Preparation and Applications of New Highly Active P-Chiral Phosphine Oxide Catalysts

The manufacturing processes that lead to high value fine chemicals used in pharmaceutical and related industrial applications require low-cost, efficient and safe technologies that have minimal environmental impact. Catalytic processes are especially attractive in this respect, and the area of catalytic asymmetric reduction, where the elements of hydrogen gas are added across a suitable substrate with suitable control of the selectivity, has been dominated by the use of transition metal catalysts in conjunction with hydrogen gas. This field is now fairly mature, and although employed in many applications, still suffers from the safety issues associated with using hydrogen gas and the cost and recovery of transition metal catalysts and ligands. In recent years, alternative processes which employ organic molecules as catalysts have become increasingly attractive, using alternatives to hydrogen gas, such as isopropanol and trichlorosilane. Catalysts for the latter are usually classified as Lewis bases and are typically easily accessible, low molecular weight species. Usually just 10% of a catalyst is required to efficiently produce the desired product, usually in excellent yield and selectivity for one isomer over another, although a few catalysts of this class are active enough for only 1% to be employed.
Recent research from our laboratories has developed a catalyst that may be used routinely with only 1% of the active species being employed. More recent work has established an improved catalyst that is two orders of magnitude more active, and with only 0.01% needed, represents the most active catalytic species in the world for this type of transformation. Our unique understanding of the activity of this new catalyst has allowed us to develop new catalyst architectures based on phosphine oxides, a hitherto unexplored class of catalyst for this reaction. This proposal aims to develop efficient chemical methods to prepare these catalysts and then evaluate, optimise and exemplify their use in the preparation of chiral amines, a class of molecule found in around a third of all active pharmaceutical ingredients. In parallel with our current ventures, this new technology could offer an exciting low cost manufacturing solution for the pharmaceutical industry, at the same time reducing the cost and risk of using hydrogen gas and transition metal species. The use of environmentally acceptable solvents, with little waste, further accentuate the benefits of this process.
In parallel with this, we aim to apply these new catalyst species in a selection of varied chemical transformations, thus exemplifying their use as an emerging new class of catalyst.

The primary beneficiaries from this work will of course be the wider academic chemistry community, consisting of scientists in areas as diverse as synthesis (both organic and inorganic), catalysis and polymer chemistry. In addition to the core science behind the proposal, we aim to deliver additional material on reaction mechanisms, the application of this protocol in scale-up situations and reaction diversity of this class of substrate. Within this arena, the researcher working on this project will receive a rich and diverse training in many aspects of modern synthetic chemistry.
The methodology has significant potential to be translated from laboratory scale synthesis to quantities used in manufacturing. If successful, it could signal a substantial step-change in the use of such methodology for the manufacture of related molecules and will continue in this vein with the chemistry described in this work. We will use contacts developed through the S3 network and FusionIP to continue discussions with industrial partners to gain insights into their precise needs and requirements to adopt such technologies. With this knowledge we will be to enable the translation of traditionally 'bench-top' chemistry to manufacturing protocols. This in turn has potential benefit to any downstream users of the technology, especially in the fine chemical manufacturing sector, where catalytic methods of this type have huge potential to provide substantial economic and environmental savings. In this respect, target molecules have already been identified where annual cost savings could amount to six figure sums, with little environmentally harmful waste materials. Depending on the exact nature of the short-term commercialisation plan, the preferred exploitation route for FusionIP might well be through formation of a spin-out company, who will again liaise with appropriate industrial partners, but with the benefit of short to medium term investment and job creation in this area to support the development of an early stage company.
An offshoot of this project will be to act as a personal case study in the development of a schools lectures based on the 'Catalysis' theme to complement those already routinely delivered by the PI. This lecture will show the benefits of using catalysis to prepare molecules and the impact that these molecules have on our everyday lives, from medicines, to herbicides, and the clothes we wear. The long term impact and value of enthusing and informing school children of the importance of chemistry in this respect cannot be understated, and is an pre-requisite for maintaining growth and interest in STEM subject essential for long term economic growth in this area.