A Formal [3+3] Cycloaddition Approach To The Synthesis Of Natural Product Arisugacin E And Trichodermatide C

In this project, we introduce the formal [3+3] cycloaddition approach to thenatural products Arisugacin E and Trichodermatide C synthesis. The formal [3+3]cycloaddition reaction has been investigated for several years in our laboratory.During these years we have not only demonstrated the versatility of the [3+3]cycloaddition reaction but also applied it to the syntheses of several natural products.Mechanistically, this tandem process commences with a C-1,2-addition of6-alkyl-or6-aryl-4-hydroxy-2-pyrones to the iminium salt generated in situ from α,β-unsaturated aldehydes and a secondary amine. A subsequent β-elimination gives1-oxatriene intermediates, which culminates a Knoevenagel-type condensation, andthe sequence concludes with a6π-electron electrocyclic ring-closure to give2H-pyrans.Arisugacins were isolated from Penicillium sp. Fo-4259and identifed as aninhibitor of acetyl-cholinesterase (AChE), thereby possessing signifcance intreatment of dementias. In this project, the substrate2-methyl-1,3-cyclohexanedioneundergoing methylation, Grignard reaction, reduction and intramolecular Diels-Alderreaction to get the intermediate triol. After oxidation, the formal [3+3] cycloadditionof the aldehyde and the pyrone derivant to generate the five-ring skeleton, then, afterreduction and oxidation, I obtained the important intermediate of the natural product.Trichodermatide C was isolated from the marine-derived fungus Trichodermareesi, these special metabolites display significant antibiotic activity. These twonatural products Arisugacin E and Trichodermatide C all have a2H-pyrane structurewhich can be constructed by the formal [3+3] cycloaddition. In this progect, oursynthesis commenced with propargyl alcohol and1,3-cyclohexanedione. Throughalkylation reaction, the formal [3+3] cycloaddition, elimination and hydroxylationreaction, etc., for the first time to the total synthesis of natural productTrichodermatide C. The structures of the compounds were characterized by NMRspectra, LCMS, HRMS and so on.