Total Synthesis Of Sphingofungin F And Lysidicins

Part1:Total synthesis of Sphingofungin F based on chiral tricyclic iminolactoneSphingofungin F was a new class of sphingosine-like compound with antifungal agents, was first isolated from the fermentation broth of Paecilomyces variotii by a Merck group in1992. It had novel structure which bearing a C20straight carbon chain with E-olefin and four contiguous asymmetric centers polyhydroxyl a-amino acid head with a quaternary chiral center at a position. Besides that it exhibits inhibitory effects toward the serine palmitoyl transferase (SPT), an enzyme essential in the biosynthesis of sphingolipid, with antifungal activities against several human pathogenic fungi.In this essay, the discovery of sphingofungins, confirmination of the structure and chemical synthesis were summarized and concluded detailedly. A new strategy of total syntehsis of Sphingofungin F was designed based on chiral tricyclic iminolactone, a useful chiral auxiliary for the preparation of a-amino acids especially β-hydroxy-a-amino acids which has been reported by our group recently. Firstly, a convenient one-pot methodology for the synthesis of ω-hydroxyketones from available lactone was used in the synthesis of long chain lipid fragement, shorten the steps. In the synthesis of polyhydroxyl amino acid head, L-(+)-tartaric acid was used as chiral source and the other two chiral centers were constructed by the asymmetric aldol reaction with aldehyde and methyl tricyclic iminolactone. Finaly, an effective one-step deprotection strategy to remove all protecting groups using diluted hydrochloric acid in the mild condition. The total synthesis of Sphingofungin F has been accomplished with10.4%overall yield in15step.Part two:Total synthesis of Lysidicins, natural products of phloroglucinol derivatives.Lysidicins is one of the phloroglucinol derivatives with novel structure. They were isolated from Chinese medicinal plant, Lysidice rhodostegia Hance (Fabaceae) which has been used for the treatment of ache, fractures, and hemorrhage for a long time, by Yu shi-shan group recently. Lysidicins exhibit vasodilation activity and antioxidant activity, provide the pilot structure for the research of heart blood-vessel drugs. All these compounds contain a3-methylbutyryl phloroglucinol moiety. Lysidicin A, B and J have spirocyclic benzodihydrofuran skeleton, and Lysidicin F have unprecedented benzyl benzo[b]furo[3,2-d]furan skeleton, besides that Lysidicin F is the first example of natural product with trans-fused furan rings. However, The research of Lysidicins is rarely, the full details of biological activity of Lysidicins have not been clarified yet, and only the relative configuration of Lysidicins was determined. Therefor it is important for the total synthesis of Lysidicins, confirm the absolute configurations and the relevance of their structure to activity.We study the total synthesis of Lysidicin A-C and a new convergent synthesis route was designed. Lysidicin A, B and C can be synthetized respectively by adjusting the reaction sequence or protective groups. Three segments contain3-methylbutyryl and phloroglucinol were synthetized by Friedel-Crafts Acylation, Vilsmeier-Haack Formylation, Henry Reaction and Claisen Rearrangement. After that, Claisen-Schimidt and Michael reaction were used to connect the segments, and we also study the different methodlogy of segments connection. In the Michael reaction of nitro compound with unsaturated ketone, primary amine thiourea was used and catalyzed the reaction efficiently, which provide the foundation for the further asymmetric total synthesis of Lysidicin A-C. Finaly, We accomplished the first total synthesis of Lysidicin C and the investigation of synthesizing Lysidicin A using Nef reaction and the different sequence of deprotection and cyclization, and Lysidicin A can be obtained in further deprotection. But the spectrogram of Lysidicin C of synthetized was different with that of separated and the confirmation of Lysidicin C is ongoing.