Carbene‐Catalyzed Desymmetrization and Direct Construction of Arenes with All‐Carbon Quaternary Chiral Center

Abstract

Multisubstituted arenes such as indanes with attached all-carbon quaternary centers are unique scaffolds in synthetic functional molecules and sophisticated natural products.Akey challenge in preparing such molecules lies in the enantioselective installation of the quaternary carbon centers.C onventional methods in this direction include asymmetric substitution reactions and substrate-controlled cyclization reactions.T hese reactions lead to poor stereoselectivities and/or require long and tedious synthetic steps.Disclosed here is ao ne-step organic catalytic strategy for enantioselective access to this class of molecules.T he reaction involves an Nheterocyclic carbene catalyzedp rocess for direct benzene construction, indane formation, remote-carbon desymmetrization, and excellent chirality control. This approach will enable the concise synthesis of arene-containing molecules,i ncluding those with complex structures and challenging chiral centers. Figure 1. Arenes bearing challenging chiral centers.

Chiral N-Heterocyclic-Carbene-Catalyzed Cascade Asymmetric Desymmetrization of Cyclopentenediones with Enals: Access to Optically Active 1,3-Indandione Derivatives

“…In addition, 3, 4, and 5 Å molecular sieves were investigated as the additives, and slight improvement of both yield and enantioselectivity was observed in the reaction using 4 Å MS (54% yield, 90% ee; decreasing the reaction temperature was found to have a detrimental effect (see SI for more details). To balance both reactivity and enantioselectivity, the optimal reaction conditions were finally established as those shown in Table 2, entry 16.…”

“…During the preparation of our paper, Chi’s group reported independent work about chiral NHC-catalyzed enantioselective formal [4 + 2] construction of multisubstituted phenols, which were then readily transformed to challenging chiral tribenzotriquinacenes in three steps. The reported method displayed an efficient shortcut for the design of concise routes in complex molecular synthesis …”

“…The reported method displayed an efficient shortcut for the design of concise routes in complex molecular synthesis. 16 We initiated our study by first examining the model reactions between (E)-3-phenylbut-2-enal 1a and prochiral cyclopentene-1,3-dione 2a, in the presence of 10 mol % of a chiral N-heterocyclic carbene salt as the precatalyst. The reactions were typically performed in toluene at room temperature for 24 h with 20 mol % of Cs 2 CO 3 as the base and 2 equiv of 3,3′,5,5′-tetra-tert-butyldiphenoquinone 4 as the oxidant.…”

Exploring Molecular Complexity by N‐Heterocyclic Carbene Organocatalysis: New Activation and Reaction Diversity

“…The highly enantioselective desymmetrization is controlled by the chiral indane moiety of NHC inducing the more steric bulky R 2 moiety on the top face (Scheme 10, II to III), provding a general route for the stereoselective synthesis of fused benzene derivatives (Scheme 10). [22] The synthesis of heteroarenes, such as pyridines have also been achieved by the NHC-catalyzed arene-forming strategy. For example, in 2017, we reported an effective [3 + 3] cycloadditions of alkyne esters 32 with enamides 11 by NHCcatalyzed LUMO activation of alkyne esters.…”

“…The highly enantioselective desymmetrization is controlled by the chiral indane moiety of NHC inducing the more steric bulky R 2 moiety on the top face (Scheme 10, II to III ), provding a general route for the stereoselective synthesis of fused benzene derivatives (Scheme 10). [22] …”