Synthesis of Chiral cis-Cyclopropane Bearing Indole and Chromone as Potential TNF alpha Inhibitors

Conformationally restricted analogues of SPD-304, the first small-molecule TNF alpha inhibitor, in which two heteroaryl groups, indole and chromone, are connected by chiral methyl- or ethyl-cis-cyclopropane, were designed. Synthesis of these molecules was achieved via Suzuki Miyaura or Stille coupling reactions with chiral bromomethylenecyclopropane or iodovinyl-cis-cyclopropane as the substrate, both of which were prepared from chiral methylenecyclopropane as a common intermediate, constructing the heteroaryl-methyl or -ethyl-cis-cyclopropane structures as key steps. This study presents an efficient synthesis of a series of chiral cis-cyclopropane conjugates with two heteroaryl groups.