2 + 2 + 2 Cyclotrimerization with Propargyl Halidesas Copartners: Formal Total Synthesis of the Antitumor Hsp90 InhibitorAT13387

摘要

Heat shock protein 90 (Hsp90) inhibitors play a remarkable role in cellular growth, and they were shown to exhibit antitumor activity. The Hsp90 inhibitor AT13387 (onalespib) is under clinical trials for the treatment of refractory gastrointestinal stromal tumors. Recently, it was demonstrated that this compound also exhibits inhibition against bladder cancer. Here, we report isoindoline- and isoindolinone-based (halomethyl)benzenes via a [2 + 2 + 2] cyclotrimerization in the presence of catalytic amounts of Mo(CO)6. This strategy has been extended to synthesize the key precursor of the Hsp90 inhibitor, AT13387.