Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis.
Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis.
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氧化模式分析指导下的复杂二萜化合物的合成
DOI：
10.1021/acs.accounts.0c00858
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发表时间：
2021-03-16
影响因子：
18.3
通讯作者：
Reisman, Sarah E.
中科院分区：
文献类型：
--
作者：
Dibrell, Sara E.;Tao, Yujia;Reisman, Sarah E.
二萜类天然产物具有复杂的分子结构、复杂的氧化模式和广泛的生物活性，对有机化学研究和药物发现产生了重大影响。我们的实验室已经完成了几个高度氧化的二萜，包括ent-kauranoids maoecrystal Z，trichorabdal A和longikaurin E的全合成;抗生素截短侧耳素;和杀虫剂ryanodol，ryanodine和perseanol。在这个帐户中，我们展示了如何分析氧化模式和固有的官能团关系可以告知关键的C-C键断开，大大简化了多环结构的复杂性，并简化了它们的总合成。在阐述这些概念时，我们大量借鉴了埃文斯、科里、塞巴赫等人编纂的合成策略方法，这些方法基于杂原子在碳骨架上施加交替的受体和供体反应模式的形式主义。我们发现这些想法特别有用时，考虑氧化二萜作为合成目标。在第一部分的帐户，我们描述了使用还原环化作为战略策略，建立多环系统与γ-羟基酮基序。我们在Isodon ent-kauranoid二萜（-）-maoecrystal Z、（-）-longikaurin E和（-）-trichorabdal A的全合成中利用Sm-酮基自由基环化反应作为“反应性推测”生成γ-羟基酮。在这项工作之后，我们在二萜抗生素（+）-截短侧耳素中鉴定了相同的γ-羟基酮模式，这再次激发了SmI 2介导的还原环化的使用，这次是为了构建桥接的八元环。这四个总合成的集合突出了还原环化在用于同时形成环和引入1，4-二氧化模式时是如何特别有效的umpolung策略。在帐户的第二部分中，我们详细介绍了复杂的和高度氧化的ryanodane和isoryanodane二萜的合成，并提出了氧化模式分析，指导我们的合成设计。我们首先讨论了我们的15步全合成（+）-ryanodol，其中纳入了五个八个氧原子在只有两个转换：（S）-胡薄荷酮的二羟基化和SeO 2介导的三氧化的A-环戊烯酮。后者的转化引起了一个独立的调查SeO 2介导的简单的双环cyclohexane-2-en-1-ones的过氧化作用。还介绍了（+）-ryanodine和（+）-20-deoxyspiganthine的合成，其需要改进的最终策略以选择性地掺入关键的吡咯-2-羧酸酯。最后，我们描述了我们的片段偶联方法来制备isoryanodane二萜（+）-perseanol。使用类似的氧化模式分析中开发的合成ryanodol，我们再次确定了一个两阶段的战略，安装五个羟基。该策略通过Pd介导的碳钯化/羰基化级联实现，并利用意外的紧急反应性来对一系列后期氧化进行测序。虽然本帐户中讨论的每种二萜天然产物都提出了独特的合成问题，但我们希望通过他们的集体讨论，我们提供了一个概念框架，可以浓缩和总结我们所学到的化学知识，并激发未来的话语和创新策略设计和方法开发。
With complex molecular architectures, intriguing oxidation patterns, and wide-ranging biological activities, diterpene natural products have greatly impacted research in organic chemistry and drug discovery. Our laboratory has completed total syntheses of several highly oxidized diterpenes, including the ent-kauranoids maoecrystal Z, trichorabdal A, and longikaurin E; the antibiotic pleuromutilin; and the insecticides ryanodol, ryanodine and perseanol. In this Account, we show how analysis of oxidation patterns and inherent functional group relationships can inform key C–C bond disconnections that greatly simplify the complexity of polycyclic structures and streamline their total syntheses. In articulating these concepts, we draw heavily from the approaches to synthetic strategy that were codified by Evans, Corey, Seebach, and others, based on the formalism that heteroatoms impose an alternating acceptor and donor reactivity pattern upon a carbon skeleton. We find these ideas particularly useful when considering oxidized diterpenes as synthetic targets. In the first part of the Account, we describe the use of reductive cyclizations as strategic tactics for building polycyclic systems with γ-hydroxyketone motifs. We have leveraged Sm-ketyl radical cyclizations as ‘reactivity umpolungs’ to generate γ-hydroxyketones in our total syntheses of the Isodon ent-kauranoid diterpenes (−)-maoecrystal Z, (−)-longikaurin E, and (−)-trichorabdal A. Following this work, we identified the same γ-hydroxyketone pattern in the diterpene antibiotic (+)-pleuromutilin, which again inspired the use of a SmI2-mediated reductive cyclization, this time to construct a bridging eight-membered ring. This collection of four total syntheses highlights how reductive cyclizations are particularly effective umpolung tactics when used to simultaneously form rings and introduce 1,4-dioxygenation patterns. In the second part of the Account, we detail the syntheses of the complex and highly oxidized ryanodane and isoryanodane diterpenes, and present the oxidation pattern analysis that guided our synthetic designs. We first discuss our 15-step total synthesis of (+)-ryanodol, which incorporated five of the eight oxygen atoms in just two transformations: a dihydroxylation of (S)-pulegone and a SeO2-mediated trioxidation of the A-ring cyclopentenone. This latter transformation gave rise to an independent investigation of SeO2-mediated peroxidations of simple bicyclic cyclopent-2-en-1-ones. The syntheses of (+)-ryanodine and (+)-20-deoxyspiganthine are also presented, which required modified end-game strategies to selectively incorporate the key pyrrole-2-carboxylate ester. Finally, we describe our fragment coupling approach to prepare the isoryanodane diterpene (+)-perseanol. Using a similar oxidation pattern analysis to that developed in the synthesis of ryanodol, we again identified a two-stage strategy to install the five hydroxyl groups. This strategy was enabled by a Pd-mediated carbopalladation/carbonylation cascade and leveraged unexpected, emergent reactivity to sequence a series of late-stage oxidations. While each of the diterpene natural products discussed in this Account present unique synthetic questions, we hope that through their collective discussion, we provide a conceptual framework that condenses and summarizes the chemical knowledge we have learned, and inspires future discourse and innovations in strategy design and methodology development.
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影响因子：
5.2
作者：
Egi, Masahiro;Ota, Yuya;Akai, Shuji
通讯作者：
Akai, Shuji
DOI：
10.1039/c39860000624
发表时间：
1986-04-15
影响因子：
--
作者：
FUKUZAWA, S;NAKANISHI, A;SAKAI, S
通讯作者：
SAKAI, S
影响因子：
3.5
作者：
Brooks, G;Burgess, W;Woodnutt, G
通讯作者：
Woodnutt, G
影响因子：
1.1
作者：
DESLONGCHAMPS, P;BELANGER, A;SOUCY, P
通讯作者：
SOUCY, P
DOI：
10.1126/science.aag1028
发表时间：
2016-08-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chuang KV;Xu C;Reisman SE
通讯作者：
Reisman SE