First Example of s-BuLi/(-)-Sparteine-Mediated Chiral Deprotonation of a Piperazine and Proof of the Sense of Induction

This paper describes the first known example of a (-)-sparteine-mediated asymmetric deprotonation of a piperazine. Reaction of TERT-butyl 4- TERT-butylpiperazine-1-carboxylate with S-BuLi in the presence of (-)-sparteine at -78 °C and quenching with carbon dioxide proceeded in good yield and with a high degree of selectivity (er = 89:11). X-ray crystal structure analysis on a chiral derivative confirmed the R-enantiomer was the major product. This methodology was employed as a route to an advanced chiral intermediate that was used in parallel synthesis of a range of molecules of medicinal interest. Optimisation of the chemistry used to introduce a TERT-butyl group onto a piperazine nitrogen is also described.