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

Compared to gamma-addition, the alpha-addition of alpha-branched beta,gamma-unsaturated aldehydes faces larger steric hindrance and disrupts the pi-pi conjugation, which might be why very few examples are reported. In this article, a highly diastereo- and enantioselective alpha-regioselective Mannich reaction of isatin-derived ketimines with alpha-, beta- or gamma-branched beta,gamma-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 alpha-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 alpha-regioselectivity.

Automated summary

In this article, a highly diastereo- and enantioselective alpha-regioselective Mannich reaction is achieved by using chiral N,N'-dioxide/Sc-III catalysts. A series of chiral alpha-quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good diastereomeric ratios, and excellent enantiomeric excess values. Experimental studies and DFT calculations reveal the critical factors for the alpha-regioselectivity to be the large steric hindrance of the ligand and the Boc protecting group of imines.