Cycloaddition of benzo[d]thiazoles with imidazol-4-one-activated donor–acceptor cyclopropanes: synthesis of spirocyclic inhibitors of HIV-1

Abstract

The reaction of benzo[d]thiazoles with imidazol-4-one-activated donor–acceptor cyclopropanes (DACs) represents a practicable cycloaddition resulting in new spirocyclic compounds. DACs, upon being activated with camphorsulfonic acid, react with a variety of benzo[d]thiazoles bearing electron-donating or electron-withdrawing substituents, producing cycloadducts in 29–87% yields in an equilibrium mixture of two diastereomers in a ca. 2 : 1 ratio. We have found a significant reduction in the rate of equilibrium upon including electron-withdrawing groups on the benzothiazole scaffold, making the isolation of individual diastereomers feasible. Introducing the 1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]thiazole core into the spiro products significantly improves biological activity, providing inhibition of the early stages of HIV-1 replication. The hit compound trans-3ga demonstrates an EC₅₀ of 15 μM, similar to that of the previously discovered inhibitor s17, while also showing low toxicity.