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A catalyst‐ and additive‐free decarbonylative trifluoromethylthiolation of aldehyde feedstocks has been developed. This operationally simple, scalable, and open‐to‐air transformation is driven by the selective photoexcitation of electron donor‐acceptor (EDA) complexes, stemming from the association of 1,4‐dihydropyridines (donor) withN‐(trifluoromethylthio)phthalimide (acceptor), to trigger intermolecular single‐electron transfer events under ambient‐ and visible light‐promoted conditions. Extension to other electron acceptors enables the synthesis of thiocyanates and thioesters, as well as the difunctionalization of [1.1.1]propellane. The mechanistic intricacies of this photochemical paradigm are elucidated through a combination of experimental efforts and high‐level quantum mechanical calculations [dispersion‐corrected (U)DFT, DLPNO‐CCSD(T), and TD‐DFT]. This comprehensive study highlights the necessity for EDA complexation for efficient alkyl radical generation. Computation of subsequent ground state pathways reveals that S_H2 addition of the alkyl radical to the intermediate radical EDA complex is extremely exergonic and results in a charge transfer event from the dihydropyridine donor to theN‐(trifluoromethylthio)phthalimide acceptor of the EDA complex. Experimental and computational results further suggest that product formation also occursviaS_H2 reaction of alkyl radicals with 1,2‐bis(trifluoromethyl)disulfane, generated in‐situ through combination of thiyl radicals.

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An oxidative catalytic vanadium(V) system was developed to access the naturally nonabundant diastereomers of carpanone from the corresponding alkenyl phenol monomer in one pot by tandem oxidation, oxidative coupling, and 4+2 cyclization. This system was applied to the synthesis of two other analogues of carpanone. Mild oxidizing silver salts were used as the terminal oxidant to minimize background oxidation which produces the natural diastereomer of carpanone. Further, the first examples of enantioselective oxidative benzoxanthenone formation are reported. Solvent polarity has a strong effect on enantioselectivity, consistent with a mechanism involving binding of vanadium Schiff base catalysts to the alcoholic moiety of the alkenyl phenols during the cyclization step.

 

A facile method to oxidatively trimerize phenols using a catalytic aerobic copper system is described. The mechanism of this transformation was probed, yielding insight that enabled cross‐coupling trimerizations. With this method, the natural product pyrolaside B was synthesized for the first time. The key strategy used for this novel synthesis is the facile one‐step construction of a spiroketal trimer intermediate, which can be selectively reduced to give the natural product framework without recourse to stepwise Ullmann‐ and Suzuki‐type couplings. As a result, pyrolaside B can be obtained expeditiously in five steps and 16 % overall yield. Three other analogues were synthesized, thus highlighting the utility of the method, which provides new accessibility to this area of chemical space. A novel xanthene was also synthesized through controlled Lewis acid promoted rearrangement of a spiroketal trimer.

 

Thioamides, single atom oxygen‐to‐sulfur substitutions of canonical amide bonds, can be valuable probes for protein folding and protease studies. Here, we investigate the fluorescence quenching properties of thioamides incorporated into the side‐chains of amino acids. We synthesize and incorporate Fmoc‐protected, solid‐phase peptide synthesis building blocks for introducingN^ε‐thioacetyl‐lysine andγ‐thioasparagine. Using rigid model peptides, we demonstrate the distance‐dependent fluorescence quenching of these thioamides. Furthermore, we describe attempts to incorporate ofN^ε‐thioacetyl‐lysine into proteins expressed inEscherichia coliusing amber codon suppression.

 

Discovery of epigenetic chemical probes is an important area of research with potential to deliver drugs for a multitude of diseases. However, commercially available libraries frequently used in drug discovery campaigns contain molecules that are focused on a narrow range of chemical space primarily driven by ease of synthesis and previously targeted enzyme classes ( e.g. , kinases) resulting in low hit rates for epigenetic targets. Here we describe the design and synthesis of a compound collection that augments current screening collections by the inclusion of privileged isosteres for epigenetic targets. 

DNA-encoded library (DEL) technology features a time- and cost-effective interrogation format for the discovery of therapeutic candidates in the pharmaceutical industry. To develop DEL platforms, the implementation of water-compatible transformations that facilitate the incorporation of multifunctional building blocks (BBs) with high C(sp 3 ) carbon counts is integral for success. In this report, a decarboxylative-based hydro alkylation of DNA-conjugated trifluoromethyl-substituted alkenes enabled by single-electron transfer (SET) and subsequent hydrogen atom termination through electron donor–acceptor (EDA) complex activation is detailed. In a further photoredox-catalyzed hydro arylation protocol, the coupling of functionalized, electronically unbiased olefins is achieved under air and within minutes of blue light irradiation through the intermediacy of reactive (hetero)aryl radical species with full retention of the DNA tag integrity. Notably, these processes operate under mild reaction conditions, furnishing complex structural scaffolds with a high density of pendant functional groups.