Organocatalyst-Controlled Stereoselective Head-to-Tail Macrocyclizations

Chiral macrocycles are key to the discovery of new medicines. Their synthesis is, however, challenging and requires the often-cumbersome installation of stereochemical information in a linear precursor. Here, 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 12–18‐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.