Merging the Non‐Natural Catalytic Activity of Lipase and Electrosynthesis: Asymmetric Oxidative Cross‐Coupling of Secondary Amines with Ketones

Abstract

We describe the enantioselective oxidative cross-coupling of secondary amines with ketones by combining the non-natural catalytic activity of lipase with electrosynthesis. Various 2,2-disubstituted 3-carbonyl indoles with a stereogenic quaternary carbon center were synthesized from 2-substituted indoles in yields up to 78 % with good enantioand diastereoselectivities (up to 96 : 4 e.r. and > 20 : 1 d.r.). This unprecedented protocol demonstrated that hydrolase catalysis is compatible with electrosynthesis, and the reaction can be carried out in organic solvents with a broad substrate scope and good stereoselectivity. This work provides insights into enzymatic electrosynthesis.

Electrochemical Oxidative Addition of Nucleophiles on 2-Arylindoles: Synthesis of C2-Heteroquaternary Indolin-3-ones

“…The cyclic voltammogram was plotted using the IUPAC convention (Figure 2); the oxidation potential was measured for 1 (E ox = 1.30 V vs Ag/AgCl as the reference electrode) and TEMPO (E ox = 0.89 V vs Ag/AgCl as the reference electrode), while 1, 3h, and TEMPO showed oxidation potential (E ox = 1.40 V vs Ag/AgCl as the reference electrode). A probable mechanism has been proposed on the basis of the literature available in this direction 71,72 and a control experiment with the radical scavenger butylated hydroxytoluene (BHT) (see the Supporting Information). As shown in Scheme 2, TEMPO underwent oxidation at the anode to generate TEMPO + , which could oxidize 2-arylindole 1 to radical cation A.…”

“…A probable mechanism has been proposed on the basis of the literature available in this direction , and a control experiment with the radical scavenger butylated hydroxytoluene (BHT) (see the Supporting Information). As shown in Scheme , TEMPO underwent oxidation at the anode to generate TEMPO + , which could oxidize 2-arylindole 1 to radical cation A .…”

“…71 While writing this publication, Long et al developed an exciting method for the direct asymmetric to access 2,2-disubstituted 3-carbonyl indoles by combining electrochemistry with lipase catalysis [Scheme 1b(ii)]. 72 Despite the presence of these graceful electrochemical methods in combination with another catalysis, developing a more general approach that could overcome the nucleophile's limitation is still required. Thus, here we describe a simple study for accessing C2-tertiary carbon indolin-3-one via oxidative dearomatization followed by in situ addition of several nucleophiles under mild electrochemical conditions (Scheme 1c).…”

“…Under electrochemical conditions, oxidative dearomatization of 2-arylindoles and subsequent direct Mannich reaction of ketones using amine catalysis have recently been developed to access 2,2-disubstituted indolin-3-ones. − In this context, Guan and co-workers have created a direct enantioselective synthesis of C2-quaternary indolin-3-ones by combining electrocatalysis with organocatalysts [Scheme b­(i)] . While writing this publication, Long et al developed an exciting method for the direct asymmetric to access 2,2-disubstituted 3-carbonyl indoles by combining electrochemistry with lipase catalysis [Scheme b­(ii)] . Despite the presence of these graceful electrochemical methods in combination with another catalysis, developing a more general approach that could overcome the nucleophile’s limitation is still required.…”

Cobalt-Catalyzed Enantioselective Intramolecular Reductive Cyclization via Electrochemistry

“…These advantages render electrochemistry a sustainable, economical technique for chemical synthesis. However, rare examples have been realized in the eld of asymmetric electrosynthesis [49][50][51][52][53] . To our best knowledge, there is only one enantioselective report involving cobalt via electrochemistry, in which moderate enantioselectivity was reported with one single example (Fig.…”