Organocatalystic Asymmetric Synthesis Of Dihydroquinazolinones And Chromans Derivatives

Heterocyclic compounds widely exist in the nature with widespread biological activities,which attract scientist's interests significantly.Dihydroquinazolinones and chromans derivatives play important roles on medicinal chemistry.This dissertation mainly foucuses on the asymmetric synthesis of potential bioactive dihydroquinazolinones and chromanes derivatives promoted by organocatalysts.We have developded enantioselective addition reactions of cyclic trifluoromethyl ketimines allowing direct access to trifluoromethyl dihydroquinazolinones and chiral secondary amine catalytic asymmetric[4+2]cycloaddition of in situ generated ortho-Quinone Methides(o-QM)with aldehydes.This dissertation consists of three parts.The first part is introduction.N-and O-containing heterocycles which have various structures and diversity of properties are two major classes of heterocycles and widely used in medicine,pesticides,dye,materials and other fields.Chiral dihydroquinazolinones and chromanes have been synthesized for their physiological activity,which promotes the rapid development of asymmetric organocatalysis,especially for chiral hydrogen bond donor catalyst and chiral amine catalyst.Asymmetric organocatalysis synthesis of chiral heterocyclic compounds was one of heated topic in recent research.In the second part of dissertation we focuses on the enantioselective addition reactions of cyclic trifluoromethyl ketimines.Dihydroquinazolinones are a class of intriguing molecules,displaying various bioactivities,including anti-obesity and antiviral.Chiral dihydroquinazolinones DPC 961 and DPC 083,featuring a trifluoromethyl group on the chiral quaternary carbon center,are potent HIV nonnucleoside reverse transcriptase inhibitors.A highly enantioselective aza-Friedel-Crafts(aza-F-C)reaction of cyclic trifluoromethyl ketimines and naphthols/phenols was developed with fluorenyl-substituted quinine-squaramide as catalyst.This protocol enables direct access to biologically important chiral trifluoromethyl dihydroquinazolinones with up to 99%yields and up to 99%ee's.N-substituted-free ketimines can also undergo the aza-F-C process smoothly with excellent yields,and even better asymmetric induction than their N-protected counterparts in most cases.The mild conditions and excellent substrate tolerance of this approach will facilitate many potential applications.In addition,with alcohols as the new nucleophiles,we have disclosed an efficient enantioselective addition to trifluoromethyl dihydroquinazoline derived ketimines to give chiral N,O-ketals in good to excellent yields and with good to high enantioselectivities.The process is effectively catalyzed by a bifunctional chiral quinine-thiourea catalyst.Moreover,a procedure by combining the asymmetric addition with an intramolecular cyclization process has been realized for facile access to new interesting bicyclic trifluoromethyl-containing 1,3-oxazinanes with high enantioselectivities.We also found sevaral compounds inhibite the activity of HeLa cell to a certain degree by preliminary trial.The third part of this dissertation describes a secondary amine-catalyzed[4+2]cycloaddition of in situ-generated o-QM with aldehydes.The skelecton of chromanes and dihydrocoumarins are featured in a number of biologically interesting natural products.Firstly,we have developed pyrrolidine promoted[4+2]annulation of aldehydes and o-QM.By further oxidation with PCC,this approach can facile access to potential bioactive dihydrocoumarins in moderate to good yields.Furthermore,the application of chiral secondary amine catalyst in this process can furnish optically active dihydrocoumarins with up to 92%ee.Secondly,chiral secondary amine catalytic asymmetric[4+2]cycloaddition of in situ oxidation generated o-QM with aldehydes has been realized.A series of 2-hydroxychromans with high yields and enantioselectivities could be obtained by this protocol.In this process,2-methyl-1-naphthol derivatives was firstly used as o-QM precursors formed by unactivated MnO2,Under mild condition,the compatibility of the highly reactive o-QM with a nucleophilic amine catalyst have been resolved.The potential for unproductive behavior of transient o-QMs such as dimerization was greatly slashed under the reaction conditions.This method also applies to 2-methyl-1-phenols derivatives.Many transformations of 2-hydroxychromans have been carried out to obtain interesting compound such as chromans and dihydrocoumarins.According to the approach,we have synthesized chiral Rhinacanthins analogue with antitumor activity in five steps.