Oxidative processes - from amino acids to heterocycles, complexity from simplicity

氧化过程 - 从氨基酸到杂环，从简单到复杂

基本信息

批准号：
EP/J011355/1
负责人：
Christopher Moody
金额：
$ 43.48万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FJ011355%2F1
关键词：
Oxidative processes amino acids heterocycles

项目摘要

In our search for better medicines to improve healthcare in an ageing population, for safer agrochemicals to aid food production for a growing population, and for improved materials for reprographics and electronics to match our insatiable desire for new technology, chemical synthesis will play a dominant role. Without synthesis the new molecules required to address such issues will simply not be available.In searching for efficiency in synthesis, we can learn much from Nature, whose biochemical machinery can convert simple building blocks into complex molecules. Hence the overall aim of this Proposal is to emulate the ingenuity and efficiency of Nature in the arena of oxidation, a topic that is fundamental not only to chemical synthesis, but to life processes in general. We will develop new strategies using oxidative processes for the construction of complex biologically active molecules that comprise nitrogen-containing (heterocyclic) rings from simple amines or amino acids - complexity from simplicity.Oxidative processes in Nature depend upon oxygen, and therefore we propose to develop new oxidative protocols that use a catalytic amount of a non-metal oxidant, compounds known as quinones, in the presence of air/oxygen as oxidant. This protocol will then be employed in the oxidation of a simple tryptophan tetrapeptide to form more complex molecules that will then serve as precursor to the structurally unique anticancer compound diazonamide A. Two further oxidative processes are then planned to finalise the complete diazonamide framework, an overall increase in complexity from five rings to ten in just three oxidative steps.We will further demonstrate the power of oxidative processes in the synthesis of the unusual heterocycle violatinctamine, a fascinating molecule very closely related to the natural pigments of human red hair. Again, we approach the problem using oxidative transformations of simple building blocks - amines and aminoacids such as dopamine, cysteine and phenethylamines - to form a more complex, and biologically relevant molecule.Natural compounds from the oceans often possess potent medicinal activity, and there are already three marine derived drugs in clinical use. However, full biological evaluation of such natural substances is usually hampered by lack of material, and chemical synthesis is the only recourse to obtain enough material for study. The pterocellins are a case in point. They possess anticancer, antibacterial and antifungal activity, and although they have been obtained by chemical synthesis, a more efficient route is required. We speculate that well known naturally occurring substances known as beta-carbolines serve as precursors to the pterocellins via a series of oxidative processes, and propose to demonstrate this in the laboratory. Thus simple beta-carbolines, readily available from tryptamines, can undergo oxidative transformation into the complex oxygenated structures exemplified by the medicinally active heterocyclic compound pterocellin A.The Proposed Research derives inspiration from natural routes to complex molecules that possess biological activity. Oxidative processes are at the heart of all the proposed work, and feature throughout as pivotal steps, often initiating a cascade of reactions that result in extremely efficient syntheses, embodying the principle of complexity from simplicity. The methodology is illustrated in routes to a range of heterocyclic molecules, a class of compounds of enormous commercial importance. The strategies and chemistry embodied in the Proposal will enable the facile preparation of a wide range of heterocyclic ring systems, and will impact on the UK fine chemicals industry. All concerned with the development of new medicines, agrochemicals, reprographic materials etc, where heterocyclic compounds completely dominate the field, will benefit immediately from the proposed research programme.

在我们寻找更好的药物以改善人口老龄化的医疗保健、寻找更安全的农用化学品以帮助不断增长的人口生产粮食、以及寻找改进的复印和电子材料以满足我们对新技术的永不满足的渴望时，化学合成将发挥主导作用。如果没有合成，解决这些问题所需的新分子将根本无法获得。在寻求合成效率时，我们可以从大自然中学到很多东西，大自然的生化机制可以将简单的构建模块转化为复杂的分子。因此，该提案的总体目标是在氧化领域模仿大自然的独创性和效率，氧化领域不仅对化学合成而且对一般生命过程都至关重要。我们将开发使用氧化过程构建复杂生物活性分子的新策略，这些分子包含由简单胺或氨基酸组成的含氮（杂环）环 - 复杂性来自简单性。自然界中的氧化过程依赖于氧气，因此我们建议开发新的氧化方案在空气/氧气作为氧化剂的情况下使用催化量的非金属氧化剂（称为醌的化合物）。然后，该方案将用于氧化简单的色氨酸四肽，形成更复杂的分子，然后将其作为结构独特的抗癌化合物重氮酰胺 A 的前体。然后计划进行两个进一步的氧化过程，以最终确定完整的重氮酰胺框架，即只需三个氧化步骤，复杂性就从五个环增加到十个。我们将进一步展示氧化过程在合成不寻常的杂环紫丁胺中的威力，这是一种与人类红色天然色素密切相关的迷人分子头发。再次，我们通过简单结构单元（胺和氨基酸，如多巴胺、半胱氨酸和苯乙胺）的氧化转化来解决这个问题，以形成更复杂的、具有生物学相关性的分子。来自海洋的天然化合物通常具有有效的药用活性，并且有已有三种海洋衍生药物投入临床使用。然而，对此类天然物质的全面生物学评估通常因缺乏材料而受到阻碍，化学合成是获得足够研究材料的唯一途径。翼龙素就是一个很好的例子。它们具有抗癌、抗菌和抗真菌活性，尽管它们是通过化学合成获得的，但仍需要更有效的途径。我们推测，众所周知的天然存在的物质β-咔啉通过一系列氧化过程成为翼龙素的前体，并建议在实验室中证明这一点。因此，简单的β-咔啉（很容易从色胺中获得）可以氧化转化为复杂的含氧结构，例如具有药用活性的杂环化合物pterocellin A。拟议研究的灵感来自于具有生物活性的复杂分子的自然途径。氧化过程是所有拟议工作的核心，并且始终是关键步骤，通常引发一系列反应，从而产生极其有效的合成，体现了从简单到复杂的原则。该方法通过一系列杂环分子的路线进行了说明，杂环分子是一类具有巨大商业重要性的化合物。该提案中体现的策略和化学将能够轻松制备各种杂环系统，并将对英国精细化工行业产生影响。所有关注新药、农用化学品、复印材料等（杂环化合物完全主导该领域）开发的人都将立即从拟议的研究计划中受益。