Dehydroalanine modification sees the light: a photochemical conjugate addition strategy

Abstract

Amino acid synthesis and modification has become a protagonist of organic synthesis and chemical biology research. Owing to mild condition and broad functional group tolerance, visible-light photochemical strategy has recently emerged as an ideal tool to address the acute need within this field. Visible-light-mediated radical conjugate addition reactions of dehydroalanine (Dha) derivatives and chiral Beckwith-Karady alkenes allowed facile access to a wide range of unnatural amino acid derivatives in good yields, excellent selectivities, and great structural diversities. The synthetic value was further demonstrated by site-selective modification of Dha residues in peptides and proteins under mild and even biocompatible conditions. Efforts directed to this interdisciplinary research shall open new opportunities for manipulating the activity or function of related biomacromolecules. The oxidative potential of photocatalysts and radical precursors, along with all types of covered transformations, is summarized as a graphic description, which ought to serve as a valuable selection guide for practitioners. Post-translational modifications of peptides and proteins are not only driving new therapeutic discoveries, but also provide a powerful impetus for the disruptive innovations of synthetic organic chemistry and chemical biology. This central research field has been rapidly evolving, with recent progress encompassing a green and sustainable photocatalytic tool kit. In particular, the past 5 years have witnessed impressive progress on visible-light-driven radical conjugate addition (RCA) of dehydroalanine (Dha) and its application to site-selective functionalization of peptides or proteins, which remarkably advanced the scope of unnatural amino acid (UAA) synthesis as well as state-of-the-art bioconjugation and bioorthogonal chemistry. Herein, we provide a comprehensive overview on the reactivity and mechanistic aspects involved in up-to-date reports on dehydroamino acid (dhAA) modification, aiming to offer inspiration for future discovery. Post-translational modifications of peptides and proteins are not only driving new therapeutic discoveries, but also provide a powerful impetus for the disruptive innovations of synthetic organic chemistry and chemical biology. This central research field has been rapidly evolving, with recent progress encompassing a green and sustainable photocatalytic tool kit. In particular, the past 5 years have witnessed impressive progress on visible-light-driven radical conjugate addition (RCA) of dehydroalanine (Dha) and its application to site-selective functionalization of peptides or proteins, which remarkably advanced the scope of unnatural amino acid (UAA) synthesis as well as state-of-the-art bioconjugation and bioorthogonal chemistry. Herein, we provide a comprehensive overview on the reactivity and mechanistic aspects involved in up-to-date reports on dehydroamino acid (dhAA) modification, aiming to offer inspiration for future discovery. a general term describing the ability to be in contact with a living system without producing an adverse effect. a chemical technique that links two molecules covalently, at least one of which is a biomolecule (such as a carbohydrate, protein, lipid, DNA, etc.). a set of chemical reactions that manipulate non-native functional groups in biological environments, while not interacting with biomolecules or interfering with biochemical processes. a molecular aggregate formed by the reversible association of an electron-donating substrate with an electron-accepting molecule. Upon light irradiation, the EDA complex turns into excited state and allows electron transfer to initiate radical-type reactions. a chemical transformation that consists of a concerted movement of both an electron and a proton from the substrate to another chemical species (hydrogen abstractor) in a single kinetic step. compounds that are able to mimic the structural elements and functionalities of natural peptides or proteins and retain the capability to interact with biological targets, often displaying comparable or even better bioactivities. a modern catalysis tool that harnesses light energy to accelerate a chemical reaction through single-electron transfer events. refers to chemical or enzymatic modification of translated proteins, which occurs either at distinct amino acid side chains or peptide linkages. the addition reaction of nucleophilic radicals to electron-deficient olefinic moiety in α,β-unsaturated compounds, also known as the Giese-type reaction. an event involving the transfer of an electron from one atom/molecule (donor) to another atom/molecule (acceptor), leading to the oxidative state change.