Synthesis Of Chiral Tertiary α-hydroxycarbonyl Compounds Catalyzed By Proline-derived Metal Complexes

Chiral tertiary α-hydroxycarbonyl skeletons are ubiquitous structural moieties in organic chemistry and widely exist in many synthetic drugs and bioactive molecules.The dissertation focuses on synthesis of chiral tertiary α-hydroxycarbonyl compounds catalyzed by proline-derived metal complexes,which includes the following four parts:Firstly,we developed an asymmetric direct aldol reaction betweenβ,γ-unsaturated α-ketoesters and coumaran-3-ones under the catalysis of proline-derived tridentate ligand copper complexes.A series of coumaran-3-one derivatives containing chiral tertiary α-hydroxycarbonyl were obtained.In this reaction,the nucleophilic addition of coumaran-3-ones to carbonyl group can be realized without activation pretreatment to highly active enol silyl ether.The reaction can be manipulated easily with high atomic economy.The reaction can be carried out on gram-scale and the products can be further reduced.In addition,the possible transition state and corresponding mechanism were proposed by the control experiments and DFT calculations.Secondly,we developed an asymmetric Michael/N-hemiacetalization cascade reaction between β,γ-unsaturated α-ketoesters and 5-aminoisoxazoles by the same copper complexs as that above.A series of chiral N,O-hemiaminals containing chiral tertiary α-hydroxycarbonyl were obtained.It was found that the addition of trace amount of water could greatly improve the reaction yield.The reaction has a wide range of substrate applications and can be carried out smoothly on gram-scale.According to the control experiments and DFT calculations,the Van der Waals force and hydrogen bonding are very important for the control of the stereocenter chirality.Thirdly,we developed an asymmetric allylation reaction of isatins with allylboronic acid pinacol ester to give the corresponding products under the catalysis of proline-derived tridentate ligand zinc complexes.A series of 3-allyl-3-hydroxyoxindole derivatives were obtained.The adverse effect of the protecting group on N atom of isatins in the reaction can be eliminated and the scope of the substrates for such reaction was extended.The possible six-membered ring Zimmerman-Traxler transition state was supported by DFT calculation and the possible catalytic mechanism was proposed.The gram-scale experiment and further functionalization of the products showed the practicability of this method.Finally,the asymmetric allenylation reaction of isatins with allenylboronic acid pinacol ester was developed with high chemoselectivity by the same zinc complexs as that in the third part.A series of 3-allenyl-3-hydroxyoxindoles were obtained.The addition of anhydrous sodium sulfate to the reaction can effectively reduce the background reaction.The possible mechanism was supported by DFT calculation.The reaction can be carried out smoothly on gram-scale and the products can also be derived further,which provide an alternative synthesis of various chiral 3-oxo-2-oxindoles derivatives.