Studies Toward The Total Synthesis Of Natural Product Rubradirin B And Cu Catalyzed Intramolecular C-X Bond Formation Reaction

This thesis is divided into two parts:（1）synthetic studies toward the asymmetric total synthesis of antimicrobial natural product Rubradirin B;（2）copper catalyzed intramolecular C-X bond formation reaction.（1）Rubradirin was isolated from Streptomyces achromogenes var.rubradiris NRRL3061 in 1964.Further investigation resulted in the isolation of Rubradirin B,Rubradirin C and Rubradirin aglycon.Rubradirin exhibits a potent antimicrobial activity against MRSA（MIC=0.125μg/mL）and anti-HIV reactivity.Mechanism studies revealed that rubradirin acted as a selective inhibitor of the initiation factor dependent chain initiation process.Thus,the polypeptide biosynthesis was blocked.Development of new antibiotics was extremely urgent because of the increasing antimicrobial resistance.Total synthesis of natural products and their related structure-activity relationship study help in discovery of more potent,non-toxic compounds.Rubradirins contain unique structural features including a strained,densely functionalized 13-member macrocycle and O-bridge.These four natural rubradirins share almost the same core structure and differs from the configuration at the C7-C8olefin.The unique architecture and potent activity of rubradirin promoted us to study its total synthesis.In this chapter,two strategies towards the synthesis of skeleton were described,1)synthesis of the 15-member macrocycle through intramolecular N-alkylation reaction,then construction of the O-bridge;2)formation of C ring via Lewis acid catalyzed intramolecular olefin-migration/epoxide opening cascade reaction and construction of the C9-C10 bond via NHK reaction.The first strategy proved to be unsuccessful at the end due to the instability of the key 15-member macrocycle in the absence of the O-bridge.Activation of C17 at late stage failed as presumably due to the steric hindrance of tested system.We then turned to construct C ring first.The installation of C17 hydroxyl group through epoxide opening method at early stage paved the way a for novel intramolecular olefin-migration/epoxidation opening cascade reaction.The intramolecular NHK reaction went smoothly and furnished the key13-member macrocycle.Selective oxidation of olefin was achieved via modulation of electron density on ABC ring system.Eventually,we were able to synthesize key intermediate 2-165 which contains all required functional groups in target molecule.We hope to confirm absolute structure of 2-165 through comparison of NMR data with reported compound or X-ray method.The total synthesis of rubradirin B is expected to be completed based on these studies.The structure-activity relationship study will follow after completion of the total synthesis in the hope to find structurally-simplified and more potent derivatives.（2）Copper catalyzed coupling reaction was a powerful tool in organic synthesis,especially in total synthesis of natural products.Rubradirin and hygrocin B contain unusual naphthalene amine part,but limited methods to access these compounds were reported.We herein developed a method to synthesize the ABC ring of rubradirin through a copper catalyzed intramolecular C-O bond formation reaction.In addition,this method could be applied in the synthesis of core naphthalene part of Hygrocin B.This chapter described the method,an intramolecular coupling reaction of compounds3-18,3-20 and 3-22 in presence of CuI and ligand 1,10-phenanthroline at elevated temperature afforded 3,4-dihydro-2H-naphtho[2,3-b][1,4]oxazine-5,10-dione and2,3,4,5-tetrahydro-1H-naphtho[2,3-b]azepine-6,11-dione with good yield.This method has a broad substrate scope and shows no influence on enantiomeric excess of chiral substrate.We synthesized the ABC ring system of rubradirin through this method.At the same time,these new coupling products were evaluated for biological activities,and some compounds showed good antitumor activities(IC₅₀=1.8μM,A549 cells).