Application Of Chiral Phosphoric Acid-based Multicatalyst Systems To The Asymmetric Synthesis

Recently, multicatalyst systems have emerged as a new important field in asymmetric synthesis. The modular combination of distinct catalysts for consecutive transformations in a single flask, holds great potential in the creation of new transformations that neither type of catalysts is able to afford alone. Multicatalysis avoids costly and time-consuming intermittent work-up and purification steps, thus preventing yield losses, saving energy, time and effort, and reducing waste. As a consequence, the multicatalytic protocols lead to overall high step economy.In this paper, a highly enantioselective Friedlander condensation has been established by using chiral phosphoric acid in combination with achiral amines (achiral amine promoter plays crucial role in the stereocontrol). The efficient desymmetrization of4-substituted cyclohexanones derivatives in the reaction with a variety of electron-donating and withdrawing orthoaminobenzaldehydes gives chiral quinolines in high yields and excellent enantioselectivities. In particular, this work first demonstrated that Bransted acid is able to catalyze enantioselective Friedlander condensations.We have designed a highly enantioselective three-component relay reaction, consisting of a catalytic Friedlander condensation and a transfer hydrogenation by using a combination of an achiral Lewis acid and a chiral Bronsted acid, providing a unique method for the preparation of structurally diverse and complex substituted tetrahydroquinoline derivatives in high optical purity, and thereby can be considered an efficient alternative to known procedures. Kinetic studies revealed that the Friedlander condensation is catalyzed either by Lewis acid or the chiral phosphoric acid while the asymmetric transfer hydrogenation is promoted solely by the chiral Bransted acid. The compatibility and synergism of the Lewis acid and chiral Bransted acid may provide a new reaction mode potentially amenable to disclosing other relay catalytic asymmetric transformations.A highly enantioselective three-component aldol-type reaction of3-diazooxindoles and anilines with glyoxylates cooperatively catalyzed by a rhodium complex and chiral phosphoric acid has been established to gives highly functionalized3-amino oxindoles with excellent enantioselectivities. The protocol not only offers a straightforward and efficient route to access highly functionalized and structurally diverse3-amino oxindoles in high optical purity, but also provides a new reaction mode for the construction of natural product skeleton and active drug molecule. More importantly, these findings offer a platform for the rhodium/chiral phosphoric acid binary catalyst that could be applied to realize enantioselective versions of other aldol-type transformations that involve either ammonium or oxonium ylide intermediates formed from diazo carbonyls.