【作者】 曹威；

【导师】 刘波；

【作者基本信息】 四川大学 ， 有机化学， 2022， 博士

【摘要】 C-20氧化的对映-贝壳杉烷型二萜类天然产物不仅数量众多,而且具有良好的生物活性,因此,备受合成工作者的关注。然而,与其它对映-贝壳杉烷型二萜相比,该类天然产物的合成难度更高;因此,发展针对该类天然产物的简洁高效合成路线,对于开展生物活性的构效关系研究具有重要意义。本论文以C-20氧化的对映-贝壳杉烷型二萜类天然产物oridonin(冬凌草甲素)和sculponin U作为目标分子,开展合成研究,包括以下三部分内容:一、简要介绍了 C-20氧化的对映-贝壳杉烷型二萜类天然产物的分离、分类、生物活性和合成研究进展。二、以oridonin为目标分子,尝试了三种策略开展合成研究。策略Ⅰ-自由基串联环化合成ACE三环:首先合成了含E环的关键前体化合物,但通过自由基串联环化仅获得AE双环化合物,未能合成得到ACE三环。策略Ⅱ-分子间自由基加成合成ACE三环:从策略I中合成的AE双环化合物出发引入C环,但由于底物和自由基捕获剂的位阻原因,无法实现所需的自由基加成反应。策略Ⅲ-酯基链接的分子内自由基加成合成ACE三环:从策略Ⅰ中合成的AE双环化合物出发,利用酯基链接C环,期望经分子内自由基加成形成新的碳碳键合成ACE三环;但由于酯基构象原因导致反应位点无法靠近,最终未成功。因此,由于电性匹配和位阻的原因,无法实现自由基串联环化构建中间体ACE三环,未能完成oridonin的合成。三、以sculponin U为目标分子,尝试了三类烯醇硅醚底物开展合成研究,基于烯醇硅醚氧化自由基串联环化反应的关键策略,成功构建了含二环[3.2.1]辛烷子结构的ABCD四环骨架结构。第一类底物-6/6顺式双环烯醇硅醚:经Diels-Alder热环加成反应构建6/6顺式双环烯醇硅醚后,在光引发条件下,得到了 6/6/5/5并环四环化合物,未能实现含二环[3.2.1]辛烷的桥环子结构的构建。第二类底物-含有季碳的烯醇硅醚六元环:在光引发条件下,能够获得所需的二环[3.2.1]辛烷子结构的BCD三环桥环副产物,以及含6/5/5三环并环结构的主产物。第三类底物-无季碳的烯醇硅醚六元环:经构象设计,该类化合物可采取所需的半椅式构象,在光引发条件下,以较高收率、高选择性合成二环[3.2.1]辛烷子结构的BCD三环桥环主产物;随后,在酯基邻位的B环上立体选择性地引入烷基边链,构建季碳中心;再通过Fe(acac)3催化的氢原子转移(HAT)串联关环反应成功构建A环,获得ABCD四环骨架,但其中的AB并环为6/6顺式构型,与目标分子不一致;最后,经在B环中引入缺电子烯烃和后续的锂氨还原,翻转6/6顺式并环为6/6反式并环,完成了天然产物sculponin U立体化学一致的核心ABCD四环骨架的构建。上述工作为后续实现天然产物sculponin U的全合成打下良好基础。更多还原

【Abstract】 C20-oxygenated ent-kaurane diterpenoids are widely distributed in nature and exhibit diverse biological activities,which have drawn a lot of attention from synthetic chemists.Compared to other types of natural ent-kaurane diterpenoids,Synthesis of C20-oxygenated ent-kauranes are more challenging due to higher degree of oxidation.Therefore,it is of great significance to develop a concise and efficient synthetic route for this type of natural products,aiming at further exploration of structure-activity relationship among their analogs in future.This dissertation focuses on synthetic studies toward C20-oxygenated ent-kaurane diterpenoids,oridonin and sculponin U,and is divided into three parts:Part 1:Isolation,classification,bioactivity and research progress on syntheses of C20-oxygenated ent-kaurane diterpenoids was summarized.Part 2:Three synthetic strategies have been attempted toward oridonin.The first strategy-A radical cascade cyclization to build ACE tricycle:After a key precursor involving ring E was synthesized,a radical cascade was examined;a compound embracing an AE bicycle was obtained instead of the desired compound with ACE tricycle.The second strategy-Intermolecular radical addition to construct ACE tricycle:The obtained compound with an AE bicycle in the first strategy was used to introduce ring C;however,the required radical addition reaction could not be achieved due to steric hindrance between the substrate and the radical acceptor.The third strategy-Intramolecular radical addition tethered by an ester group to establish ACE tricycle:An ester was introduced to connect ring C and the obtained compound with an AE bicycle in the first strategy,and an intramolecular radical addition was anticipated to take place to form a new C-C bond achieving ACE tricycle;unfortunately,it did not work due to the conformation of the ester tether making the reactive centers far away from each other.In general,due to mismatch of electronic and steric factors between reactive centers,synthetic attempts with radical cascade to achieve oridonin failed and thus other synthetic tactics should be tested.Part 3:Photoinduced electron transfer (PET) mediated oxidative radical cascade cyclization was developed as the key reaction by evaluating three types of silyl enol ethers,and construction of ABCD tetracyclic skeleton of sculponin U involving bicyclo[3.2.1]octane motif was finally accomplished.The first type of substrate-silyl enol ether with cis-fused 6/6 bicycle:After construction of silyl enol ethers with cis-fused 6/6 bicycle were achieved through Diels-Alder cycloaddition,PET-mediated oxidative radical cascade reactions were tested;however,only the fused 6/6/5/5 tetracyclic compounds as undesired products were obtained instead of the desired tetracyclic product with bicyclo[3.2.1]octane motif.The second type of substrate-silyl enol ether in six-membered ring with a quaternary center:Under PET-mediated cyclization condition,the desired tricyclic compound with bicyclo[3.2.1]octane motif was obtained as the minor product,while the underside compound with 6/5/5 fused tricycle was obtained as the major product.The third type of substrate-silyl enol ether in six-membered ring without quaternary center:Based on the half chair conformation of this type of substrates,the BCD tricyclic compound embracing bicyclo[3.2.1]octane motif was obtained as the major product with good yield and high regio-and stereo-selectivity under PET condition.Then an alkyl side chain was introduced onto the position at ring B adjacent to the ester group to generate a quaternary center;subsequently,a cascade cyclization triggered by Fe(acac)3-mediated hydrogen atom transfer (HAT)succeeded in construction of ring A to achieve the ABCD tetracyclic skeleton with a false cis-fused 6/6 bicycle;finally,inversion of the cis-fused 6/6 bicycle to the desired trans-fused 6/6 bicycle was completed after generation of a double bond in ring B and reduction with Li/liquid ammonia sequentially,to afford the core ABCD tetracyclic skeleton of sculponin U with proper stereochemistry.Collectively,the above achievements paved the way for the success on total synthesis of sculponin U in the future.更多还原