Total Synthesis Of 1,10-Diphenylbicyclo[8.8.8]hexacos-5-ene

Abstract

A multi-gram, flexible, customizable, scalable total synthesis of 1,10-diphenylbicyclo[8.8.8]hexacos-5-ene over 15 steps has been developed. The synthesis was engineered pushing most difunctional intermediates to quantitative completion thereby mini-mizing purification steps. The multi-gram synthesis can be conveniently performed by a single worker. Only four major purification steps are required, one involving the separation of dia-stereomers on 50-gram scale, and two chromatographic separations late in the synthesis on a conventionally manageable scale. The features of the work include a rare example of a large-scale RCM macrocyclization method useful on industrial scales, and the development of a multi-gram chromatographic method that allows reasonable separations using minimal amounts of silica (close to dry-loading amounts) and solvent. LAH workup was developed that is fast and safe, not requiring liquid-liquid extraction or the use of solvent drying agents. In-stead, the reaction mixture is simply quenched, filtered, and evaporated under reduced pres-sure. Another notable feature is the use of DCM as the hydrogenation solvent using the palla-dium on carbon catalyst.