Enantioselective Organocatalytic Desymmetrization of Cyclopentene-1,3-diones through Formal C(sp²)–H Amidation

Abstract

An enantioselective organocatalytic desymmetrization of 2,2-disubstituted cyclopentene-1,3-diones via a formal C­(sp2)–H amidation is reported. The reaction was carried out with N-methoxy amide as the nitrogen source and commercially available cinchonidine as the catalyst under mild reaction conditions, releasing methanol as the only byproduct. It provides an efficient way to synthesize enantioenriched chiral cyclopentenyl amines bearing an all-carbon quaternary stereogenic carbon center.

Recent advances towards organocatalytic enantioselective desymmetrizing reactions

“…Additionally, the same group simultaneously realized an organocatalytic Michael addition reaction of 3-substituted oxindoles with cyclopentenediones in the same year [52]. Later in 2019, the Wang group observed that the application of N-methoxy amides as nucleophiles and commercially available cinchonidine as the catalyst could lead to a formal C(sp 2 )−H amidation of cyclopentenediones [53] and a practically identical case was reported by Chegondi [54]. Simultaneously, an asymmetric Diels-Alder reaction of 3-hydroxy-2-pyrones with prochiral cyclopentenediones was developed by…”

“…Apart from aldehydes, Morita-Baylis-Hillman carbonates could also act as the substrates and an asymmetric allylic alkylation was conducted via the catalysis of commercially available (DHQ) 2 PHAL by Li [68]. Later in 2020, Yeung and coworkers described an unprecedented enantioselective site-specific ortho-halogenation to provide privileged chiral bisphenol derivatives (53) [69]. This potent skeleton could be applied to the scalable synthesis of CPAs and phosphoramidite ligands, which may find utilization in asymmetric catalysis.…”

Desymmetrization of Cyclopentene‐1,3‐Diones via Alkylation, Arylation, Amidation and Cycloaddition Reactions

“…In the year 2019, Jun Wang and co-workers developed the almost same type of enantioselective desymmetrization of prochiral cyclopentene-1,3-dione (1) via C(sp 2 )À H amidation to produce cyclopentenyl amines (38) with all carbon-bearing quaternary stereocentre (Scheme 9). [34] N-methoxy amide (37) was used as a nitrogen source and easily available cinchonidine (C10) as an efficient organocatalyst and chlorobenzene as a solvent in this reaction. The reaction condition was very simple and methanol was the only by-product.…”

“…C(sp 2 )À H amidation of prochiral cyclopentene-1,3-dione via organocatalytic method. [34] pentene1,3-dione with 3-hydroxy-2-pyrone was optimized using a different bifunctional amine À thiourea derivative of cinchona alkaloid as a catalyst, DCM as solvent atÀ 20°C. The generality of the developed methodology was tested with a series of 2,2 disubstituted cyclopentene-1,3-diones with several 3-hydroxy-2-pyrones.…”

“…Possible mechanism for the C(sp 2 )À H amidation to produce cyclopentenyl amines. [34] product. A similar effect was observed in enantioselectivity (83-97 %) and product yield (70-90 %) when they used different isocyanoacetates as the reacting partner.…”