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

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. Electrophilic double bond functionalization - intramolecular enolate alkylation sequence (EDIEA) is an efficient approach to bicyclic fused and bridged mono- and bifunctional building blocks. The method is applicable for the multigram preparation of the target compounds, which is illustrated by synthesis of over 50 building blocks on up to 150 g scale. Physicochemical and structural parameters of the title scaffolds illustrate their utility as promising benzene and cycloalkane isosteres and provide a rationale for fine-tuning the compound's properties during drug optimization.image