| Natural products provide a rich source for medicinal molecules.Preparation of bioactive natural products and natural product-like molecules plays an important role in drug discovery and chemical genetics study.Diversity-oriented synthesis?DOS?is the most widely used strategy to efficiently synthesize libraries of skeletally diverse natural product-like molecules.The first chapter of this dissertation detailedly introduces the definition and features of DOS and commonly utilized strategies in DOS.Furthermore some representative DOS examples were reviewed,which mainly focused on the application of the Build/Couple/Pair three-phase algorithm.However,DOS was rarely applied to natural product total synthesis.In order to construction of both natural products and their skeletally diverse analogues,we introduce a novel Build/Couple/Pair synthetic approach inspired by the functional group pairing patterns in natural products.In the second chapter,this approach was fully illustrated,which was applied to the diversity-oriented synthesis of skeletally diverse Lycopodium alkaloids.Starting from commercially available 4-aminobutan-1-ol,10distinct complex scaffolds including 4 natural products,?+?-serratezomine A,?-?-serratinine,?+?-8?-hydroxyfawcettimine and?-?-lycoposerramine-U were synthesized within seven to nine steps by pairing the functional groups within a multifunctional intermediate.Tuberculosis is a severe infectious disease,since it is second only to AIDS as a leading cause of death from infectious disease.Through cell-based phenotypic screening,our collaborator Lixin Zhang group identified a potent anti-tuberculosis gilvocarcin family C-aryl glycoside natural product chrysomycin A.The third chapter of this dissertation focuses on the total synthesis and diversification of chrysomycin A.The first total synthesis of chrysomycin A has been accomplished in 11 steps?longest linear sequence?from commercially available 1,8-naphthalenediol.Key to success included a regioselective C–H borylation facilitated by a removable blocking group to realize the regioselective functionalization of an unsymmetric naphthalenediol mono-ether,a K2S2O8-AgNO3 mediated C–H oxygenation to afford the critical lactone,and a stereo-and regioselective late-stage C-glycosylation to realize the C4-functionalization.Gram-scale preparation of the aryl part was accomplished by using this synthetic method,providing enough material for derivatization.Eventually,diversification of chrysomycin A was achieved at several sites,including the synthesis of another member of this family natural product polycarcin V.Through structure-activity relationship study,a new compound that showed better anti-bacterial activity than chrysomycin A was found. |
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