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 from the synthetic community. The synthesis of 2,6-disubstitued 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 was also performed, which suggests cuneanes could serve as isosteric replacements of trans-1,4-disubstituted cyclohexanes and 1,3-disubstituted benzenes.

(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-Cuneanes can be obtained by metal-induced isomerisation of 1,4-cubanes [69]. Recent reports of their synthesis indicate that silver salts enable the isomerisation to occur efficiently (Scheme 18A) [70][71][72]. Experimental results and computational investigations by Stephenson and co-workers showed that the obtained ratio of 1,3-cunanes to 2,6-cuneanes is dependent on the cubane substituents [71].…”

“…Recent reports of their synthesis indicate that silver salts enable the isomerisation to occur efficiently (Scheme 18A) [70][71][72]. Experimental results and computational investigations by Stephenson and co-workers showed that the obtained ratio of 1,3-cunanes to 2,6-cuneanes is dependent on the cubane substituents [71]. Generally, at least one of the substituents needs to be electron donating to obtain the 1,3-cuneane selectively.…”

Bicyclo[m.n.k]alkane Building Blocks as Promising Benzene and Cycloalkane Isosteres: Multigram Synthesis, Physicochemical and Structural Characterization

“…[42] For further discussions, exit vector parameter (EVP)based method was used, [43,44] which had been applied by our group for analysis of various cyclic systems previously [45][46][47][48][49][50][51] and is being adopted by a wider chemical community. [25,27,[52][53][54] The basic idea of this approach is simulating the functional groups mounted onto the scaffold by two exit vectors. Carbon atoms of the (bi)cyclic ring system bearing the functional groups are used as the starting points of these vectors, whereas the direction is defined by the attached bonds (Figure 2, A).…”

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

“…When a 1,6disubstituted 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, 34 Nagasawa, 35 and Stephenson 36 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 1).…”