Hydrogenation of ketones without transition metal catalysts.

许多分子有可能以两种镜像形式中的一种存在，即所谓的“对映体”(就像你的手一样)。最重要的是，构成生物有机体(细胞、动物、植物和我们)的很大一部分分子，包括碳水化合物、蛋白质和DNA，主要以单一的对映体形式存在，即以单一镜像存在。这给制药、农用化学品和精细化工行业带来了一个具有挑战性的问题。如果制造了一种新的化学品，例如潜在的药物、杀虫剂、中间体等，那么根据其结构，这可能也必须以对映体的混合物的形式存在。尽管这些分子在许多方面都是相同的(就像你的手一样)，但它们与生物系统的相互作用很可能是非常不同的(例如，如果我们吞下它们)，因为它们将被视为两种完全不同的化合物(试着与朋友的右手握手，然后与他们的左手握手)。然而，生物效应的差异可能如此之大，以至于现在法律要求化学公司在每一种手性药物中分别制造所有新的“对映体”化合物，并测试每一种化合物的安全性和活性(有时只有一种对映体起到药物的作用，有时一种是危险的，另一种是有益的)。问题是，这项(看似容易的)任务实际上往往是相当困难的，因为大多数获得新化合物的最常见和最简单的途径形成了两种‘对映体’的50：50的混合物。这类似于抛硬币--当每个分子都被制造出来时(硬币的每一次抛出)，那么产生任何一种用手的可能性都是50%。为了得到一种“惯用手”的产物，有必要让每个分子都以相同的方式旋转(每次翻转头部，或每次翻转尾巴)。在我们在Warwick的研究中，我们开发了一系列催化剂，通过一步法有选择地将氢添加到底物中以生成一种左手显著高于另一手的产品(即，它翻转的正面比反面更多，反之亦然)。然而，我们迄今开发的催化剂的一个缺点是它们是基于相对有毒的过渡金属，如果要用作药物或用于人类或动物，必须小心地从产品中去除所有痕量的过渡金属。本项目的目标是开发用于上述对映体反应(即手性选择性)反应的新催化剂，这些反应包含更多的良性金属来代替过渡金属。例如，这些金属可能是钠、钾或铁基的，尽管需要测试的金属范围很广。这项提议中的工作有文献先例，这表明该过程在高温和高压下是可行的，使用钾作为中心金属。在这个项目中，我们的目标是制备在更低的温度和压力下具有活性的新配体，以使该过程更加通用。同时，我们还将对催化剂进行改进，以获得高反应速率和高选择性(对于产物的一种利手)，并将制备范围广泛的产品。所提出的目标化合物代表了广泛的生理上重要的目标，并包括几个具有有用的生物学特性的化合物。所选择的酮代表了一系列不同的底物(因此确保了该项目的最大效益)，并包括一些特别具有挑战性的分子，目前还没有令人满意的方法。

Many molecules have the potential to exist in one of two mirror image forms, known as 'enantiomers' (like your hands). Most significantly, a large proportion of the molecules from which biological organisms (cells, animals, plants, us) are made, including carbohydrates, protein and DNA, exist predominantly in a single enantiomeric form, i.e. as a single mirror image.This creates a challenging problem for the pharmaceutical, agrochemical and fine chemicals industries. If a new chemical is made, e.g. a potential drug, pesticide, intermediate etc., then this may also have to potential to exist as a mixture of enantiomers as well, depending on its structure. Although these molecules will be identical in many ways (as your hands are), they are likely to interact very differently with a biological system (i.e. if we swallow them), because they will be seen as two totally different compounds (try shaking hands with a friend's right hand and then with their left hand). The difference in biological effects, however, can be so great that now it is a legal requirement for chemical companies to make all new 'enantiomeric' compounds separately in each 'handedness' and to test each of these for safety and activity (sometimes only one enantiomer works as a drug, sometimes one is dangerous and one is beneficial). Furthermore, it is also often necessary for 'enantiomeric' compounds to be marketed in the single (i.e. most beneficial) handedness.The problem is that this (seemingly easy) task is in fact often quite difficult, because most of the most common and simple routes to new compounds form a 50:50 mixture of both 'enantiomers'. This is analogous to flipping a coin - as each molecule is made (each flip of the coin) then there is a 50:50 chance of making either handedness. To get a product of one 'handedness' it is necessary to make every single molecule the same way round (flip a head every time, or a tail every time). In our research at Warwick, we have developed a series of catalysts which generate 'enantiomeric' molecules through a single step process in which hydrogen is selectively added to a substrate to give a product in which one handedness significantly predominates over the other (i.e. it flips more heads than tails, or vice versa). However a drawback of the catalysts that we have so far developed is that they are based on relatively toxic transition metals, all traces of which must be carefully removed from the products if they are to be used as a drug or for human or animal use.The objective of this project is to develop new catalysts for the enantiomeric reactions (i.e. hand selective) reactions described above which contain more benign metals in place of the transition metals. These might be, for example, sodium, potassium or iron based, although a wide range of metals shall be tested. There is literature precedent for the work in this proposal, which indicates that the process is viable at high temperatures and pressures using potassium as the central metal. In this project we would aim to prepare new ligands which are active at much lower temperatures and pressures, in order to make the process more versatile.As well as modifying the catalyst so that the high reaction rates and highest selectivity (for one 'handedness' of product) can be obtained, a broad range of products will be prepared. The proposed target compounds represent a wide range of physiologically-important targets and include several compounds which have useful biological properties. The selected ketones represent a range of diverse substrates (hence ensuring the maximum benefit from the project) and include a number of particularly challenging molecules for which no satisfactory methods currently exist.