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Catalytic Paradigms for 100% Efficient Synthesis

Catalysis will clearly be central to any efforts to address the Grand Challenge. Recent years have seen phenomenal advances in the application of catalysis to complex molecules, with recent Nobel prizes recognising contributions in asymmetric catalysis (Knowles, Noyori and Sharpless, 2001), olefin metathesis (Chauvin, Grubbs and Schrock, 2005) and cross-coupling reactions (Heck, Negishi and Suzuki, 2010).Ā  In the last 5-10 years, enormous advances have been made in the long-held goal of selective C-H functionalization (mainly of aromatic molecules), but there remain significant challenges before these key 21st-century transformative methods can be regarded as robust or mature.

Contemporaneously, the field of organocatalysis has been clearly established as a new paradigm for non-metal catalysis, offering complementary methods with advantages for sustainability and environmental agendas. The issue of sustainability itself presents both a key challenge and opportunity for the development of modern catalysis. Enormous strides have been made in commercial biotechnology (e.g. directed evolution of enzymes, re-engineered biosynthetic pathways) but there remain (and will likely always remain) key constructs and transformations which are beyond the scope of biocatalysis, especially when considering formation of carbon-carbon bonds:Ā  selecting and developing the most appropriate catalyst whether man-made or biological, for each task, and dovetailing these catalytic technologies is key. Shifting landscapes in terms of the economics and acceptability of petroleum-based versus alternative feedstocks will drive new developments, while the long-term security of precious metal supplies creates a further challenge.

Three broad challenge-led focus areas for the catalysis theme have emerged:

The notion underpinning this focus area is that to enable sustainable catalysis with a minimal footprint will require control of selectivity, reactivity and catalyst lifetime. To be truly useful, the design or choice of catalyst for a particular transformation ought to be predictable without recourse to extensive screening regimes. Without a fundamental insight into and understanding of the modes of reactivity (and decomposition) of catalysts and active intermediates on the catalytic cycle, this is unlikely to be achieved.

The ultimate goal of this focus area is to create integrated multi-catalytic systems that are capable of sequentially and controllably processing multiple synthetic operations in a mutually compatible manner to allow complex synthesis to occur with minimal external intervention. One inspiration for this is obviously the biosynthetic machinery operating in nature: here, potentially incompatible chemical transformations are separated by compartmentalisation, with reactive intermediates being passed from one unit to the next. In a chemical sense, remarkable recent progress has been made in automated sequential chemical synthesis, with supported reagents/catalysts/scavengers being physically engineered in sequence to allow a similar in-line synthesis: the quid pro quo for this is the effort expended in delivering the engineering solutions. This theme aims to develop innovative technologies that will underpin the next generations of synthesis with minimal intervention, which may be tagged conveyor belt catalysis.

This focus area aims to define, prioritise and address the key new reactivity principles that will be required to underpin the aims of Dial-a-Molecule. Particularly there is a recognition that most efforts in, for example, C-H activation are directed towards (hetero)aromatic functionalisation and that the overall range of transformations is limited. Additional consideration needs to be given to feedstocks: although petrochemical feedstocks are unlikely to disappear (particularly for high value products) in the lifetime of Dial-a-Molecule, there may be good ethical, commercial, regulatory or practical reasons to utilise sustainable feedstocks, which will require new catalytic technology.