【摘要】：天然產(chǎn)物由于其經(jīng)歷了上億年的演化,其結(jié)構(gòu)穩(wěn)定、骨架復(fù)雜多樣、活性廣泛,與人工合成分子相比具有獨特的優(yōu)越性,一直以來備受合成化學(xué)家和藥物化學(xué)家的青睞。本文介紹了全新的天然產(chǎn)物Garcibracteatone A的全合成和幾種相關(guān)金催化方法學(xué)研究。針對Garcibracteatone A的骨架的合成,設(shè)計了邁克爾加成/aldol反應(yīng)／酯交換的串聯(lián)策略作為關(guān)鍵反應(yīng),并根據(jù)該策略設(shè)計了三代全合成路線。每條路線都是對前一條的補充以及優(yōu)化并取得了階段性的進展。最終可以由廉價的底物γ丁內(nèi)酯出發(fā),分別經(jīng)過8步以及10步反應(yīng)合成天然產(chǎn)物骨架中的左側(cè)骨架以及右側(cè)骨架。在全合成的過程中,發(fā)現(xiàn)了環(huán)張力對于環(huán)合反應(yīng)具有很大的影響,并設(shè)計了具有環(huán)張力的丙炔基乙烯基醚類底物,該類底物在金催化劑的催化下的區(qū)域選擇性由5-exo-trig完全轉(zhuǎn)變?yōu)?-endo-trig環(huán)合。對該方法學(xué)的適用性進行了探索,并借助計算機化學(xué)對該反應(yīng)的機理進行了深入的探討,并且將該方法應(yīng)用到天然產(chǎn)物合成中。其次,在該方法學(xué)的基礎(chǔ)上,進一步發(fā)展了該類底物在親核性試劑存在的條件下,由取代基調(diào)控生成不同環(huán)系的方法。該方法巧妙地將底物中的取代基與反應(yīng)中間體聯(lián)系在一起,并通過一系列氘代實驗對該方法學(xué)進行了深入的機理研究。將所合成的化合物利用依據(jù)結(jié)構(gòu)骨架相似性原理進行了抗真菌的初步生物活性測試。發(fā)現(xiàn)部分化合物確實具有抗真菌活性,并且其活性較好,有待于深入研究。最后,基于之前對于丙炔基乙烯基醚類的研究基礎(chǔ),以該類底物為原料繼續(xù)發(fā)展了一種合成聯(lián)苯的方法,并且對該方法的反應(yīng)條件進行了詳細的優(yōu)化。通過使用對稱以及不對稱的親雙烯體,證明了該方法的適用性比較廣泛。
[Abstract]:Natural products have undergone hundreds of millions of years of evolution, their structures are stable, their skeletons are complex and diverse, and their activities are wide. Compared with synthetic molecules, natural products have unique advantages, and have been favored by synthetic chemists and pharmaceutical chemists all the time. In this paper, the total synthesis of a new natural product, Garcibracteatone A, and several related gold catalytic methods are introduced. The series strategy of Michael addition / aldol reaction / transesterification was designed as the key reaction for the synthesis of Garcibracteatone A skeleton. According to the strategy, the third generation full synthesis route was designed. Each route complements and optimizes the former and has made periodic progress. Finally, the left skeleton and the right skeleton of the natural product skeleton can be synthesized from the cheap substrate 緯 -butyrolactone through the reaction of 8 steps and 10 steps, respectively. In the whole synthesis process, it was found that the ring tension had great influence on the cyclization reaction, and the propargyl vinyl ether substrates with ring tension were designed. The regioselectivity of the substrates changed from 5-exo-trig to 6-endo-trig cyclization under the catalysis of gold catalyst. The applicability of the method was explored and the mechanism of the reaction was discussed by computer chemistry. The method was applied to the synthesis of natural products. Secondly, on the basis of the methodology, the method of generating different ring systems by substituents in the presence of nucleophilic reagents was further developed. The method cleverly links the substituents in the substrates with the reaction intermediates and studies the mechanism of the method through a series of deuterium substitution experiments. The synthetic compounds were tested for their antifungal activity based on the principle of structural skeleton similarity. It is found that some compounds do have antifungal activity, and their activity is better, which needs further study. Finally, based on the previous studies on propargyl vinyl ethers, a synthesis method of biphenyl was developed using this kind of substrate as raw material, and the reaction conditions of the method were optimized in detail. By using symmetric and asymmetric dienophiles, the applicability of this method is proved to be more extensive.
【學(xué)位授予單位】：沈陽藥科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R914.5
，

本文編號：2381229