Acid-catalyzed Rearrangement Of Cyclopropene Methanol Derivatives And Its Application In Total Synthesis Of Natural Products

As important skeleton units,γ-alkylidene butenolides and benzofulvenes are existed widely in natural products with important biological activities,and they are also important organic synthesis intermediates.It has been widely used in the synthesis of multi-substituted organic intermediates with complex structure.Studies have shown that the natural products withγ-alkylidene butenolides and benzofulvenes are existing in nature have very good biological activities,such as anticancer,antiviral,anti-inflammatory,antibacterial and so on.Therefore,it has attracted much attention to carry out extensive research on organic synthesis methodology for these two kinds of structures!In this paper,an unreported and novel synthesis route is designed that based on the ring-opening reaction mechanism of cyclopropene structure,which is important scientific significance for the rapid and efficient construction of these two structures and their related natural products.At the same time,it also lays the foundation for the creation of a rich library of analogs and further screening of drug activities.Cyclopropene compounds have extremely high ring tension energy and alkyne-like reaction characteristics,so they are ideal candidate substrates to realize the cleavage of C-C bonds.The release of ring tension energy provides the main driving force for the breaking of C-C bonds,and the resulting highly active intermediates provide an important basis for subsequent transformations,thus resulting many interesting transformations.In this paper,we mainly used cyclopropenyl methanol derivatives as substrate structure,and through the screening of synthesis conditions,we found that using toluene as the reaction solvent,cyclopropenyl methanol derivatives were catalyzed by BF₃·OEt₂,firstly remove the hydroxyl group and then induce cyclopropene bond breaking and ring opening,then decompose to form diene-positive-ions,finally,γ-alkylidene butenolides and benzofulvenes can be constructed by isomerization rearrangement in one-pot.In addition,we was continuously changed the substrate structures to investigate the effects of different substituents,electronic effects,site resistance effects,and reaction temperature on the total yields of these two structures and the changes of the ratios of the two and it was found that the synthesis method has wide substrate universality,and the total yields of the two types of compounds can reach 68%～99%;under the reaction condition of low temperature（-40℃）,it is beneficial to the formation ofγ-alkylidene butenolide structure,and generally has a high formation ratio（γ-alkylidene butenolide:benzofulvene=1.8:1）;under the condition reaction of high temperature（>rt）,the proportion of benzofulvene structures synthesized is increased（γ-alkylidene butenolide:benzofulvene=1.3:1）,and the more electrically enriched the substrate structure,the more favorable the formation of this structure;relatively speaking,the para-substituent is beneficial to the formation ofγ-alkylidene butenolide structure,while the ortho-substituent is beneficial to the formation of benzofulvene structure.In order to highlight the superiority of this synthetic method,the total synthesis of anmindenol A（1）,which is a natural product of benzofulvene,was successfully achieved by using this reaction strategy in four steps,but the overall yield was only 5%.The reason is that the designed substrate structure using this reaction strategy brings more isomersby applying this reaction strategy.Therefore,this reaction strategy will certainly be greatly applied in the total synthesis of such natural products in the future experimental research through the reasonable substrate structure design.