Design and Application of Chiral Bifunctional 4-Pyrrolidinopyridines: Powerful Catalysts for Asymmetric Cycloaddition of Allylic N-Ylide

Abstract

We designed bifunctional 4-pyrrolidinopyridines as powerful Lewis base catalysts. The catalyst structure features a 4-hydroxy-2-(hydroxydiphenylmethyl)­pyrrolidine-1-formyl group at the pyridine’s C3 site and a chiral side arm at the C2 position of the p-pyrrolidine ring. An operationally simple three-step synthetic route allows for efficient and economical catalyst preparation. In comparison with other Lewis bases, the catalyst exhibits excellent efficiency and stereoselectivity in the asymmetric (3 + 2) cycloaddition of allylic N-ylide generated in situ from a pyrazolone-derived Morita–Baylis–Hillman carbonate, providing a powerful platform for the construction of chiral spiropyrazolone derivatives. The reaction mechanism was thoroughly studied. Control experiments and DFT calculations illustrated the origin of the chemoselectivity and the stereocontrol model. H-bonding is crucial for the control of enantioselectivity and diastereoselectivity. The catalyst was also successfully applied in other reactions, such as an acylative dynamic kinetic resolution to synthesize a chiral phthalidyl ester, including the prodrug Talmetacin.

COAP-Pd Catalyzed Asymmetric Allylic Alkylation of Azlactones with MBH Carbonates: Access to Unnatural α-Quaternary Stereogenic Glutamic Acid Derivatives

“…The development of an efficient asymmetric catalytic approach to construct enantiomerically rich glutamic acid derivatives has drawn much attention from chemists. , In the past years, some significant asymmetric catalytic methods for the synthesis of optically active glutamic acid derivatives were reported, including PTC catalysis, Lewis acid catalysis, and Lewis base catalysis (Scheme ). − In 2005, a practical procedure for asymmetric synthesis of γ-alkylidenyl glutamic acid derivatives was reported by the use of a Schiff base of glycine tert -butyl ester with activated allylic acetates, which underwent asymmetric tandem conjugate addition–elimination in the presence of a cinchona-alkaloid derived phase-transfer reagent (Scheme a) . Then, Jørgensen’s group developed an organocatalytic enantioselective conjugate addition of glycine imine derivatives to electron-deficient allenes under phase-transfer conditions using either cinchona-alkaloid-derived or biphenyl-based chiral quaternary ammonium salts as the catalysts, affording several β-methylene glutamic acid derivatives in high yields and with good enantioselectivity (Scheme a) .…”

Cu-Catalyzed N-Arylation of Prolinamides: Access to Enantioenriched DMAP Analogues and Its Application in Black Rearrangement

“…The amino group, a common fragment in chiral sources such as amino acids, amino alcohols, and chiral amines, often appears as a substituent of enantioenriched DMAP analogues. Enantioenriched DMAP analogues C3 – C5 contain amino fragments at C-3 substituents . Particularly, in enantioenriched DMAP analogues C6 – C9 , an amino group is directly introduced at the C-3 position of the pyridine ring, resulting in enhanced nucleophilicity. − Therefore, the development of an efficient route to chiral 3-amino DMAP through a C–N coupling reaction is highly desirable.…”

Lewis-Base-Catalyzed Enantioselective Formal [4 + 2] Annulations of Morita–Baylis–Hillman Carbonates: Access to Tetrahydroquinolines Derivatives

“…It can undergo catalyst-controlled divergent intramolecular cyclizations to obtain 1,2-dihydroquinolines and 4H-3,1-benzoxazines. 16 Subsequently, we developed the Lewis-base-catalyzed [4 + 2] annulation 17 and Bronsted-basecatalyzed [6 + 2] annulation 18 be constructed efficiently by using multisubstituted alkenes as a two-atom synthon. Herein, we reported the chiral-aminecatalyzed formal [4 + 2] cyclization using o-acylamino-aryl MBH carbonates and 2-aroyl-3-arylacrylonitriles, providing tetrahydroquinolines in good to excellent yields with moderate to good enantioselectivity under mild conditions (Scheme 1c).…”