Chiral Primary Amine Catalyzed Asymmetric Michael Reactions

The strategy of organocatalytic asymmetric Michael addition reaction to form new C-C bond for complex molecular structures from simple precursors has been widely developed in the recent years and also greatly expand the field of organocatalytic applications in asymmetric synthesis. In this dissertation, recent advances in the chiral primary amines catalyzed asymmetric reactions were summarized and reviewed, particularly the asymmetric Michael reactions. On this basis of above, the primary amine catalyzed Michael reactions ofα,β-unsaturated ketones with 2-hydroxy-1,4-naphthoquinone andβ-ketoesters were made in-depth study respectively.An enantioselective Michael reaction of substitutedα,β-unsaturated ketones with 2-hydroxy-1,4-naphthoquinone has been developed by using a chiral primary amine organocatalyst derivated from cinchona combined with a co-catalyst TFA for the asymmetric synthesis of lapachol analogues. The corresponding products were obtained in moderate to good yields (up to 93% yield) with up to 98% ee under mild conditions. To determine the absolute configurations of the final adducts, a useful technique by comparing the electronic circular dichroism (ECD) spectra of the chiral product with calculated time-dependent density functional theory (TDDFT) results was adopted. Based on the experimental results and ESI-MS of several key intermediates, the activation mechanism of iminium ion was confirmed.In the following study, an enantioselective Micheal reaction ofα,β-unsaturated ketones withβ-ketoester promoted by simple chiral primary amine organocatalysts was presented. A variety of substrates could be utilized to give corresponding chiral adducts with good to high enantioselectivities (up to >99.5% ee) and high yields (up to 93%). The chiral primary amine catalysts derivated from cinchona could activate both the substances smoothly. Furthermore, with the aid of ESI-MS, several intermediates and adducts were determined, a reaction model involving both hydrogen-bonding interactions and iminium ion amongst the primary amine catalyst and the reactants has been confirmed.