Palladium-Catalvzed Site-selective ?-C(sp~3)-H Alkenvlation And Synthetic Studies Toward The Mannopeptimycin ?

Transition-metal-catalyzed C-H bonds activation has recently emerged as the most powerful and straightforward strategy for the synthesis of drugs and complex natural products.However,site-selective functionalization of unactivated aliphatic C-H bonds remains a fundamental and ongoing challenge in organic chemistry.First,alphatic C-H bonds are unreactive because of their high bond energy and low acidity.Second,alphatic compounds contain many similar C-H bonds.To address these problems,one of the most successful strategies to achieve the site-selectivity is the use of directing group,and chemists have also developed various transition metal catalysts.Palladium-catalyzed C(sp~3)-H bonds activation has become the most important part of C-H bonds activation,most of these reactions proceed through a kinetically favored five-membered palladacycle over other cyclopalladation ways,leading to the selective cleavage of ?-C(sp~3)-H bonds.Only scattered examples of 8-C(sp~3)-H functionalizations through a six-membered palladacycle have been achieved when the y-C(sp~3)-H bonds were sterically or conformationally less accessible.Therefore,site-selective functionalization of 8-C-H bonds in the presence of more accessible y-C-H bonds has become a challenge.On the other hand,antibiotics are the third highest selling drug in the world.But due to the abuse of antibiotics,many bacteria that cause human disease have already produced drug-resistance.Mannopeptimycins is a new type of glycopeptide antibiotic with important physiological activity,which extracted from the fermentation product of Streptomyces hygroscopicus.It is highly active against Gram-positive bacteria and is expected to play an important role of treatment in severe infection caused by resistant Gram-positive bacteria.However,the samples currently used for the study are mostly extracted from the fermentation products,and the synthesis of its analogues is semi-synthetic,limiting the study of its biological activity.Therefore,the total synthesis of Mannopeptimycins is of great significance.This dissertation is mainly focused on palladium-catalyzed site-selective ?-C(sp~3)-H alkenylation and synthetic studies toward the Mannopeptimycin s,which includes:1.Palladium-Catalyzed Site-Selective ?-C(sp~3)-H AlkenylationThe first palladium-catalyzed site-selective alkenylation of 8-C(sp~3)-H in the presence of more accessible ?-C(sp~3)-H has been developed,using picolinamide(PA)-protected isoleucine methyl ester as the model substrate and internal alkynes as the alkenylation reagent.A wide range of functional groups are tolerated,and the PA group could be removed under mild conditions by using a three-steps,one pot protocol.Then the unique protocol can be applied to the synthesis of chiral piperidines.Moreover,mechanistic insights have been conducted to elucidate the origin of the unusual site-selectivity,which is linked to the use of alkyne reactant via a selectivity-determining migratory insertion.2.Synthetic Studies toward the Mannopeptimycin ?The asymmetric synthesis of the orthogonally protected D-?-hydroxyenduracididine(D-?hEnd)and L-?-hydroxyenduracididine(L-?hEnd)in 7 total steps from Garner's aldehyde is described.The key steps are:(i)substrate-control asymmetric Aldol reaction;(ii)guanidinylation;(iii)Mitsunobu reaction caused cyclic guanidine formation.The newly formed two chiral centers in D-?hEnd and L-?hEnd are both controlled by the asymmetric Aldol reaction step.In addition,unnatural amino acid L-MePhe can be synthesized by palladium-catalyzed 8-aminoquinoline-directed C(sp~3)-H alkylation or arylation.At the same time,other amino acid fragments L-Ser,Gly,D-Tyr and monosaccharides and disaccharide fragments are synthesized orthogonally,and the amino acid fragments are preliminarily ligated to obtain dipeptides.These work have laid a solid foundation for the total synthesis of Mannopeptimycin ?.