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Title: Asymmetric hydroformylation : a powerful tool for the synthesis of pharmaceutical intermediates
Author: Noonan, Gary M.
ISNI:       0000 0004 2722 432X
Awarding Body: University of St Andrews
Current Institution: University of St Andrews
Date of Award: 2011
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The hydroformylation of unfunctionalised olefins (such as prop-1-ene and oct-1-ene) is an extremely valuable process and is practised on a massive scale industrially in the synthesis of commodity chemicals. In fact, it represents the worlds largest scale application of homogeneous catalysis. As a result, the majority of research carried out on this reaction has been in the study of catalytic systems which provide high rates and selectivity for the production of linear aldehydes from terminal unfunctionalised olefins, with the products finding use in the production of plasticizers and detergents. Asymmetric hydroformylation, the enantioselective variant of this reaction is extremely attractive, as low cost or easily accessible olefins are transformed into highly versatile value-added enantioenriched aldehydes in a single step. However synthetic organic chemists interested in the synthesis of fine chemicals, both in academia and industry, have been slow to adopt this attractive protocol for the production of chiral aldehydes. This is mainly due to the fact that in the past catalysts for this reaction exhibited low activity and/or selectivity in this process. However, the last two decades have seen major advances, mainly in the development of highly effective chiral ligands, and with these developments the time has come to tackle the vastly under-explored area of asymmetric hydroformylation of more functionalised olefins. To set the scene for the research carried out during this project a brief introduction will be given which highlights the historical development of highly efficient catalysts for the hydroformylation of olefins. This will be accompanied by some examples of the use of this methodology in the synthesis of pharmaceutically relevant compounds. It should become apparent from the introduction that the asymmetric hydroformylation of functionalised olefins and in particular nitrogen containing olefins, has received very little attention despite the fact that over half of all medicinal compounds contain at least one nitrogen containing functional group. Firstly we describe hydroformylation as a useful alternative to the classical synthesis of a delicate chiral building block, namely α-formyl amides. These compounds, traditionally only available through multi-step synthetic procedures from enantiopure starting materials, have been accessed by asymmetric hydroformylation of readily accessible and in some cases commercially available acrylamides. By judicious choice of reaction conditions and selection of the appropriately active chiral ligand enantioenriched α-formyl amides (e.e. up to 82%) were produced in high yield. A comparison is made between the classical route and the hydroformylation route to illustrate the potential of this efficient transformation. We have studied the hydroformylation of enamides, a much under-studied substrate class in hydroformylation and developed knowledge of how some more functionalised 1,1- and 1-2-subtituted olefinic amides react under hydroformylation conditions. This research illustrates the work still to be done in terms of development of more active and selective catalysts for this reaction but despite limitations we developed a potential route to gamma amino aldehyde derivatives which could be used in turn in the synthesis of physiologically important gamma amino butyric acid (GABA) derivatives. We provide an example of the highly efficient and selective asymmetric hydroformylation of a bicyclic olefinic lactam, which is of industrial importance in the synthesis of carbocyclic nucleosides. We demonstrate the efficiency of this synthetic methodology by synthesising the central pharmacophore of a potent anti- HSV-1 (herpes simplex virus) carbocyclic nucleoside via a hydroformylationreduction protocol. The classical synthesis of this pharmacophore involves nine synthetic transformations to produce racemic material, whereas the hydroformylationreduction protocol produces highly enantioenriched material in just two steps. We also demonstrate some downstream chemistry of the aldehyde products showcasing the synthetic versatility of the aldehyde functionality in the production of a variety of functionalised cyclopentanes. Finally the synthesis and catalytic testing of a group of novel phosphine-phosphite ligands for use in asymmetric hydroformylation is described, one of which produces unprecedented regioselectivity and state of the art enantioselectivity in the asymmetric hydroformylation of styrene. Highly selective asymmetric hydroformylation of the other two ‘model substrates' in this reaction namely, vinyl acetate and allyl cyanide is also achieved. Having shown high activity and selectivity over these ‘model substrates' this ligand takes its place among the small group of highly active and selective ligands available for asymmetric hydroformylation and may also help to broaden the substrate scope of this efficient and atom-economic transformation.
Supervisor: Clarke, Matt Sponsor: Chirotech Technology Ltd
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Catalysis ; Asymmetric hydroformylation ; Asymmetric synthesis ; Green chemistry