Catalytic Enantioselective Desymmetrizing Fischer Indolization through Dynamic Kinetic Resolution

Abstract

The first catalytic enantioselective Fischer indolization of prochiral diketones containing enantiotopic carbonyl groups is developed and shown to proceed through dynamic kinetic resolution (DKR). Catalyzedb yt he combination of as pirocyclic chiral phosphoric acid and ZnCl 2 (Lewis acid assisted Brønsted acid), this direct approach combines 2,2disubstituted cyclopentane-1,3-diones with N-protected phenylhydrazines to furnish cyclopenta[b]indole derivatives containing an all-carbon quaternary stereocenter with good to excellent enantioselectivities. Scheme 1. Catalytic enantioselective Fischer indolizations.

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

“…Very recently, Mukherjee and co-workers, [30] inspired by List's first chiral phosphoric acid catalyzed asymmetric Fischer indolization reaction, [31] developed an elegant method involving chiral phosphoric acid catalyzed enantioselective desymmetrization of 2,2-disubstituted cyclopentane-1,3-diones 3'' via Fischer indolization with substituted phenylhydrazines 36 to form cyclopenta[b]indolones 37 containing an all-carbon quaternary stereocentre with although moderate yield (31%-67%) but excellent enantioselectivity (up to 98:02 er). This reaction is catalyzed by spirocyclic P-chiral catalyst (S)-STRIP C14 with ZnCl 2 as the co-catalyst and Amberlite-IR 120 as a strong acidic cation exchange resin for scavenging ammonia by-product to suppress side-reactions (Scheme 21).…”

“…Parallel to the Mukherjee's work, [30] Zhuo and co-workers developed enantioselective desymmetrization of prochiral cyclic and acyclic 2,2-disubstituted 1,3-diones 3'' with phenylhydra-Scheme 20. Recyclable polymer-supported chiral phosphoric acid catalyzed desymmetrization of meso-diones.…”

Desymmetrization of Cyclic 1,3-Diketones under N -Heterocyclic Carbene Organocatalysis: Access to Organofluorines with Multiple Stereogenic Centers

“…Asymmetric desymmetrization represents one of the most facile and efficient methods for the generation of enantioenriched organic compounds, especially with multiple stereogenic centers, from meso or prochiral raw materials [1][2][3][4]. In this area, catalytic desymmetrization of prochiral 1,3-diketones has been investigated widely, including asymmetric reduction, intramolecular adol-type reactions, and others [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Furthermore, this desymmetric strategy as the key step has shown wide application in diverse natural product synthesis associated with diverse promising biological activities [22,23].…”