Annulative Methods in the Synthesis of Complex Meroterpene Natural Products
Annulative Methods in the Synthesis of Complex Meroterpene Natural Products
复制标题
复杂二萜天然产物的合成方法
DOI：
10.1021/acs.accounts.0c00781
复制
发表时间：
2021
影响因子：
18.3
通讯作者：
Maimone, Thomas J.
中科院分区：
文献类型：
--
作者：
Shen, Xingyu;Thach, Danny Q.;Ting, Chi P.;Maimone, Thomas J.
结论从历史悠久的罗宾逊环化反应到不可替代的Diels-Alder环加成反应，环化反应在过去的世纪里推动了天然产物合成领域的发展。从广义上讲，从两个或更多个简单片段直接形成环状分子的能力几乎改变了化学科学的各个方面，从有机材料的合成到生物共轭化学和药物发现。在本报告中，我们描述了过去五年来我们的部分萜烯合成计划的演变，主要是通过开发定制的阴离子成环工艺来实现的，该工艺用于从烯醇化锂和含反应性β-内酯的原料化学品双乙烯酮合成羟基化1，3-环己二酮。我们提供了原型多环聚异戊二烯化酰基间苯三酚（PPAP）天然产物贯叶金丝桃素和garsubellin A的短全合成的细节，其具有复杂的双环[3.3.1]壬烷结构。值得注意的是，这些分子几十年来一直作为引人注目的合成靶点，并诱导许多与神经科学和医学相关的生物学效应。通过将我们的双烯酮成环过程与高价碘介导的氧化性扩环合并，可以仅在两个化学操作中从简单的5，6-稠合双环二酮容易地制备双环[3.3.1]壬烷结构。利用这两个关键的化学反应与其他各种立体选择性的转换相结合，使这些生物活性的目标，以制备外消旋形式在只有10 steps.Next，我们扩展这一战略的合成复杂的真菌衍生merotenees生物合成产生的耦合3，5-dimethylorsellinic acid（DMOA）和焦磷酸法呢酯。使用Ti（III）介导的末端环氧化物的自由基环化来快速制备6，6，5-稠合三环酮，其用作我们的环化/重排过程的输入，最终使得能够全合成原奥斯汀素A（在DMOA衍生的部分萜合成中的重要生物合成中间体）及其氧化产物伯克利酮A。通过基于自由基的非生物重排过程，这些天然产物的双环[3.3.1]壬烷核心可以再次异构化，产生andrastin家族的6，5-稠环系统，并最终提供andrastin D和preterrenoid的全合成。值得注意的是，这些异构化转化证明具有挑战性时，采用经典的，酸诱导的碳阳离子生成的条件，从而突出了自由基仿生在全合成的力量。最后，进一步的氧化和重排允许进入terrenoid和含内酯的代谢产物terretonin L.总体而言，合并成环双烯酮方法与氧化重排转化已被证明是一个广泛适用的策略，以合成双环[3.3.1]壬烷含天然产物，一类小分子，具有超过1000个已知的成员。
ConspectusFrom the venerable Robinson annulation to the irreplaceable Diels–Alder cycloaddition, annulation reactions have fueled the progression of the field of natural product synthesis throughout the past century. In broader terms, the ability to form a cyclic molecule directly from two or more simpler fragments has transformed virtually every aspect of the chemical sciences from the synthesis of organic materials to bioconjugation chemistry and drug discovery. In this Account, we describe the evolution of our meroterpene synthetic program over the past five years, enabled largely by the development of a tailored anionic annulation process for the synthesis of hydroxylated 1,3-cyclohexanediones from lithium enolates and the reactive β-lactone-containing feedstock chemical diketene.First, we provide details on short total syntheses of the prototypical polycyclic polyprenylated acylphloroglucinol (PPAP) natural products hyperforin and garsubellin A, which possess complex bicyclo[3.3.1]nonane architectures. Notably, these molecules have served as compelling synthetic targets for several decades and induce a number of biological effects of relevance to neuroscience and medicine. By merging our diketene annulation process with a hypervalent iodine-mediated oxidative ring expansion, bicyclo[3.3.1]nonane architectures can be easily prepared from simple 5,6-fused bicyclic diketones in only two chemical operations. Leveraging these two key chemical reactions in combination with various other stereoselective transformations allowed for these biologically active targets to be prepared in racemic form in only 10 steps.Next, we extend this strategy to the synthesis of complex fungal-derived meroterpenes generated biosynthetically from the coupling of 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate. A Ti(III)-mediated radical cyclization of a terminal epoxide was used to rapidly prepare a 6,6,5-fused tricyclic ketone which served as an input for our annulation/rearrangement process, ultimately enabling a total synthesis of protoaustinoid A, an important biosynthetic intermediate in DMOA-derived meroterpene synthesis, and its oxidation product berkeleyone A. Through a radical-based, abiotic rearrangement process, the bicyclo[3.3.1]nonane cores of these natural products could again be isomerized, resulting in the 6,5-fused ring systems of the andrastin family and ultimately delivering a total synthesis of andrastin D and preterrenoid. Notably, these isomerization transformations proved challenging when employing classic, acid-induced conditions for carbocation generation, thus highlighting the power of radical biomimicry in total synthesis. Finally, further oxidation and rearrangement allowed for access to terrenoid and the lactone-containing metabolite terretonin L.Overall, the merger of annulative diketene methodology with an oxidative rearrangement transformation has proven to be a broadly applicable strategy to synthesize bicyclo[3.3.1]nonane-containing natural products, a class of small molecules with over 1000 known members.