An Exploration of Helical Asymmetry - Development and Application of Helical Organocatalysts

螺旋不对称性的探索——螺旋有机催化剂的开发与应用

• 批准号: EP/E017495/1
• 负责人: David Carbery
• 金额: $ 25.93万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FE017495%2F1
• 关键词: Exploration; Helical; Asymmetry; Development; Application

Within the biochemical world, the helix is of prime importance. This corkscrew shaped three-dimensional structure is found in two biological polymer systems of vast importance: deoxyribonucleic acid (DNA) and many protein structures. DNA consists of two interwoven strands of polynucleotide groups and form what has become known as the double helix . This helical structure is vitally important for the safe keeping and replication of the genetic code for all life, making the shape of the helix uniquely important. Likewise, many proteins (which act as vital biological catalysts which enable so many of the body's chemical reactions to occur) have large sections that consist of a helical structure. As a result, we can appreciate the importance that this helical shape holds in biological chemistry (i.e. within our bodies). The helix also posses another important attribute. The helix is also known to be chiral, that is, it twists in either a right- or left-hended manner. These two handed twists can not be superimposed upon each other, in the same way human hands cannot be laid upon each other.In contrast to nature, mankind has not utilised this exciting design feature when performing synthetic chemistry; not in the body, but in the laboratory. The ability to form chiral molecules (that is right or left handed compounds) selectively is of huge importance, especially in the context of producing new medicines for society. This point is still pertinent as we are still greatly aware of the horrors that the lack of understanding of chiral molecules caused with the use Thalidomide (one handed form of thalidomide was effective for mothers suffering from morning sickness, the other handed form caused the birth defects of children). This helical concept will be married with the use of organic molecules which can act as molecular catalysts (like a very small enzyme) and form compounds in a selective fashion (one hand in preference to another). Often toxic transition metals are used for such purposes which may also be extremely expensive. Organic catalysts offer the chance of effective, clean and cheap formation of complicated compounds which would be of great benefit in forming new medicinal treatments. It is proposed to incorporate the unique properties of the helix when designing my new organic catalysts. As the helix forms either left or right handed corkscrews it is chiral: if the catalyst incorporates a helix, the catalyst will be chiral and can be used to form chiral molecules selectively, producing one handed form of the product over the other (e.g. left handed in preference to right). The special properties of helical compounds (shape, lack of symmetry and crystallinity) make them perfect targets for new organic catalysts. This proposal is exciting as the concept helical organic catalysts have never been investigated before. This research would offer the chance to investigate whether the special nature of the helix in biology translates to mankind's efforts to make molecules as efficient and selectively as nature can. Can the special feature of the helix in biology work in synthetic chemistry as practised by mankind? If successful, it is envisaged we will be able to synthesise new and complicated amino acids from very inexpensive malonic acid compounds. Such amino acids may be of use in designing new small proteins with potential use in medicine. The benefits to synthetic chemistry could be large. New methods for forming chiral compounds are always required, especially if they are effective and cheap. This may have significant benefits for the pharmaceutical industry in this country and potentially, for medicines in the future.

在生物化学世界中，螺旋是最重要的。这种螺旋形的三维结构存在于两种非常重要的生物聚合物系统中：脱氧核糖核酸（DNA）和许多蛋白质结构。DNA由两条多核苷酸链交织而成，形成了所谓的双螺旋结构。这种螺旋结构对于所有生命的遗传密码的安全保存和复制至关重要，使得螺旋的形状具有独特的重要性。同样，许多蛋白质（作为重要的生物催化剂，使许多身体的化学反应发生）具有由螺旋结构组成的大部分。因此，我们可以理解这种螺旋形状在生物化学中（即在我们体内）的重要性。螺旋结构还有另一个重要的特征。螺旋也被认为是手性的，也就是说，它以右旋或左旋的方式扭曲。这两个手的扭曲不能相互叠加，就像人类的手不能相互叠加一样。与自然相反，人类在进行合成化学时并没有利用这种令人兴奋的设计特征;不是在体内，而是在实验室。选择性地形成手性分子（即右手或左手化合物）的能力非常重要，特别是在为社会生产新药的背景下。这一点仍然是相关的，因为我们仍然非常清楚的恐怖，缺乏了解的手性分子造成的使用沙利度胺（一只手形式的沙利度胺是有效的母亲患有晨吐，另一方面的形式造成的出生缺陷的儿童）。这种螺旋概念将与有机分子的使用相结合，有机分子可以作为分子催化剂（像一种非常小的酶），并以选择性的方式形成化合物（一方面优先于另一方面）。通常，有毒的过渡金属被用于这种目的，这也可能是非常昂贵的。有机催化剂提供了有效、清洁和廉价地形成复杂化合物的机会，这将对形成新的药物治疗非常有益。建议在设计我的新有机催化剂时将螺旋的独特性质结合起来。当螺旋形成左旋或右旋螺旋时，它是手性的：如果催化剂包含螺旋，则催化剂将是手性的，并且可以用于选择性地形成手性分子，产生产物的一种手性形式而不是另一种（例如，左手优先于右手）。螺旋化合物的特殊性质（形状，缺乏对称性和结晶性）使其成为新有机催化剂的理想目标。这一建议是令人兴奋的螺旋有机催化剂的概念从来没有被调查过。这项研究将提供一个机会来研究生物学中螺旋的特殊性质是否会转化为人类努力使分子尽可能有效和有选择性。生物学中螺旋结构的特殊性能在人类所从事的合成化学中发挥作用吗？如果成功的话，我们将能够从非常便宜的丙二酸化合物合成新的复杂氨基酸。这些氨基酸可能用于设计具有潜在医学用途的新的小蛋白质。这对合成化学的好处可能是巨大的。总是需要新的方法来形成手性化合物，特别是如果它们是有效的和便宜的。这可能对该国的制药业以及未来的药品产生重大利益。