Enantioselective Synthesis of Unsymmetrical Diaryl‐Substituted Spirocyclohexanonepyrazolones through a Cascade [4+2] Double Michael Addition

Abstract

The spirocyclic pyrazolones are an important class of molecular structures with significant biological and pharmaceutical activities. Herein, we demonstrate that the combination of a Cinchonabased chiral primary amine and an ortho-fluorobenzoic acid is an efficient catalyst system for the double Michael addition of arylidenepyrazolones with a,b-unsaturated ketones, providing chiral unsymmetrical 6,10-diaryl-substituted spiro[cyclohex-A C H T U N G T R E N N U N G anone-pyrazolone] derivatives in high yields (up to 98%) with good diastereoselectivities and excellent enantioselectivities (up to 88:12 dr, 99% ee).

Catalytic Asymmetric Synthesis of Spiropyrazolones and their Application in Medicinal Chemistry

“…Almost simultaneously, Xingwang Wang and co‐workers demonstrated the Cat. 21 ‐catalyzed double Michael addition of the same substrates by using ortho ‐fluorobenzoic acid ( o ‐FBA) as additive, and more attempt was made in the exploration of the reaction scope (Scheme b) . Electron‐donating substituents on the phenyl ring of benzylideneacetones 74 yielded better reactivity and stereoselectivity than that with electron‐donating substituents.…”

“…21-catalyzed double Michael addition of the same substrates by using ortho-fluorobenzoic acid (o-FBA) as additive, and more attempt was made in the exploration of the reaction scope (Scheme 30b). [40] Electrondonating substituents on the phenyl ring of benzylideneacetones 74 yielded better reactivity and stereoselectivity than that with electron-donating substituents. The steric hinderance possibly caused the inferior properties of the phenyl group at the C-5 position of unsaturated pyrazolones 1 compared with methyl group, while the trifluoromethyl group was proved ineffective.…”

Asymmetric Synthesis of Pyrazolone Fused Spirocyclohexeneimines via a Vinylogous Michael/Cyclization Cascade Reaction

“…Most of these studies were inspired by natural and synthetic bioactive compounds, bearing heterocyclic and carbocyclic units, with the idea to create new hybrid spirocylic compounds of potentially widespread biological activities. Among the classes of spirocyclic compounds, those bearing the pyrazolone unit and the carbocyclic cyclohexane, [2] cyclohexanone, [3] cyclohexenone [4] and cyclohexadiene rings, [5] have attracted considerable interest due to their relevance in medicinal chemistry ( Figure 1). [6] Some selected examples, illustrated in Figure 1, showed that these compounds display diverse and valuable biological activities as phosphodiesterase inhibitor, [2b] antimicrobial, [3a] anticancer [4] and antiinflammatory agents.…”

Asymmetric synthesis of pyrazoles and pyrazolones employing the reactivity of pyrazolin-5-one derivatives

“…This domino sequence is initiated by the addition of the aliphatic aldehydes 85 to the unsaturated pyrazolones 86 through the enamine intermediate followed by A double Michael reaction of a,b-unsaturated ketones 81 with a,b-unsaturated pyrazolones 86 provided a simple and effective entry to the spiropyrazolonecyclohexanones 55 with three consecutive stereogenic centers (Scheme 29). 49,50 The reaction pathway of this domino sequence involves HOMOactivation via dienamine A formed between the a,b-unsaturated ketone and the primary amine catalyst. This dienamine adds to the unsaturated pyrazolones to initiate another Michael addition to the resulting iminium ion B (LUMO-activation).…”

“…49 The quinidine derived primary amine XXIII and 2-fluorobenzoic acid as an additive also catalyzed the similar double Michael reaction with good yields, excellent enantioselectivities and good diastereoselectivities. 50 Recently our group reported a one-pot sequential Michael/ Michael/1,2-addition reaction involving b-dicarbonyl compounds 93, nitroalkenes 24 and a,b-unsaturated pyrazolones 86 to provide an efficient entry to a new series of spirocyclohexanepyrazolones 94 (Scheme 30). 51 This transformation involves a low loading of the squaramide V to catalyze a Michael addition of the b-dicarbonyl compounds to the nitroalkenes followed by a DBU promoted Michael/1,2-addition reaction to afford various spirocyclohexanepyrazolones 94 bearing six stereocenters including two tetrasubstituted ones in good yields and excellent stereoselectivities.…”