Organocatalytic Remote Stereocontrolled (4+2) Annulation of 2-(4H-Benzo[d][1,3]oxazin-4-yl)acrylates with 4-Methyleneisoxazol-5(4H)-Ones

Abstract

Despite the formidable challenge of concurrently managing both the regiochemistry and stereochemistry of the process, organocatalytic remote stereocontrol has emerged as an appealing approach to establish stereocenters at specified locations distant from reactive functional groups. Herein, we achieved the first organocatalyzed remote stereocontrolled (4+2) annulation of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates with 4-methyleneisoxazol-5(4H)-ones. The nucleophilic attack of a suitable chiral amine to 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates generated the key amine-dipole intermediate, followed by the enantioselective aza-1,4-addition of 4-methyleneisoxazol-5(4H)-ones and intramolecular annulation cascade reaction to construct spiro[isoxazole-4,3’-quinolin]-5-one frameworks bearing continuous three stereocenters. More importantly, different from the well-established reactions of MBH carbonates, this work successfully established a novel platform for the direct enantioselective synthesis of continuous three stereocenters, inclusive of an ϵ-stereocenter.