3/8/2023 0 Comments Svat petr ryba![]() These are unique features that contrast with sensitive ground-state organic reductants (22a,4b,c,24,25) and other photocatalyzed reactions. The system tolerates water as cosolvent (50% v/v entry 9) and air atmosphere (entry 10). Moreover, the performance of BuNAH ( 10) is only marginally affected by concentrations as low as 1 mM (entry 8). This result can be rationalized by the slightly more reductive character of BuNAH ( 10) (26) than the N-benzyl- and N-aryl-dihydronicotinamides 5,8. (25) Interestingly, the N-butyl dihydronicotinamide BuNAH ( 10), which is the closest structural homologue to NADH among the photoreductants explored, was optimal both in terms of yield and rate (entry 7). In line with seminal studies by Overman (8h) and recent work by Shang, (24) the dihydropyridine 9 was found to promote the reaction, but it was slower and less efficient than the more biocompatible dihydronicotinamides (entry 6). It was found that the dihydronicotinamide moiety is essential for high activity (entry 3) as well as the appropriate substitution at the heterocyclic nitrogen (entries 4,5). Given the importance of maximizing the reaction rate for its implementation at higher dilution, (3,4,4c−i) we explored related photoreductants. The reaction was found to be surprisingly fast, reaching 66% yield after 5 min of illumination (entry 2). (8f−l) To our delight, the desired decarboxylative coupling product 4a was obtained in high yield using DMSO as solvent (entry 1). Toward this end, the reaction of the NADH model BNAH ( 5) with the redox-active ester 2a and the acrylate acceptor 3a was studied under blue light illumination (λ = 450 nm) without photocatalysts or additives ( Scheme 2). The redox potential of NADH and its analogs ( E ox > 5 g/kg). (8a,b,f−l) Recent methods based on desymmetrization (8n) and late-stage carbene transfer (12) illustrate the potential of redox-active esters to be introduced through strategies unavailable to the parent carboxylic acids. ![]() (8c−e) In contrast, the N-hydroxyphthalimide (NHPI) esters ( 2) can be orthogonally activated in the presence of other carboxylates via single-electron reduction. (8) The abundance of endogenous carboxylic acids in biomolecules or biomatrices poses a selectivity challenge for carboxylic acid substrates ( 1), due to their similar oxidation potentials. (1b,11) Despite their success, radical addition reactions are slow (6–12 h) and require additional catalysts, inorganic reducing suspensions, and/or additives that are not native to biological systems. (8,9) These methods take advantage of the abundance of carboxylic acids (8,10) and the various technologies developed with Michael acceptors. (8) Scheme 1ĭecarboxylative radical addition reactions ( Scheme 1A) have recently emerged as prime tools to create aliphatic ligations in biomolecules. (8,9) Aliphatic linkages are particularly attractive due to their small size, robustness, and flexibility, which maximize the chances to obtain functional and metabolically stable conjugates. (7) As such, developments in self-sensitized, phototriggered, and fast C–C photocoupling between simple functionalities are still highly sought after ( Scheme 1A). (5a,6) On the other hand, recent C–C coupling reactions using photobiocatalytic systems have shown great promise but these are still limited to activated substrates with auxiliary photosensitizers and electron donors. (5) On one hand, photo-cross-linking methods still rely on unstable precursors like azirines or cyclopropanones. (1a,2) The phototriggered formation of chemical bonds can enable frontier research in medicine and biology, (3) but their development is still a challenge in comparison to thermal click reactions (4) due to the slower rate and the need for UV-light and/or photocatalysts. Visible light is a prime stimulus to control the conformation of chemical bonds, (1) or their cleavage. ![]()
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