Strategy‐Level Prodrug Synthesis

Organic synthesis uniquely provides opportunities to access molecules that serve defined purposes. Medicinal chemistry illustrates this attribute well with prodrug design, whereby a drug undergoes a late‐stage conversion to a conditionally responsive active medicinal agent (AMA), being a notable example. Prodrugs are becoming increasingly important in medicinal chemistry but common approaches to introduce biologically responsive groups are limited in the chemoselectivity and scope of available functionalization reactions. This Concept article describes strategy‐level prodrug synthesis, which is a powerful extension of classical prodrug formation that initiates sequences with the objective of introducing functionality early in a sequence to achieve greater scope, site‐selectivity, and chemoselectivity for the incorporation of the biologically responsive group. Examples of functionalization using alkyne hydroaminations, Curtius reaction, and alkene metathesis are highlighted along with the use of the prodrugs for biological applications.