Catalytic Asymmetric Dearomative Spirocyclisations

催化不对称脱芳香螺环化

• 批准号: EP/M018601/1
• 负责人: Richard Taylor
• 金额: $ 44.03万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FM018601%2F1
• 关键词: Catalytic; Asymmetric; Dearomative; Spirocyclisations

The design of new methods to synthesize and manipulate complex heterocyclic molecules is extremely important , especially given that such compounds form the basis of a vast array of biologically useful natural products, pharmaceuticals and crop protection products. In particular, procedures which allow complex 3D molecular architectures to be constructed quickly from simple precursors are of great importance, as they facilitate the biological testing of previously unexplored regions of 'chemical space' for potential applications (e.g. in drug discovery). As part of our on-going research programme geared towards the synthesis of diverse heterocyclic scaffolds, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to biologically active heterocycles. This proposal centres on the formation and subsequent elaboration of spirocyclic 3D scaffolds from far simpler, readily available 2D aromatic precursors. A series of two-step protocols based of 'dearomatisation' (to form the key 3D building block) and 'functionalisation' (to exploit its high reactivity and further increase molecular complexity) are proposed. Highly promising preliminary studies have been carried out which establish the viability of this novel approach; the key dearomatsation step is performed using a very small quantity of a simple copper or silver catalyst and is easy to perform, employing mild conditions and non-toxic reagents. The discovery of a number of extremely versatile one-pot protocols is anticipated. The methods developed will also be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry. The main aims of the proposal are therefore:(i) to establish electrophilic alkyne activation as versatile method for the dearomatisation of heteroaromatics leading to novel spirocycles;(ii) to investigate the use of solid supported catalysts and 'flow' variants of the key dearomatisation / spirocyclisation reaction;(iii) to develop asymmetric variants (building on the 77% ee, 99% yield obtained in preliminary studies);(iv) to exploit the synthetic potential of the 3D 'building blocks' generated by examining additional functionalisation modes, including reactions with a range of nucleophiles, cross-coupling reactions and redox processes;(v) to investigate alternative electrophilic activation modes; (vi) to develop cascade reaction sequences and to apply these methods in target synthesis: Satavaptan, spirobacillene B, plicamine, coerulescine, spirobenzofuran, coixspiroeneones A-E, rychnophylline, mollenine A and cephalotaxine have all been identified as potential natural product/pharmaceutical targets. In addition, medicinal targets suggested by collaborators will also be considered.It is our aim that the dearomatisation/functionalisation protocols will become indispensable tools for the construction of biologically important 3D scaffolds, with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes.This ambitious programme will be carried out by a PDRA over a 3 year period.

设计合成和操纵复杂杂环分子的新方法是极其重要的，特别是考虑到这些化合物构成了大量生物有用的天然产品、药物和作物保护产品的基础。特别是，允许从简单前体快速构建复杂3D分子结构的程序非常重要，因为它们有助于对以前未开发的“化学空间”区域进行潜在应用（例如药物发现）的生物测试。作为我们正在进行的杂环支架合成研究项目的一部分，我们非常重视设计流线型和环境友好的级联和伸缩工艺，从而产生具有生物活性的杂环。这个建议的中心是形成和随后的细化螺旋环3D支架从更简单的，容易获得的2D芳香前体。提出了一系列基于“去芳香化”（形成关键的3D构建块）和“功能化”（利用其高反应性并进一步增加分子复杂性）的两步方案。已经进行了非常有希望的初步研究，确定了这种新方法的可行性；关键的脱芳步骤是使用非常少量的简单铜或银催化剂，使用温和的条件和无毒的试剂，易于执行。预计会发现许多非常通用的一锅协议。所开发的方法也将是对现有的“多样性导向”合成方案的宝贵补充，对学术界和工业界的合成化学家都有很大的用处。因此，该提案的主要目的是：(i)建立亲电炔活化作为杂芳烃脱芳化的通用方法，从而产生新的螺环；（ii）研究固体负载催化剂的使用和关键的去芳香化/螺旋环化反应的“流动”变体；（iii）发展不对称变体（以初步研究中获得的77% ee和99%产量为基础）；（iv）通过研究其他功能化模式，包括与一系列亲核试剂的反应、交叉偶联反应和氧化还原过程，开发3D“构建模块”的合成潜力；(v)研究其他亲电活化模式；（vi）开发级联反应序列并将这些方法应用于靶标合成：沙他伐坦、螺杆菌烯B、plicamine、蓝胺、螺苯并呋喃、coixspiroeneones A- e、茶碱、mollenine A和头孢噻嗪都已被确定为潜在的天然产物/药物靶标。此外，合作者提出的药物靶点也将被考虑。我们的目标是，去芳香化/功能化协议将成为构建生物学上重要的3D支架不可或缺的工具，在学术研究、工业药物化学和规模化过程中具有深远的应用。这一雄心勃勃的方案将由PDRA在三年期间内执行。

项目成果

Catalyst-Driven Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles and Quinolines from Indolyl Ynones.

• DOI: 10.1002/chem.201601836
• 发表时间: 2016-06-20
• 期刊: CHEMISTRY-A EUROPEAN JOURNAL
• 影响因子: 4.3
• 作者: Liddon, John T. R.;James, Michael J.;Clarke, Aimee K.;O'Brien, Peter;Taylor, Richard J. K.;Unsworth, William P.
• 通讯作者: Unsworth, William P.

Divergent Reactivity of Indole-Tethered Ynones with Silver(I) and Gold(I) Catalysts: A Combined Synthetic and Computational Study

• DOI: 10.1055/s-0037-1610181
• 发表时间: 2018-12-01
• 期刊: SYNTHESIS-STUTTGART
• 影响因子: 2.6
• 作者: Liddon, John T. R.;Rossi-Ashton, James A.;Unsworth, William P.
• 通讯作者: Unsworth, William P.

Catalytic Dearomatization Approach to Quinolizidine Alkaloids: Five Step Total Synthesis of (±)-Lasubine II

• DOI: 10.1021/acs.orglett.6b03017
• 发表时间: 2016-12-16
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: James, Michael J.;Grant, Niall D.;Unsworth, William P.
• 通讯作者: Unsworth, William P.