Theoretical insight into phosphoric acid-catalyzed asymmetric conjugate addition of indolizines to α,β-unsaturated ketones

Phosphoric acid catalysis is a powerful tool for the construction of new C-C bonds because of its unique LUMO-lowering activity. Theoretical calculations were employed to investigate phosphoric acid catalyzed asymmetric conjugate addition of indolizines to alpha,beta-unsaturated ketones. The calculation results showed that this transformation proceeds via a reaction pathway involving nucleophilic addition, deprotonation-aromatization, and tautomerization. The computational results showed that deprotonation-aromatization is the rate-determining step and the enantioselectivity-determining step. The S-configured product was preferentially generated via a pathway starting from the s-cis conjugated ketone, whereas the s-trans isomer led to a side product with the R configuration. Non-covalent interaction analysis showed that the enantioselectivity is mainly caused by bond-rotation strain in the transition states of the deprotonation-aromatization step. (C) 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.