New Methods and Strategies in the Synthesis of Terpenoid Natural Products.
New Methods and Strategies in the Synthesis of Terpenoid Natural Products.
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DOI：
10.1021/acs.accounts.0c00809
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发表时间：
2021-03-16
影响因子：
18.3
通讯作者：
Pronin, Sergey, V
中科院分区：
文献类型：
--
作者：
Thomas, William P.;Pronin, Sergey, V
吲哚萜类化合物是一大类次生代谢物，具有独特的分子结构和多种生物活性。到目前为止已发现的100多个同系物共享一个共同的结构基序，该基序包含一个与重排的二萜片段融合的吲哚部分。这类天然产物具有代表性的生理和细胞效应包括神经和杀虫活性、调节脂质平衡和抑制有丝分裂。在过去的四十年里，多环结合的基序，以及不同的结构特征和广泛的生物活性使有机化学家们着迷，并导致了许多合成的发展。在这篇文章中，我们描述了我们对这一领域的贡献，以及它们如何反过来塑造了我们实验室正在发展的新方向。我们首先讨论我们的策略，以合成共享的吲哚萜核。为了解决先前报告中遇到的立体化学挑战，我们计划在多环化反应中利用适当取代的环戊酮来形成所需的反式十氢萘基序。这种多环化反应依赖于氢原子转移引发的自由基-极性交叉级联。原来的方法表现出较差的非对映选择性，但我们发现了一个有效的解决这个问题的方法，利用分子内的链结效应，最终合成了亚吲哚Sb。在这些研究中，我们还确定了铟催化的硅烯醇醚与炔烃的烯基化反应是合成高度取代的β，γ-不饱和酮的一种合适的方法，这对实现我们的路线简洁性至关重要。我们随后开发了这种转化的催化版本，允许进行形式上的双分子烯反应，该反应在构建四元中心方面显示出不寻常的和潜在有用的选择性。为了测试我们对花生碱吲哚萜类化合物的研究范围和局限性，并确定潜在的改进措施，我们开发了一种更复杂的同系物根瘤孢酸C的合成方法。这种天然产物的收敛组装是通过鉴定自由-极性交叉多环化中新的立体控制元素来获得多环萜类基序，以及开发高度非对映选择性的烯炔环异构化来获得吲哚基序和酮芳基化协议来结合两个复杂片段来实现的。在随后的研究中，我们将我们的方法基础上的自由基-极性交叉级联扩展到双分子环境，允许两个不饱和的羰基组分环化以产生官能化的环己烷。这种转化特别适合于安装完全取代的碳，并且可以补充历史悠久的Diels-Alder反应。新的环在Forskolin的合成中进行了测试，允许在这种密集官能化的Labdane二萜类化合物中快速构建复杂的多环基序。在过去的五年里，我们最初尝试合成紫杉碱吲哚萜类化合物，现已发展成为一个包含新合成方法开发的项目，并致力于对几个不同家族的萜类天然产物进行人工组装。我们对通过应用这一化学而获得的结构基序的日益多样化感到鼓舞，并继续发现潜在反应性的新方面。
Indoloterpenoids of the paxilline type belong to a large family of secondary metabolites that exhibit unique molecular architectures and a diverse set of biological activities. More than 100 congeners identified to date share a common structural motif that contains an indole moiety fused to a rearranged diterpenoid fragment. The representative physiological and cellular effects attributed to this family of natural products include neurological and insecticidal activities, modulation of lipid balance, and inhibition of mitosis. The uniting polycyclic motif combined with the diversity of individual structural features of paxilline indoloterpenoids and the broad scope of their biological activities have fascinated organic chemists for the past four decades and have led to the development of numerous syntheses. In this Account, we describe our contributions to this field and how they in turn shape new directions that are developing in our laboratory. We begin with the discussion of our strategy for the synthesis of the shared indoloterpenoid core. To address stereochemical challenges encountered in earlier reports, we planned to leverage a suitably substituted cyclopentanone in a polycyclization to form the desired trans-decalin motif. This polycyclization relied on a radical-polar crossover cascade initiated by hydrogen atom transfer. The original process exhibited poor diastereoselectivity, but we discovered an efficient solution to this problem that took advantage of intramolecular tethering effects, culminating in short synthesis of emindole SB. During these studies, we also identified indium-mediated alkenylation of silyl enol ethers with alkynes as a suitable method for the synthesis of highly substituted β,γ-unsaturated ketones that was critical to achieving brevity of our route. We subsequently developed a catalytic version of this transformation that allowed for a formal bimolecular ene reaction that exhibited unusual and potentially useful selectivity in construction of quaternary centers. To test the scope and limitations of our approach to paxilline indoloterpenoids and identify potential improvements, we developed a synthesis of the more complex congener nodulisporic acid C. The convergent assembly of this natural product was enabled by identification of new elements of stereocontrol in the radical-polar crossover polycyclization en route to the polycyclic terpenoid motif and development of a highly diastereoselective enyne cycloisomerization to access the indenopyran motif and a ketone arylation protocol to unite the two complex fragments. In subsequent studies, we expanded the radical-polar crossover cascade underlying our approach to paxilline indoloterpenoids to a bimolecular setting, which allowed for annulation of two unsaturated carbonyl components to produce functionalized cyclohexanes. This transformation is particularly well suited for installation of fully substituted carbons and can be complementary to the venerable Diels–Alder reaction. The utility of the new annulation was tested in the synthesis of forskolin, allowing for rapid construction of the complex polycyclic motif in this densely functionalized labdane diterpenoid. Over the past five years, our initial forays into the synthesis of paxilline indoloterpenoids have grown into a program that incorporates development of new synthetic methods and pursues artificial assembly of terpenoid natural products from several different families. We are encouraged by the increasing diversity of structural motifs made accessible by application of this chemistry and continue to discover new aspects of the underlying reactivity.
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影响因子：
4.9
作者：
Harrak, Youssef;Simonneau, Antoine;Fensterbank, Louis
通讯作者：
Fensterbank, Louis
影响因子：
15
作者：
Holmbo, Stephen D.;Godfrey, Nicole A.;Pronin, Sergey V.
通讯作者：
Pronin, Sergey V.
N-取代的2-氨基苯基 - 甲基磺酸甲烷二硫酸盐预催化剂及其在C-C和C-N交叉偶联中的使用。
DOI：
10.1021/jo500355k
发表时间：
2014-05-02
期刊：
The Journal of organic chemistry
影响因子：
--
作者：
Bruno NC;Niljianskul N;Buchwald SL
通讯作者：
Buchwald SL
影响因子：
1.8
作者：
BHAT, SV;BAJWA, BS;FEHLHABER, HW
通讯作者：
FEHLHABER, HW
DOI：
10.1039/p19830001863
发表时间：
1983-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
影响因子：
--
作者：
DE JESUS, AE;GORSTALLMAN, CP;HULL, WE
通讯作者：
HULL, WE