Tailored Modification of Thioacrylates in a Versatile, Sequence‐Defined Procedure

Abstract

A strategy for the synthesis of sequence-defined oligomers using a selective side-group insertion approach making use of thiophenol-catalyzed amidation reactions is herein reported. In this context, a new thiolactone-based, multistep, iterative protocol is designed, utilizing thioacrylates in combination with solid-phase synthesis for step-by-step growth, resulting in sequence-defined oligomers. Sequence definition and structure variation are introduced by substituting the thioacrylate side groups with a wide variety of amines. The step-by-step growth of the oligomers is followed by liquid chromatography-mass spectrometry and high-resolution mass spectroscopy to determine both conversion and purity.

Automated Synthesis Protocol of Sequence‐Defined Oligo‐Urethane‐Amides Using Thiolactone Chemistry

“…Thiolactone was reintroduced every second step using thiolactone isocyanate, which can be made on a 150 g scale . Thus, this protocol represents a much simpler strategy, compared to the work using thioacrylates reported earlier, enabling automation, which not only improves purity, but also provides scope for enhanced throughput and up‐scaling because of the possibility for the robot to handle up to 72 reactions in parallel. Moreover, automation in general has already been shown to be a highly effective, scalable, labor‐saving technique for iterative, solid‐phase methods …”

“…Many sequence‐defined synthesis approaches are based upon a strategic combination of highly efficient and orthogonal reactions . As such, the facile and effective route to polymer functionalization using thiolactone chemistry has been harnessed by our group as a tool for sequence‐defined oligomer synthesis . This chemistry has been explored on the solid phase by immobilizing a functional thiolactone molecule on a solid resin in a Merrifield‐inspired synthesis route .…”

“…It also reduces the length of the side chains, thus limiting their flexibility which could be potentially important for applications such as cell interaction. Thus, a new sequence‐defined protocol was developed in collaboration with Becer and co‐workers, which explored the incorporation of thioacrylates and their modification using primary amines …”

“…An ABC‐type functional trimer (where A, B, and C represent three different functional side chains) was synthesized and conversion was followed by liquid chromatography mass spectrometry (LCMS) ( Figure a,b). LCMS is a very effective technique for analyzing the conversion and purity of the obtained sequences . At a wavelength of 214 nm, one can quantitatively see the disappearance of the starting material, the formation of product, and eventually appearance of side‐products.…”

Transformation of Thioester‐Initiated Star Polymers into Linear Arms via Native Chemical Ligation

“…However, complete dissociation of the star polymer into its arms was observed, once Cys-ME was introduced in the presence of TEA and thiophenol, which has earlier been shown to catalyze the amidation reaction (Scheme 3). [25] The progress of this reaction could easily be followed via GPC by the gradual decrease of the P8 trace and increase of the newly formed polymeric species (P9) at higher retention times (Figure 2).…”