Synthesis Of Cyclobutene-type Homoisoflavones

Cyclobutene-type homoisoflavone are belong to the flavonoids natural products.They have novel and unique structures with more than twenty members have been isolated and found have antiinflammation bioactivities,but its asymmetric synthesis and further biological activity studies are rarely reported.The racemic synthesis method of the core skeleton benzocyclobutene has been reported,but the asymmetric synthesis method is limited.Based on its biological source and structural characteristics,this thesis explores a general and efficient method for the synthesis of such natural products.The content of this thesis is divided into four parts:The first part introduces cyclobutene-type homoisoflavone compounds,including the research background and significance,plant source and the structure summary of 20 cyclobutene-type homoisoflavones;a review of its biogenic synthesis research,classic homoisoflavone synthesis strategy,and preparation methods of racemic/asymmetric benzocyclobutene.The main content of the second part is to explore the synthesis of natural cyclobutene-type homoisoflavone 1,including the following:1)Constructing the benzocyclobutene through semi-pinacol rearrangement as the key reaction was tried.This route commenced from 3,4-dimethoxyphenylacetic acid and the cyclopentene intermediate was prepared in 7 steps which was further optimized into 5 steps,however this strategy was halted due to the failure of synthesis pyran ring.2)Several reactions through bio-inspired strategy to construct benzocyclobutene was also explored.The corresponding homoisoflavone precursors were prepared through established synthetic route,but four-membered formation through intramolecular dearomatization,attacking p-benzoquinone intermediates or capturing carbocations all turned out to be unsuccessful.The main content of the third part reported the first asymmetric total synthesis of the natural cyclobutene-type homoisoflavone 1 through ester hydrolysis mediated by PLE enzyme and C-H activation catalyzed by Pd catalyst as the key reaction.This strategy was used to synthesize five natural product analogs.Through the anti-inflammatory activity test,it was found that compound 4C showed a 98.2%inhibitory effect on LPS-induced NO production in microglia BV-2 at 20μM,and its IC₅₀ value was 11.01μM,which was equivalent to the control agent quercetin.