Stereocontrolled Synthesis of Bispirooxindole-Based Hexahydroxanthones with Five Contiguous Stereocenters

Abstract

A bifunctional oxindole−chromone synthon 1 directed tandem reaction is developed, serving as a fruitful strategy for facile access to optically active hexahydroxanthones 3 bearing two spirooxindoles with five contiguous stereocenters. All of the bispirooxindole-based hexahydroxanthones 3 are smoothly obtained with up to 91% yield, >20:1 dr, and >99% ee. Biological evaluation of selected compounds 3 revealed that they exerted good cytotoxic effects on human K562, A549, and PC-3 cells.S mall molecules based on privileged natural product frameworks and rich in three-dimensional complexity are in high demand in drug-discovery programs. 1 Therefore, new approaches to build novel and complex natural product-based scaffolds in an asymmetric manner remain highly desirable but challenging. 2 In this context, hexahydroxanthone bearing four or more contiguous stereocenters represents a prominent structural motif encountered in a number of natural products and pharmacologically active compounds (Figure 1). 3

Synthetic and Computational Study of the Enantioselective [3+2]-Cycloaddition of Chromones with MBH Carbonates

“…With respect to an enantioselective variant, Toste reported Pd-catalyzed enantioselective Conia-ene reaction, in which a methylene cyclopenta­[ b ]­chromanone was afforded in 41% conversion with 82% ee (Scheme a) . Zhou developed a strategy of domino Michael cycloaddition of oxindole chromones to construct ring-fused chromanones with excellent enantioselectivities (Scheme b) . Schneider and Feng also established efficient methods for synthesizing chiral chromanes fused with a five-membered ring, and excellent outcomes were obtained (Scheme c,d).…”