Multigram Synthesis of Dimethyl Stellane‐1,5‐Dicarboxylate as a Key Precursor for ortho‐Benzene Mimics**

Abstract

AbstractHerein, we present previously unavailable C(sp3)‐rich polycyclic hydrocarbon scaffolds that have the potential to become valuable tools in medicinal chemistry and crop science as saturated bioisosteres of benzenoids. We have developed a scalable protocol (up to 50 g from a single synthetic run) for the synthesis of tricyclo[3.3.0.03,7]octane (bisnoradamantane or stellane) 1,5‐dicarboxylic acid derivatives. X‐ray crystallographic analysis of the stellane 1,5‐dicarboxylic acid dimethyl ester has revealed that this scaffold is an optimal saturated isostere for ortho‐disubstituted benzene where substituents exhibit in‐plane topology. The synthetic protocol is based on the oxidative cyclization of dimethyl octahydropentalene‐2,5‐dicarboxylate (DMOD) through lithiation followed by I2 oxidation. The reaction outcome is determined by the stereochemistry of the substrate. While the endo,endo cis‐DMOD, exclusively gives the “unwanted” Claisen cyclization product, the exo,endo cis‐ and exo,exo cis‐ stereoisomers afford the desired stellane 1,5‐dicarboxylic acid dimethyl ester quantitatively. DFT computations have revealed that the reaction proceeds via the dianion of dimethyl octahydropentalene‐2,5‐dicarboxylate, which undergoes SET oxidation by I2 to form a radical anion. The subsequent cyclization followed by a second SET oxidation gives the desired stellane derivative.