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.

A short total synthesis of (±)-mersicarpine via visible light-induced cascade photooxygenation

“…68 : 32), when using 30 mol% of the chiral phosphoric acid 18 combined with Amberlite IR 120 acidic ion exchange resin as an ammonia scavenger. 22 The cyclization of hydrazone 17 to tetrahydrocarbazole 20 gave a similar result (52% yield, e.r. 66 : 34).…”

Recent Advances in (Dynamic) Kinetic Resolution and Desymmetrization Catalyzed by Chiral Phosphoric Acids

“…During the revision of this manuscript, Mukherjee and co‐workers reported the enantioselective desymmetrization of 2,2‐disubstituted cyclopentane‐1,3‐diones 149 through chiral phosphoric acid ( CPA‐12 ) and ZnCl 2 co‐catalyzed Fischer indolizations with N ‐protected phenylhydrazine 150 (Scheme 48). [64] A series of cyclopenta[b]indolones 151 , which possessed an all‐carbon quaternary stereocenter, were produced in these reactions with high enantioselectivities. The combinational use of ZnCl 2 co‐catalyst in these reactions was believed to play the role of Lewis acid assisted enhancement of Brønsted acidity of the CPA catalyst.…”

Construction of Chiral Cyclobutanone-Fused 4-Aminoquinolines via Sequential Chiral Phosphoric Acid and Palladium Catalysis

“…Early in 2011, the List group reported the first catalytic asymmetric Fischer indolization for the synthesis of chiral tetrahydrocarbazole via dynamic kinetic resolution of 4-substituted cyclohexanone-derived hydrazones . Recently, Mukherjee and co-workers developed an enantioselective desymmetric Fischer indolization of 2,2-disubstituted cyclopentane-1,3-diones and phenylhydrazine . In the meanwhile, Zhao and Lan achieved an unprecedented desymmetrization of meso 1,3-diones by enantioselective intermolecular condensation, the product of which could be converted into indole-fused cyclohexanone bearing an all-carbon quaternary center .…”

“…3 Recently, Mukherjee and co-workers developed an enantioselective desymmetric Fischer indolization of 2,2-disubstituted cyclopentane-1,3-diones and phenylhydrazine. 4 In the meanwhile, Zhao and Lan achieved an unprecedented desymmetrization of meso 1,3-diones by enantioselective intermolecular condensation, the product of which could be converted into indole-fused cyclohexanone bearing an all-carbon quaternary center. 5 Though widely used in the formation of chiral polycyclic indole rings, the application of asymmetric carbonyl-amine condensation to construct other optically active polycyclic structures was largely unexplored.…”

“…On the other hand, transition-metal-catalyzed cyclization of 2haloaniline-derived enaminones has been proved as an effective method to synthesize N-heterocyclic rings. The directed intramolecular coupling reaction of N-2-haloaryl enaminones could afford indole derivatives or multisubstituted benzo [b]- [1,4]oxazepines, 6 whereas the intramolecular coupling reaction of enaminones with another component could give rise to a series of 6-membered benzo rings. 7 For example, Ji and coworkers reported a Pd-catalyzed cascade reaction of isocyanides with enaminones for the synthesis of 4-aminoquinoline derivatives in 2014 (Scheme 1a).…”