Conjugate Addition of Carbon Acids to β,γ-Unsaturated α-Keto Esters: Product Tautomerism and Applications for Asymmetric Synthesis of Benzo[a]phenazin-5-ol Derivatives

Abstract

A correlation between the equilibrium ratio of tautomeric products generated by the asymmetric Michael reactions of cyclic carbon acids with β,γ-unsaturated α-keto esters and the chemical shift of the α-proton in starting nucleophilic substrates was revealed which makes equilibration predictable. New tetrahydropyran-fused benzo­[a]­phenazins were enantioselectively (up to 99% ee) synthesized from β,γ-unsaturated α-keto esters and benzo­[a]­phenazin-5-ol, a powerful anti-cancer agent sAJM589. Facile recyclability of catalyst Ia in the catalytic reactions was demonstrated.

Efficacy of Selenourea Organocatalysts in Asymmetric Michael Reactions under Standard and Solvent-Free Conditions

“…Thereby, Michael addition/hemiacetalization of diketones to the benzylidene pyruvate esters, leading to bicyclic compounds with two stereogenic centers, were studied. Particularly, the reaction of dimedone 11 with benzylidene pyruvate 10 has been successfully carried out with the use of various types of catalysts [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. An asymmetric Michael–hemiacetalization cascade reaction ( Scheme 3 ) was used for the screening of chiral selenoureas’ performance under standard and solvent-less conditions.…”

A review on lawsone-based benzo[a]phenazin-5-ol: synthetic approaches and reactions

“…In 2019, Kucherenko and co-workers reported synthesis of enantioselectively tetrahydropyran-fused benzo[ a ]phenazins 120 in 85–95% yields from β,γ-unsaturated α-keto esters and benzo[ a ]phenazin-5-ol (4) in the presence of bifunctional tertiary amine-squaramide catalyst in THF at room temperature for 4–6 h ( Scheme 38 ). 69 …”

“…67 Further, Yazdani-Elah-Abadi and his co-workers reported an efficient and environmentally benign procedure for the synthesis 68 In 2019, Kucherenko and co-workers reported synthesis of enantioselectively tetrahydropyran-fused benzo[a]phenazins 120 in 85-95% yields from b,g-unsaturated a-keto esters and benzo[a]phenazin-5-ol (4) in the presence of bifunctional tertiary amine-squaramide catalyst in THF at room temperature for 4-6 h (Scheme 38). 69 A one pot three-component reaction for the synthesis of benzo 73…”

Further developments of β,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis

“…The unprecedented desymmetrization of the parent C- and O-centered dinucleophiles led to hemiacetals 94 with high stereoselectivities (91–99% ee), which were readily transformed to 1,4-dihydropyridines without erosion of optical purity. Moreover, other dinucleophile analogues, such as enols 90b-d ( Kostenko et al., 2018 ; Liu et al., 2019 ; Modrocka et al., 2018 ; Pratap Reddy Gajulapalli et al., 2016 ; Tukhvatshin et al., 2019 ; Yin et al., 2016 ), as well as pyrazolones 95 ( Kumarswamyreddy and Kesavan, 2016 ) and 1,3-cyclohexanediones 92 ( Dajek et al., 2018 ; Yang et al., 2020 ), which could easily be tautomerized to its enol form, served as suitable C3 synthons in catalytic asymmetric [3 + 3] annulation reactions with β,γ -unsaturated α -ketoesters.

Scheme 13 Catalytic asymmetric [3 + 3] annulation reactions with dinucleophile analogues

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