Study On Enantioselective PEDA Reaction And Its Synthetic Application

Chemical synthesis of complex molecules with chiral stereogenic centers and three-dimensional skeletons has been a significant topic in organic synthesis.As for the bond-forming reaction,it is very important to control the reactivity and the stereoselectivity.This thesis focuses on the development of asymmetric photoenolization Diels-Alder reaction（PEDA reaction）promoted by chiral Lewis acid,and its application to the total synthesis of natural napyradiomycins.Yang reported the first PEDA reaction in 1961,and o-methyl aryl ketones as substrate were excited by ultraviolet light to form a highly active electron-rich diene,which was then trapped by the electron-deficient dienophile,resulting in a Diels-Alder reaction.This reaction can construct a more complex polycyclic skeleton in one step through simple fragments,and the step-and atom-economy are high.Therefore,chemists continue to expand the practicability of this reaction,and also conduct the studies to control its enantioselectivity.However,for the PEDA reaction using large steric hindrance and multi-substituted dienophiles,how to control its reactivity and stereoselectivity are unresolved challenges.On the basis of the racemic PEDA reaction promoted by Ti（Oi-Pr）₄ developed by our group recently,we successfully realized the asymmetric PEDA reaction of tri-and tetra-substituted dienophiles by adding TADDOL-type chiral ligands.We found that the diene species in-situ formed under UV light and the large sterically hindered dienophile undergoes cycloaddition with high efficiency and enantioselectivity through the coordination of dinuclear Lewis acid containing a chiral ligand.In the process,the ligand acceleration effect and the additives can reduce the racemic background reaction rate,thereby increasing the ee value of the product and reducing the loading of chiral ligand.As a result,a polycyclic-ring skeleton containing a single or continuous quaternary carbon center can be constructed in one step,which provides a new solution for the synthesis of related natural products and drug molecules.In addition,through the mechanism studies,we also found that for the dienophiles bearing a large benzoyl moiety,exo cycloaddition is the predominant pathway in the presence of ligands.On the basis of the newly developed asymmetric PEDA reaction,we conducted the total synthesis of napyradiomycin natural products.Under standard conditions,a tricyclic skeleton containing continuous quaternary carbon centers was successfully constructed through the asymmetric PEDA reaction,and one of them was an oxa-quaternary carbon center.Next,the sterically hindered benzylic oxidation was realized through the Barton reaction,and the molecular skeleton of the unsaturated ketone structure was generated through the oxidative rearrangement reaction.Finally,the side chain was connected by the Wittig reaction,and the all-carbon skeleton of napyradiomycins was built.In addition,we have also studied the one-pot oxidation of aldehyde substrates by tandem decarboxylation and chlorination reactions,as well as the allylic halogenation of unsaturated ketones,laid the foundation for the synthesis of such natural products.