Study On Phosphonyl Pyridazines?Oxirane And Pyrazoline Based On ?-Diazophosphonates

Heterocyclic compound is an important member in organic chemistry,which is the key target that chemists have been studying because of its diversity and effective biological properties.The importance of heterocyclic compounds is not only reflected in biology and industrial applications,but also in the development of human society.Most pharmaceuticals are heterocyclic compounds that mimic natural products with biological activity.Therefore,the development of new and efficient methods for the synthesis of heterocyclic compounds is of great significance.Organophosphorus compounds are of great research value as biomolecules,metabolic probes,peptide analogues,antibiotics,agents and other biologically relevant molecules.In the study of biological and pharmaceutical chemistry,phosphonate often acts as isosteres of carboxylates,can affect the biological process of enzymes,become a class of important synthetic derivatives.The organophosphorus compounds to which a heterocyclic moiety is attached often display greater important biological activities.?-diazophosphonates bear both diazo and phosphonate groups,on the one hand can be used as a nucleophile in the asymmetric reaction,is an efficient method to obtain chiral diazo and phosphonate derivatives;on the other hand,?-diazophosphonates can also be used as important carbene precursors,with which varieties of chemical transformations,such as X-H(X= C,N,O,S,Si,etc.)insertions,cyclopropanations and 1,2-hydrogen migration reactions can be proceeded under transition metal catalysts,providing effective means for the construction of varieties of pharmaceuticals,natural products and biologically active molecules.Furthermore,Diazophosphonates,acting as 1,3-dipole,can be used to construct azocyclophosphonate derivatives directly and efficiently though asymmetric cyclic addition reactions with a series of dipolarophile.This thesis describes the construction of three classes of chiral organic phosphonylheterocyclic compounds based on the asymmetric reaction involving ?-diazophosphonates as synthons:Part I: A novel methodology for the construction of chiral phosphoryl 1,4-dihydropyridazine derivatives has been developed.A series of catalysts with a tertiary amine derived from the cinchona alkaloids was designed and synthesized to catalyze the asymmetric allylation bettwen ?-diazophosphonates and MBH carbonates.The products were obtained with good yield and enantioselectivity,which undergoe intramolecular 1,3-dipolar cycloaddition and rearrangement under the catalysis of Lewis acid,to give the chiral phosphoryl 1,4-dihydropyridazine derivatives with potential biological and pharmaceutical activities.Part II: The first asymmetric nucleophilic addition of ?-diazophosphonates to ?-ketoester was successfully carried out by designing bifunctional thiourea catalyst.A methodology was established to access a series of chiral ?-diazo-?-hydroxyphosphonate derivatives containing various functional groups in high enantioselectivities and yields.The resulting products could be further transformed into chiral tertiary ?-hydroxyphosphonate and ?-halogenated phosphonyloxirane derivatives,especially ?-fluoride analogues.Part III: Quaternary ammonium salt phase transfer catalysts derived from the cinchona alkaloids and BINOL was used to catalyze the asymmetric 1,3-dipole cycloaddition reactions of ?-diazophosphonates and dipolarophilic alkenes which was obtained by the Knoevenagel reaction of benzaldehyde and malonate,series of multifunctional chiral phosphonazopyrazoline derivative was synthesized.