Study On Amide CN Bond Activation And Total Synthesis Of Ent-kaurane-type Diterpenes Based On Free Radical Chemistr

In recent years,radical-based coupling reactions have gained rapid development with unique chemical reactivity relative to traditional transition metal-catalyzed coupling reactions.For example,the free radical-based cross-reductive coupling reaction between two electrophiles,and oxidative cross coupling between two nucleophiles.With the indepth study of coupling reactions involving free radicals,the application of free radical chemistry in organic synthesis is also increasing.However,the application in the total synthesis of complex natural products is very challenging.The main reasons are:(1)Many methods for generating free radicals are not suitable for complex substrates;(2)The predictability of radical reactions on complex substrates is poor and difficult to control due to the high reactivity of free radicals.In this thesis,oriented to the total synthesis of natural products,two radical-based synthesis methodologies were developed:(1)Nickel catalyzed reductive cross-coupling of easily-prepared acyl-imidazolides with aryl/alkyl bromides to form ketones via amide C-N bond activation,and successfully applied this method to the synthesis of a furan diterpene and the precursor of drug Tolcapone;(2)It was found that TEMPO can regulate the process of free radical[3+2]cyclization reaction,and successfully constructed the[3.2.1]bridged ring structure in the molecular skeleton of entkaurane and beyerane diterpenoids.Using this strategy,11 different oxidation states tetracyclic diterpene natural products with[3.2.1]bridged ring structures were synthesized.Based on this,this thesis is divided into two parts.The first part introduces the nickel-catalyzed reductive cross-coupling reaction of acyl imidazolides with alkyl/aryl bromides:We found that primary,secondary and tertiary alkyl acyl imidazolides can be coupled with various aryl bromides,alkyl bromides as well as heteroaromatic bromides to form ketones in moderate to good yields under the reaction conditions of NiI2 as catalyst,bipyridine as ligand,Zn as reducing agent,ZnBr2 as additive,DMF as solvent,and reacted at 60℃ for 20 hours.The detailed mechanism study found that the sterically less-hindered acyl imidazolides undergo C-N bond cleavage by singleelectron transfer,whereas sterically encumbered acyl imidazoles go through C-N bond cleavage via oxidative addition(two-electron process).The second part introduces the TEMPO-mediated free radical[3+2]cyclization reaction to construct the[3.2.1]bridged ring structure in the ent-kaurane and beyerane diterpenoids molecular frameworks.There are multiple chiral centers on the[3.2.1]bridge ring,and the spatial structure is crowded,which is the difficulty in synthesizing these diterpene natural products.We found that using homoallyl tertiary alcohol methyl oxalate as raw material,Zn as reductant,PBI as ligand,DMA as solvent,under the action of TEMPO,Lewis acid MgCl2 and TMSCI,reacted with benzyl acrylate at 40℃ for 16 hours gave the bicyclo[3.2.1]octane motif in moderate yield.Detailed mechanistic studies revealed that TEMPO plays a key role in regulating the radical[3+2]cyclization reaction.Under this reaction system,TEMPO was quickly reduced to Zn(TEMPO)2,and then selectively reacted with less steric hindrance free radical intermediates to obtain the target product via SH2 pathway.Using this strategy,we successfully synthesized 10 ent-kaurane and one beyerane diterpenoids.