Organocatalyst-controlled stereoselective head-to-tail macrocyclizations

Chiral macrocycles are key to the discovery of new medicines. Their synthesis is, however, challenging and typically requires the often-cumbersome installation of stereochemical features in a linear precursor. In this study, we report a catalyst-controlled stereoselective head-to-tail macrocyclization. The method utilizes a bifunctional peptide catalyst to template the terminal functional groups of the linear precursor, thereby favoring intra- over intermolecular reaction and enabling exquisite control over the stereochemistry of the emerging stereogenic centers. Diverse 12- to 18-membered macrocyclic lactones and lactams were obtained from achiral linear precursors. The organocatalyst even dictates the stereochemical outcome upon cyclizing a chiral linear precursor. This catalyst-controlled stereoselective head-to-tail macrocyclization provides a practical route to chiral macrocycles with predictable stereochemical outcomes. The utility was highlighted by synthesizing the core of the natural product robotnikinin.