Total Syntheses Of Pyrrole-type Stemona Alkaloids And Discovery Of Anti-Alzheimer’s Hits Based On A New Method For Pyrrole Synthesis

Stemona alkaloids possess complex structures and have various activities,and there are many reports on their insecticidal activities.Studies have shown that their insecticidal activity is related to the inhibition on cholinesterase,and cholinesterase inhibitors are the main first-line drugs for the treatment of AD,therefore,it is expected to find lead compounds against AD from Stemona alkaloids.Currently,most of researches mainly focus on the syntheses of pyrrolidone-type alkaloids,while research on the synthesis and biological activity of pyrrole-type alkaloids is rare,which is limited by the lack of efficient synthetic methods to construct the pyrrole ring.Most of the reported strategies to construct the pyrrole ring involve the use of multicomponent reactions,and the compatibility of reagents,catalysts,solvents,and temperature etc.in different sequential steps and the issues of selectivity should be attached with great importance,which make it difficult to be applied in building the pyrrole ring of complex natural products.In view of the structural correlation and synthetic status of Stemona alkaloids,herein we developed a new method for pyrrole synthesis,which could not only be applied in the syntheses of generally substituted pyrroles,but also be used to accomplish the transformation of pyrrolidone-type to pyrrole-type Stemona alkaloids,to further promote the collectively total syntheses of natural products and provide chemical new entities for drug discovery.To be specific,this thesis mainly consists of the following parts:Part 1: synthetic methodology development for the synthesis of the core skeleton of pyrrole-type Stemona alkaloids.In view of the currently synthetic status of Stemona alkaloids and the advantages and disadvantages of synthetic methods toward pyrroles,we choose γ-hydroxypyrrolidone as the starting material,resorted to the deoxygenation of Lawesson’s reagent,and developed a new method of Lawesson’s reagent promoted deoxygenation of γ-hydroxypyrrolidone for the syntheses of pyrroles.Considering that the net result of this reaction is that the hydroxyl and carbonyl groups are respectively converted to a double bond,we then applied this strategy to the deoxygenation of succinimides to render pyrroles.In this reaction,92 examples were reported with yields up to 94%,and multiple functional groups were compatible.This method provided a new strategy for the synthesis of substituted pyrroles.Part 2: Total syntheses of natural products stemoamide,parvistemonine A,3-nbutylneostemonine,10-epi-3-n-butylneostemonine and isomer(E)-3-nbutylneostemonine.By resorting to the new method we developed in Part 1,the transformation from the key intermediate of the pyrrolidone-type 5/7/5 skeleton to the pyrrole-type 5/7/5 skeleton was accomplished.On this basis,the aldehyde group was introduced through Vilsmeier-Haack reaction,the n-butyl side chain was introduced through Wittig reaction and reductive hydrogenation,and natural product parvistemonine A was asymmetrically synthesized for the first time.Next,the lactone ring was opened through reduction reaction.After a series of functional group transformations,the resulting aldehyde group reacted with the nucleophilic fivemembered ring,followed by boron trifluoride ether and Martin’s sulfurane-promoted ring closing reactions.At this point,the first total syntheses of natural products 3-nbutylneostemonine and its isomer(E)-3-n-butylneostemonine was accomplished.However,potassium carbonate could not promote the direct epimerization of C10-Me in 3-n-butylneostemonine to render 10-epi-3-n-butylneostemonine.Part 3: in vitro anti-AD activity studies of synthesized pyrroles and related natural products.By evaluation of the activity of cholinesterase,compounds 2as,2at,and 2aab showed selective inhibition against butyrylcholinesterase(eq Bu Ch E);and enzyme kinetic studies and molecular docking revealed the mixed competitive inhibition of 2at on Bu Ch E.In studies of neuroprotective activity,antioxidant activity,metal chelation study,and prediction of drug-likeness,compound 2at presented weak protective activity on HT22 cells and compound 2aab has certain metal chelating activity.This study has revealed a kind of skeleton with selective Bu Ch E inhibitory activity,neuroprotective activity,or metal chelation.