RESUMO
Dearomatization reactions involving radical cyclizations can facilitate the synthesis of complex polycyclic systems that find applications in medicinal chemistry and natural product synthesis. Here we employ redox-neutral photocatalysis to affect a radical spirocyclization that transforms biaryls into spirocyclic cyclohexadienones under mild reaction conditions. In a departure from previously reported methods, our work demonstrates the polarity mismatched addition of a nucleophilic radical to an electron rich arene, and allows the regioselective synthesis of 2,4- or 2,5-cyclohexadienones with broad functional group tolerance. By transforming biaryls into spirocycles, our methodology accesses underexplored three-dimensional chemical space, and provides an efficient means of creating quaternary spirocenters that we apply to the first synthesis of the cytotoxic plant metabolite denobilone A.
RESUMO
Phenols and their derivatives are ubiquitous in nature and critically important industrial chemicals. Their properties are intimately linked to the relative substitution pattern of the aromatic ring, reflecting well-known electronic effects of the OH group. Because of these ortho-, para-directing effects, meta-substituted phenols have historically been more difficult to synthesize. Here we describe a procedure to transpose phenols that hinges on a regioselective diazotization of the corresponding ortho-quinone. The procedure affords the meta-substituted phenol directly from its more common and accessible para-substituted isomer, and demonstrates good chemoselectivity that enables its application in late-stage settings. By changing the electronic effect of the OH group and its trajectory of hydrogen bonding, our transposition can be used to diversify natural products and existing chemical libraries, and potentially shorten the length and cost of producing underrepresented arene isomers.
RESUMO
The calculation of accurate reaction energies and barrier heights is essential in computational studies of reaction mechanisms and thermochemistry. To assess methods regarding their ability to predict these two properties, high-quality benchmark sets are required that comprise a reasonably large and diverse set of organic reactions. Due to the time-consuming nature of both locating transition states and computing accurate reference energies for reactions involving large molecules, previous benchmark sets have been limited in scope, the number of reactions considered, and the size of the reactant and product molecules. Recent advances in coupled-cluster theory, in particular local correlation methods like DLPNO-CCSD(T), now allow the calculation of reaction energies and barrier heights for relatively large systems. In this work, we present a comprehensive and diverse benchmark set of barrier heights and reaction energies based on DLPNO-CCSD(T)/CBS called BH9. BH9 comprises 449 chemical reactions belonging to nine types common in organic chemistry and biochemistry. We examine the accuracy of DLPNO-CCSD(T) vis-a-vis canonical CCSD(T) for a subset of BH9 and conclude that, although there is a penalty in using the DLPNO approximation, the reference data are accurate enough to serve as a benchmark for density functional theory (DFT) methods. We then present two applications of the BH9 set. First, we examine the performance of several density functional approximations commonly used in thermochemical and mechanistic studies. Second, we assess our basis set incompleteness potentials regarding their ability to mitigate basis set incompleteness errors. The number of data points, the diversity of the reactions considered, and the relatively large size of the reactant molecules make BH9 the most comprehensive thermochemical benchmark set to date and a useful tool for the development and assessment of computational methods.