Phosphoric Acid-Catalyzed Asymmetric Classic Passerini Reaction

Abstract

An efficient enantioselective classic three-component Passerini reaction with a broad substrate scope in the presence of a chiral phosphoric acid catalyst has been developed. This represents the general example for classic three-component Passerini reaction with good to excellent enantioselectivies involving aromatic aldehydes and the bulky pivalaldehyde under mild reaction conditions. The feature of this method is highlighted by using a chiral phosphoric acid to activate carboxylic acid, aldehyde, and isocyanide for the facile construction of widely useful complex compounds.

Indole‐N‐Carboxylic Acids and Indole‐N‐Carboxamides in Organic Synthesis

“…[9] For example, the world-renowned Passerini three component reaction and Ugi four component reaction (4-MCR), which could deliver α-hydroxyl amide derivatives and α-amino amide derivatives respectively, have been widely applied in organic chemistry and medicinal chemistry, especially in peptide synthesis. [10] As a type of unique carboxylic acids, indole-N-carboxylic acids show great potential to act as new components in MCRs. In 2019, our group reported a novel Ugi type 4-component MCR using single reactant replacement strategy.…”

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

“…Dömling and co-workers, 2003 [37] (1 equiv) Ti(OiPr) 4 (1.35 equiv) THF (0.5 M), overnight 12-48 [32][33][34][35][36][37][38][39][40][41][42] Schreiber and co-workers, 2004 [38] (20 mol %) Cu(OTf) 2 ( [23,24] reactions that rely on the ability of organic isocyanides to participate in the nucleophilic attack onto the carbonyl or imine group are among the most studied MCRs. Accordingly, a wide range of post-MCR transformations have been elaborated allowing to upgrade the Passerini and Ugi adducts into potentially bioactive heterocycles [25][26][27][28][29][30][31][32].…”

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

“…While the prototypical Ugi 4CR provides al inear peptide-like adduct, many heterocycles [2] and even macrocycles [3] are now readily accessible by modification of this versatile and powerful reaction. Since one stereogenic center is generated in this transformation, the ability to control the stereochemical outcome would expand significantly its synthetic utilities.H owever,t he development of ac atalytic, enantioselective Ugi reaction remains an unsolved problem in spite of the progress recorded in the field of asymmetric Passerini reactions, [4][5][6][7][8][9] ac losely related three-component condensation of an aldehyde,carboxylic acid, and isonitrile. [10] Our group [11] and that of Maruoka [12] have independently reported chiral phosphoric acid (CPA) and chiral dicarboxylic acid catalyzed Ugi-type three-component reactions in which the transient nitrilium intermediate was trapped by an internal carboxamide function (Scheme 1a,b).…”