The construction of chiral 3-acyl bicyclolactams via a RuPHOX/Pd catalyzed asymmetric allylic substitution cascade of α-carbonylamides

A RuPHOX/Pd catalyzed asymmetric allylic substitution cascade of alpha-carbonylamides with an allylic meso-dicarbonate has been developed, providing chiral 3-acyl bicyclolactams bearing three vicinal carbon stereocenters in high yields and with up to 99% ee and >20 : 1 dr. Mechanistic studies based on control experiments and DFT calculations revealed that a dynamic kinetic resolution process should occur during the second step of the cascade reaction, which is responsible for the excellent diastereoselectivities of the desired products. The protocol could proceed on a gram-scale and the resulting products allow for various transformations, especially for the preparation of several natural products.

Automated summary

A RuPHOX/Pd catalyzed asymmetric allylic substitution cascade of α-carbonylamides with an allylic meso-dicarbonate has been developed to synthesize chiral 3-acyl bicyclolactams bearing three vicinal carbon stereocenters in high yields. The products exhibited excellent enantioselectivity with up to 99% ee and high diastereoselectivity with >20:1 dr. Mechanistic studies revealed a dynamic kinetic resolution process during the second step of the cascade reaction, which contributed to the high diastereoselectivity. The protocol can be scaled up and the resulting products are versatile for further transformations, especially in the synthesis of natural products.