A Series Of Novel Asymmetrical Aldol Decarboxylation Reactions And Their Applications On The Synthesis Of Hydroxyindole Derivatives

Alcohols with multiple functional groups are of great interests in organic chemistry with synthetically and biologically. In recent years, the decarboxylation Aldol reaction and MBH reaction for the synthesis of alcohols have received much attention for their quick ways of constracting functionized alcohol derivatives.In this dissertation, the studies focused on two aspects:(1) The decarboxylation Aldol reaction of p-ketoacids. (2) The MBH reaction of isatins with a,p-unsaturated-butyrolactam.1. Enantioselective decarboxylative addition of β-ketoacids to isatins3-hydroxyoxindoles with substituents at 3-position were encountered in a large number of natural and designed bioactive compounds. The biological activities of these compounds are greatly affected by the configuration of the hydroxyl group and the substituents at the C3 position of the oxindole. To synthesise those 3-hydroxyoxindoles, we have successfully developed the highly enantioselective catalytic decarboxylative addition of β-ketoacids to isatins catalysed by ytterbium(III)-indapybox. Based on the optimised reaction conditions, A series of biologically valuable 3-hydroxy oxindoles were obtained in high yields and excellent enantioselectivities. Substitution at the 6-position with electron-donating and electron-withdrawing groups afforded consistently high yields and excellent enantioselectivities. The method described valuable for practical chemical synthesis. We carried out a gramscale synthesis the decarboxylative aldol product obtained in high yield and excellent enantioselective. The absolute configurations of the products were confirmed by crystallography.2. Enantioselective decarboxylative aldol reaction of β-ketoacids with a-ketoesterCompounds that contain chiral a-hydroxyester moiety are important in the biological sciences and pharmaceutical industry. Meanwhile, the chiral a-hydroxyester can be readily converted to sth construct more complex chiral compounds. We conducted the decarboxylative aldol reaction of β-ketoacid with a-ketoester in the presence of chiral base organocatalyst. yields were obtained, low enantioselectivities. Lewis acid-catalyzed the reaction. After optimizing conditions, The first enantioselective decarboxylative aldol reaction of β-ketoacids with a-ketoesters by employing Sc(OTf)3-pybox complex as efficient catalysts. A series of chiral a-hydroxyesters were obtained in good to high yields (81-93%) and enantioselectivities (41%-84% ee). Both aromatic and aliphatic a-ketoesters gave excellent yields with good enantiomeric excess. In addition, the decarboxylation reaction of β-ketoacid and unsaturated ketoester was also described in this chapter, can get 38% ee in the double function catalyst alkaloid catalyzed.3. The decarboxylative aldol reaction of β-ketoacids with ethyl pyruvateHydroxyesters containing fluorine are important synthetic intermediates, which can be transformed into a variety of complex functional compounds, we conducted the decarboxylative aldol reaction of β-ketoacid with ethyl pyruvate in the absence of solvent or catalyst at room temperature, the reaction efficiency is very high, almost quantitatively obtained products. Based on optimised reaction conditions, A series of fluorinated a-hydroxyesters were obtained in high yields. The addition of chiralbisthiourea was unable to offer enantioselectivity product. We conducted the decarboxylative aldol reaction of β-ketoacid with ethyl pyruvate in the presence of chiral bases as an organocatalyst, all the chiral bases offered low enantioselectivities.4. Asymmetric MBH reaction of isatins with a,β-unsaturated y-butyrolactamThe development of a suitable synthetic method for the preparation of novel chiral 3-hydroxy oxindoles has significant vaule for medicinal research. α,β-unsaturated y-butyrolactam are present in a variety of natural products as well as bioactive compounds. These frameworks are also very important synthetic intermediates to many organic compounds. We have explored the first MBH reaction of　α,β-unsaturated y-butyrolactam with isatin derivatives catalyzed by organocatalyst. Chiral bases gave low enantioselectivities, which the (DHQD)2AQN catalyzed can get 49% ee. Chiral bisthiourea and organocatalyst gave 75%—91% yield and up to 78% ee. It is notable that the substituent position on the phenyl moiety of the N-benzyl isatin derivatives had obvious influence on the enantioselectivity. The 6-position substituent for the phenyl ring of N-benzyl isatins gave higher enantioselectivity than the substituent group on other positions.