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CatHet Report Summary

Project ID: 639594
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - CatHet (New Catalytic Asymmetric Strategies for N-Heterocycle Synthesis)

Reporting period: 2015-04-01 to 2016-09-30

Summary of the context and overall objectives of the project

Medicinal chemistry requires more efficient and diverse methods for the asymmetric synthesis of chiral scaffolds. Over 60% of the world’s top selling small molecule drug compounds are chiral and, of these, approximately 80% are marketed as single enantiomers. There is a compelling correlation between drug candidate “chiral complexity” and the likelihood of progression to the marketplace. Surprisingly, and despite the tremendous advances made in catalysis over the past several decades, the “chiral complexity” of drug discovery libraries has actually decreased, while, at the same time, for the reasons mentioned above, the “chiral complexity” of marketed drugs has increased. Since the mid-1990s, there has been a notable acceleration of this “complexity divergence”. Consequently, there is now an urgent need to provide efficient processes that directly access privileged chiral scaffolds. It is our philosophy that catalysis holds the key here and new processes should be based upon platforms that can exert control over both absolute and relative stereochemistry. In this proposal we outline the development of a range of N-heteroannulation processes based upon the catalytic generation and trapping of unique or unusual classes of organometallic intermediate derived from transition metal insertion into C-C and C-N sigma-bonds. We will provide a variety of enabling methodologies and demonstrate applicability in flexible total syntheses of important natural product scaffolds. The processes proposed are synthetically flexible, operationally simple and amenable to asymmetric catalysis. Likely starting points, based upon preliminary results, will set the stage for the realisation of aspirational and transformative goals. Through the study of the organometallic intermediates involved here, there is potential to generalise these new catalysis manifolds, such that this research will transcend N-heterocyclic chemistry to provide enabling methods for organic chemistry as a whole.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Medicinal chemistry requires more efficient and diverse methods for the asymmetric synthesis of chiral scaffolds. There is a compelling correlation between drug candidate “chiral complexity” and the likelihood of progression to the marketplace. Consequently, there is now an urgent need to provide efficient processes that directly access privileged chiral scaffolds. It is our philosophy that catalysis holds the key here and new processes should be based upon platforms that can exert control over both absolute and relative stereochemistry.

Based upon the catalytic generation and trapping of unique or unusual classes of organometallic intermediate, we have developed several new N-heterocyclic methodologies. Key highlights in the current reporting period are:

(1) A new route to 7-membered heterocyclic ring systems has been defined (J. Am. Chem. Soc. 2015, 137, 8054-8057).
(2) A versatile entry to substituted diazepanes has been developed (J. Am. Chem. Soc. 2016, 138, 11465-11468).
(3) Bifunctional amine reagents have been developed in the context of new aza-Heck reactions (Angew. Chem. Int. Ed. 2016, 55, 11198-11202).

The studies summarized above have set the ground work for current research efforts, which will expand considerably the scope of each new approach.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

"The work outlined above has provided new synthetic methodologies that go some way to fulfilling the broad goals of the project (see "Summary of the context and overall objectives of the project"). These methods are likely to be of use to medicinal chemists as they search for new lead compounds in the development of small molecule drug compounds. In each area, the new methodologies are enabled by the identification and development of novel reactivity modes. These reactivity modes are likely to be of interest to other academic researchers and may provide inspiration for the development of further synthetic methodologies. The results achieved so far build towards long term goals of providing general new cycloaddition and cyclisation reactions for the provision of medicinally important N-heterocyclic ring systems."

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