State of the art
- Late-stage modification of peptides and proteins represents a highly valuable tool to access functionalized non-proteinogenic analogues with tailored properties and/or improved therapeutic capabilities compared to their natural counterparts
- While transition-metal-promoted C-H functionalizations have emerged as a powerful tool in this area, the highly unreactive nature of Csp3-H bonds typically translates into harsh reaction conditions that are incompatible with multiple functional groups present in advanced targets and lack chemo-, regio- and stereoselectivity.
- In contrast, 1,n-hydrogen transfer (HAT) represents a potential useful entry to functionalize, in a site-selective manner, aliphatic C-H bonds via H-atom abstraction thus circumventing the pre-functionalization of substrates or the use of directing groups.
Scheme 6. Photocatalytic functionalization of isoleucine or lysine residues
Progress beyond the state of the art
- Recently, our group has reported the successful generation of amidyl radicals under mild photoredox conditions that enabled remote functionalization reactions with saturated alkanes via 1,n-HAT processes.
- Since the use of fluorinated alcohol solvents can, via polarity reversal, deactivate the C-H bonds that are proximal to polar groups (such as NH or OH), we will tackle the functionalization of peptide substrates at C-H bonds that are remote from the backbone (and side-chain) polar groups.
- Site selective functionalization of inert Csp3-H bonds with concomitant formation of new C-C and C-X bonds in a chemo- and regioselective fashion under water-compatible conditions.
- Demonstration that photochemistry can be applied to more complex and elaborated peptide substrates.
- Use React-IR and NMR in combination with advance kinetic processing software (Dynochem) to determine the mechanism of the reactions and the factors governing the selectivity.
- Construct predictability models of the reactions ́ selectivity using computational tools (DFT calculations) and kinetic data.