N‐Heterocyclic Carbene/Copper Cooperative Catalysis for the Asymmetric Synthesis of Spirooxindoles

Abstract

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...

An Update of Transition Metal-Catalyzed Decarboxylative Transformations of Cyclic Carbonates and Carbamates

“…Moreover, the coupling of malononitrile and alkynyl-carbonates proved to be feasible resulting in a series of chiral polysubstituted dihydrofurans with high enantioselectivities (up to 97% ee) (Scheme 11b) [52]. Most recently, the Gong group achieved the asymmetric synthesis of numerous spiro compounds with this strategy using both ethynylethylene carbonates and carbamates as starting materials through a NHC/copper cooperative catalytic system (Scheme 11c) [53].…”

Kinetic Resolution of Aziridines Enabled by N‐Heterocyclic Carbene/Copper Cooperative Catalysis: Carbene Dose‐Controlled Chemo‐Switchability

“…The addition of aziridine 2 l caused the signal for the Cu I ( L2 ) complex to disappear again, together with the release of L2 (Figure 5 b, b7). These observations suggest that NHC can be released from the Cu I ( L2 )( 4 c ) complex [8g] along with the addition of enal 1 a and can continue acting as an organocatalyst to activate the enal. In addition, the absence or presence of the Cu I ( L2 ) complex governs the reaction pathway toward the enantioselective KR or DyKAT of 2 l .…”

“…However, to date, NHC‐bound nucleophiles [16] have not been applied to stereoselectively open the aziridine ring [17] for manufacturing enantiomerically enriched N‐heterocyclic compounds. We envisioned that an NHC‐based homoenolate [18] could associate with copper complex‐activated styrenyl aziridines [13g, 15] to accomplish NHC/copper cooperatively catalyzed [8b,e,g] asymmetric [3+3] annulation, leading to KR‐produced enantioenriched spirooxindolyl lactams [19] and aziridines, [9] which have been both recognized as functional core units in numerous natural products and biologically active molecules (Figure 1 d,e). Herein, we report highly enantioselective KR of racemic aziridines via asymmetric [3+3] annulation with enals enabled by copper/NHC cooperative catalysis.…”

Transition‐Metal Free Catalytic Synthesis of Trifluoromethyl Indolines by [4+1] Cycloaddition of Trifluoromethyl Benzoxazinones with Sulfur Ylides

“…Column chromatography was carried out on columns packed with silica gel (60 N spherical neutral size 63-210 nm). The 1 H-NMR (700 MHz), 19 F-NMR (282 MHz), 13 Infrared spectra were recorded on a JASCO FT/IR-4100 spectrometer. Chemicals were purchased and used without further purification unless otherwise noted.…”

“…In the last few decades, transition‐metal catalyzed cycloadditions using zwitterionic species have emerged as a powerful strategy for constructing heterocyclic compounds [8–24] . Recently, vinyl‐benzoxazinone appears to be a useful zwitterion precursor as it can generate a Pd‐π‐allyl zwitterionic intermediate by oxidative addition, followed by decarboxylation [9–15] .…”