Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct

Abstract

Reaction of isonitriles with 3-(arylamino)isobenzofuran-1(3H)-ones in the presence of a catalytic amount of an octahydro (R)-binol-derived chiral phosphoric acid afforded 3-oxo-2-arylisoindoline-1-carboxamides in high yields with good to high enantioselectivities. An enantioselective Ugi four-center three-component reaction of 2-formylbenzoic acids, anilines, and isonitriles was subsequently developed for the synthesis of the same heterocycle. Mechanistic studies indicate that the enantioselectivity results from the dynamic kinetic resolution of the primary Ugi adduct, rather than from the C-C bond-forming process. The resulting heterocycle products are of significant medicinal importance.

An Efficient Nickel‐Catalyzed Asymmetric Oxazole‐Forming Ugi‐Type Reaction for the Synthesis of Chiral Aryl‐Substituted THIQ Rings

“…The transformation presented a broad substrate scope and yielded the corresponding products with good yields and ee values. It should be noted that the direct reaction of 2‐carboxybenzaldehydes, amines, and isonitriles was also possible in their work …”

Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct

“…Thea bsolute configuration of 4j was determined by X-ray crystallographic analysis [21] and that of other isoindolinones was assigned accordingly since all these compounds have very similar CD spectra. With regard to the isonitrile,t ertiary,s econdary,a nd primary alkyl isonitriles,including a-isocyanoacetate,were all tolerated to afford the corresponding isoindolinones (4o-s).…”

Catalytic Asymmetric Synthesis of Isoindolinones

“…Enantioselectivity through dynamic kinetic resolution has alwaysb een challenging. In 2016, [30] an enantioselective transformation of anilines 53,i sonitriles 54,a nd 2-formylbenzoic acids 52 wasreported as an efficient route to 3-oxo-2-arylisoindoline-1-carboxamides 55 by Zhu's group (Scheme 11). Under the same reactionc onditions, transformation of substrates 51 with isonitriles 54 also could afford the same desired heterocycles 55 efficiently.The authors documented that the enantioselectivity was the result of dynamic kinetic resolutionp rocesses.…”