New catalytic strategies for chemical synthesis: Catalytic Enantioselective Dearomatization

The increasingly complex synthetic problems being posed by nature, medicine and materials, demand new reactivity concepts and strategies in order to meet these challenges. However, the types of molecules that we require to address these issues, for example single enantiomer natural products or therapeutic agents, are significantly more difficult to synthesize. In recent years, asymmetric catalytic methods have become a key factor in chemical synthesis of architecturally complex molecules. These methods have unlocked access to a plethora of non-racemic small molecules and building blocks, however the formation of structurally and functionally complex architectures using these tactics is an unmet need in synthesis.Chemists have often strived to mimic Nature's elegant synthesis machinery in achieving this goal. In spite of some very notable efforts, we still cannot yet come close to the efficiency and flexibility with which Nature builds these structures (in fact, by being bio-mimetic, a synthesis can presumably never be better that nature). So the question becomes, can a chemist design syntheses of bioactive molecules as efficiently as Nature? Moreover, can we provide rapid, robust and efficient methods to synthesize significant and useful amounts of these compounds and their analogues; can we improve on Nature's molecule building process; and can we make the next step in understanding biological function on a molecular level armed with any molecule we require.Acetyl co-enzyme A provides a common building block for the biosynthetic molecule building processes that result in alkaloids, steroids, terpenes and polyketides.7 Remarkably, different enzymes use this acyl-donor in a variety of ways to form the plethora of natural product architectures. This proposal outlines part of a 'grand challenge' synthesis blueprint towards the development of new catalytic strategies, wherein a simple functional motif is transformed to generate a diversity of enantiopure natural product like architecture. This could provide an unprecedented and pioneering strategy to approach the efficiency of Nature with respect to the synthesis of complex molecular architecture (1A).The hypothesis behind our synthesis blueprint involves the development of a catalytic enantioselective dearomatization (CED) process that comprises phenol oxidative dearomatization and organocatalytic desymmetrization, generating highly functionalized, non-racemic architectures (see 1.6). A key aspect of the CED process is the formation of quaternary centres embedded within a complex structural framework containing valuable orthogonal functionality. With this in mind, we have identified a range of molecules that could be accessed through exploitation and developments of CED methodology. The natural product targets encompass structures of alkaloid, polyketide, steroid and terpene biosynthetic origin, as well as complex non-natural frameworks that may have interesting properties as the basis for novel small-molecule libraries. The proposal is split into two objective research plans comprising (i) the development of CED methodology for natural product synthesis (RP1, 1B) and (ii) CED as a Platform to Access Novel and Complex Molecular Architecture (RP2, 1C).

A. THE PHARMACEUTICAL AND BIOTECH INDUSTRIES. 1. The major beneficiaries from this research programme, outside the academic community, will be those working in Medicinal and Process chemistry in the Pharmaceutical, Biotech, and Custom Synthesis Industries. 2. The benefits of this are clear: we can provide knowledge and education for a new chemical methodology that leads to a new drug or a better understanding of a biological process that may ultimately impact strongly in society through a improved treatment of disease. What we can provide to these communities is knowledge and expertise in how to make and design the systems outlined in this proposal. 3. It is essential that we can demonstrate how this new technology will work before others will take it on board. We intend to set up a small representative compound library of CED molecules to use as a validation for finding new molecules that perturb useful biological function. We have an excellent track record of working with industry to educate and interact with them about our new science. For example, we have played a role in moving UK pharma industry to consider metal catalyzed CH activation as a viable technology for the future. B. ACADEMIC RESEARCH. It is clear that academic chemical research in synthetic organic chemistry will benefit from this research due to the development of a new methodology and strategy that will be broadly useful for synthesis. 1. A major beneficiary will be the synthetic, chemical biology community, and those interested in drug discovery and medicinal chemistry as we are providing access to a novel class of complex molecules. 2. They can benefit by using these molecules in their own studies to perturb biological function and to identify leads for new medicines. 3. We will assemble a representative CED library and send it to any academic groups that would be interested. Therefore, we can foster new collaboration if the compounds show interesting activity. C. GENERAL PUBLIC. 1. The research programme also has the potential to benefit the general public and society and this will mainly be realised through a longer-term application in health, towards finding solution to unmet medical needs. 2. This will be realized if any of the compounds that we find lead to the discovery of a new medicine. 3. In order to impact this research on the general public it will be via beneficiaries A and B, essentially through the development of new drugs. The impact in society will be significantly further down the line, but if this chemistry can contribute or lead to the development of a new medicine then we will have achieved truly global impact! D. ECONOMY. This type of ground-breaking research provides the driving force for Britain's 'knowledge-based' economy. 1. The major economic beneficiaries will be the pharmaceutical and biotech sectors, the general public, the University of Cambridge and other academic institutions and the Government. 2. The pharmaceutical and biotech sectors benefit because we will provide them with a new chemical technology that could lead to the discovery of a new medicine. The University of Cambridge benefits in the event that we are able to create a spin out company. Other academic institutions benefit as we will make new compounds available to other research groups that will stimulate new research, and all of the above factors are linked to the benefit to the government as all of these activities will play a role in stimulating growth. 3. We will work with (a) the Pharma, biotech, and academic sectors to help them use our chemistry to discover drugs, ultimately benefitting the public; (b) with Cambridge Enterprise about spin out companies for our research. This would create jobs in an already stagnant chemical sector and provide a further foundation for supporting Britain's knowledge based economy.