Discrete and Stereospecific Oligomers Prepared by Sequential and Alternating Single Unit Monomer Insertion

Abstract

Natural biopolymers, such as DNA and proteins, have uniform microstructures with defined molecular weight, precise monomer sequence, and stereoregularity along the polymer main chain that affords them unique biological functions. To reproduce such structurally perfect polymers and understand the mechanism of specific functions through chemical approaches, researchers have proposed using synthetic polymers as an alternative due to their broad chemical diversity and relatively simple manipulation. Herein, we report a new methodology to prepare sequence-controlled and stereospecific oligomers using alternating radical chain growth and sequential photoinduced RAFT single unit monomer insertion (photo-RAFT SUMI). Two families of cyclic monomers, the indenes and the N-substituted maleimides, can be alternatively inserted into RAFT agents, one unit at a time, allowing the monomer sequence to be controlled through sequential and alternating monomer addition. Importantly, the stereochemistry of cyclic monomer insertion into the RAFT agents is found to be trans-selective along the main chains due to steric hindrance from the repeating monomer units. All investigated cyclic monomers provide such trans-selectivity, but analogous acyclic monomers give a mixed cis- and trans-insertion.

Upscaling single unit monomer insertion to synthesize discrete oligomers

“…The synthetic chemistry of discrete oligomers with up to five monomer units shown in Scheme presents five successive SUMI steps starting from the monomer (PMI) insertion into RAFT agent, n ‐butyl‐1‐phenylethyl trithiocarbonate (BETC). The starting RAFT agent (BETC) is different from that in our previous report ( n ‐butyl benzyl trithiocarbonate, BBTC), as BETC contains a better leaving group (1‐phenylethyl) compared to BBTC (benzyl); BETC gave higher conversion than BBTC while PMI was inserted into the RAFT agents ( vide infra ). Before investigating the feasibility of employing a homemade flow reactor to scale up the production of sequence‐defined oligomers using PET‐RAFT SUMI approach, the oxygen tolerance of this approach has to be confirmed first.…”

“…(a,b)]. The experimental procedure followed our previous study, in which a glass NMR tube was used as a reaction vessel [Fig. (c)].…”

“…As a result, highly pure trimers were synthesized for the first time under mild reaction conditions in a total yield of 95% . More recently, to circumvent the limitations of synthetic oligomer chain length and chemical diversity, we significantly improved this approach by employing two families of non‐homopolymerizable monomers with electron donating (indene and its derivatives) and electron withdrawing ( N ‐substituted maleimides) properties; this allows “infinite” sequential and alternating chain‐growth to give discrete oligomers with multiple functionalities . Despite this success, the reaction conditions were not optimized to increase the scale of production, due to the research focus on structure verification and analysis of stereochemistry of the final products.…”

Homogeneous Oligomeric Ligands Prepared via Radical Polymerization that Recognize and Neutralize a Target Peptide

“…Boyer et al. demonstrated a sophisticated polymerization procedure for the synthesis of sequence‐controlled discrete oligomers by inserting the monomers individually . Inspired by their reports, we utilized the RAFT block polymerization, and the scalable oligomer separation technique to prepare a library of bi‐functional, discrete oligomers.…”

“…Specificity and affinity to targets may be further improved via cycles of library expansion, using a variety of functional monomers, followed by affinity screening and specificity assay. The isolation of multifunctional oligomers with uniform stereochemistry is far more challenging, although it will be applicable in future to achieving higher affinity and specificity. The atomic yields of specific oligomers can be improved by optimizing the polymerization and purification processes for mass production.…”