Synthesis Of The Analogues Of Linear Sesterterpene Variabilin

Background: Sesterterpene is an important class of terpenoids. These compounds are synthesized by geranylfarnesyl pyrophosphate in biogenic source, which are mostly non-linear structure(multi-ring) complex compounds. Linear Sesterterpenes which belongs to a category of Sesterterpene is less than multi-ring terpenoids in quantity. What's more ,the structure of them is chain-like in most situation .So far, the amount of Sesterterpene found in nature is more than 200,which most comes from sponges. As a kind of sponge's secondary metabolites, the study indicated that majority of these compounds have favourable biological activity such as anti-bacterial, anti-virus, anti-inflammatory, anti-tumor and the activity of inhibiting biological enzymes.Natural product variabilin is linear Sesterterpene isolated from marine sponges called Ircinia variabilis.Variabilin's structure contains a Furan ring and a tetrnic acid terminal, they are bridged by three isopentenyl. More than 60 isomers and ramifications of variabilin was discovered currently. What's more, there are also double bond isomers, degradation products and salty compounds of variabilin. Thanks to the foundation structure of these compounds all comprise alkene made from three isoprenes, five membered heterocycle, tetrnic acid terminal or degradation products of them, this kind of compounds are collectively referred to variabilins.Variabilins have favourable biological activity such as anti-bacterial, anti-virus, anti-inflammatory, anti-tumor and the activity of inhibiting biological enzymes. The study have showed variabilins not only have cytotoxicity to tumor cells but can also activate the hypoxia-inducible factor-1 in tumor cells to inhibit the proliferation of them. What's more, variabilins have double immunosuppressive action to tissue imflammation. Variabilins are mainly come from sponge, however, the content of these compounds in sponge is extremely low and the extraction of separate technology is very complicated,morever the cost is expensive.what's more, variabilins are not so stable that can easily to be oxidated. These conditions limit the systematic research and exploitation of the compounds in large degree.In views of the study domestic and abroad in this area, this issue sets the representative compound variabilin as the target molecular, establishing a simple and effective way of complete synthesis, lucubrating the key reaction, optimizing the condition of reaction to get the goal and extend the method to synthesize the compounds all in this category. Meanwhile, the establishing of methodology is worth carrying out. In addition, our work will settle a foundation to track, total synthesis, structural modification and research the structure-activity relationship in active Substance of marine linear Sesterterpene.Research content:1. A review on the linear sasterterpene research progress. Summary and detailed description of the linear sesterterpene structure and classification, structure-activity relationship, synthesis, etc. Research and research prospects.2. Study on synthesis the analogues of marine Linear sesterterpene variabilin. This paper mainly consists of two parts: (1) Terpene synthesis. This synthesis method based terpene designed two different synthetic routes.The important intermediate product 4 ((2E, 6E) -2,6-dimethyl-8-(phenyl thioperoxy)octa- 2,6-dien-1-ol) was synthesized in the total yield of 66% by halogenate reaction, addition reaction and Sharpless Asymmetric oxidation reaction using monoterpene geraniol as the raw material. Then,using product 4 as the material, anoher intermediate carboxylic acid 9 ((4E, 8E)-4,8-dimethyl-10- (phenylthioperoxy) deca-4 ,8-dien-1-ol) was synthesized by compound 4 with diethyl malonate addition. Compound 18 addition with ethyl propionate in the LDA, the chain-ene 9 ((6E, 10E) -2,6,10-trimethyl-12- (phenylsulfonyl) dodeca-6 ,10-dien-1-ol) was synthesized by reduction reaction. (2) Variabilin synthesis. Based chain with five heterocyclic alkene and tetronate terminal designed to connect two synthetic routes, the paper design in accordance with the second line to Compound 9 was synthesized by oxidation of primary alcohols, Knoevenagel reaction, Biellmann-Ducep coupling reaction ,and so on, the reaction of variabilin precursor compound 26 was synthesis by six-step, yield 36.5%.In this paper, variabilin`s analogues compound 26 was synthesized by 16-step reaction from geraniol, all compounds were identificated by ESI-MS, 1H-NMR and some compounds need further identification by 13C-NMR.Results and Prospect:In this paper, linear sesterterpene variabilin as the target molecules. The analogues compound 26 of variabilin was obtained. According to the structural characteristics , an effective and simple synthesis method was established. As the basic synthesis method we plan to synthesize the variable's analogues and exploit the general synthesis method of the sesterterpene which will solve the sources of sample in variable's compounds study. Meanwhile, According to variabilin and its derivatives and analogues, we can totally and systematically study the activity and mechanism of these compounds. The in-depth study of its structure-activity relationships to further research and exploiting the simpler structure stable, higher activity and less toxicantivity .innovative drug.