Hydrogenation of ketones without transition metal catalysts.

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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.