Organocatalytic, Asymmetric [2+2+2] Annulation to Construct Six-Membered Spirocyclic Oxindoles with Six Continuous Stereogenic Centers

Abstract

Lactols and cyclic hemiaminals were directly used in a one-pot organo/organo dual catalytic system induced [2+2+2] tandem reaction for the asymmetric construction of six-membered carbocycles. The enamine-based stereoselective Michael addition of lactols or cyclic hemiaminals to electron-deficient olefinic oxindole motifs provided chiral C4 components, which were further combined with triethylamine catalyzed Michael/Henry sequential reactions affording spirocyclic oxindole derivatives containing six continuous stereogenic centers with excellent enantioselectivities as a single diastereoisomer. All these desired products have versatile molecular complexity, which might have potential applications in synthetic organic chemistry and the pharmaceutical industry.

Organocatalytic Diversity-Oriented Asymmetric Synthesis of Structurally and Stereochemically Complex Heterocycles

“…As part of our continued interest in the efficient synthesis of spirooxindoles, the easily prepared 3-keto-oxindole derivatives 2 were finally chosen as the bifunctional substrate I to test our hypothesis (Scheme , bottom, EWG = electron-withdrawing group), for the following reasons: (1) the 3-keto-oxindole derivatives 2 have never been used in this designed Michael–aromatization–spiroketalization sequence to synthesize chroman-2-ol-containing heterocycles; (2) the high nucleophilicity at the C3 position of 2 could potentially promote the reaction to afford chiral 3-alkyl-3-aryloxindoles and spirooxindoles, both of which are recognized as attractive structures and important synthons because of their prevalence in a large number of natural and unnatural bioactive molecules; (3) the functionalized oxindole derivatives containing the hemiketal or hemiacetal moiety may be used as highly versatile functional handles for the facile preparation of biologically useful molecules.…”

Metal-Free Organocatalysis

“…Asymmetric organocatalysis for the synthesis of spirocyclic compounds is represented by two papers. The one by Rui Tan, Zhi-Ping Tong, Yan-Kai Liu et al [5] shows how lactols and cyclic hemiaminals can be directly used in a one-pot asymmetric [2+2+2] tandem reaction for the asymmetric construction of six-membered spirocyclic oxindoles with six continuous stereogenic centers. This one-pot multicomponent reaction consists of an enamine-based stereoselective Michael addition followed by triethylamine-catalyzed Michael/Henry sequential reactions.…”