Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols.

ReO-Catalyzed Approach to Spirocyclic Ether Formation from Acyclic Precursors: Observation of Remote Stereoinduction.

Ketones that are flanked by an allylic alcohol and an alkene isomerize to spirocyclic ethers in the presence of ReO through allylic alcohol transposition, oxocarbenium ion formation, and Prins cyclization. These processes provide significant increases in molecular complexity, with multiple stereocenters being set relative to a stereocenter in the substrate. Stereoselectivity arises from the initial reversible steps being more rapid than the final step, thereby allowing for thermodynamically controlled stereochemical equilibration prior to product formation.