Benzyne 1,2,3-Trisubstitution Via A Tandem C-C σ-Bond Insertion And Photo-Nazarov Cyclization: Application To The Synthesis Of (±)-5-epi-Asterogynin B

There are many polysubstituted benzenes in natural products.For example,natural products Asterogynins isolated from endophytic fungus in costa rican,have potential biological activities for the drug target Pf Hsp86 for malaria treatment.The core structure of Asterogynins is [6,5,6]-hydrofluorenone containing C-C bonds in several consecutive positions of the benzene ring.Therefore,the efficient synthesis of benzo-polycyclic structures with continuous carbon-carbon bonds is a research focus of synthetic chemists.As a highly reactive intermediate,benzyne is widely used in the synthesis of drugs,active natural products,and functional materials.Our group has been committed to the study of aryne multi-functionalization,breaking the limitation that single benzyne can only realize ortho-difunctionalized.In order to efficiently assemble multiple substituents arenes,our group developed two feasible research strategies: 1)using the self-created domino aryne precursors(TPBT,TTPM)to realize multi-functionalization;2)combining single aryne reactions with the following C-H functionalization.In recent years,our team developed a number of protocols that allowed for single benzyne polyfunctionalization from allyl sulfoxides to simultaneously incorporate a C-O,C-S,and C-C bond.Regiospecific anionic [3,6]-or [4,5]-rearrangement occurs on the generated sulfonium intermediate after the insertion of benzyne into the S=O bond of the allyl sulfoxide.In view of the previous successful experience,we explored other tandem reactions that can be compatible with single benzyne reactions to construct multiple chemical bonds in one operation.A benzyne 1,2,3-trifunctionalization process was then successfully developed,which proceeds through a tandem benzyne insertion into the C-C bond of σ-ketone esters and a photo-Nazarov cyclization.Three C-C bonds were generated on the consecutive positions of a benzene ring with the concomitant construction of a [6,5,6]-tricyclic system.In this transformation,UV light was found to be orthogonal to the benzyne insertion step and could only promote the subsequent photo-Nazarov cyclization.In addition,a tandem C-C bond insertion,photo-Nazarov cyclization,and 1,3-silyl shift process was discovered as well.Mechanistic studies disclosed that the enolate intermediate generated in the C-C bond insertion step could promote the successive photo-Nazarov reaction.At last,this protocol was applied to the synthesis of(±)-5-epi-asterogynin B.In summary,the second research strategy,which may have employed a single benzyne to create several substituted benzene rings,is usefully extended by this study.