Bromodifluoroacetic acid derivatives as linkers for the synthesis of hybrid biomolecules using photoredox catalysis

• Grant number: 23/12718-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: February 01, 2024
• End date: January 31, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Márcio Weber Paixão
• Grantee: Emanuele Ferrari Pissinati
• Supervisor: Till Opatz
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Institution abroad: Johannes Gutenberg University Mainz (JGU), Germany
• Associated to the scholarship: 22/04597-0 - Synthesis of non-proteinogenic amino acids and modification of peptides using photocatalysis, BP.DR

Abstract

The precise modification of biomolecules (such as amino acids, peptides, and saccharides) is highly challenging due to the delicacy of these compounds. Consequently, mild protocols are desirable, and certain requirements are necessary to avoid damaging the original structure. Concurrently, one of the most employed strategies to selectively modify organic biomolecules is photocatalysis, in which these compounds can undergo processes involving single-electron transfer or energy transfer under mild reaction conditions, using visible light to facilitate the desired modifications. The modification of amino acids, peptides, and proteins with the goal of utilizing these mimetics as pharmaceuticals has been extensively studied by various research groups to enhance stability and improve the pharmacokinetics of biomolecules. Due to its mild and physiologically compatible conditions, as well as its high functional group tolerance, photocatalysis is a powerful tool for the chemoselective modification of these compounds. An example of a modification aimed at maximizing physiological activities and consequently improving the bioavailability of drug candidates is the incorporation of glycans into the original chemical architecture. Although there are reactions that allow for the incorporation of saccharides into serine and threonine (O-linked glycosylation) or asparagine (N-linked glycosylation) using polar and chemoenzymatic methods, similar processes also occur naturally. In the context of photoredox chemistry, most of the reported examples involve glycosyl radicals adding to electrophiles, thereby facilitating new C-C bond formation. The incorporation of fluoroalkylated or perfluoroalkylated electrophilic radicals into rich olefins has also been explored, primarily in the context of styrenes. This exploration is driven by the significant impact of fluorine on organic molecules, which discloses unique chemical, physical, and biological properties when compared to their non-fluorinated counterparts. When considering saccharides as acceptors of fluorinated radicals in photocatalytic reactions, two examples of glycals derivatives, and one of exo-glycal exclusively feature in examples of catalytic radical protocols. Considering all these findings, we aim to develop three novel photocatalytic procedures for the insertion of ±-gemdifluoroacetamides, derived from amino acids and on-resin peptides, into unsaturated saccharides. Therefore, the formation of ±-difluoroglycosyl bromides, ±-difluoroglycosyl olefins, and ±-hydrodifluoroglycosylated compounds are desirabed chemical scaffolds to be produced under sustainable photochemical conditions. (AU)