Silver(I)-Catalyzed Synthesis of Cuneanes from Cubanes and their Investigation as Isosteres

Abstract

Bridged or caged polycyclic hydrocarbons have rigid structures that project substituents into precise regions of 3D space, making them attractive as linking groups in materials science and as building blocks for medicinal chemistry. The efficient synthesis of new or underexplored classes of such compounds is, therefore, an important objective. Herein, we describe the silver(I)catalyzed rearrangement of 1,4-disubstituted cubanes to cuneanes, which are strained hydrocarbons that have not received much attention since they were first described in 1970. The synthesis of 2,6-disubstituted or 1,3-disubstituted cuneanes can be achieved with high regioselectivities, with the regioselectivity being dependent on the electronic character of the cubane substituents. A preliminary assessment of cuneanes as scaffolds for medicinal chemistry suggests cuneanes could serve as isosteric replacements of trans-1,4-disubstituted cyclohexanes and 1,3-disubstituted benzenes. An analogue of the anticancer drug sonidegib was synthesized, in which the 1,2,3-trisubstituted benzene was replaced with a 1,3-disubstituted cuneane.

Scaffold Editing of Cubanes into Homocubanes, Homocuneanes via Cuneanes

“…While the syntheses of homo‐ and bishomocubanes have been well studied from the viewpoint of the “build‐up” method via cycloaddition and cyclization, [6a] there are limited reported cases of the Wagner‐Meerwein type rearrangement from cubane to homocubane. For instance, there are acid‐catalyzed reactions of cubane derivatives bearing a tertiary alcohol group on the cubane, [6b,c] and the rearrangement of bromomethylcubane to bromohomocubane in the presence of SiO 2 [11] or AgNTf 2 [9b] . To date, no efficient catalysts have been reported for the rearrangement of esters of cubylmethanol, a primary alcohol, except in the present case.…”

A Photochemical Strategy for the Conversion of Nitroarenes into Rigidified Pyrrolidine Analogues

“…With a streamlined method to access 2-azabicyclo[3.2.0]­heptanes, we wanted to understand if these motifs could function as potential bioisosteres for other N-heterocycles commonly found in MedChem libraries. Typically, new bioisostere identification has taken a targeted approach, in which specific bond vectors of novel chemotypes are compared with the ones of few selected parent compounds. − We decided to utilize a different approach where the bicyclic cores were compared with a virtual database of >250 potentially interesting N-heterocycles with two vectors appended. , This strategy would allow an expansive area of chemical space to be efficiently surveyed, including unreported species. To map the chemical space to the goal of bioisostere identification, we decided to create a high-dimensional data set of relevant descriptors , where the chemical space could then be visualized and interpreted by a principal component analysis (PCA). , Such a data set would also offer the opportunity to apply unsupervised learning algorithms, to identify machine-guided relationship. − Therefore, we envisioned that applying methods such as the relatively straightforward k -Medoids clustering − would provide an unbiased insight into bioisostere identification.…”

Computational Research on Ag(I)-Catalyzed Cubane Rearrangement: Mechanism, Metal and Counteranion Effect, Ligand Engineering, and Post-Transition-State Desymmetrization

“…When a 1,6-disubstituted cubane is used as the substrate, two products, Prod1 and Prod2 , can be generated depending on the metal, ligand, and counteranion employed. In 2023, Lam, Nagasawa, and Stephenson reported new progress on this reaction nearly at the same time. In Lam’s report, a mild strategy using AgNTf 2 as the catalyst selectively yielded Prod1 at room temperature with dichloromethane (DCM) as the solvent (Figure ).…”