A bifunctional pyrazolone–chromone synthon directed organocatalytic double Michael cascade reaction: forging five stereocenters in structurally diverse hexahydroxanthones

Abstract

The merging of two or more known natural product-based scaffolds is a powerful and routine strategy to develop bioactive small molecules.

Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis

“…In 2019, novel bifunctional pyrazolone–chromone synthons 2bc were designed by Zhou and co-workers (Scheme 19). 42 With α,β-unsaturated ester derivatives 90 as reaction partners, the chiral squaramide C8 could efficiently catalyze this enantioselective double Michael addition cascade reaction, affording the intriguing spirocyclic pyrazolones 91 with five continuous stereocenters in high yields and with excellent stereoselectivities.…”

Recent Advances in Squaramide‐Catalyzed Asymmetric Mannich Reactions

“…A lot of efforts have been devoted to develop a series of new compounds containing pyrazolone moiety, generally we make use of pyrazolone's own reaction site to directly introduce pyrazolone into these compounds. For example, the C-4 position of pyrazolone has nucleophilicity, it often occurs Michael reaction, [54] Mannich reaction, [55] aldol reaction, [56] etc. Similarly, at N-1, OH-5 of pyrazolone also have nucleophilicity.…”

Recent Advances in Catalytic Enantioselective Synthesis of Pyrazolones with a Tetrasubstituted Stereogenic Center at the 4-Position

“…In 2018, Zhou, Liu, and co-workers developed the asymmetric and organocatalytic double Michael addition of bifunctional pyrazolone-chromone compounds to 3-substituted methyleneoxindoles to construct dispirooxindole-hexahydroxanthone-pyrazolones with five contiguous stereocenters (two of them quaternary centers and spirocenters) in good yields and excellent diastereo-(all >20:1 dr) and enantioselectivity (all >90% ee) (Scheme 24). 57 These conditions allow electron-donating and electron-withdrawing substituents in arene ring of the chromone (R 1 ) as well as in its oxindolederived partner (R 2 ).…”

“…In addition, they extended their methodology to different methylenebenzofuranones to obtain dispirobenzofuranone-hexahydroxanthone-pyrazolones in moderate yields but excellent diastereoselectivities and extraordinary enantiomeric excesses (all >96% ee) (Scheme 25). 57 Aliphatic and halogen substituents are perfectly tolerated without any significant change in enantioselectivity.…”