Mechanism and Origin of Stereoselectivity in Chiral Phosphoric Acid-Catalyzed Aldol-Type Reactions of Azlactones with Vinyl Ethers.

The precise mechanism of the chiral phosphoric acid-catalyzed aldol-type reaction of azlactones with vinyl ethers was investigated. DFT calculations suggested that the reaction proceeds through a Conia-ene-type transition state consisting of the vinyl ether and the enol tautomer of the azlactone, in which the catalyst protonates the nitrogen atom of the azlactone to promote enol tautomerization. In addition, the phosphoryl oxygen of the catalyst interacts with the vinyl proton of the vinyl ether. The favorable transition structure features dicoordinating hydrogen bonds. However, these hydrogen bonds are not involved in the bond recombination sequence and hence the catalyst functions as a template for binding substrates. From the results of theoretical studies and experimental supports, the high enantioselectivity is induced by the steric repulsion between the azlactone substituent and the binaphthyl backbone of the catalyst under the catalyst template effect.

Molecular Design of a Chiral Brønsted Acid with Two Different Acidic Sites: Regio-, Diastereo-, and Enantioselective Hetero-Diels-Alder Reaction of Azopyridinecarboxylate with Amidodienes Catalyzed by Chiral Carboxylic Acid-Monophosphoric Acid.

A chiral Brønsted acid containing two different acidic sites, chiral carboxylic acid-monophosphoric acid 1a, was designed to be a new and effective concept in catalytic asymmetric hetero-Diels-Alder reactions of azopyridinecarboxylate with amidodienes. The multipoint hydrogen-bonding interactions among the carboxylic acid, monophosphoric acid, azopyridinecarboxylate, and amidodiene achieved high catalytic and chiral efficiency, producing substituted 1,2,3,6-tetrahydropyridazines with excellent stereocontrol in a single step. This constitutes the first example of regio-, diastereo-, and enantioselective azo-hetero-Diels-Alder reactions by chiral Brønsted acid catalysis.

Chiral Brønsted acid-catalyzed enantioselective Friedel-Crafts reaction of 2-methoxyfuran with aliphatic ketimines generated in situ.

An enantioselective Friedel-Crafts reaction with aliphatic ketimines generated in situ from hemiaminal ethers catalyzed by a chiral Brønsted acid was investigated. The reaction of 2-methoxyfuran with (thio)hydantoin-derived hemiaminal methyl ether proceeded under the influence of a chiral phosphoric acid catalyst to afford the corresponding adduct possessing a quaternary stereogenic center in high yield with high enantioselectivity. Theoretical studies were also conducted to clarify the mechanism of the stereochemical outcome and the major factors contributing to the efficient enantioselection.