Synthesis of a versatile metacyclophane macrolactam.

As Hsp90 has emerged as a promising target for the development of cancer chemotherapeutics, so has the need for systematic evaluation of structure-activity relationships between natural product inhibitors and this molecular chaperone. Utilizing our chimera approach, which encompasses the quinone moiety of geldanamycin and the resorcinol moiety of radicicol, molecules have been produced that are highly effective inhibitors of the Hsp90 protein folding machinery. These chimeric inhibitors contain metacyclophane macrolactams that are difficult to cyclize and modify for incorporation of functional diversity. To circumvent this problem, a highly diversifiable alpha-bromo-alpha,beta-unsaturated ester has been prepared, which allows for the introduction of various functionalities that enable elucidation of structure-activity relationships between chimeric compounds and Hsp90. The rationale, synthesis, and optimization for such a molecule is reported herein.