Total Synthesis Of Naphthoquinone Natural Product Kalafungin And Evaluation Of Antifungal Activity

Pyranonaphthoquinones are a class of natural products with anti-fungal,anti-bacterial and anti-tumor bioactivities,which structure is composed of naphthoquinones and disubstituted pyran.The synthetic study of these natural products followed by bioactivities test will accelerate the summary of structure-activity relationship of these natural products.In this thesis,racemic kalafungin was obtained with a total yield of 0.82% in 13 steps.Commenced from commercially available 2,5-dihydroxybenzaldehyde,after aldehyde protection with 1,3-propanediol and the generated acetal group was used as directing group to construct the tetra-substituted benzene ring.And the key precursor compounds 1g was obtained after functional groups modification.Then the key intermediate 2r was synthesized by a cascade reaction including Cu I catalyzed coupling reaction between alkynes and diazoacetate,isomerization to allenoate and intramolecular oxy-Michael addition.The double bond in the pyran ring is reduced with TFA and triethylsilane system,and intermediate 16 was obtained as a single diastereomer as cis-pyran.Then,intermolecular Diels-Alder reaction between para-benzene quinone and diene was carried out to construct the naphthoquinone system.And the total synthesis of Kalafungin was completed by the construction of lactone ring followed by acid-catalyzed epimerization of cis-pyran.Expansion of the substrate scope and preliminary mechanism of above developed synthetic methodology were also investigated.The preliminary results showed that the nine intermediate compounds exhibited certain antifungal activities against the tested fungus at the concentration of 50 μg/m L;Compounds3-3,3-4 and 3-5 showed better inhibitory activity against Pyricularia grisea,Alternaria solani,Alternaria longipes and Curvularia lunata than the positive drug antimicrobial agent thiabendazole(TBZ).