天然产物Garcibracteatone A的全合成及相关金催化方法学研究
发布时间：2018-12-15 20:20
【摘要】：天然产物由于其经历了上亿年的演化,其结构稳定、骨架复杂多样、活性广泛,与人工合成分子相比具有独特的优越性,一直以来备受合成化学家和药物化学家的青睐。本文介绍了全新的天然产物Garcibracteatone A的全合成和几种相关金催化方法学研究。针对Garcibracteatone A的骨架的合成,设计了迈克尔加成/aldol反应／酯交换的串联策略作为关键反应,并根据该策略设计了三代全合成路线。每条路线都是对前一条的补充以及优化并取得了阶段性的进展。最终可以由廉价的底物γ丁内酯出发,分别经过8步以及10步反应合成天然产物骨架中的左侧骨架以及右侧骨架。在全合成的过程中,发现了环张力对于环合反应具有很大的影响,并设计了具有环张力的丙炔基乙烯基醚类底物,该类底物在金催化剂的催化下的区域选择性由5-exo-trig完全转变为6-endo-trig环合。对该方法学的适用性进行了探索,并借助计算机化学对该反应的机理进行了深入的探讨,并且将该方法应用到天然产物合成中。其次,在该方法学的基础上,进一步发展了该类底物在亲核性试剂存在的条件下,由取代基调控生成不同环系的方法。该方法巧妙地将底物中的取代基与反应中间体联系在一起,并通过一系列氘代实验对该方法学进行了深入的机理研究。将所合成的化合物利用依据结构骨架相似性原理进行了抗真菌的初步生物活性测试。发现部分化合物确实具有抗真菌活性,并且其活性较好,有待于深入研究。最后,基于之前对于丙炔基乙烯基醚类的研究基础,以该类底物为原料继续发展了一种合成联苯的方法,并且对该方法的反应条件进行了详细的优化。通过使用对称以及不对称的亲双烯体,证明了该方法的适用性比较广泛。
[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 纬 -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.
【学位授予单位】：沈阳药科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914.5
，
本文编号：2381229
[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 纬 -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.
【学位授予单位】：沈阳药科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914.5
，
本文编号：2381229
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