Highly enantioselective [3+ +3] and [3+ +4] annulations of isatin-derived enals with ethynylethylene carbonates and ethynyl benzoxazinanones are enabled by NHC/cooper cooperative catalysis,leading to abig library of spirooxindole derivatives in high structural diversity and enantioselectivity (up to 99 %e e). Both reactions represent an icely synergistic integration of NHC and copper catalysis,i nw hichb oth catalysts activate the substrates and the chiral NHC perfectly controls the stereochemistry.The 3,3'-spirocyclicoxindole unit is aprivileged heterocyclic moiety that is prevalent in ag reat number of biologically active natural products and pharmaceutical molecules. [1] Consequently,t he catalytic enantioselective construction of the spirooxindole skeleton with an all-carbon quaternary stereogenic center at the C3-position has received longstanding interest, but still remains asignificant challenge in organic synthesis. [2] In the past two decades,t he chemistry of Nheterocyclic carbenes (NHCs) has witnessed significant development in terms of stereoselective synthesis,a nd now provides apowerful approach to build molecular complexity, primarily through polarity-reversal approaches. [3] In particular, studies on the homoenolate species generated by NHC catalysis have gained widespread popularity in recent years. [3c, f] In 2016, the Enders group successfully established an NHC-catalyzed asymmetric [3+ +4] cyclization of isatinderived enals with in situ generated aza-o-quinone methides, azoalkenes,and nitrosoalkenes,which proceeds though NHCbased three-carbon homoenolates,l eading to as eries of highly enantioenriched spirooxindoles (Scheme 1a). [4] Since then, an umber of methods have been developed to access 3,3'-spirocyclic oxindole skeletons through NHC-catalyzed [3 + n]annulations of isatin-derived enals [5] by using asimilar concept. [6] Recently,c ooperative catalysis between metals and Nheterocyclic carbenes (NHCs) has greatly enhanced the synthetic repertoire of carbene catalysis. [7] Activation modes accessible through cooperative catalysis have resulted in remarkable improvements in reactivity,e fficiency,a nd selectivity for as eries of new enantioselective transformations. NHCs are routinely used as strongly coordinating ligands due to their strong propensity for binding to transition metals with high affinity. [8] As such, the combination of these nucleophilic organocatalysts with transition metals [9] typically leads to the deactivation of either or both of the two catalysts.B yn ow, several groups have figured out solutions to such problems through careful evaluations of catalytic systems,a nd the combination of NHCs with palladium, [10] ruthenium, [11] and copper [12] catalysts has enabled av ariety of unprecedented asymmetric reactions (Scheme 1b). Remarkably,s everal pioneering reports from Scheidt, [10a] Liu, [10b,c] and co-workers have demonstrated synergy between NHC and p-allylpalladium in catalysis.Since then, cooperative catalysis with NHC and palladium, as reported by Glorius and c...
Organocatalytic enantioselective Biginelli and Biginelli-like reactions by chiral phosphoric acids derived from 3,3'-disubstituted binaphthols have been investigated. The size of 3,3'-substituents of the catalysts is able to control the stereochemistry of the Biginelli reaction. By tuning the 3,3'-disubstituents of the phosphoric acids, the stereochemistry of the Biginelli reaction can be reversed. This organocatalytic Biginelli reaction by Brønsted acids 12b and 13 is applicable to a wide range of aldehydes and various beta-keto esters, providing a highly enantioselective method to access DHPMs. 3,3'-Di(triphenylsilyl) binaphthol-derived phosphoric acid afforded Biginelli-like reactions of a broad scope of aldehydes and enolizable ketones with benzylthiourea, giving structurally diverse dihydropyrimidinethiones with excellent optical purity. Theoretical calculations with the ONIOM method on the transition states of the stereogenic center forming step showed that the imine and enol were simultaneously activated by the bifunctional chiral phosphoric acid through formation of hydrogen bonds. The effect of the 3,3'-substituents in phosphoric acids on the stereochemistry of the Biginelli reaction was also theoretically rationalized. The current protocol has been applied to the synthesis of some pharmaceutically interesting compounds and intermediates, such as chiral thioureas, dihydropyrimidines, guanidines, and the precursor of (S)-l-771688.
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