5'-Carboxy-Nucleoside Decarboxylation for the Synthesis of C-Nucleoside-Amino Acids and Peptides

Given the synthetic challenges posed by the labile N-glycosidic bond and diverse nucleobases, which have historically complicated stereochemical control and necessitated protecting-group manipulations in the synthesis of C-nucleoside-amino acid/peptide conjugates, we have developed a general strategy for the efficient synthesis of C-nucleoside-amino acid/peptide conjugates via a photoredox-catalyzed decarboxylative Giese reaction of readily accessible 5'-carboxy-nucleosides. This method tolerates a broad range of nucleoside substrates with unprotected nucleobases and either unprotected or minimally protected sugars, providing C5'-nucleoside-modified alanine building blocks in moderate to good yields and stereoselectivities. Direct C5' nucleoside modification of peptides was also achieved, affording C5' nucleoside peptides that resemble nucleoside antibiotics, albeit without any selectivity at the peptide α‑position (C6'). This approach offers a streamlined and modular platform for exploring this novel class of bioactive hybrids.