Asymmetric synthesis of β-substituted Baylis–Hillman products via lithium amide conjugate addition

A three-step protocol for the asymmetric synthesis of a range of β-substituted Baylis–Hillman products has been developed. This procedure involves the diastereoselective conjugate addition of lithium (R)-N-methyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester to generate an N-protected β-amino ester in high de. Subsequent asymmetric aldol reaction via deprotonation with LDA, transmetallation with B(OMe)3 and addition of an aldehyde gives a range of syn-aldol products in moderate to high de. Purification of the syn-aldol products to homogeneity followed by tandem N-oxidation and Cope elimination gives the desired β-substituted Baylis–Hillman products in good yield and high de and ee.

Graphical abstractThe conjugate addition of lithium (R)-N-methyl-N-(α-methylbenzyl)amide, followed by an asymmetric aldol reaction and subsequent tandem N-oxidation and Cope elimination affords homochiral β-substituted Baylis–Hillman products in good yield.Figure optionsDownload full-size imageDownload as PowerPoint slide