Late-stage chirality generation strategies for the total synthesis of macrocyclic natural products

Macrocyclic natural products, including macrolactones, macrolactams, macrocyclic (depsi)peptides, and macrocyclic cyclophanes, occupy a chemical space that does not overlap significantly with that of traditional low molecular weight and sp²-carbon rich pharmaceuticals. Traditionally, total synthesis toward macrocyclic natural products has been typically based on installation of backbone stereogenic centers at early- to mid-stage and closure of the macrocyclic backbone at late stage. However, these synthesis strategies suffer from multiple concession steps, making them less attractive in terms of step-economy. In this review, we provide an overview of late-stage chirality generation strategies in macrocyclic natural product synthesis, embodying stereoselective functional group and/or skeletal transformations that take advantage of macrocyclic conformational constraints. Expanding our repertoire of transformations amenable to late-stage chirality generation as well as advancing controllability over the conformational property of macrocycles will facilitate future developments in the total synthesis of macrocyclic natural products.