Sterically Hindered and Deconjugative α-Regioselective Asymmetric Mannich Reaction of Meinwald Rearrangement-Intermediate

Abstract

Compared to γ-addition, the α-addition of α-branched β,γ-unsaturated aldehydes faces larger steric hindrance and disrupts the π-π conjugation, which might be why very few examples are reported. In this article, a highly diastereo- and enantioselective α-regioselective Mannich reaction of isatin-derived ketimines with α-, β- or γ-branched β,γ-unsaturated aldehydes, generated in situ from Meinwald rearrangement of vinyl epoxides, is realized by using chiral N,N'-dioxide/Sc^III catalysts. A series of chiral α-quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good d.r. and excellent ee values. Experimental studies and DFT (density functional theory) calculations reveal that the large steric hindrance of the ligand and the Boc (tButyloxy carbonyl) protecting group of imines are critical factors for the α-regioselectivity.

Keywords: Lewis Acid Catalysis; Mannich Reaction; Meinwald Rearrangement; Protecting Groups; Vinyl Epoxide.