Building heterocyclic architectures on steroid frameworks

Steroid heterocyclic hybrids (SHHs) are a highly promising class of compounds of relevant interest in the field of drug discovery and material science. The advancement of synthetic strategies plays a key role in achieving the access to the required structural diversity of SHHs and in overcoming the bottle neck of their availability for SAR studies and interpretation of their mode of action at the molecular level. This overview summarizes the main synthetic approaches to SHHs, focusing on reactions that achieve the introduction of heterocyclic units onto steroidal frameworks with defined regio- and stereochemical control. Methods based on transition-metal catalyzed sequential reactions, including cross-coupling reactions and heteroatom-directed cyclizations, are examined together with domino processes starting from ketosteroids and epoxy steroids. Late stage functionalization, photochemical, radical-mediated, and cycloaddition reactions are also discussed as tools for the assembly of fused and pendant heterocyclic motifs. The collected examples highlight how contemporary organic synthesis can be adapted to steroidal substrates, providing, from simple starting materials with easy operation through sustainable processes, functional molecular libraries of challenging SHHs of high complexity and diversity.