Organocatalytic stereodivergent synthesis of β,β-disubstituted-α-aminoacids

In this work, we present an organocatalytic stereodivergent synthesis of β,β-disubstituted-α-aminoacids using arylidene azlactones as starting materials. The developed two step synthesis involves a sequential catalysis approach, in which two different catalysts act sequentially to control the absolute configuration of two different stereocenters. With an accurate selection of the catalysts absolute configuration it is possible to obtain all the stereoisomers of the product. The first synthetic step is a catalytic asymmetric transfer hydrogenation of the azlactone C=C double bond. A Jacobsen type thiourea and a Hantzsch ester were chosen as chiral catalyst and hydride donor, respectively. Different azlactones, Hantzsch esters and thioureas were synthetized and tested in the asymmetric transfer hydrogenation to achieve the best stereoselectivity. The second step involves a dynamic kinetic resolution on the reduced azlactone, through a nucleophilic addition to the carbonyl moiety promoted by a bifunctional chiral catalyst. A wide range of nucleophiles and organocatalysts were tested; the best results were reached with alcohols as nucleophiles and squaramide-based cinchona alkaloids as a chiral catalysts. With the optimized conditions two stereodivergent syntheses were then performed, enabling the selective obtainment of both diastereoisomeric product with high enantioselectivities.