In medicinal chemistry, substituting benzene rings with sp3 hybridized bioisosteres often improves key pharmacokinetic characteristics (e.g., solubility, metabolic stability) of drug candidates. At the same time, bioisosteres can simulate the size and rigid spatial relationship of substituents in the benzene ring unit, thereby maintaining biological activity and reducing the overall C(sp2) properties. In addition, cubane, like most benzene bioisosteres, is only used as an alternative framework for mono- or para-substituted benzene rings in current drug design.
Recently, some researchers have prepared 1,3- and 1,2-disubstituted cubanes by using the simple and easy-to-obtain cyclobutadiene as a precursor and using the photolytic C-H bond carboxylation reaction. C-N, C-C(sp3), C-C(sp2) and C-CF3 bond cross-coupling reactions of disubstituted cubanes were developed. This method easily converts all cubane isomers and provides a new strategy for the preparation of bioisosteres of ortho-, meta-, and para-substituted benzene skeletons in drug candidates.
As early as 1966, Pettit et al. used the Diels-Alder reaction of in situ generated cyclobutadiene and 2,5-dibromobenzoquinone to obtain 1,3-cubanedicarboxylic acid in only three steps . Inspired by the research work of Masamune group (1975), the researchers improved the synthesis route of cyclobutadiene, using cheap and easy-to-obtain 1,2-dihydro pyridazine as the starting material, synthesis of 1,3-cubane dicarboxylate (35% overall yield) was achieved with only one column chromatography purification, while providing sufficient quantities for medicinal chemistry research in only three days. In order to avoid the installation and removal of guiding groups and in combination with Bashir Hashemi's research, researchers used commercially available 1,4-cubanedicarboxylic acid methyl ester as the starting material, and obtained 1,2-cucubanedicarboxylic acid ester through four steps of reaction with a total separation yield of 21%.
After achieving a neat synthesis of cubane dicarboxylates, the researchers attempted to develop a general modular cross-coupling platform to obtain a large number of functionalized cubane isomers. Using commercially available 1,4-disubstituted cubanes as template substrates, the researchers realized copper-catalyzed decarboxylation amination reactions, and obtained a series of cubane amination products in good yields. Notably, besides the Curtius rearrangement, this method is another straightforward, convenient, and versatile strategy for the synthesis of aminated cubanes.
Next, the researchers utilized a copper-catalyzed strategy to realize the cross-coupling reaction of cubic alkyl radicals and alkyl/aryl radicals to construct C–C bonds. In order to be compatible with most alkyl and aryl halides, the researchers first used silicon-based radical-mediated halogenation to generate alkyl and aryl radicals, and then used copper to catalyze their crossover coupling reaction with cubic alkyl radicals. In addition, the researchers chose non-nucleophilic tertiary aminosilanes to participate in the reaction, and under optimal conditions, alkyl bromides and tertiary cubanes can effectively undergo cross-coupling reactions, and at the same time, they can tolerate a variety of functional groups.
Finally, the researchers also explored the cross-coupling reactions of the newly synthesized 1,3- and 1,2-disubstituted cubane isomers, showing that both isomers can be aminated and alkylated smoothly . In addition, the researchers also applied the synthetic route and cross-coupling reaction developed in this paper to the rapid synthesis of cubane analogs of benzene-containing drugs, such as: Cuba-Lumacaftor and Cuba-Acecainide, and these two compounds have good metabolism stability.
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Reference
- General Access to Cubanes as Benzene Bioisosteres
Mario P. Wiesenfeldt, James A. Rossi-Ashton, Ian B. Perry, Johannes Diesel, Olivia L. Garry, Florian Bartels, Susannah C. Coote, Xiaoshen Ma, Charles S. Yeung, David J. Bennett, David W. C. MacMillan
