Chiral Lewis Acid - Applications of CLAs in Asymmetric Synthesis - Diels-Alder Reaction

Diels-Alder Reaction

Diels-Alder reactions occur between a conjugated diene and an alkene (commonly known as the dienophile). This cycloaddition process allows for the stereoselective formation of cyclohexene rings capable of possessing as many as four contiguous stereogenic centers.

Diels-Alder reactions can lead to formation of a variety of structural isomers and stereoisomers. The molecular orbital theory considers that endo transition state, instead of the exo transition state, is favored (endo addition rule). Also, augmented secondary orbital interactions have been postulated as the source of enhanced endo diastereoselection.

The addition of a CLA selectively activates one component of the reaction (the diene or dienophile) while providing a stereodefined environment that permits unique enantioselectivity.

Koga and coworkers disclosed the first practical example of a catalytic enantioselective Diels-Alder reaction promoted by a CLA - menthoxyaluminum dichloride - derived from menthol and ethylaluminum dichloride.

A decade later, Elias James Corey introduced an effective aluminum-diamine controller for Diels-Alder reaction. Formation of the active catalyst is achieved by treatment of the bis(sulfonamide) with trimethylaluminum; recovery of the ligand was essentially quantitative. The proposed tetracoordinate aluminum prevent the imide acting as a chelating Lewis base, while enhance the α-vinyl proton of the dienphile and the benzylic proton of the catalyst.

The X-ray structure of the catalyst showed a stereodefined environment.

In 1993, Wulff and coworkers found a complex derived from diethylaluminium chloride and a “vaulted” biaryl ligand below catalyzed the enantioselective Diels-Alder reaction between cyclopentadiene and methacrolein. The chiral ligand is recovered quantitatively by silica gel chromatography.

Hisashi Yamamoto and coworkers have developed a practical Diels-Alder catalyst for aldehyde dienophiles. The chiral (acyloxy)borane (CAB) complex is effective in catalyzing a number of aldehyde Diels-Alder reactions. NMR spectroscopic experiments indicated close proximity of the aldehyde and the aryl ring. Also, Pi stacking between the aryl group and aldehyde was suggested as an organizational feature which imparted high enantioselectivity to the cycloaddition.

Yamamoto and co-wokers have introduced a conceptually interesting series of catalysts that incorporate an acidic proton into the active catalyst. This kind of what so called Bronsted acid-assisted chiral Lewis acid (BLA) catalyzes a number of diene-aldehyde cycloaddition reactions.