Bifunctional Monothiosquaramide-Catalyzed Enantioselective Addition of Masked Acyl Cyanide to Isatins: Umpolung Strategy for the Total Synthesis of ( S )-(−)-Dioxibrassinin and ( R )-(+)-Spirobrassinin

The enantioselective addition of masked acyl cyanide (MAC) to isatin is a highly efficient strategy for synthesizing bioactive chiral spirooxindoles. Herein, we report the utility of this strategy in an asymmetric total synthesis of (S)-(-)-dioxibrassinin and (R)-(+)-spirobrassinin, which are well-known phytoalexin alkaloids present in Brassicaceae plants. We developed a bifunctional monothiosquaramide (9b)-catalyzed addition of MAC to isatin, affording chiral oxindole esters (11a-11j) with excellent enantioselectivities (>99% ee) under mild conditions and catalyst loadings around 10 mol %. We accomplished the total synthesis of (S)-(-)-dioxibrassinin (1) and (R)-(+)-spirobrassinin (2) from oxindole ester 11a in a few subsequent steps with high overall yields (65%) and selectivities (99% ee).