Hydrogenation of ketones without transition metal catalysts.

无需过渡金属催化剂的酮氢化。

• 批准号: EP/G036993/1
• 负责人: Martin Wills
• 金额: $ 17.1万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FG036993%2F1
• 关键词: Hydrogenation; ketones; without; transition; metal

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.

许多分子有可能以两种镜像形式存在，称为“对映体”（就像你的手）。最重要的是，构成生物有机体（细胞、动物、植物和人类）的大部分分子，包括碳水化合物、蛋白质和DNA，主要以单一对映体形式存在，即作为单一镜像。这给制药、农化和精细化工行业带来了一个具有挑战性的问题。如果一种新的化学物质被制造出来，例如一种潜在的药物、农药、中间体等，那么它也可能以对映体的混合物的形式存在，这取决于它的结构。尽管这些分子在很多方面是相同的（就像你的手一样），但它们与生物系统的相互作用可能非常不同（例如，如果我们吞下它们），因为它们会被视为两种完全不同的化合物（试着先和朋友的右手握手，然后再和他们的左手握手）。然而，生物效应的差异可能是如此之大，以至于现在法律要求化学公司以每种“手性”分别制造所有新的“对映体”化合物，并测试每种对映体的安全性和活性（有时只有一种对映体作为药物起作用，有时一种对映体是危险的，而另一种是有益的）。此外，“对映体”化合物通常也有必要以单（即最有益的）手性销售。问题是，这个看似简单的任务实际上往往相当困难，因为大多数生成新化合物的最常见和最简单的途径都会形成两种“对映体”的50:50混合物。这类似于抛硬币——当每个分子都被制造出来（每次抛硬币），那么就有50:50的机会产生任何一个手性。为了得到一个“单手性”的产物，有必要使每个分子都以相同的方式转动（每次翻转正面，或每次翻转反面）。在我们沃里克大学的研究中，我们开发了一系列催化剂，通过一个单步过程产生“对映体”分子，在这个过程中，氢被选择性地添加到底物中，从而得到一个手性明显优于另一个手性的产物（即它翻转的正面多于反面，反之亦然）。然而，迄今为止我们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，如果它们要用作药物或供人类或动物使用，就必须小心地从产品中去除所有痕量的过渡金属。该项目的目标是为上述对映体反应（即手选择性）开发新的催化剂，这些反应含有更多的良性金属来代替过渡金属。这些可能是，例如，钠，钾或铁为基础的，尽管要测试的金属范围很广。在这项提议中有文献先例，这表明该过程在高温高压下是可行的，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，以便使该过程更加通用。除了对催化剂进行改性以获得高反应速率和最高的选择性（对于产物的单“手性”）外，还可以制备各种各样的产物。提出的靶标化合物代表了广泛的生理重要靶标，包括几种具有有用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。

项目成果

Development of catalysts for asymmetric hydrogenation

不对称加氢催化剂的开发

• 发表时间: 2013
• 作者: Jolley Katherine E.

Synthesis of Enantiomerically Pure and Racemic Benzyl-Tethered Ru(II)/TsDPEN Complexes by Direct Arene Substitution: Further Complexes and Applications

• DOI: 10.1021/acs.organomet.7b00731
• 发表时间: 2018-01
• 期刊: Organometallics
• 影响因子: 2.8
• 作者: R. Soni;Katherine E. Jolley;S. Gosiewska;G. Clarkson;Z. Fang;T. H. Hall;Ben N. Treloar;Richard C. Knighton;M. Wills

Tethered Ru(II) catalysts containing a Ru-I bond

• DOI: 10.1016/j.jorganchem.2014.10.033
• 发表时间: 2015-01-15
• 期刊: JOURNAL OF ORGANOMETALLIC CHEMISTRY
• 影响因子: 2.3
• 作者: Jolley, Katherine E.;Clarkson, Guy J.;Wills, Martin
• 通讯作者: Wills, Martin