Synthesis Of Novel Dipeptede Of Pyrazinylformyl-L-Phenylalanyl-L-Valnit Rile And Pyrazolo[5,1-a] Isoquinolines With Heterocyclic Ketene Aminals As New Ligands

Peptide plays an important role in the biological body and influences manyimportant physiological functions in the organism. The use of peptides in the field ofbiology and pharmacy is becoming more and more important, alongside thedevelopment of biological technology. many peptide-based proteins have theoutstanding importance in the process of the life，such as DPP-IV inhibitors,which cani nhibit the activity of the body dipeptidyl peptidase IV, protect intestinal insulin fromdegrading，improve glucose tolerance and increase the sensitivities of insulin，whereas,Aminopeptidase N is the one of membrane-bound Zinc-dependent exopeptidase, and itis reported that APN has played an important role in the invasion and metastasis ofmaliganant tumor cells in vitro．Relative science and technology fields such as medicinal chemistry, molecularimmunology, zoology, agriculture and food industry, require a large number of variousstructures of peptide analogues in order to study the relationship of the structure andactivity. However, it faces the great difficulties in separating peptides from natralsources, therefore, synthesis of peptides become one of the most important directions inorganic chemistry．Oligopeptides have been concerned commonly by chemists recently because oftheir strong bioactivity and activity as drug or precursor of drug. The key issue isactivation of carboxyl group for the formation of amide． Especially, to avoidracemization is the vital problem in peptide synthesis．After the modification of the existed dipeptide drugs, two novel dipeptides ofpyrazinylformyl-L-phenylalanyl-L-valnitrile compounds were synthesized by combination use of mixed-carbonic anhydride method and catalytical hydrogenationthrough a six-step reaction from Cbz-L-valine, their structures were characterized by IR,1H NMR,13C NMR and HR-MS. The synthetic procedures have been optimized.Isoquinolines and pyrazolo[1,5-a]pyridines have been recognized as twoprominent types of privileged heterocyclic scaffolds, which have shown to interactwith a variety of biologically receptors. Hence, the synthesis of pyrazoloisoquinolineincorporating two privileged heterocycles could be a valuable strategy to discovernew bioactive compounds. However, the synthesis of pyrazolo[5,1-a]isoquinolineshas received scant attention with only Wu and co-workers outlining.Ullmann reactions are always the universal, easy method in constructing C-C,C-N, C-O, C-S(Se), C-P bond etc. since it was found in1901. These couplingreactions provide us convenient way to approach desired heterocyclic compounds.During the development of Ullmann reactions， Ligand identification has played animportant role in improving both the efficiencies and scope. Although variouswell-known and excellent N,N-, N,O-, O,O-ligands have been reported, but the use ofheterocyclic ketene aminals (HKAs) as new ligands for the copper-catalyzed couplingreactions has not been disclosed. we felt that O,O-or N,N-compounds--heterocyclicketene aminals would serve as appropriate copper-catalyzed ligands, enhancing thechelating ability of the two O atoms with a copper ion by forming a stablesix-membered ring, to allow us to achieve a mild and general procedure for thesynthesis pyrazolo[5,1-a]isoquinoline derivatives.we report here the use of HKAs as new ligands and β-(2-bromoaroyl)thioacetanilides as building blocks to develop an alternative and concisecopper-catalyzed tandem reaction for the synthesis of pyrazolo[5,1-a] isoquinolines.The structures of all the target compounds were confirmed by IR,1H NMR,13CNMR and HRMS, and the plausible mechanism was also presented.