手性磷酰胺催化的2,3’-二吲哚基取代的三芳基甲烷的不对称合成
文献类型：学位论文
| 作者 | 亓帅 |
| 学位类别 | 博士 |
| 答辩日期 | 2015-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 中国科学院长春应用化学研究所 |
| 导师 | 韩福社 |
| 关键词 | 2-吲哚甲基醇 手性磷酰胺 不对称合成 2 3’-二吲哚基取代的三芳基甲烷 绝对构型 |
| 中文摘要 | 杂-三芳基甲烷是一类结构比较特殊的骨架，在材料科学、生物化学以及药物化学等领域都有广泛的应用，其中双吲哚取代的三芳基甲烷因其在抗肿瘤方面所表现出的广阔前景而倍受关注。由于缺乏对映选择性合成双吲哚取代的三芳基甲烷的有效方法，这就制约了其手性分子在生物活性方面的研究。目前，仅有两例关于不对称合成3,3’-二吲哚基取代的三芳基甲烷的策略，而针对2,3’或2,2’-二吲哚基取代的三芳基甲烷的不对称合成尚未见报道。本论文以2-吲哚甲基醇衍生物和吲哚作为反应底物，在手性磷酰胺的催化作用下，首次实现了2,3’-二吲哚基取代的三芳基甲烷的不对称合成，并通过NMR波谱分析方法和CD光谱确定了其绝对构型。 首先，我们综述了吲哚C-3、C-2和N-1位参与的手性碳中心构建方法的研究进展，在此基础上提出了选题依据，设计了一种通过2-吲哚甲基醇和吲哚的不对称反应来合成2,3’-二吲哚基取代的三芳基甲烷的策略。接着设计并合成了一系列2-吲哚甲基醇衍生物以及BINOL为手性基本骨架的Br?nsted酸催化剂。 其次，我们通过一种在吲哚C-2位构建手性中心的新方法实现了2,3’-二吲哚基取代的三芳基甲烷的不对称合成。该方法以低反应活性的2-吲哚甲基醇衍生物作为反应底物，在最简单BINOL衍生 的N-Tf取代磷酰胺的催化作用下，经碳正离子与吲哚的不对称亲电取代反应而得以实现，且唯一副产物是水，具有简单、清洁和原子经济性的优点。同时，该反应具有较好的普适性，对于不同结构的底物，所得产物的收率几乎都大于90%，ee值35-96%。 最后，我们借助NMR波谱分析方法和CD光谱确定了手性2,3’-二吲哚基取代的三芳基甲烷类化合物的绝对构型。我们将手性2,3’-二吲哚基取代的三芳基甲烷分别与(R)-和(S)-甲氧基苯乙酸缩合，得到了一对非对映异构体结构。通过1H-NMR、1H-1H NOESY、1H-13C HSQC和1H-13C HMBC波谱分析，我们对每一个非对映异构体质子化学位移做了归属并建立了优势构象模型。最终，我们通过这对非对映异构体质子化学位移差别判定了手性2,3’-二吲哚基取代的三芳基甲烷类化合物的绝对构型。另外，CD光谱分析结果也与前面NMR判定的手性2,3’-二吲哚基取代的三芳基甲烷的绝对构型一致。这些结果为将来研究手性对2,3’-二吲哚基取代的三芳基甲烷的生物活性影响具有重要意义。 |
| 英文摘要 | Hetero-triarylmethanes are unique structural motifs and have a broad range of applications in areas such as materials science, biochemistry, and pharmaceuticals. Among which, diindolylarylmethanes represent appealing hetero-triarylmethanes due to their highly promising therapeutic utility as anticancer agents. Despite these important advances, the biological properties of the chiral derivatives remain unexplored due to the lack of effective methods for enantioselective synthesis of such compounds. So far, two protocols for the asymmetric synthesis of 3,3’-diindolylarylmethanes have been developed. However, methods for the asymmetric synthesis of 2,3’- or 2,2’-diindolylarylmethanes have not been achieved. In this dissertation, we present the first asymmetric reaction of indol-2-yl carbinol derivatives with indoles catalyzed by chiral phosphoramides for the enantioselective synthesis of 2,3’-diindolylarylmethanes and the determination of the absolute configuration of these compounds by using the combination of NMR spectroscopic and circular dichroism (CD) techniques. First, we summarised the progress of methods for the asymmetric construction of stereogenic carbon centers adjacent to the indole C-3, C-2 and N-1 positions. Based on existing works, we designed a strategy for the enantioselective synthesis of 2,3’-diindolylarylmethanes by the asymmetric reaction of indol-2-yl carbinols with indoles. Then, a series of indol-2-yl carbinol derivatives and BINOL-based chiral Br?nsted acids were designed and synthesized. Second, we have developed a novel methodology for the construction of a stereogenic carbon center adjacent to the indole C-2 position to achieve the enantioselective synthesis of 2,3’-diindolylarylmethanes successfully. The reaction of indol-2-yl carbinol derivatives was achieved in the presence of the most readily available BINOL-based N-triflylphosphoramide as catalyst through the asymmetric electrophilic substitution reaction of carboncations with indoles. The reaction can proceed in a very simple, clean, and atom-economical manner, bacause the only byproduct of the reaction was water. The method exhibited a broad generality. Excellent yields of over 90% as well as high enantioselectivity ranging from 35% to 96% ee were obtained for a rich range of both substrates. Finally, we present the determination of the absolute con?guration of chiral 2,3’-diindolylarylmethanes by using the combination of NMR spectroscopic and circular dichroism (CD) techniques. Namely, by condensation of a chiral 2,3’-diindolylarylmethane with the two enantiomers of (R)- and (S)-methoxyphenylacetic acid (MPA), respectively, we could obtain a pair of diastereoisomers. The proton chemical shifts and the favored conformers for each of the diastereoisomers were assigned by utilizing the combination of 1H-NMR, 1H-1H NOESY, 1H-13C HSQC, and 1H-13C HMBC spectroscopics. Consequently, the absolute con?guration of chiral 2,3’-diindolylarylmethanes could be determined on the basis of the observed differences in 1H NMR chemical shifts of the two diastereoisomers. Moreover, the CD analytical conclusion is entirely consistent with the previous determination of the absolute con?guration of chiral 2,3’-diindolylarylmethanes by NMR.The results would be useful for the future study of the effect of chirality on the bilogical activity of 2,3’-diindolylarylmethanes. |
| 语种 | 中文 |
| 公开日期 | 2016-05-03 |
| 源URL | [http://ir.ciac.jl.cn/handle/322003/64482]  |
| 专题 | 长春应用化学研究所_长春应用化学研究所知识产出_学位论文 |
| 推荐引用方式 GB/T 7714 | 亓帅. 手性磷酰胺催化的2,3’-二吲哚基取代的三芳基甲烷的不对称合成[D]. 中国科学院长春应用化学研究所. 中国科学院研究生院. 2015. |
入库方式： OAI收割
来源：长春应用化学研究所
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