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

基本信息

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

项目摘要

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，医学和材料构成的越来越复杂的综合问题，需要新的反应性概念和策略，以应对这些挑战。但是，我们需要解决这些问题的分子类型，例如单一对映异构体的天然产品或治疗剂，更难以合成。近年来，不对称催化方法已成为建筑复杂分子化学合成的关键因素。这些方法已经解锁了对多种非流行小分子和组成部分的访问，但是使用这些策略在结构和功能上复杂的结构形成是综合中的一种未满足的需求。化学主义者经常努力模仿自然的优雅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，但我们仍然无法接近自然建立这些结构的效率和灵活性（实际上，通过是生物模仿的，综合可能永远不会比大自然更好）。因此，问题变成了，化学家设计的生物活性分子的合成是否可以像自然一样有效吗？此外，我们是否可以提供快速，健壮和有效的方法来综合这些化合物及其类似物的大量且有用的方法；我们可以改善自然的分子建设过程吗？并且我们可以采取下一步了解具有我们需要的任何分子的分子水平的生物学功能。乙酰辅酶A为生物合成分子构建过程提供了一个常见的构建块，这些过程会导致生物碱，类固醇，terpenes和polyketides。该提案概述了“大挑战”综合蓝图的一部分，用于开发新的催化策略，其中简单的功能图案被转换为产生多样的对映射天然产品（如建筑）。 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）。 CED过程的一个关键方面是形成了嵌入了包含有价值的正交功能的复杂结构框架中的第四纪中心。考虑到这一点，我们已经确定了一系列可以通过CED方法的剥削和发展来访问的分子。天然产物的目标包括生物碱，聚酮化合物，类固醇和萜烯生物合成起源的结构，以及复杂的非天然框架，这些框架可能具有有趣的特性，作为新型小分子文库的基础。该提案分为两个客观的研究计划，包括（i）自然产品合成方法（RP1，1B）的开发和（ii）CED作为访问新颖和复杂的分子体系结构（RP2，1C）的平台。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
M. Tissot;Robert J. Phipps;C. Lucas;Rafael León;R. Pace;Tifelle Ngouansavanh;M. Gaunt
通讯作者：
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