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 react with a variety of benzo[d]thiazoles with electon-donating or electron-withdrawing substituents upon activation with camphorsulfonic acid producing cycloadducts in 29-87% yields in an equilibrium mixture of 2 diastereomers in ca. 2:1 ratio. We have revealed that the rate of equilibrium is significantly reduced in the case of electron-withdrawing groups at the benzothiazole scaffold, which makes the isolation of individual diastereomers feasible. The introduction of 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 EC50 = 15 μM similar to the previously discovered inhibitor s17, maintaining low toxicity.