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Diversity-Oriented Synthesis of Spirooxindoles via Asymmetric Organocatalytic Regiodivergent Cascade Reactions.

Org Lett

December 2024

Molecular Synthesis Center & Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.

A regiodivergent strategy for the asymmetric diversity-oriented synthesis of spirooxindoles via organocatalytic cascade reactions is developed. Two regioselective pathways can be precisely controlled with different aminocatalysts in the reaction of 2-hydroxycinnamaldehydes and β,β-disubstituted 3-alkylidene oxindoles. The cascade vinylogous Michael/oxa-Michael/aldol reactions gave spiro-bridged oxindoles bearing two adjacent quaternary stereocenters, while the cascade oxa-Michael/Michael reactions gave spirooxindoles.

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Two different cascade pathways to access spirobutenolides were achieved based on the substrate-controlled regioselectivity of deconjugated butenolides. A new class of functional deconjugated butenolides was designed and exhibited superior γ-regioselectivity in the vinylogous Michael/Michael cascade reactions with cinnamaldehydes. The aryl-substituted deconjugated butenolides and cinnamaldehydes underwent a Michael/Michael/aldol/dehydration cascade process induced by double α-regioselectivities.

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Pallamolide A is a 7,8--labdane terpenoid possessing a unique bicyclo[2.2.2]octane core and a spiro-butenolide moiety.

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Herein we report that readily available 4-alkenylisocoumarins can be regarded as potent dienolate equivalents. For example, lactol silyl ethers derived from 4-alkenylisocoumarins were selectively converted to the corresponding benzo-homophthalates through a fluoride-induced ring opening step that was followed by a ring closure through a vinylogous intramolecular aldol condensation. Likewise, nucleophilic activation of 4-alkenylisocoumarins directly yields diversely poly-substituted naphthalenes and anthracenes without formation of any regioisomer.

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Two substrate-controlled regiodivergent annulation protocols for 2,3-dioxopyrrolidines with 3-alkylidene oxindoles have been developed, which furnished a series of fused dihydropyrrolidone derivatives in high yields with excellent stereoselectivities. Plausible mechanistic pathways for both annulation reactions are proposed that [3 + 3] annulation reaction involves vinylogous Michael addition followed by intramolecular aldol cyclization, while [4 + 2] annulation reaction occurs through a vinylogous Michael addition and a subsequent intramolecular -Michael cyclization.

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