Reaction generality is crucial in determining the overall impact and usefulness of synthetic methods. Typical generalization protocols require a priori mechanistic understanding and suffer when applied to complex, less understood systems. We developed an additive mapping approach that rapidly expands the utility of synthetic methods while generating concurrent mechanistic insight. Validation of this approach on the metallaphotoredox decarboxylative arylation resulted in the discovery of a phthalimide ligand additive that overcomes many lingering limitations of this reaction and has important mechanistic implications for nickel-catalyzed cross-couplings.
The synthesis of stereochemically complex molecules in the pharmaceutical and agrochemical industries requires precise control over each distinct stereocenter, a feat that can be challenging and time consuming using traditional asymmetric synthesis. Although stereoconvergent processes have the potential to streamline and simplify synthetic routes, they are currently limited by a narrow scope of inducibly dynamic stereocenters that can be readily epimerized. Here, we report the use of photoredox catalysis to enable the racemization of traditionally static, unreactive stereocenters through the intermediacy of prochiral radical species. This technology was applied in conjunction with biocatalysts such as ketoreductases and aminotransferases to realize stereoconvergent syntheses of stereodefined γ-substituted alcohols and amines from β-substituted ketones.
Herein we disclose an efficient method for the conversion of carboxylic acids to trifluoromethyl groups via the combination of photoredox and copper catalysis. This transformation tolerates a wide range of functionality including heterocycles, olefins, alcohols, and strained ring systems. To demonstrate the broad potential of this new methodology for late-stage functionalization, we successfully converted a diverse array of carboxylic acid-bearing natural products and medicinal agents to the corresponding trifluoromethyl analogues.
Two introductory organic chemistry laboratory experiments are described based on the Diels−Alder reaction of 2,3,4,5-tetraphenylcyclopentadienone, which is synthesized prior to or in a one-pot reaction, with styrene. Students are presented with three possible products, the endo and exo diastereomers and the decarbonylated product, for the beautiful crystalline compound isolated. Analysis by IR and 1 H NMR spectroscopy aid investigators in proposing an initial structure for the product, but the solved X-ray crystal structure provides unequivocal evidence of its stereochemistry. Both versions of the synthesis introduce two important and atom economical reactions, employ the Karplus relationship for 1 H NMR interpretation, and illustrate the power of X-ray crystallography for molecular structure determination.
Reaction generality is crucial in determining the overall impact and usefulness of organic synthetic methods. In contrast, contemporary generalization processes seem unable to meet the growing demand for robust methodology. We sought to develop an accelerated approach towards achieving generality, inspired by phenotypic screening, that rapidly expands the scope and utility of synthetic methods. This approach was validated by example of the metallaphotoredox decarboxylative arylation, resulting in the discovery of a novel additive that overcomes many lingering limitations of this method and has significant mechanistic implications for nickel-catalyzed cross couplings in general.
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