Asymmetric Synthesis Of 3-Substituted-3-hydroxy-2-oxindole Derivatives

Background:Since the serious thalidomide event in the 1960s,the discovery and clinical study of chiral drugs has emerged as the hot topic in the worldwide research.Nowadays,more than 60%of the commonly used chemical drugs in the world are chiral.However,most of chiral drugs have long been available only from the extraction of animal and plant as well as natural compounds'transformation,leading to severe shortages of chiral drugs.The development of concise,environmentally benign and efficient asymmetric synthetic methodologies is of great importance in chiral drug synthesis and has draw particular attention of organic and medinical chemists.On account of the ubiquitous prevalence in a large number of pharmaceuticals and natural products,the 3-hydroxy-2-oxindole is a very important and well-known privilegd chiral scaffold bearing the C3 quaternary chiral center.It exhibits the unprecedented structural diversity and biological activities,for example,antimicrobial,antitumor,antiinflammatory,antioxidant and growth hormone secretagogues.However,most of strategies have been reported about the asymmetric construction of this motif catalyzed by transition metal,which restricts its application in drug synthesis because of metal contamination.Therefore,the development of novel organocatalytic asymmetric strategies for the assembly of(S)-3-substitued-3-hydroxy-2-oxindole is of key research value and practical significance in pharmacy.Objective:This dissertation aims to development an efficient and concise asymmetric oxidation methodologies in the presence of cheap and commercially available triethyl amine as the organocatalyst,construct the 3-hydroxy-2-oxindole scaffold bearing the C(3)quaternary stereocerter,synthesize a great deal of enantiopure(S)-3-substituted-3-hydroxy-2-oxindoles with excellent enantioselectivities and establish a small chiral oxindole library,providing important data for innovative drug discovery.Method:Firstly,a large array of racemic 3-substituted-2-oxindole derivatives were synthesized with isatin derivatives with substrates.Next,various reaction parameters were evaluated in the asymmetric oxidation of racemic 3-substituted-2-oxindole,including oxidant,catalyst,temperature,solvent and so on.With the optimal reaction condition in hand,versatile chiral(S)-3-substituted-3-hydroxy-2-oxindole derivatives were generated with enantiopure oxaziridines as efficient oxidants.Furthermore,the desired target compounds were characterized by ¹H NMR,¹³C NMR,high performance liquid chromatography,high resolution mass spectrometry and polarimeter.Results:The optimal reaction condition was confirmed via the systematic modification by single factor experiments as follows:the amount of triethylamine catalyst was 10 mol%,the solvent was toluene,the oxidant is(1-S)-(+)-10-camphorsulfonyl oxaziridine,the reaction temperature was-40?,the yield of desired(S)-3-phenyl-3-hydroxy-2-oxindole was 99%with excellent enantioselectivity(93%).With the optimal reaction condition in hand,the convergent asymmetric oxidation of racemic 3-substitued-2-oxindole derivatives affored a variety of the corresponding(S)-3-substituted-3-hydroxy-2-oxindole compounds in moderate to excellent yields(34?99%)and with moderate to excellent enantioselectivities(32?96%).Tert-butoxycarbonyl(Boc)group on N-(1)atom was of geat significance to the efficiency and stereoselectivity.Moreover,the electron-withdrawing groups on both the oxindole scaffold and phenyl ring benefited the catalytic efficiency and enantioselectivity of asymmetric oxidative transformation.Additionally,the electron-donating group improved the enantioselectivies of desired products with erosion of yields.Furthermore,the heteroaryl and alkyl groups were also well tolerated in this enantioselective oxidation transformation.Conclusion:In summary,an expeditous,enocomic and efficient methodology with(1-S)-(+)-10-camphorsulfonyl oxaziridine as the optimal oxidant was developed for the assembly of various densly functionalized enantiopure(S)-3-substituted-3-hydroxy-oxindole derivatives in the presence of cheap and commercially available triethylamine.This organocatalytic transformation featured the operational simplicity,high reation rate,no metal contamination,easy work-up and excellent enantioselectivities.Furthermore,the established enantiopure(S)-3-substituted-3-hydroxy-2-oxindole library could be further evaluated by the biological activity assay,resulting in opening up a new avenue to innovative drug discovery.