Modular access to substituted cyclohexanes with kinetic stereocontrol

Substituted six-membered cyclic hydrocarbons are common constituents of biologically active compounds. Although methods for the synthesis of thermodynamically favored, disubstituted cyclohexanes are well established, a reliable and modular protocol for the synthesis of their stereoisomers is still elusive. Herein, we report a general strategy for the modular synthesis of disubstituted cyclohexanes with excellent kinetic stereocontrol from readily accessible substituted methylenecyclohexanes by the implementation of chain-walking catalysis. Mechanistically, the initial introduction of a sterically demanding boron ester group adjacent to the cyclohexane is key to guiding the stereochemical outcome. The synthetic potential of this methodology has been highlighted in late-stage modification of complex bioactive molecules and in comparison with current cross-coupling techniques.

Automated summary

In this study, we present a reliable and modular synthesis strategy for the excellent kinetic stereocontrol of disubstituted cyclohexanes from readily accessible substituted methylenecyclohexanes. By introducing a sterically demanding boron ester group adjacent to the cyclohexane, the stereochemical outcome can be guided. The synthetic potential of this method has been demonstrated in late-stage modification of complex bioactive molecules and compared with current cross-coupling techniques.