复杂二倍半萜的合成研究

SYNTHESIS OF COMPLEX SESTERTERPENOIDS

任攀

11649172

硕士

化学工程

徐晶

2018

2018.7.10

哈尔滨工业大学

深圳

目前人类已发现两万多种萜类天然产物。其中，二倍半萜类天然产物不到一千种。虽然，二倍半萜仅仅占萜类天然产物的一小部分，但其抗炎、抗细胞病毒、抗癌、抗菌活性等生物特性以及其特殊的结构特性引起了有机合成化学家的关注。Astellatol 和Aspterpenacids A/B 是分别从Aspergillus stellatus 和红树林内生真菌Aspergillus terreus H010 分离而出的两种二倍半萜天然产物。这两种二倍半萜都具有类似的异丙基反式-茚满基团，这似乎暗示了两种二倍半萜在生物体内可能具有类似的合成路线。本论文以Astellatol 和Aspterpenacids A/B 为研究对象，合成5-7 并环和5-3-7 并环的骨架结构，为后续研究两种二倍半萜的全合成做准备。主要工作内容如下：（1）Astellatol 5-7 并环结构片段的合成，5-7 并环的合成主要包含以下步骤：（a）以廉价易得的手性（+）-长叶薄荷酮为起始原料，经溴加成反应，Favoskii 重排反应以及臭氧氧化得到β-酮酸酯中间体，碱性条件下，β-酮酸酯通过底物控制完成α-烷基化，接着通过联烯亲核加成后，在酸性条件下水解得到烯烃复分解关环反应（RCM）前体；（b）通过筛选Grubbs 催化剂、溶剂、温度等反应条件，高效的合成5-7 并环化合物。在此基础上，将5-7 并环化合物经催化氢化和SmI2 介导的脱氧反应来完成羰基α位构型翻转，得到最终所需的5-7 并环骨架结构。（2）Aspterpenacids A/B 5-3-7 并环结构片段的合成，主要包含以下步骤：（a）以廉价易得的5-己炔-1-醇出发，先用TMS 基团保护端炔，再用PCC 氧化伯醇，接着通过格氏反应，PDC 氧化反应，在酸性条件下脱保护得到醛酮中间体，在碱性条件下，醛酮中间体通过Aldol 反应得到烯酮化合物；（b）烯酮化合物经硼氢化钠还原并与二乙烯酮发生烷基化反应，紧接着重氮化得到分子内环丙烷化前体；（c）通过筛选环丙烷化催化剂、溶剂、温度等反应条件，合成环丙烷中间体，然后将环丙烷中间体反应生成烯醇硅醚，得到Conia-ene 反应的前体，最后通过筛选Conia-ene 环化反应的催化剂以完成我们所需构建的5-3-7 三环骨架系统。（3）Aspterpenacids A/B 5-3-7 并环结构片段合成路线的转变，主要包含以下步骤：（a）以廉价易得的2-环戊烯酮为原料，经碘代反应和Heck 反应得到二羰基化合物。在适当的条件下，二羰基化合物通过Wittig 反应选择性亚甲基化得到烯酮化合物；（b）烯酮化合物经硼氢化钠还原并与二乙烯酮发生烷基化反应，紧接着重氮化得到分子内环丙烷化前体，最后在催化剂Cu(TBSal)2 的条件下合成环丙烷化产物；（c）环丙烷内酯中间体与N,N-二甲基亚甲基碘化胺和碘甲烷反应得到二烯中间体，随后通过硼氢化钠还原以增加烯酮侧链的烯烃片段活性，再通过筛选Grubbs 催化剂、溶剂、温度等反应条件，高效的合成5-3-7 并环骨架片段。本文Astellatol 和Aspterpenacids A/B 的骨架合成中，均会使用Grubbs 催化剂来完成七元环的构建，同时，两个骨架片段的整条合成路线尽量避免反复的保护与脱保护，提高了原子经济型，这使得Astellatol 和Aspterpenacids A/B 骨架片段的合成更为简洁高效。这也为随后的全合成研究及其生物活性的探索过程打下坚实的基础。

At present, more than 22000 terpenoid products have been isolated, among which sesterterpenoids are less than 1000 kinds. Although sesterterpenoid is only a small part of the natural products of terpenoids, its anti-inflammatory, antiviral, anticancer, antibacterial activity and other biological properties, as well as its special structural characteristics, have attracted the attention of organic synthesis chemists.Astellatol and Aspterpenacids A/B are two kinds of sesterterpenoid natural products separated from Aspergillus stellatus and mangrove endophytic fungi Aspergillus terreus H010, respectively. The two kinds of sesterterpenoids have similar isopropyl trans-hydrindane skeleton, which apparently suggests that they have close biosynthetic relation in organisms. In this paper, we take Astellatol and Aspterpenacids as the research object and synthesizes the skeleton structures of 5-7 ring and 5-3-7 ring, which are prepared for the follow-up study of the total synthesis of these two sesterterpenoids. The main contents of the work are as follows:(1) The synthesis of the Astellatol 5-7 ring structure fragment mainly includes the following steps: (a) Using the cheap and readily available chiral (+)-Pulegone as the starting material, after bromination reaction, Favoskii rearrangement reaction and ozone cleavage, the intermediate of β-ketoester was obtained. The α-alkylation reaction was stereoselectively completed under the substrate control. The precursor of olefin metathesis reaction was obtained after the nucleophilic addition of allene and hydrolysis under acidic conditions; (b) By screening the reaction conditions of RCM catalysts, solvent and temperature, we can efficiently synthesize 5-7 ring skeleton. On this basis, the 5-7 ring skeleton is synthesized by hydrogenation and SmI2 mediated deoxygenation reaction to complete the inversion of the carbonyl α-configuration and get the final, desired 5-7 ring motif.(2) The synthesis of the Aspterpenacids A/B 5-3-7 ring structure fragment mainly includes the following steps: (a) Using the cheap and readily available 5-hexyne-1- alcohol as the starting material. Firstly, use the TMS group to protect the terminal alkyne and oxidize the primary alcohol with PCC. And then through Grignard reaction, PDC oxidation reaction and the aldehyde ketone intermediate is obtained under the acid condition. Finally, the ketene compound is obtained by Aldol reaction under the alkaline condition; (b) The ,-unsaturated ketone compound was reduced by sodium borohydride, after alkylation and diazotization, we got the precursors for intramolecular cyclopropanation reaction; (c) We synthesized cyclopropane intermediates by screening the cyclopropanation catalyst, solvent, temperature and other reaction conditions, then the cyclopropane intermediate was reacted to the enol silyl ether, the precursor of the Conia-ene reaction. Finally, we screened the catalyst for the Conia-ene cyclization reaction to synthesize the 5-3-7 tricyclic framework system we need to build.(3) The synthetic route of Aspterpenacids 5-3-7 ring motif includes the following steps: (a) Using the cheap and readily available 2- cyclopentenone as the starting material, dicarbonyl compounds were obtained by iodation reaction and Heck reaction. And under suitable conditions, ,-unsaturated ketone was obtained by selective methylation of Wittig reaction; (b) The ,-unsaturated ketone was reduced by sodium borohydride, after alkylation and diazotization, we got the precursors for intramolecular cyclopropanation reaction. Finally, the cyclopropane product was synthesized under conditions using catalyst Cu(TBSal)2; (c) The product from cyclopropanation was reacted with Eschenmoser's salt and methyl iodide to obtain diene intermediates. Subsequently, it was reduced by sodium borohydride to increase substrate reactivity for the RCM reaction. Then, through screening the reaction conditions of RCM catalyst, solvent and temperature, we can efficiently synthesize 5-3-7 ring skeleton.In the synthesis of Astellatol and Aspterpenacids A/B, Grubbs catalysts are used to complete the construction of seven membered rings. At the same time, the entire synthesis route of the two skeleton fragments avoids repeated protection and deprotection and improves the atomic economy, which makes the synthesis of Astellatol and Aspterpenacids skeleton fragments more concise and efficient. It will lay a solid foundation for their total synthesis and further biological investigation.

二倍半萜 有机合成 astellatol aspterpenacids A/B

sesterterpenoids organic synthesis astellatol aspterpenacids A/B

中文

联合培养

南方科技大学

任攀. 复杂二倍半萜的合成研究[D]. 深圳. 哈尔滨工业大学,2018.