Radical Ring-Opening Single Unit Monomer Insertion: An Approach to Degradable and Biocompatible Sequence-Defined Oligomers

Abstract

Sequence-defined polymers prepared from vinyl monomers attract tremendous research interests in mimicking the precise primary sequence and remarkable biological functions of natural biopolymers. Sequential single unit monomer insertion (SUMI) via the reversible addition–fragmentation chain-transfer (RAFT) mechanism shows the ability to assemble vinyl monomers in defined orders efficiently with high yields. However, the approach of RAFT SUMI to produce both degradable and biocompatible sequence-defined oligomers has not been reported yet. In this research, we report the radical ring-opening SUMI of a cyclic ketene acetal monomer, 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), with the alternating insertion of N-substituted maleimides to afford sequence-defined oligomers. The oligomers can be degraded into shorter fragments due to the ester bonds incorporated in the backbone. Moreover, one prepared trimer demonstrates the biocompatibility to the investigated human normal cells while showing the cytotoxic effect against the studied human cancer cells. The properties of the produced oligomers endowed by BMDO hold promise for decoding information stored in sequence-defined polymers and the potential in biomedical applications.

Development of Sequence‐Controlled, Degradable, and Cytocompatible Oligomers with Explicit Fragmentation Pathways

“…[ 20 ] Subsequently, the facile introduction of BMI or EMI probably benefited from two factors: I) maleimides were related to the donor‐acceptor monomer principle [ 8,21 ] showing a high addition rate to the BMDO‐derived radicals to give trimers (BBTC‐PMI‐BMDO‐BMI (BPBB) and BBTC‐PMI‐BMDO‐EMI (BPBE)); II) the homolysis of the trithiocarbonate in BBTC‐PMI‐BMDO produced benzylic radicals to accept the second maleimidyl monomer in the presence of ZnTPP. [ 9 ] The trimers were characterized by NMR spectroscopy as represented in Figures S1–S5 (Supporting Innformation) which demonstrated the successful synthesis of the products.…”

Cationic Single-Unit Monomer Insertion (cSUMI): From Discrete Oligomers to the α-/ω-End and In-Chain Sequence-Regulated Polymers

“…Analysis of the reported cases of SUMI’s efficiency shows that (1) all SUMI cases are based on a radical process (rSUMI); (2) pairing of monomer and CTA plays an important role because the appropriate monomer/CTA pairs can prevent propagation or multiple additions of the monomer (Scheme ). Two strategies can limit the chain-growth reaction: (1) using unhomopolymerable monomers or a CTA with a highly reactive R group (making the rate of single addition of the monomer higher than that of propagation); , (2) increasing the favorability of R group fragmentation over the monoadduct via the chain transfer process. ,,, However, mechanistic limitations (all reported SUMIs are based on a free-radical mechanism) will result in a limited number of monomer/CTA pairs being capable of SUMI or in a specific sequence of monomer units in the chain that cannot be designed as desired. Therefore, the development of SUMI with new mechanisms will be beneficial to broaden the scope of monomer/CTA pairs and/or sequences of structure units in sequence-controlled vinyl polymers.…”

Rational design of a multi-in-one heterofunctional agent for versatile topological transformation of multisite multisegmented polystyrenes

“…In general, LMMPs can be synthesized by either sequential chain polymerization or step-growth polymerization. [24][25][26][27][28][29][30][31]61,62 The former affords well-defined multisegmented polymers as monomers are compatible with the polymerization technique; in particular, the emergence of a single unit monomer insertion (SUMI) strategy [63][64][65] holds great promise in achieving LMMPs with precise compositions and sequences. The latter involves click or click-like polymerization using pre-synthesized telechelic polymers, in which efficient coupling reactions such as the DA reaction, [9][10][11][12] atom transfer radical coupling (ATRC) 24,27,66,67 and nitroxide radical coupling (NRC) 49,[68][69][70][71] can be ideal choices for the synthesis.…”

“…Sequential polymerization of vinyl monomers has been adopted to achieve multiblock (co)polymers with tunable segment numbers and chain sequences, yet the SUMI-generated linker usually lacks the nature of lability. [63][64][65] By virtue of coupling reactions such as DA, NRC and hydroxylisocyanate 60,62 addition reactions, the resultant LMMPs with stimuli-labile DA, alkoxyamine and urethane linkers are difficult to transform into intrachain folding and branched polymers via intra/intermolecular cross-linking. Starting from some linear and hyperbranched LMMPs, intriguing multisegmented-to-one-segment (with reduced M n ), 16,17 linear/ branched-to-intrachain folding (with similar M n ) 16,49,52 and linear/branched-to-graft (with enhanced M n ) 17,65,66 transitions have been achieved.…”

“…[63][64][65] By virtue of coupling reactions such as DA, NRC and hydroxylisocyanate 60,62 addition reactions, the resultant LMMPs with stimuli-labile DA, alkoxyamine and urethane linkers are difficult to transform into intrachain folding and branched polymers via intra/intermolecular cross-linking. Starting from some linear and hyperbranched LMMPs, intriguing multisegmented-to-one-segment (with reduced M n ), 16,17 linear/ branched-to-intrachain folding (with similar M n ) 16,49,52 and linear/branched-to-graft (with enhanced M n ) 17,65,66 transitions have been achieved. However, the related types of topological transformations are relatively scarce, and it remains a great challenge to construct abundant architectural polymers with reduced, similar and enhanced molar masses via molecular tailoring and structural rearrangement of the same precursor.…”