Organocatalytic Michael/Michael Cycloaddition Enabled Asymmetric Construction of Hexahydroxanthones with Skeletal Diversity

Abstract

A highly efficient strategy for stereocontrolled construction of potentially bioactive and structurally rigid isoxazole‐fused spirocyclohexane oxindole‐based hexahydroxanthones via an organocatalytic domino Michael/Michael cycloaddition of multifunctional chromone‐based oxindole as a 4C building block and 3‐methyl‐4‐nitro‐5‐alkenyl‐isoxazole as an activated Michael acceptor is reported. Complex and skeleton‐diversified hexahydroxanthones bearing five continuous stereocenters including one spiro quaternary carton center were smoothly afforded in up to 92% yield, >20:1 d.r. and >99% ee. Further transformation of the product into other potentially bioactive molecules has also been demonstrated. This method could also forge the libraries of medicinally relevant molecules with skeletal diversity, thus to facilitate the search for new bioactive entities.magnified image

Asymmetric Phase Transfer Catalysed Michael Addition of γ-Butenolide and N-Boc-Pyrrolidone to 4-Nitro-5-styrylisoxazoles

“…Compounds 1 are stable solids and reacted in Michael reactions as an acceptor. A special feature of compounds 1 is the presence of two electrophilic centres that can be independently reacted [29,30], with the exocyclic "soft" one that found extensive application in 1,6-conjugate enantioselective additions particularly under organocatalytic conditions [44][45][46][47][48][49][50][51][52][53]. Compounds 1 were also used in a large-scale industrial context, for example in the preparation of active pharmaceutical ingredients (APIs) (R)-Baclophen [54] and (S)-Pregabalin [55].…”

Step Economy in the Stereoselective Synthesis of Functionalized Oxindoles via Organocatalytic Domino/One-pot Reactions

“…In 2019, Liu and Zhou group reported two different methodologies yielding the spiro-bis-heterocycles starting from substrates 78 and alkenyl-isoxazoles 79 [42] or nitroalkenes 69 [43] (Scheme 15, a & b, respectively).…”

Palladium-catalyzed decarboxylation [2 + 2 + 2] annulation approach to chromone-containing polycyclic compounds

“…2 Therefore, exploring novel approaches for the construction of diverse chromone derivatives has been the focus of intensive efforts, and numerous significant advances have been made in the field of catalysis. 3 Transition metal-catalyzed domino reaction has been proven as an effective approach to assemble complex molecules by forging two or more new chemical bonds from readily available substrates in one single operation. 4 In this context, the Catellanitype annulation cooperatively catalyzed by palladium and nor-bornene (NBE) represents a powerful tool for the construction of complex arenes.…”