Concurrent Asymmetric Reactions Combining Photocatalysis and Enzyme Catalysis: Direct Enantioselective Synthesis of 2,2‐Disubstituted Indol‐3‐ones from 2‐Arylindoles

Abstract

The combination of photoredox and enzymatic catalysis for the direct asymmetric one‐pot synthesis of 2,2‐disubstituted indol‐3‐ones from 2‐arylindoles through concurrent oxidization and alkylation reactions is described. 2‐Arylindoles can be photocatalytically oxidized to 2‐arylindol‐3‐one with subsequent enantioselective alkylation with ketones catalyzed by wheat germ lipase (WGL). The chiral quaternary carbon center at C2 of the indoles was directly constructed. This mode of concurrent photobiocatalysis provides a mild and powerful strategy for one‐pot enantioselective synthesis of complex compounds. The experiments proved that other lipases containing structurally analogous catalytic triad in the active site also can catalyze the reaction in the same way. This reaction is the first example of combining the non‐natural catalytic activity of hydrolases with visible‐light catalysis for enantioselective organic synthesis and it does not require any cofactors.

Oxidative Dearomative Cross-Dehydrogenative Coupling of Indoles with Diverse C-H Nucleophiles: Efficient Approach to 2,2-Disubstituted Indolin-3-ones

“…Direct C-H functionalization of indoles with different C-H nucleophiles presents an atom-economic protocol without prior installation of activating groups and is thus very attractive. However, most of these reactions focus on the construction of di-or trimerization of indoles [50,[77][78][79][80], and the reactions of indoles with dissimilar C-H nucleophiles are considerably rare [81][82][83]. Recently, we reported an efficient oxidative dearomatization reaction of indoles [84,85].…”

Biocatalysis Fueled by Light: On the Versatile Combination of Photocatalysis and Enzymes

“…Photo‐biocatalytic concurrent oxidation and alkylation reactions were recently explored by the groups of He and Guan (Scheme ) . The indol‐3‐ones 88 were generated from the corresponding starting 2‐arylindoles 86 by visible‐light‐driven Ru II photoredox catalysis.…”

“…Photo-biocatalytic concurrent oxidation and alkylation reactions were recently explored by the groups of Hea nd Guan (Scheme18). [74] The indol-3-ones 88 were generated from the correspondings tarting 2-arylindoles 86 by visible-light-driven Ru II photoredox catalysis. Mechanistically,e xcitation of the photosensitizer to Ru II *i sp ostulatedt ob ef ollowed by reductive quenching by 86 (SET) to form Ru I .T he photosensitizer is then oxidized to its ground state by O 2 ,w hile releasing the su-peroxide anion (O 2 À· ), andt his in turn reacts with the oxidized 2-arylindole radicalcation to give the intermediate 88.…”

Photoenzymatic Approaches in Organic Synthesis

“…In this field, hydrolases have received special attention as they can accommodate broad spectrum of substrates, require no cofactors and possess high stability in organic solvents . Recently, our group achieved the first combination of photocatalysis and catalytic promiscuity of hydrolase for concurrent oxidization and asymmetric alkylation of 2‐arylindoles (Scheme ) . With 2‐phenylindole 17 a and acetone 18 a as the model substrates under the optimized conditions, which consist of Ru(bpy) 3 Cl 2 as the photocatalyst, wheat germ lipase (WGL) as the biocatalyst, DMF as the solvent and 32 W compact fluorescent lamp (CFL) as the light source, the product 19 a was obtained with 62% yield and 78% ee.…”