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

Abstract

Electrophilic double bond functionalization – intramolecular enolate alkylation sequence was used to obtain a series of bridged and fused bicyclo[m.n.k]alkane derivatives (i.e., bicyclo[4.1.1]octanes, bicyclo[2.2.1]heptanes, bicyclo[3.2.1]octanes, bicyclo[3.1.0]hexanes, and bicyclo[4.2.0]heptanes). The scope and limitations of the method were established, and applicability to the multigram synthesis of target bicyclic compounds was illustrated. Using the developed protocols, over 50 mono‐ and bifunctional building blocks relevant to medicinal chemistry were prepared. The synthesized compounds are promising isosteres of benzene and cycloalkane rings, which is confirmed by their physicochemical and structural characterization (pKa, LogP, and exit vector parameters (EVP)). “Rules of thumb” for the upcoming isosteric replacement studies were proposed.

Lewis acid catalyzed [4+2] annulation of bicyclobutanes with dienol ethers for the synthesis of bicyclo[4.1.1]octanes

“… 12 In comparison, bicyclo[4.1.1]octane (BCO) is rarer in nature, 13 it has been much less studied, and the very few preparative methods that have been established so far are limited in scope and lack convergence. 14 In a recent study, the group of Grygorenko showcased the improved lipophilicity of this unique motif and its potential function as an isosteric replacement for both aromatic and saturated monocyclic carbocycles. 14 c Further investigations on BCO ring systems would be of great benefit in the perspective of their applications in medicinal chemistry.…”

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes

“…During the preparation of this manuscript, Deng described an elegant Lewis acid-catalyzed [4π+2σ] cycloaddition of BCBs with nitrones to synthesize 2-oxa-3-aza-BCHeps . Besides all-carbon BCHs and BCHeps, bicyclo­[ n .1.1] ( n > 3) systems and heterobicyclo­[ n .1.1]­alkanes are also valuable molecules for isosteric replacements . Furthermore, Baran’s report revealed that replacing benzenoids by either R - or S -enantiomers of BCPs may lead to distinct bioactivities of the drug .…”

A BN-Benzvalene

“…Among them, benzvalene has captured the attention of synthetic chemists due to its unique bonding and reactivity . The development of a practical and facile synthesis of benzvalene by Katz has led to the access to additional strained hydrocarbon scaffolds, including bicyclo[1.1.1]pentane , and bicyclo[2.1.1]hexane derivatives that are of current interest as 3D bioisosteres of benzene in medicinal chemistry …”