H2 - Late-stage functionalization (LSF) of peptides via Ni-catalyzed decarboxylative photochemical reaction. 

Sunit Pal(a), Anaïs Noisier(b), Peter ‘t Hart(*a )

a. Chemical Genomics Centre, Max Planck Institute for Molecular Physiology, Germany

b. MedicinalChemistry, Research and Early Development Cardiovascular, Renal and Metabolism BioPharmaceutical R&D, AstraZeneca, Gothenburg (Sweden) 

Peptides are the essential building block of proteins, and often play a major role in regulating protein structures and functions. Like small molecules, peptides have tremendous opportunities for being able to modulate several biological targets. Gratifyingly, approximately hundreds of FDA-approved peptide drugs are available in the market to treat cardiovascular diseases, oncology and many more related to metabolic diseases.[1] However, the proteolytic cleavage of peptides is the major hindrance to their wide drug applications compared to the small molecules. Influenced by the natural peptide drugs, incorporating unnatural residues into the peptide sequence has been well-implemented to improve the peptide stability significantly.[2] Therefore, developing a methodology to rapidly generate peptide libraries with unnatural constraints is highly desirable to discover new peptide drugs. In the last decade, late-stage functionalization (LSF) of peptides has been attracted by the scientific community to modify peptides with numerous functionalities. LSF is somewhat similar to post-translational modification (PTM) where the post-synthetic modification of the linear peptide takes place. 

Here, we demonstrate an easy, convenient photochemical decarboxylative strategy to modify peptides containing Aspartic acid (Asp) and Glutamic acid (Glu) into various phenylalanine (Phe) and homophenylalanine (hPhe) analogues. The linear peptide was synthesized on the solid support, followed by the selective activation of the free acid group of the Asp and Glu side chains by coupling with N-hydroxyphthalimide (NHPI) to obtain the photoactive activated ester. Afterwards, the primary radical was generated by forming the in situ EDA-complex between NHPI and hantzsch ester, followed by illuminating with purple light.[3] The radical then undergoes a Ni-catalyzed cross-coupling reaction with different aryl-bromides to provide modified peptides. The current strategy is cost-effective due to the fact that NHPI is inexpensive to form the activated ester whereas expensive metallaphotoredox is needed for generating radicals from a free carboxylic acid. An optimized protocol has been achieved to successfully modify peptides with moderate to good yield. In fact, the entire synthesis starting from linear peptide up to photochemistry was carried out on solid support without isolating any intermediates. The methodology was equally efficient with the unnatural D-Asp/Glu amino acids. Furthermore, the current LSF protocol was compatible with peptides containing natural amino acids with more reactive side-chain functionalities eg. Trp, Tyr, His, Met and Cys. Finally, the methodology was utilized to modify some biologically relevant peptides with excellent conversion of the starting materials. 

[1] J. Med. Chem. 2018, 61, 1382−1414.

[2] Pharmaceuticals 2022, 15,1283.

[3] Chem. Sci. 2021, 12, 5450.