Synthesis of Heterospirocycles through Gold-(I) Catalysis: Useful Building Blocks for Medicinal Chemistry

Gold-(I) catalysis was used for the intramolecular cyclization of tertiary alcohols with terminal alkynes to form diverse aza-spirocycles. The reaction was carried out with low catalyst loading under microwave irradiation to give both sulfonylated and acylated spirocyclic nitrogen derivatives. Gram scale spirocyclization was carried out to demonstrate the robustness of the reaction. An intramolecular Mizoroki-Heck reaction was performed to give several tetracyclic spirocycles. Double bond reduction and selective protecting group manipulation gave spiropiperazine and spiromorpholine derivatives. These compounds were incorporated into biologically relevant scaffolds to give the first selective spirocyclic inhibitors of LIMK1.

Automated summary

Gold(I) catalysis was used for the intramolecular cyclization of tertiary alcohols with terminal alkynes to form diverse aza-spirocycles. The reaction produced both sulfonylated and acylated spirocyclic nitrogen derivatives, demonstrating the robustness of the method. These compounds were then incorporated into biologically relevant scaffolds to give the first selective spirocyclic inhibitors of LIMK1.