Methodological Study On The Construction Of Heterocyclic Skeleton Basing On The Trapping And Tandem Strategies

Heterocyclic ring(oxidized indole,tetrahydrofuran,etc.)is a kind of potential bioactive skeleton,which is widely existed in natural products and drugs.In the latest global sales of top 10 listed drugs,there are 8 cases.So,the pursuit of its efficient,green,atomic economy synthesis method is the goals of many chemists.The diazo compound is an important component in organic chemistry;according to their specifical reactivates,scientists classified it as an independent subject,named diazo chemistry.Based on electrophilic reagents can trape the ylide or zwitterionic intermediates forming by diazo compounds and hydroxyl,amino,indole or other our compounds in the catalyzing of transition metals,our group have maken many advanced achievements and these compose an important subclass of diazonium chemistry--multicomponent trapping reaction.However,for the participation of electrophilic reagents,the range is not large enough,mainly confined to imines,aldehydes,ketones,nitroenes and so on.As an important component of the trapping reaction,the intramolecular trapping reaction is undoubtedly a very efficient strategy for the construction of complex heterocyclic compounds containing complex substitutions.Our group has also reported some examples.However,for the active intermediates of MBH carbonate or the low active allenoate(?,?-unsaturated ester)serving as electrophile,that trapping reaction has not been reported so far.Taking these complex and diverse functional groups into account,if they are introduced into the heterocyclic compounds in their entirety,it would provide numerous shortcuts for the derivatization of the late compounds and the synthesis of more types of active compounds.In this paper,we first applied the above-mentioned electrophilic reagents to this type of reaction and complete the efficient construction of indole and multi-substituted tetrahydrofuran heterocyclic compounds,within possible application value.In the preface,we briefly introduce the contents of diazo,metal carbene,trapping reaction,MBH carbonates and allenoates.At the same time,according to the reactivities of MBH carbonates and allenoates,we put forward our research schemes.In the second part,we validated the designed reaction between zwitterions and intermediates formed in situ by MBH carbonate.This nucleophilic substitution reaction is indeed working in moderate yield,with moderate to good enantioselectivity,and exellent diastereoselectivity.But after the mechanism study,we confirmed this reaction as an tandem reaction:The Pd complex,APC,catalyzed the in situ C-H insertion reaction.At the same time,the ?-ICD nucleophile attacked the MBH carbonate to generate the ammonium cation intermediate and release the tBuO anion as a strong base.Finally,the oxindole nucleophile produced via tBuO-mediated deprotonation and with the help of palladium attacked the ammonium intermediate from the Re face to provide the observed product.In the third part,we first introduced the allenoate to the multicomponent trapping reaction,and completed with high diastereoselectivity.For ?,?-unsaturated compounds,the electrophilic activity of aldehydes,ketones and imines is significantly higher than that of esters.We applied the strategy of intramolecular trapping to improve its reactivity,affording the tetrahydrofuran with exocylic bond.At the same time,the mechanism of Michael-type intramolecular capture was confirmed.Unfortunately,followed by several asymmetric investigations,we could only produce up to 60%of the enantiomeric excess.