Spiro 4//-pyran-3.3 -oxindoles

SCHEME 2.34 Asymmetric synthesis of spiro[4//-pyran-3,3 -oxindoles] 117 via three-component reactions. 

W.-B. Chen, Z.-J. Wu, Q.-L. Pei, L.-E. Cun, X.-M. Zhang, W.-C. Yuan, Org. Lett. 2010, 12, 3132-3135. Highly enantioselective construction of spiro[4//-pyran-3,3 -oxindoles] through a domino Knoevenagel/Michael/cychzation sequence catalyzed by cupreine. 

In a separate investigation by Porco, Jr. and coworkers, the isatin derivative 134 (R = H) was converted to spirooxindole pyran 141 in 13 1 dr and 99% ee by means of a Prins-type cyclization involving homoaUyhc alcohol 140 [79]. The diastereos-electivity of the transformation has been proposed to arise from a preferred chairlike transition state with the benzenoid ring of oxindole in a pseudoequatorial orientation. Spirooxindole oxepenes also were prepared via diastereoselective spiro-annulation of isatins with bis-homoallyhc alcohols. 

The heterocyclic spiro-oxindole moiety is found in a large number of alkaloids, which are important pharmaceutical compounds [44]. Several synthetic protocols are reported in the literature for the synthesis of these compounds [45]. Recently, Tao et al. [46] developed a direct asymmetric domino Michael/reduction/cychzation sequence for the construction of spiro[2H-pyran-3,4 -indohne] 99 from isatyhdene malononitrile 97 and acetone 98 in the presence of the chiral compound 100 (Scheme 9.20). 

A quite elegant example of one-pot three-component reaction via a domino Michael/cyclization sequence was reported by Yuan et al. to provide a wide range of optically active spiro[4 f-pyran-3,3 -oxindoles] 117 [64]. Among all the tested chiral organocatalyst, cupreine (CPN) 116 resulted to be the most effective in terms of yield (up to 99%), enan-tioselectivity (up to 97% ee), and tolerance to the substrate modification (Scheme 2.34). 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

Basavaiah developed a convenient, one-pot stereoselective synthesis of spiro-oxindoles via TiCU catalyzed coupling of 2-acetyl-6-methyl-2,3-dihydro-4H-pyran with various isatin derivatives [328]. The reaction involves a tandem construction of C-C and C-0 bonds and its catalytic asymmetric version remained to be developed (Scheme 14.145). 

Catalyst 3 was also used in the construction of substituted 3-hydroxy-2-oxindoles by the reaction of 5-methoxy substituted isatins with various indoles [28]. Up to 91% ee could be obtained in 1,4-dioxane as the solvent and benzoic acid as an additive. Similarly, 3 was apphed as catalyst for the formation of spiro[4H-pyran-3,3 -oxindoles] via a one-pot domino Knoevenagel, conjugate addition, cyclization sequence (Scheme 6.12) [29]. 

---