Formal [4+2] Cycloaddition of Azlactones to β,γ-Unsaturated α-Keto Esters

Significance

A highly stereoselective formal [4+2] cycloaddition of azlactones 1 to β,γ-unsaturated α-keto esters 2 catalyzed by an axially chiral guanidine base 3 is reported by the authors. With 2 mol% of 3 as catalyst, a series of [4+2] cycloaddition products 4 can be obtained in good yields, diastereo- and enantioselectivities. A plausible pathway involving three consecutive transformations was proposed: 1) Michael addition of the azlactone enolates to β,γ-unsaturated α-keto ­esters; 2) subsequent intramolecular nucleophilic addition of the enolate oxygen of B to the C5 ­position of the azlactone moiety; and 3) a final ring opening of the azlactone moiety in C to give α-amino-δ-lactone derivatives 4. The Michael addition as the initial step was confirmed by the isolation of the acyclic product (B-H) by quenching the reaction at a low temperature.