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.

Organocatalytic Enantioselective Desymmetrization of Prochiral 2,2‐Disubstituted Cyclic 1,3‐Diones

“…Same research group in 2019 further explored chiral NHCcatalyzed desymmetrization reaction involving [4 + 2]-cyclization beween α,β-unsaturated ketones 44 and 1,3-diones 3 to form substituted 1,3-indandiones 45 with an all-carbon quaternary centre in good to high yields (62-86%) and excellent enantioselectivity (up to 95 : 5 er). [37] The scope with respect to β-aryl enals and 1,3-diones was examined (Scheme 25). Substituents with electron-donating and withdrawing groups at the para and meta-position of the phenyl group were well tolerated (45 a-c).…”

Recent Advances in Organocatalyst‐Mediated Benzannulation Reactions

“…Recently, Chi and Chai et al reported a very efficient catalytic strategy to construct indane derivatives with an all-carbon quaternary chiral center using an NHC catalyst. [69] The strategy included two key simultaneous processes: the one was a direct construction of benzene by cascade cyclization/oxidation/isomerization processes; the second was a desymmetrization process that built the all-carbon quaternary chiral center. Optimization conditions suggested that with THF as the solvent, Cs 2 CO 3 as the base, and quinone as the oxidant, the desired product 170 was obtained in 85% yield and 94:6 er in the presence of NHC pre-catalyst 167 (Scheme 41).…”

Recent Progress towards Organocatalyzed Asymmetric (Hetero)Arene Formation

“…The quaternary all-carbon centers adjacent to arenes have remained difficult to install using conventional synthetic strategies. Recently, Chi, Chai and we 61 Recently, our group 62 developed an organocatalytic intermolecular benzannulation strategy to prepare polysubstituted axially chiral biaryls (Scheme 41). In the presence of NHC catalyst C30, DABCO and an oxidant, ,,,-unsaturated aldehydes 149 and benzyl ketones 150 underwent an enantioselective [4+2] cycloaddition to generate the corresponding atropisomeric arenes 151 in good yields (up to 95% yield) and excellent enantioselectivities (90-98% ee).…”

“…The quaternary all-carbon centers adjacent to arenes have remained difficult to install using conventional synthetic strategies. Recently, Chi, Chai and we 61 introduced a desymmetrization strategy and uncovered a facile [4+2] approach for asymmetric arene formation to build indane and its analogues containing a chiral all-carbon center (Scheme 40). With carbene catalyst C30, the reaction of enal 146 and cyclic unsaturated diketone 147 bearing a prochiral carbon yielded the indane derivative 148 with high efficiency (85% yield) and excellent chirality control (88% ee).…”