New catalytic strategies for chemical synthesis: Catalytic Enantioselective Dearomatization

化学合成的新催化策略：催化对映选择性脱芳构化

• 批准号: EP/I002065/1
• 负责人: Matthew Gaunt
• 金额: $ 79.54万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FI002065%2F1
• 关键词: New; catalytic; strategies; chemical; synthesis

The increasingly complex synthetic problems being posed by nature, medicine and materials, demand new reactivity concepts and strategies in order to meet these challenges. However, the types of molecules that we require to address these issues, for example single enantiomer natural products or therapeutic agents, are significantly more difficult to synthesize. In recent years, asymmetric catalytic methods have become a key factor in chemical synthesis of architecturally complex molecules. These methods have unlocked access to a plethora of non-racemic small molecules and building blocks, however the formation of structurally and functionally complex architectures using these tactics is an unmet need in synthesis.Chemists have often strived to mimic Nature's elegant synthesis machinery in achieving this goal. In spite of some very notable efforts, we still cannot yet come close to the efficiency and flexibility with which Nature builds these structures (in fact, by being bio-mimetic, a synthesis can presumably never be better that nature). So the question becomes, can a chemist design syntheses of bioactive molecules as efficiently as Nature? Moreover, can we provide rapid, robust and efficient methods to synthesize significant and useful amounts of these compounds and their analogues; can we improve on Nature's molecule building process; and can we make the next step in understanding biological function on a molecular level armed with any molecule we require.Acetyl co-enzyme A provides a common building block for the biosynthetic molecule building processes that result in alkaloids, steroids, terpenes and polyketides.7 Remarkably, different enzymes use this acyl-donor in a variety of ways to form the plethora of natural product architectures. This proposal outlines part of a 'grand challenge' synthesis blueprint towards the development of new catalytic strategies, wherein a simple functional motif is transformed to generate a diversity of enantiopure natural product like architecture. This could provide an unprecedented and pioneering strategy to approach the efficiency of Nature with respect to the synthesis of complex molecular architecture (1A).The hypothesis behind our synthesis blueprint involves the development of a catalytic enantioselective dearomatization (CED) process that comprises phenol oxidative dearomatization and organocatalytic desymmetrization, generating highly functionalized, non-racemic architectures (see 1.6). A key aspect of the CED process is the formation of quaternary centres embedded within a complex structural framework containing valuable orthogonal functionality. With this in mind, we have identified a range of molecules that could be accessed through exploitation and developments of CED methodology. The natural product targets encompass structures of alkaloid, polyketide, steroid and terpene biosynthetic origin, as well as complex non-natural frameworks that may have interesting properties as the basis for novel small-molecule libraries. The proposal is split into two objective research plans comprising (i) the development of CED methodology for natural product synthesis (RP1, 1B) and (ii) CED as a Platform to Access Novel and Complex Molecular Architecture (RP2, 1C).

自然、药物和材料带来的日益复杂的合成问题，需要新的反应性概念和策略来应对这些挑战。然而，我们解决这些问题所需的分子类型，例如单一对映体天然产品或治疗剂，明显更难合成。近年来，不对称催化方法已成为化学合成结构复杂分子的关键因素。这些方法已经打开了获得大量非外消旋小分子和构筑块的途径，然而使用这些策略形成结构和功能复杂的结构在合成中是一个未得到满足的需求。化学家们经常努力模仿大自然优雅的合成机制来实现这一目标。尽管有一些非常值得注意的努力，我们仍然无法接近大自然建造这些结构的效率和灵活性(事实上，通过模仿生物，合成可能永远不会比自然更好)。因此，问题变成了，化学家能像自然一样高效地设计生物活性分子的合成吗？此外，我们能否提供快速、可靠和有效的方法来合成大量的这些化合物及其类似物；我们是否可以改进大自然的分子构建过程；我们是否可以在分子水平上进一步了解我们需要的任何分子的生物功能。乙酰辅酶A为生物合成分子构建过程提供了共同的构建块，从而导致生物碱、类固醇、萜类和多酮。7值得注意的是，不同的酶以各种方式利用这种酰基供体来形成过多的天然产品结构。该提案概述了开发新催化策略的“重大挑战”合成蓝图的一部分，在该蓝图中，一个简单的功能基序被转化为产生不同的对映体天然产物，如建筑。这可能提供一种前所未有的开创性策略来接近大自然在合成复杂分子结构方面的效率(1A)。我们合成蓝图背后的假设涉及到催化对映选择性脱芳构化(CED)过程的开发，该过程包括苯酚氧化脱芳构化和有机催化去对称化，产生高度官能化的非外消旋结构(见1.6)。CED进程的一个关键方面是形成嵌入在包含有价值的正交功能的复杂结构框架内的四个中心。考虑到这一点，我们已经确定了一系列可以通过开发和开发CED方法学来获取的分子。天然产物的目标包括生物碱、聚酮、类固醇和萜类生物合成来源的结构，以及复杂的非自然框架，这些框架可能具有有趣的性质，作为新型小分子文库的基础。该提案分为两个目标研究计划，包括(I)开发用于天然产物合成的CED方法学(RP1，1B)和(Ii)CED作为获得新颖和复杂的分子体系(RP2，1C)的平台。

项目成果

Gram-scale enantioselective formal synthesis of morphine through an ortho-para oxidative phenolic coupling strategy.

• DOI: 10.1002/anie.201408435
• 发表时间: 2014-12
• 期刊: Angewandte Chemie
• 作者: M. Tissot;Robert J. Phipps;C. Lucas;Rafael León;R. Pace;Tifelle Ngouansavanh;M. Gaunt

Rapid Generation of Complex Molecular Architectures by a Catalytic Enantioselective Dearomatization Strategy

通过催化对映选择性脱芳构化策略快速生成复杂分子结构

• DOI: 10.1055/s-0035-1560514
• 发表时间: 2015
• 期刊: Synlett
• 影响因子: 2
• 作者: Gaunt M

A counteranion triggered arylation strategy using diaryliodonium fluorides.

• DOI: 10.1039/c4sc02856b
• 发表时间: 2015-02-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Chan L;McNally A;Toh QY;Mendoza A;Gaunt MJ
• 通讯作者: Gaunt MJ