Nonenzymatic Asparagine Motif Synthesis by Photoredox-Catalyzed Carbamoylation of Dehydroalanine

Abstract

Post-translational modifications of proteins based on the amino acid residue dehydroalanine (Dha) have been widely adopted in molecular biology to expand their structural and functional capabilities. However, the construction of highly important amide C(sp 2 )−C(sp 3 ) linkages on peptides through cross-coupling remains unexplored. In this article, we describe a photoredox-catalyzed C(sp 2 ) amidation that enables the mutation of Dha to an asparagine (Asn) motif. This amide installation strategy reported herein will guide us to create more additional derivatives of peptides, which may elucidate the mode of action and address an important area of unmet medical need.

Photocatalytic Reductive Olefin Hydrodifluoroalkylation Enabled by Tertiary Amine Reductants Compatible with Complex Systems

“…While this method proved reliable, we sought a streamlined approach employing radical conjugate addition, with the goal of broad functional group tolerance, such that late stage functionalization of complex molecules might also be possible. A number of groups have established important precedents for related strategies that involve the reductive functionalization of dehydroalanines (Figure B) . Herein, we report the development of an optimized photocatalytic reductive difluoroalkylation of various olefins (Figure C), including streamlined access to analogs of 1 , a range of other small molecules, and its compatibility with derivatization of the complex thiopeptide antibiotic thiostrepton.…”

Recent Advances in Photoinduced Modification of Amino Acids, Peptides, and Proteins

“…In 2022, Wang and co-workers described a photoredox-catalyzed C(sp 2 ) amidation by the addition of a readily accessible carbamoyl radical to the Dha residue that made possible the chemical mutation of Dha to asparagine (Asn) motif. [39] This method exhibited a broad substrate tolerance, encompassing various amino acids, fatty amines, and aniline derivatives, making it suitable for the carbamoylation of peptides using dihydropyridines as the carbamoyl radical precursor, and employing 4CzIPN as photocatalyst with its emphasis restricted to the synthesis of racemic N 4 -monosubstituted asparagine derivatives (Scheme 19a). In the sequence, Paixão's group reported a selective metal-free photocatalytic approach to access racemic, enantio-enriched, and deuterated derivatives increasing the chemical space of non-proteinogenic N 4 -substituted asparagines (Scheme 19b).…”

“…The exploration of cross‐coupling methods for constructing crucial amide C(sp 2 )−C(sp 3 ) linkages on peptides remains unexplored. In 2022, Wang and co‐workers described a photoredox‐catalyzed C(sp 2 ) amidation by the addition of a readily accessible carbamoyl radical to the Dha residue that made possible the chemical mutation of Dha to asparagine (Asn) motif [39] …”

Selective Aza‐Michael Addition to Dehydrated Amino Acids in Natural Antimicrobial Peptides

“…[6,7,8] They are carbon electrophiles because of their unsaturated side chain, which permit siteselective chemical modification. In recent years several chemoand site selective modifications of dehydroamino acids in RiPPs have been established, including: conjugate phospa-Michael additions, [9] β-silylation, [10] radical carbonÀ carbon bond formation, [11,12] cross-coupling reactions, [13,14] amidations, [15,16] cyclopropanations [17] and cycloadditions. [18,19] Recently, we reported the Cu(II) catalysed β-borylation of RiPPs (Scheme 1A), [20] with a particular focus on the thiopeptide Thiostrepton.…”