Combining Two Methods of Sequence Definition in a Convergent Approach: Scalable Synthesis of Highly Defined and Multifunctionalized Macromolecules

Article abstract of DOI:10.1002/chem.201703877

The straightforward convergent synthesis of sequence-defined and multifunctionalized macromolecules is described herein. The first combination of two efficient approaches for the synthesis of sequence-defined macromolecules is reported: thiolactone chemistry and the Passerini three-component reaction (P-3CR). The thiolactone moiety was used as protecting group for the thiol, allowing the synthesis of a library of sequence-defined α,ω-functionalized building blocks. These building blocks were subsequently efficiently coupled to oligomers with carboxylic acid functionalities in a P-3CR. Thus, larger oligomers with molecular weights of up to 4629.73 g mol^?1 were obtained in gram quantities in a convergent approach along with the introduction of independently selectable side chains (up to 15), thus clearly demonstrating the high versatility and the efficiency of the reported approach.

Full text of DOI:10.1002/chem.201703877

A Journal of
Accepted Article
Title: Combining Two Methods of Sequence Definition in a
Convergent Approach: Scalable Synthesis of Highly Defined and
Multifunctionalized Macromolecules
Authors: Susanne Solleder, Steven Martens, Pieter Espeel, Filip Du
Prez, and Michael Meier
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201703877
Link to VoR: http://dx.doi.org/10.1002/chem.201703877
Supported by

10.1002/chem.201703877
Chemistry - A European Journal
COMMUNICATION
Combining Two Methods of Sequence Definition in a Convergent
Approach: Scalable Synthesis of Highly Defined and
Multifunctionalized Macromolecules
Susanne C. Solledera, Steven Martensb, Pieter Espeelb, Filip Du Prezb * and Michael A. R. Meiera *
Abstract: This contribution describes the straightforward convergent
synthesis of sequence-defined and multifunctionalized
However, the coupling of larger sequence-defined building
blocks is desirable in terms of reaction efficiencies. In order to
synthesize sequence-defined macromolecules in a convergent
way, this contribution combines for the first time two efficient
approaches towards sequence-defined macromolecules in one
strategy.[2a, 2b, 7] Therefore, thiolactone chemistry was combined
with the P-3CR affording sequence-defined macromolecules in
an efficient manner, with individually selectable side chains in
high yields and in gram quantities.
macromolecules. Therefore, we report on the first combination of two
efficient approaches for the synthesis of sequence-defined
macromolecules: thiolactone chemistry and the Passerini three-
component reaction (P-3CR). Here, the thiolactone moiety was used
as protecting group for the thiol, allowing the synthesis of a library of
sequence-defined α,ω-functionalized building blocks. These building
blocks were subsequently efficiently coupled to oligomers with
carboxylic acid functionalities in a P-3CR. Thus, larger oligomers
with molecular weights of up to 4629.73 g/mol were obtained in gram
quantities in a convergent approach along with the introduction of
independently selectable side chains (up to 15), thus clearly
demonstrating the high versatility and the efficiency of the reported
approach.
First, thiolactone-carboxylic acid 1 was reacted in Passerini
reactions with 10-undecenal 2 as aldehyde component in
combination with different isocyanides 3a-h, allowing
subsequent thiol-ene additions with mercaptopropionic acid 5
and thus the repetition of the iterative cycle (Scheme 1).[7a, 8] All
P-3CRs were conducted in DCM, except for the reactions
leading compounds 4a-c, where the employed solvent system
was a THF water mixture (4:1) due to insolubility of 1 in DCM.
Interestingly, the previously published synthesis procedure could
be simplified: only 1.2 equivalents of mercaptopropionic acid 5
were used and the raw material was used without further
purification in the next P-3CR.[7a] The formed side product
The synthesis and characterization of sequence-defined
macromolecules are topics of high actuality and many research
groups investigate novel approaches, also trying to simplify the
procedures.[1] Inspired by naturally synthesized macromolecules
such as DNA, where the perfectly defined primary structure
enables complex processes like the replication of genetic
material, synthetic macromolecules with defined primary
structures are targeted. Hereby, conceptually different
approaches including solid phase strategies,[2] single unit
monomer insertions (SUMIs),[3] fluorous supported synthesis
strategies[4] and liquid phase reactions are currently investigated,
which were summarized in recent reviews.[1a, 5] In order to use
these highly defined materials in concrete applications, for
instance as data storage materials, anti-counterfeiting tags or as
active ingredients in pharmaceutical applications, simple
synthesis procedures along with scalability are important
issues.[6] Moreover, procedures, allowing the synthesis of larger
macromolecules, containing free to choose moieties, in an
efficient manner are very important. Most of the published works
are based on iterative additions of single monomer units.
(P-3CR of the excess of mercaptopropionic acid
5 with
10-undecenal 2 and the isocyanide) could easily be removed
during the workup of the P-3CR, thus saving one
recrystallization step for each synthesis cycle. Attractively, one
individually selectable side chain can be introduced in each
P-3CR. In the described way, α,ω-functionalized trimers bearing
a terminal double bond and a thiolactone functionality were
obtained in high purities. Subsequently, the obtained thiolactone
end group was ring-opened by aminolysis (introducing another
side chain) with 1.6 equivalents of benzyl amine and in-situ
reacted with 2.5 equivalents of acrylate-isocyanide
9
(introducing an additional side chain). Interestingly, the acrylate-
isocyanide 9 was synthesized in one step by a P-3CR of acrylic
acid with acetaldehyde and 1,6-diisocyanohexane in multigram
scale (see Supporting Information). This procedure underlines
the versatility of multicomponent reactions allowing the simple
introduction of desired functional groups in one molecule.
[a]
[b]
Susanne C. Solleder and Prof. Dr. Michael A. R. Meier
Institute of Organic Chemistry
Karlsruhe Institute of Technology (KIT)
Straße am Forum 7, 76131 Karlsruhe (Germany)
E-mail: m.a.r.meier@kit.edu
Web: www.meier-michael.com
Steven Martens, Pieter Espeel and Prof. Dr. Filip DuPrez
Polymer Chemistry Research Group, Centre of Macromolecular
Chemistry (CMaC), Department of Organic and Macromolecular
Chemistry
Ghent University, Krijgslaan 281 S4bis, 9000 Ghent, Belgium.
E-Mail: Filip.DuPrez@UGent.be
Web: http://www.pcr.ugent.be
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201703877
Chemistry - A European Journal
COMMUNICATION
Scheme 1: Synthesis of α,ω-functionalized isocyanide building blocks 10a-d by combination of thiolactone-chemistry with the P-3CR. Thiolactone carboxylic acid
1 is used as starting material for the iterative cycle of P-3CRs and thiol-ene additions to grow oligomers 8a-d. The thiolactone end-group is subsequently ring-
opened by aminolysis and in situ reacted with acrylate-isocyanide 9 to afford building blocks 10a-d, equipped with isocyanide functionalities and terminal double
bonds.
The one-pot, two-step aminolysis and Thia-Michael addition of
compounds 8a-d yielded the isocyanide building blocks 10a-d
with five individually selectable side chains, indicated by different
color coding in Scheme 1, in quantities of 0.6 to 1.3 grams. The
obtained building blocks, as well as all intermediates, were
carefully characterized by NMR, GPC, ESI-MS and infrared
spectroscopy (see Supporting Information). Figures S2-5 in the
Supporting Information show the summarized analytic results of
structures 10a-d. The GPC traces prove the high purity as well
as the monodispersity of the obtained products and the ESI-MS
spectra clearly confirm the anticipated structures by the very
good agreement of the calculated and the measured isotope
patterns. Attractively, many different and functional side chains
could be introduced including aliphatic, aromatic and ester side
chains, allowing further functionalizations and demonstrating the
versatility of the reported approach. Oligomers 10c and 11b, for
instance, bear a furan side chain, suitable for Diels-Alder
reactions. Having sequence-defined oligomers with isocyanide
end groups 10a-d in hand, the synthesis of oligomer 14 with a
and the MS results, including the isotope pattern, indicating the
high purity of the obtained products and the success of the
reactions. In order to investigate the iteration of the cycle and
thus the possibility to synthesize even larger oligomers using
this
approach,
compound
11a
was
reacted
with
3-mercaptopropionic acid 5 in a thiol-ene addition to yield
compound 15. The product 15 was isolated by precipitation,
after 1H-NMR confirmed full conversion of the terminal double
bond.
carboxylic acid end group was performed according to
a
previously published synthesis procedure[7b] in order to be
coupled with 10a,c or d (Scheme 2). Figure S1 in the Supporting
Information displays the GPC traces, the structure and the
obtained MS spectrum of compound 14 including the measured
and the calculated isotope pattern. Again, the high purity and the
success of the reactions can be proven. After successful
synthesis of the carboxylic acid building block 14 and the four
different isocyanide building blocks 10a-d, the coupling of the
oligomers in
a convergent approach via a P-3CR was
investigated (Scheme 2). Therefore, 1.0 equivalent of the
carboxylic acid trimer 14 was dissolved in DCM, 1.1 equivalents
of the isocyanide building block 10a,c or 10d were added and
the mixture was degassed with argon for ten minutes. Then, the
aldehyde compound, representing an additional free to choose
side-group, was added in large excess (7-20 equivalents) in
order to force the reaction to completion. After stirring the
reactions at room temperature for 24 hours, the products 11a-c
with 9 individually selectable side chains were isolated by
column chromatography in good yields of up to 80% and in
quantities of up to 1.5 grams. Figures S6-8 summarize the GPC
Scheme 2: Coupling of carboxylic acid oligomers with isocyanide building
blocks 10a-b in P-3CRs. The terminal double bond in the isocyanide-building
blocks 11a-c allows the iteration of the cycle after successful thiol-ene addition
with mercaptopropionic acid 5.
This article is protected by copyright. All rights reserved.

10.1002/chem.201703877
Chemistry - A European Journal
COMMUNICATION
Having 1.2 grams of oligomer 15 in hand a further P-3CR
coupling reaction with building block 11b was conducted
according to the aforementioned procedure. Thereby, 1.4 grams
of the sequence-defined macromolecule 16 with a molecular
weight of 4629.73 g/mol and 15 individually selectable side
chains was obtained. Figure 1 shows the GPC traces of the
carboxylic acid trimer 14, the coupling product 11a and the
coupling product 16, confirming the high purity of the
synthesized compounds.
yield of 82% and was also fully characterized by NMR, ESI-MS
and infrared spectroscopy (see Supporting Information). Figure
2 shows the measured ESI-MS spectrum, where the doubly,
triply and quadruply charged sodium cations were detected. The
zoom box shows the differently ionized species, leading to
multiple signals for compound 16.
Table 1: Overview of the obtained yields, amounts, MS-data and the
numbers of side chains of the synthesized oligomers.
ex. mass
yield
yield
/g
side
chains
reaction (product)
/%a/b/c
calculatede
mass founde
building block 10a
1. P-3CR (4a)
93c
1.0
3.1
1.7
0.6
505.2707
876.5201
1259.7695
1618.9904
505.2698
876.5211
1259.7716
1618.9924
1
2
3
5
2. P-3CR (7a)
3. P-3CR (8a)
Th.-M.i (10a)
88a,b
82a,b
69
building block 10b
1. P-3CR (4b)
90c
2.0
2.2
2.0
1.2
531.2863
888.5201
1295.7331
1654.9540
531.2861
888.5209
1295.7340
1654.9634
1
2
3
5
2. P-3CR (7b)
3. P-3CR (8b)
Th.-M.i (10b)
86a,b
84a,b
55b
building block 10c
1. P-3CR (4c)
95b
4.0
5.3
2.3
1.3
505.2707
878.4630
1259.6603
1618.8812
505.2700
878.4630
1259.6605
1618.8799
1
2
3
5
2. P-3CR (7c)
3. P-3CR (8c)
Th.-M.i (10c)
85a,b
79a,b
50b
Figure 1: GPC traces of the obtained oligomers 14, 11a and 16 illustrating the
high purity of the obtained products.
building block 10d
1.P-3CR (4c)
95b
4.0
5.3
1.8
0.9
505.2707
878.4630
1305.6811
1664.9020
505.2700
878.4630
1305.6818
1664.9134
1
2
3
5
Moreover, the measured isotope pattern is displayed on the left
and shows very good agreement with the calculated isotope
pattern, which is shown on the right-hand side.
2.P-3CR (7c)
3.P-3CR (8d)
Th.-M.i (10d)
85a,b
68a,b,d
51b
In conclusion, a straightforward, scalable and convergent
synthesis strategy towards sequence-defined macromolecules,
for the first time combining two different approaches of
sequence-definition, was developed and successfully applied in
the synthesis of macromolecules with up to 15 selectable side
start-block 14
1. P-3CR (12)
85b
4.0
4.0
3.5
694.5381
1019.7998
1184.9363
694.5385
1019.7997
1184.9381
1
2
3
2. P-3CR (13)
3. P-3CR (14)
87a,f
97a,g
chains.
Remarkably,
a
library
of
sequence-defined
macromolecules was synthesized and a quantity 1.37 grams of
an oligomer with a molecular weight of 4629.73 g/mol and 15
individually selectable side chains was obtained and fully
characterized. Furthermore, functional side chains, such as
esters and furans, were introduced. In addition, the high purity of
the products was evidenced by in-depth analysis including NMR,
GPC, IR and ESI orbitrap mass spectrometry. In summary, our
convergent approach demonstrates the usefulness and
efficiency of combining selected approaches for the synthesis of
sequence-defined macromolecules.
coupling of
oligomers
P-3CR of 14 and
10a (11a)
80b
1.5
0.5
0.2
1.4
2839.9827
2854.8925
2900.9133
2337.5049h
2839.9897
2854.8943
2900.9148
9
P-3CR of 14 and
10c (11b)
70a,b
50a,b
82a,b
9
P-3CR of 14 and
10d (11c)
9
P-3CR of 15 and
10b (16)
2337.5105h
15
b
a
overall yield of two steps (Thiol-Ene addition and P-3CR) after column
chromatography; c after recrystallization only 1.35 eq. of isocyanide added
d
e
[M+Na]+ f overall yield of two steps (deprotection and P-3CR) g overall yield of
three steps (2 deprotections, 1 P-3CR) h [M+2Na]2+ I Thia-Michael reaction
Table 1 gives an overview of all synthesized sequence-defined
macromolecules including the obtained amounts, yields,
MS-results and the number of selectable side chains. Most
impressively in this series, macromolecule 16 was obtained in a
This article is protected by copyright. All rights reserved.

10.1002/chem.201703877
Chemistry - A European Journal
COMMUNICATION
Acknowledgements
The authors thank Prof. Barner-Kowollik and his group for access to the
GPC-ESI-MS equipment. The authors are grateful to the Deutsche
Forschungsgemeinschaft (German Research Council, DFG) in the context of
§91b application under the auspices of Prof. C. Barner-Kowollik funding
the orbitrap mass spectrometer. S.C.S. is grateful for a PhD scholarship
from the Verband der Chemischen Industrie (VCI). We kindly thank the
Deutsche Forschungsgemeinschaft (DFG) for funding the collaborative
research center 1176 (SFB 1176, project A3).
Keywords: sequence-defined macromolecules • sequence
control • multicomponent reactions • convergent • thiolactone
[1]
a) S. C. Solleder, R. V. Schneider, K. S. Wetzel, A. C. Boukis, M. A. R.
Meier, Macromol. Rapid Commun. 2017, 38, 1600711; b) J.-F. Lutz, J.-
M. Lehn, E. W. Meijer, K. Matyjaszewski, Nat. Rev. Mater. 2016, 1,
16024; c) J.-A. Amalian, T. T. Trinh, J.-F. Lutz, L. Charles, Anal. Chem.
2016, 88, 3715-3722; d) H. Mutlu, J.-F. Lutz, Angew. Chem. Int. Ed.
2014, 53, 13010-13019.
[2]
a) P. Espeel, L. L. Carrette, K. Bury, S. Capenberghs, J. C. Martins, F.
E. Du Prez, A. Madder, Angew. Chem. Int. Ed. 2013, 52, 13261-13264;
b) S. Martens, J. Van den Begin, A. Madder, F. E. Du Prez, P. Espeel, J.
Am. Chem. Soc. 2016, 138, 14182-14185; c) J. W. Grate, K.-F. Mo, M.
D. Daily, Angew. Chem. Int. Ed. 2016, 55, 3925-3930; d) N. F. König, A.
Al Ouahabi, S. Poyer, L. Charles, J.-F. Lutz, Angew. Chem. Int. Ed.
2017, 56, 7297-7301; e) S. Srichan, H. Mutlu, J.-F. Lutz, Eur. Polym. J.
2015, 62, 338-346.
[3]
a) J. Xu, C. Fu, S. Shanmugam, C. J. Hawker, G. Moad, C. Boyer,
Angew. Chem. Int. Ed. 2017, doi: 10.1002/anie.201610223; b) J.
Vandenbergh, G. Reekmans, P. Adriaensens, T. Junkers, Chem.
Commun. 2013, 49, 10358-10360; c) J. Vandenbergh, G. Reekmans, P.
Adriaensens, T. Junkers, Chem. Sci. 2015, 6, 5753-5761.
[4]
[5]
a) M. Porel, C. A. Alabi, J. Am. Chem. Soc. 2014, 136, 13162-13165; b)
R. L. Kanasty, A. J. Vegas, L. M. Ceo, M. Maier, K. Charisse, J. K. Nair,
R. Langer, D. G. Anderson, Angew. Chem. Int. Ed. 2016, 55, 9529-9533.
a) N. Zydziak, W. Konrad, F. Feist, S. Afonin, S. Weidner, C. Barner-
Kowollik, Nat. Commun. 2016, 7, 13672; b) J. C. Barnes, D. J. C.
Ehrlich, A. X. Gao, F. A. Leibfarth, Y. Jiang, E. Zhou, T. F. Jamison, J.
A. Johnson, Nat Chem 2015, 7, 810-815; c) F. A. Leibfarth, J. A.
Johnson, T. F. Jamison, Proc. Natl. Acad. Sci. U. S. A. 2015, 112,
10617-10622.
Figure 2: top: ESI-MS spectrum of compound 16, showing the doubly, triply
and quadruply charged sodium cations. In the box, the zoom of the doubly
charged sodium cation is displayed, showing the signals for the molecule with
differently ionized species. bottom: the measured isotope pattern shown on
the left is in very good agreement with the calculated isotope pattern (right).
[6]
a) J.-F. Lutz, Macromolecules 2015, 48, 4759-4767; b) H. Colquhoun,
J.-F. Lutz, Nat Chem 2014, 6, 455-456; c) Ufuk S. Gunay, Benoît E.
Petit, D. Karamessini, A. Al Ouahabi, J.-A. Amalian, C. Chendo, M.
Bouquey, D. Gigmes, L. Charles, J.-F. Lutz, Chem, 1, 114-126.
a) S. C. Solleder, M. A. R. Meier, Angew. Chem. Int. Ed. 2014, 53, 711-
714; b) S. C. Solleder, D. Zengel, K. S. Wetzel, M. A. R. Meier, Angew.
Chem. Int. Ed. 2016, 55, 1204-1207.
Experimental Section
[7]
[8]
All experimental details and in-depth characterization can be found in the
Supporting Information of this manuscript.
S. C. Solleder, K. S. Wetzel, M. A. R. Meier, Polym. Chem. 2015, 6,
3201-3204.
This article is protected by copyright. All rights reserved.

10.1002/chem.201703877
Chemistry - A European Journal
COMMUNICATION
This article is protected by copyright. All rights reserved.