Abstract
Radical thiol-ene chemistry has been demonstrated for a range of applications in peptide science, including macrocyclization, glycosylation and lipidation amongst a myriad of others. The thiol-ene reaction offers a number of advantages in this area, primarily those characteristic of “click” reactions. This provides a chemical approach to peptide modification that is compatible with aqueous conditions with high orthogonality and functional group tolerance. Additionally, the use of a chemical approach for peptide modification affords homogeneous peptides, compared to heterogeneous mixtures often obtained through biological methods. In addition to peptide modification, thiol-ene chemistry has been applied in novel approaches to biological studies through synthesis of mimetics and use in development of probes. This review will cover the range of applications of the radical-mediated thiol-ene reaction in peptide and protein science.
Highlights
Since its discovery by Posner (1905), the thiol-ene reaction has found many diverse applications in synthetic chemistry
Radical thiol-ene chemistry has been demonstrated for many applications including, but not limited to thiosugar synthesis and carbohydrate chemistry (McSweeney et al, 2016), polymerisations (Hoyle et al, 2004), surface chemistry (Hoyle and Bowman, 2010), synthetic chemistry (Dénès et al, 2014) and in peptide chemistry, the latter being the focus of this review
The reaction was applied to an unprotected hexapeptide example, with thermal initiation providing no desired product, whilst photochemical conditions gave over 90% conversion via use of DPAP in NMP, with 5 equivalents of 48a
Summary
Since its discovery by Posner (1905), the thiol-ene reaction has found many diverse applications in synthetic chemistry. The thiol-ene reaction, or thiol-ene coupling (TEC) is considered a “click” reaction (Hoyle and Bowman, 2010) as originally defined by Shapless in Kolb et al (2001) Notable features of such “click” reactions include high yields, lack of side products, compatibility with aqueous conditions and orthogonality to many other synthetic reactions. An additional advantage of thiol-ene chemistry over other methodologies is in the formation of the naturally occurring thioether linkage. This is in contrast to commonly utilized linkages such as the triazole formed via CuAAC or other heterocycle-based linkers (Montgomery et al, 2019; Zhang et al, 2019). Applications for polypeptide modifications and in hydrogel-peptide conjugates have been reviewed elsewhere (Hoyle and Bowman, 2010; Brosnan and Schlaad, 2014; Deming, 2016)
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