Cu-catalyzed asymmetric addition of alcohols to β,γ-alkynyl-α-imino esters for the construction of linear chiral N,O-ketals

N,O-acetals are part of many synthetic intermediates and important skeletons of numerous natural products and pharmaceutical drugs. The most straightforward method of the synthesis of N,O-acetals is the enantioselective addition of O-nucleophiles to imines. However, using this method for the synthesis of linear chiral N,O-ketals still remains challenging due to the instability of raw materials under acidic or basic conditions. Herein, we developed a Cu-catalyzed asymmetric addition of alcohols to beta,gamma-alkynyl-alpha-imino esters under mild conditions, providing the corresponding linear chiral N,O-ketals with up to 96% ee. The method tolerates some variation in the beta,gamma-alkynyl-alpha-imino ester and alcohol scope, including some glucose and natural amino acid derivatives. Computational results indicate that the Boc group of the substrates assist in the extraction of hydrogen atoms from the alcohols to promote the addition reactions. These products could be synthesized on a gram-scale and can be used in several transformations. This asymmetric addition system provides an efficient, mild, gram-scale, and transition-metal-catalyzed synthesis of linear chiral N,O-ketals. N,O-acetals are part of many synthetic intermediates and important skeletons of numerous natural products and pharmaceutical drugs. Here the authors show a Cu-catalyzed asymmetric addition of alcohols to beta,gamma-alkynyl-alpha-imino esters, providing the corresponding linear chiral N,O-ketals with up to 96% ee.

Automated summary

N,O-acetals are important building blocks for many synthetic intermediates, natural products, and pharmaceutical drugs. The authors developed a Cu-catalyzed asymmetric addition of alcohols to beta,gamma-alkynyl-alpha-imino esters, providing linear chiral N,O-ketals with high enantioselectivity.