Stereoselective Nucleophilic Addition Reaction Of Sulfur-Substituted 1,2-enediolates Toward N-tert-Butanesulfinyl Ketimines

The structure of 3-Amino-3-subsituted oxindoles are important building blocks in some natural products and biologically active molecules.Molecules with such structures are known to be a common selective inhibitor and receptor antagonist with potential antimalarial,antibacterial and anti-tumor effects.N-tert-butanesulfinyl ketimines derived from isatins serve as electrophiles to undergo addition reaction with a variety of nucleophiles to construct 3-amino-3-substituted oxindoles bearing tetrasubstituted carbon stereocenter.The purpose of this thesis is to investigate the methodology on asymmetric synthesis of β-amino-α-hydroxy carboxylic acid derivatives bearing 3-amino-3-substituted oxindole as a core structure through a reaction of sulfur-substituted-1,2-enediolates and N-tert-butanesulfinyl ketimines.At low temperature,deprotonation of O-acy1-hemithioacetals generates enolatesand subsequent intramolecular acyl migration leads to the formation of sulfur-substituted 1,2-enediolate intermediates.The reactivenuclophilic intermediates were captured by N-tert-butanesulfinyl ketimines to afford 3-amino-3-alkyloxindole derivatives via a C-C bond formation.The 3-amino-3-substituted oxindole derivatives contain adjacent tetra-substituted carbon stereocenters,wherein the 3-substituent was a thioester structure substituted with an α-acetoxy-α-alkane group.Preliminary studies indicated that the stereoselectivity of the transformation could not be optimized by the swaping bases and solvents.Screening of Lewis acid additives showed that addition of copper(Ⅱ)triflate[Cu(OTf)2)]dramatically improved the stereocontrol,when Lithium bis(trimethylsilyl)amide(LHMDS)was used as base,and excellent diastereoselectivity(>20:1 dr)were obtained.Studies on the substrate scope showed that N-tert-butanesulfinyl ketimines derived from N-H and N-Triphenylmethyl isatins were all compatible with the reaction conditions,giving the corresponding products in high yields with good to excellent diastereoselectivities.In summary,we have developed a stereoselective reaction of S-substituted-1,2-enediolate and N-tert-butanesulfinyl ketimines for preparation of 3-amino-3-substituted oxindole derivatives bearing adjacent tetrasubstituted stereocenters.Good stereocontrol of the reaction was achieved through the cooperation of chiral N-tert-butylsulfinyl group and Copper(Ⅱ)triflate additives.Manipulations of the functional groups in the prepared 3-amino-3-substituted oxindoles would give access to a range of downstream derivatives with highly structural diversity.