| Divergolides (A-N) are a family of structurally novel ansa macrolides and the related derivatives produced by the endophytic strains (Streptomyces sp. HKI0576 and Streptomyces sp. HKI0595) isolated from the stem of mangrove trees which are found in southeast China, southern India, and southern Japan. Divergolides exhibit strong antibacterial activity and anticancer activity. Among them, the structure of divergolide A has been established by X-ray single crystal structural analysis but total synthesis of divergolides has not been accomplished so far. In this thesis research work, a multimodule synthesis strategy based on ring-closing metathesis (RCM) reaction is proposed, resulting in five small fragments. Synthesis of these fragments and the reactions used for their assembly are studied in great detail.Described in Chapter 1 are the background information and this thesis research plan, including the unique structural characteristics of divergolides, the proposed biosynthetic pathways, the progress in total synthesis of divergolides C and D by other research groups, and our strategy toward total synthesis of divergolide A. The following Chapters 2-5 summarize the results of this thesis research work. In Chapter 2, the methods known in the literature about synthesis of chiral vicinal diols and the syn-selective chiral glycolate asymmetric aldol reaction are briefly introduced. The preparation route toward the chiral C5-C10 vicinal diol fragment based on the syn-selective chiral glycolate asymmetric aldol reaction is discussed. Chapter 3 deals with our initial study on synthesis of the amido hydroquinone fragment. The synthesis using 3,5-dibormobenzaldehyde and methyl 3,5-dibromobenzoate, respectively, is not successful but the route starting from 1,3,5-tribromobenzene affords the expected product. The conditions for amidation of the aryl bromide intermediate are then optimized and the oxidant for transformation of the amido phenol into the corresponding amido hydroquinone is carefully screened. All these results lay down a firm foundation for the following synthetic work. Synthesis of (Z)-γ-methylglutaconic acid fragment is a major task as presented in Chapter 4. A highly efficient synthesis of γ-methylglutaconic anhydride has been established and the aminolysis of the anhydride with aniline derivatives under mild reaction conditions has been realized for accessing to the (Z)-γ-methylglutaconic acid fragment. Finally, several approaches toward the functionalized amido hydroquinone fragment have been attempted and results are compiled in Chapter 5. The synthesis using 2,5-dimethoxybenaldehyde as the protected hydroquinone has been attempted and the conditions for cleavage of the methyl aryl ethers in the key intermediates have been explored. The subsequent Mukaiyama aldol reaction of the aldehyde possessing the amido benzoquinone unit with a model silyl enol ether has been carried out to construct the C4-C5 bond. In order to search for mild oxidative deprotection method, the silyl ether- and allyl ether-protected benzaldehydes have been used, respectively, for the synthesis of the functionalized amido hydroquinone fragment. All of these experimental results are carefully compiled and discussed.In summary, the following results are delivered in this thesis research:(a) the chiral vicinal diol fragment has been successfully prepared via the syn-selective chiral glycolate asymmetric aldol reaction; (b) the (Z)-γ-methylglutaconic acid fragment has been assembled via the amidation of y-methylglutaconic anhydride with the aniline derivatives; and (c) several synthetic routes toward the functionalized amido hydroquinone fragment and the oxidation into the amido benzoquinone have been explored. All these results are valuable references for completion of our total synthesis of divergolide A. At the late part of the thesis are found the main experimental procedures, the characterization data of the key compounds, the cited references, and the copies of 1H and 13C NMR spectra of the selected compounds. |
PDF Full Text Request