Precise Synthetic Organic Chemistry of Cubanes and Cuneanes Aspiring to Medicinal Application

Abstract

In the development of small molecule drugs, a strategy that aims to adjust the physical and pharmaceutical properties of drug candidates without significantly changing their pharmacological activity is attracting attention, in which a structural unit that shows the same biological response with the original partial structure (i.e. bioisostere) is frequently employed to create a molecule with superior medicinal properties. Cubane is a caged hydrocarbon known as a bioisostere of the benzene ring due to its structural similarity. Furthermore, when cubane is treated with silver(I) or palladium(II), it undergoes isomerization to a wedge-shaped hydrocarbon called cuneane. The potential for medicinal applications of these caged hydrocarbons has been hindered by limitations in the types of cubane and cuneane compounds that can be synthesized. We have approached these issues using precise organic synthesis chemistry from two perspectives: 1) developing a methodology for introducing functional groups by converting the C-H bonds of cubane, and 2) proposing the utility of cuneane as a bioisostere of m-substituted benzenes.

Graphical Abstract