Bisspirooxindole synthesis: a comprehensive review of starting material-based strategies (2006-2026).

Abstract

Bisspirooxindole frameworks constitute an important class of heterocyclic compounds because of their unique three-dimensional architectures, the presence of two spiro carbon centers, and widespread presence in biologically active natural products, pharmaceuticals, and functional materials. Owing to their structural complexity and significant pharmacological potential, the development of efficient and selective synthetic methodologies for the construction of bisspirooxindole scaffolds has attracted continuous attention in modern organic synthesis. Despite the remarkable advances achieved over the past two decades, a comprehensive review that systematically categorizes the synthetic strategies toward bisspirooxindole and highlights recent advances has not yet been presented. This review, provides the first extensive and strategy-oriented overview of synthetic methodologies for the synthesis of bisspirooxindole scaffolds reported between 2006 and 2026. The discussed approaches are systematically categorized according to the nature and structural characteristics of the starting materials, including azomethine ylide-based strategies, transition-metal-catalysted transformations, Isatin-derived Morita-Baylis-Hillman (MBH) carbonate annulations, various 3-functionalized oxindole precursors, and aniline-derived starting materials. Particular attention is devoted to reaction mechanisms, stereoselective and enantioselective synthesis, substrate scope, regioselectivity, functional-group tolerance, and synthetic efficiency. The advantages and limitations of the various methodologies are critically evaluated in terms of reaction mechanisms, substrate scope, stereoselectivity, regioselectivity, functional-group tolerance, synthetic efficiency, and their potential for environmentally benign, scalable, and highly selective synthesis. The concluding sections focus on recent advances in modern bisspirooxindole synthesis, with particular emphasis on innovative reaction designs and newly developed synthetic methodologies. In addition, synthetic approaches to dispirooxindole frameworks featuring two spirooxindole units linked through a molecular spacer are comprehensively summarized and critically discussed.

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