Development And Application Of Pd(?)-catalyzed C–H Alkylation Reaction With Epoxides

Epoxides as coupling reagents and C2 synthons have been widely used in synthetic chemistry.Since the first report on transition-metal-catalyzed C-H alkylation reaction using epoxides as coupling reagents in 2015,various alkylation reactions based on directing group strategy or Pd/NBE cooperative catalyzed cascade reactions involving epoxides have been continuously developed.This doctoral thesis focuses on the development and application of Pd(?)-catalyzed C-H bond activation reaction involving epoxides as coupling reagents.Which includes the development of a new method for the synthesis of isoquinolones,and the application of epoxides in the total syntheseis of two kinds of natural products containing 3,4-dihydroisocoumarins.The main research contents are shown as follows:1.An efficient Pd(?)-catalyzed cascade reaction of N-alkoxylbenzamides with oxiranes for the synthesis of isoquinolones was developed.With the addition of oxidant and TEA,isoquinolones rather than isochromans were afforded.We proposed that the existence of stronger base may promote the ?-H elimination of Pd-alkoxide to afford isoquinolones.This reaction showed wide substrate scope and the coupling partners were not limited to epoxides containing an adjacent coordinating group.Notably,this coupling reaction was successfully employed in the total syntheses of rupreschstyril,siamine and cassiarin A in an expedient fashion.(?)2.Application of palladium-catalyzed C-H alkylation reaction in the total synthesis of(-)-berkelic Acid.With the chiral 3,4-dihydroisocoumarins synthesized by palladium-catalyzed C-H alkylation with epoxides,we tried to construct the tetracyclic core structure of berkelic acid in one step by using chiral induction strategy.However,the route met with failure due to the non-sequential removal of protecting groups.Thus,we directly used the chiral keto fragment to obtain(-)-berkelic acid,and studied its derivatization and biological activity.Finally,we successfully realized this chiral induction operation via selective removal of the protecting benzyl group and acid promoted isomerization,which provides a solid foundation for the efficient syntheses of(-)-Berkelic Acid and its derivatives.(?)3.Application of Pd-catalyzed C-H alkylation reaction in the total syntheses of twelve amicoumacin-type natural products.By employing the palladium-catalyzed C-H alkylation reaction,the amino fragments of amicoumacins were successfully synthesized in three steps.Meanwhile,the acid segments were obtained by the well-documented asymmetric Mukaiyama aldol reaction and optimized selective oxidation reaction of water-soluble diols.With the application of these new methods,eight of amicoumacin C related natural products and four compounds with the most anti-cancer potential in this family were concisely synthesized.After obtaining these natural products,a preliminary evaluation of their cytotoxicity was performed.The results showed that PM-94128 and Y-05460M-A had strong inhibitory activity against all the selected cancer cell lines,which provided an opportunity for our following in-depth activity research.(?)...