Late‐Stage, Stereoretentive, and Site‐Selective Modification of Synthetic Peptides by Using Photoredox Catalysis

Abstract

Late‐stage functionalisation is an attractive method to generate peptide analogues containing non‐natural residues. It is shown that cysteine residues can be activated as Crich‐type thioethers, either by alkylation of a synthetic cysteine‐continuing peptide or by incorporation of a modified cysteine unit into solid phase or solution phase peptide synthesis. Photoredox catalysed reaction of the thioether generates an alanyl radical intermediate in a stereoretentive and site‐selective manner, even in the presence of free cysteine residues. The radical can react with non‐activated alkenes to form non‐natural residues bearing aliphatic, hydrophobic units. A method to avoid unwanted alkylation of amine residues was identified and the process was applied to the functionalization of both linear and cyclic synthetic peptides.

Photo‐induced Desulfurative Processes for Carbon Radical Generation

“…In the same framework, McErlean and co‐workers have recently developed a similar strategy in which cysteine‐based thioethers 25 are employed (Scheme 10). [29] Comparatively to Niu's work, they could find conditions avoiding the formation of alanine derivatives (stemming from the defunctionalization), even though the dehalogenation of 25 was observed in large amount. In addition, to prevent the formation of both defunctionalized compounds, the use of 10–50 equivalents of radical acceptors 26 was required, while Niu and co‐workers only added 1.1 equivalent of 23 (Scheme 9–10).…”

“…In this context, several photomediated approaches have been developed based on the use of thioether derivatives. [28][29][30] Two families of thioethers have been established depending on the mechanistic steps involved in the carbon radical generation through desulfurization (Scheme 8). After an activation step, substrates belonging to family A, can be involved in an intramolecular homolytic substitution (S H ) that triggers the desulfurization and the generation of the expected carbon radicals.…”

“…[31] In all the photomediated reactions, the S H step consists in the intramolecular cyclization of aryl radicals B onto the sulfur center, releasing the expected carbon radicals along with sulfur-containing heterocycles C (Scheme 8A). [28][29][30][31] On the other hand, the desulfurization of the second class of thioethers (D or G) can be achieved by initial SET reduction of thioethers containing either tetra-fluoropyridine or thiazolium cores (Scheme 8B). [32][33][34][35][36][37][38][39][40] The splitting of the CÀ S bond in the radicals E or H then leads to the carbon radicals and either a stabilized thiolate F or the 3methylthiazolidine-2-thione J byproduct.…”

“…The occurrence of side‐reactions, especially defunctionalizations, during the desulfurization of native thiols, has fostered the exploration of strategies involving pre‐functionalized thiols to overcome certain limitations. In this context, several photo‐mediated approaches have been developed based on the use of thioether derivatives [28–30] . Two families of thioethers have been established depending on the mechanistic steps involved in the carbon radical generation through desulfurization (Scheme 8).…”

“…After an activation step, substrates belonging to family A , can be involved in an intramolecular homolytic substitution ( S H ) that triggers the desulfurization and the generation of the expected carbon radicals [31] . In all the photo‐mediated reactions, the S H step consists in the intramolecular cyclization of aryl radicals B onto the sulfur center, releasing the expected carbon radicals along with sulfur‐containing heterocycles C (Scheme 8A) [28–31] . On the other hand, the desulfurization of the second class of thioethers ( D or G ) can be achieved by initial SET reduction of thioethers containing either tetrafluoropyridine or thiazolium cores (Scheme 8B) [32–40] .…”