Decarboxylative conjugate additions and applications thereof
Synthetic methods are described herein operable to efficiently produce a wide variety of molecular species through conjugate additions via decarboxylative mechanisms. For example, methods of functionalization of peptide residues are described, including selective functionalization of peptide C-terminal residues. In one aspect, a method of peptide functionalization comprises providing a reaction mixture including a Michael acceptor and a peptide and coupling the Michael acceptor with the peptide via a mechanism including decarboxylation of a peptide reside.
1. A method of intramolecular peptide cyclization comprising:
providing a reaction mixture including a peptide comprising a C-terminal residue and a Michael acceptor functionalized N-terminal residue; and
coupling the C-terminal residue with the Michael acceptor functionalized N-terminal residue via a mechanism including decarboxylation.
2. The method of claim 1 , wherein the peptide comprises at least 3 residues.
3. The method of claim L wherein decarboxylation occurs subsequent to formation of a carboxyl radical at the C-terminal residue.
4. The method of claim 3 , wherein carboxyl radical formation is initiated by a single electron transfer (SET) process.
5. The method of claim 4 , wherein the SET process is oxidative.
6. The method of claim 4 , wherein the SET process is reductive.
7. The method of claim 3 , wherein an α-amino radical is formed by the decarboxylation at the C-terminal residue.
8. The method of claim 7 , wherein the α-amino radical undergoes conjugate addition with the Michael acceptor functionalized N-terminal residue.
9. The method of claim 4 , wherein the reaction mixture further comprises catalyst for initiating the SET process.
10. The method of claim 9 , wherein the catalyst is transition metal catalyst.
11. The method of claim 9 , wherein the catalyst is photoredox catalyst.
12. The method of claim 11 , wherein the photoredox catalyst is an iridium complex.
13. The method of claim 12 , wherein the iridium complex is heteroleptic.
14. The method of claim 13 , wherein the heteroleptic iridium complex is selected from the group consisting of Ir[dF(CF 3 )ppy] 2 (dtbbpy) + and Ir(ppy) 2 (dtbbpy) + .
15. The method of claim 9 , wherein the reaction mixture further comprises co-catalyst for hydrogen atom transfer to the intramolecular cyclized peptide.
16. The method of claim 15 , wherein the co-catalyst comprises one or more aryl thiols.
17. The method of claim 4 , wherein the reaction mixture further comprises base.
18. The method of claim 9 , wherein the catalyst also reduces an α-acyl radical formed during intramolecular cyclization of the peptide.
19. The method of claim 4 , wherein the SET process is initiated electrochemically.