Biological Evaluation of Isosteric Applicability of 1,3‐Substituted Cuneanes as m‐Substituted Benzenes Enabled by Selective Isomerization of 1,4‐Substituted Cubanes

Abstract

We herein evaluate a biological applicability of 1,3‐substituted cuneanes as an isostere of m‐substituted benzenes based on its structural similarity. An investigation of a method to obtain 1,3‐substituted cuneanes by selective isomerization of 1,4‐substituted cubanes enables this attempt by giving a key synthetic step to obtain a cuneane analogs of pharmaceuticals having m‐substituted benzene moiety. Biological evaluation of the synthesized analogs and in silico study of the obtained result revealed a potential usage of cuneane skeleton in medicinal chemistry.

(Bio)isosteres of ortho- and meta-substituted benzenes

“…While the 1,3-disubstituted cuneanes (1,3-cuneanes) have been described as early as 1970 by Eaton and co-workers [69] their selective synthesis had not been studied until recently [70]. Selected exit vector parameters showed that substituent distance d and scaffold carbon distance r of 1,3-cuneanes closely resemble the distances found at meta-benzene (Figure 26) [70][71][72]. While the substituent angle φ 1 of 1,3-cuneanes is only slightly larger than in metabenzene, the dihedral angle θ is significantly larger and strongly dependent on the specific substituents.…”

“… 1,3-Disubstituted cuneanes as isosteres of meta -benzenes: comparison of selected exit vector parameters [ 70 – 72 ]. a Reported by Lam and co-workers.…”

“…The hydroxymethyl group ( 185a, 185b, 185f ), a boronic acid pinacol ester ( 185c ), a phthalimide-protected aminomethyl group ( 185d ) and an oxazole ( 185e ) were, among others, successful as electron-donating groups yielding 1,3-cuneanes. Iwabuchi and co-workers also found that the use of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent in the isomerisation reaction changes the obtained ratio in favour of the 1,3-cuneane when compared to their alternative solvent system of H 2 O/MeOH [ 72 ]. Iwabuchi and co-workers demonstrated the suitability of 1,3-cuneanes to undergo chemical transformations in their synthesis of ketoprofen bioisostere 189 ( Scheme 18B ) [ 72 ].…”

“…Iwabuchi and co-workers also found that the use of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent in the isomerisation reaction changes the obtained ratio in favour of the 1,3-cuneane when compared to their alternative solvent system of H 2 O/MeOH [ 72 ]. Iwabuchi and co-workers demonstrated the suitability of 1,3-cuneanes to undergo chemical transformations in their synthesis of ketoprofen bioisostere 189 ( Scheme 18B ) [ 72 ]. 1,3-Cuneane 186 bearing two electron-withdrawing groups was accessible by oxidation of 1,3-cuneane 185a .…”

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

“…In recent years, cuneanes, a class of caged polycyclic hydrocarbons, have garnered interest due to their unique skeleton structure, which enables their applications in liquid crystal technology , and as bioisosteres of benzene , in medicinal development. Their rigid skeleton presents new possibilities for modulating the biological properties of medicinal compounds, while their unique topologies have attracted attention in the fields of both fundamental chemistry and molecular design.…”