A Streamlined Lithiation-Cyclization Strategy Unlocks Broad-Scope, Efficient Access to Chiral 3,4-Dihydroisoquinolones and Isoindolinones

Abstract

Chiral 3,4-dihydroisoquinolones and isoindolinones serve as important chiral building blocks in pharmaceutical and natural product synthesis. Herein, we have developed a simplified and straightforward strategy that enables rapid and scalable access to these two classes of chiral compounds via the addition reaction of laterally/ortho-lithiated aryl oxazolines to N-sulfinyl aldimines using nBuLi, followed by acid-promoted cyclization. This approach provides an excellent platform for the synthesis of chiral 3,4-dihydroisoquinolones and isoindolinones, and its synthetic utility was further demonstrated by the preparation of key intermediates for (S)-PD172938, (S)-Pazinaclone, and their analogues.