No abstract

A variety of vinyl- or alkynyl-substituted polyhydroxylated cyclopentanes and cyclobutanes are prepared in enantiomerically pure form from appropriate carbohydrate precursors, in a direct one-step ring-contraction procedure promoted by SmI2 and catalytic Pd(O). This reaction is thought to proceed through intermediate ring-opened allyl- or allenylsamarium complexes that undergo ring-closure by intramolecular carbonyl addition. A predominant trans relationship is found between vinyl (or alkynyl) and hydroxyl groups at the two newly created stereogenic centers, with good to excellent levels of stereoselectivity being observed in the formation of homopropargyl cyclopentanol products. Under appropriate conditions, preparatively useful yields are realized of stereoisomers not directly available using alternative methodology.

Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.