, T. F.; Johnson, J. A. Iterative exponential
growth of stereo- and sequence-controlled polymers. Nat. Chem.
2015, 7, 810−815.
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