Synthesis of Bioactive Molecules Enabled by Photoredox Catalysis

Abstract

Photoredox catalysis stands out as the foremost strategy for manipulating open-shell radicals in a diverse range of chemical transformations. These are often impossible or challenging to achieve using conventional ionic pathways. This method is distinguished by its gentle reaction conditions, compatibility with biological systems, and wide tolerance for various substrates. Consequently, photoredox catalysis has found applications in total synthesis of natural products, modification of biomolecules (such as proteins, DNA, and saccharides), as well as the synthesis of novel materials. In contrast to the traditional polar strategy, where certain synthons like organometal complexes may be less reactive and labile, the radicals' precursors like carboxylic acids, halogens, esters, amines, olefins, etc. are typically stable on the bench, readily available, and the radicals themselves are highly reactive. This leads to a markedly distinct approach in construction of target molecules. In this context, we have developed a series of innovative methods for synthesis of utilizing photoredox catalysis. In the first effort, a mild organophotoredox synthetic protocol for forming a Csp3−S/Se bond by reacting widespread redox-active esters with thio/selenosulfonates has been developed. The mild process serves as a viable strategy for the synthesis of both alkyl−alkyl and alkyl−aryl sulfides with outstanding functional group tolerance. Furthermore, an unrivaled feature of the process is to employ the feedstock carboxylic-acid-derived RAEs as radical progenitors, and an unprecedented broad substrate scope is achieved. These merits make this protocol a promising strategy for the construction of C−S bonds in widespread applications within organic synthesis. In the second effort, a mild metal- and oxidant-free visible-light photoredox mediated selective C3-formylation of indoles is developed. The newly uncovered process is synthetically sustainable by using readily accessible indoles and feedstock glyoxylic acid as the formylation reagent, molecular oxygen (air) as the terminal oxidant, and visible light without requiring an external PC or additional amine catalyst. A new self-activation mode by the generation of byproduct isatin as PC was found. The synthetic strategy has been successfully adopted for the practical synthesis of C1-deuterated 3-formylindoles. A cost-effective deuterated glyoxylic acid as a new formyl deuteration reagent has been developed for this demand. The mild, operationally simple protocol serves as a general powerful method for the practical synthesis of structurally diverse C1-deuerated 3-formylindoles with broad functional group tolerance and late-stage deuteration of complex structures at high level (95−99%).. In the third effort, a mild, versatile photoredox protocol for the efficient incorporation of aromatic and alkyl side chains and deuterium into (S)-methyleneoxazolidinone is developed. The method delivers structurally diverse chiral α-deuterated α-amino acid derivatives in good yields with excellent diastereoselectivity and uniformly high levels of deuterium incorporation. The employment of readily available starting materials, inexpensive and safe D2O as a deuterium reagent, mild reaction conditions, and operational simplicity makes the method practical in synthesis. Notably, the approach has significantly expanded the scope for accessing both aryl and alkyl side chain-containing α-amino acids. It is expected that the synthetic method and the valued deuterated amino acid building blocks will find broad applications in organic and medicinal chemistry.