Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

Abstract

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.