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

在我们寻找更好的药物来改善老龄化人口的医疗保健，寻找更安全的农用化学品来帮助不断增长的人口生产食品，以及寻找改进的复印和电子材料来满足我们对新技术永不满足的渴望的过程中，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。在寻求合成效率的过程中，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积木转化为复杂的分子。因此，本提案的总体目标是模仿大自然在氧化领域的聪明才智和效率，氧化不仅是化学合成的基础，也是一般生命过程的基础。我们将开发新的策略，利用氧化过程构建复杂的生物活性分子，这些分子由简单胺或氨基酸组成含氮（杂环）环-从简单到复杂。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/氧气作为氧化剂的存在下，使用催化量的非金属氧化剂，即醌类化合物。然后，该方案将用于氧化一个简单的色氨酸四肽，形成更复杂的分子，然后作为结构独特的抗癌化合物重氮酰胺a的前体，然后计划两个进一步的氧化过程来完成完整的重氮酰胺框架，在三个氧化步骤中将复杂性从五个环增加到十个环。我们将进一步证明氧化过程在合成不寻常的杂环异丁胺中的作用，异丁胺是一种与人类红头发的天然色素密切相关的迷人分子。再一次，我们用简单的构建模块——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，形成一个更复杂的、生物相关的分子。来自海洋的天然化合物通常具有强大的药用活性，目前已有三种海洋衍生药物用于临床。然而，由于缺乏材料，对这些天然物质进行充分的生物学评价通常受到阻碍，化学合成是获得足够研究材料的唯一途径。翼状细胞就是一个很好的例子。它们具有抗癌、抗菌和抗真菌的活性，虽然它们是通过化学合成获得的，但还需要更有效的途径。我们推测，众所周知的天然存在的物质，即β -碳碱，通过一系列氧化过程作为翼细胞蛋白的前体，并建议在实验室中证明这一点。因此，从色胺中容易获得的简单的β -碳碱可以经过氧化转化成复杂的含氧结构，例如具有药用活性的杂环化合物紫光细胞a。拟议的研究从具有生物活性的复杂分子的自然途径中获得灵感。氧化过程是所有提出的工作的核心，并且作为关键步骤贯穿始终，经常启动一连串的反应，导致极其高效的合成，体现了从简单到复杂的原则。该方法在一系列杂环分子的路线中得到说明，杂环分子是一类具有巨大商业重要性的化合物。提案中包含的策略和化学将使各种杂环系统的制备变得容易，并将对英国精细化工行业产生影响。所有与开发新药物、农用化学品、复印材料等有关的人，在这些领域中杂环化合物完全占主导地位，将立即从拟议的研究计划中受益。

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.