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Catalytic Methods for Sustainable Synthesis. A Merged Experimental and Computational Approach

Periodic Reporting for period 1 - CATMEC (Catalytic Methods for Sustainable Synthesis. A Merged Experimental and Computational Approach)

Reporting period: 2017-01-01 to 2018-12-31

CATMEC addresses smart synthetic route design, development of new catalytic reactions and computer modelling of chemical processes which have all been highlighted in developing and growing the knowledge base in the Fine chemicals sector and Reaction and Process Design while contributing to the goals of sustainability of Europe 2020.

The overall objectives are to:
1. Develop a doctoral programme that addresses interdisciplinary (theoretical and experimental chemistry) and intersectoral experiential development contributing to EU policy objectives in scientific training and degree assessment.
2. To deliver 6 research graduates who will become highly skilled professional researchers in state-of-the-art approaches in catalysis with a platform to advance contemporary chemical science.
3. Apply and develop novel and robust synthetic methods that will contribute powerful new strategies for the discovery of bioactive small molecules.
4. Undertake effective knowledge transfer between the Host and Secondment-Host in both the academic and non-academic sectors, ensuring lasting collaboration beyond the lifetime of the action.
• ESR1 - This project will investigate the formation and benzannulation of aza-metallocycles that are formed from isatoic anhydrides and phthalimides to allow access to heterocyclic boronates that have not yet been prepared by transition metal catalysis.

Preliminary studies on the Ni-catalysed cycloaddition reactions of alkynylboronates have been unsuccessful and the chemistry will be revisited while on Industrial secondment. A different method of making the required boronates using non-transition metal based promoters needed to carry out the cross-coupling work at SU have been achieved. These studies have uncovered an unexpected stereoselectivity which is the result of a dynamic-thermodynamic resolution and the major product has been identified by X-ray crystallography. This may offer access to these important intermediates with control of stereochemistry.

• ESR2 - This project will involve a detailed computational study focused on the M-X triple bond insertion step to help guide the design of more effective and selective catalysts for some transformations in the mechanism of many organometallic catalytic processes.

Computational methods to study insertion reactions of oxygen and nitrogen based nucleophiles into triple bonds, catalyzed by different transition metals have been applied. The gold catalyzed formation of N-heterocycles and other fused derivatives by the adition of amines to alkynes have been experimentally and computationally studied and subsequently prepared. Further studies will be systematically applied to other related systems and metals. Several manuscripts are in preparation.

•ESR3 - In this project, we will investigate the potential of multifunctionalised metal-organic frameworks (MOFs), as catalytic reactors in organic synthesis will be investigated.

The ESR has employed Scanning Electron Microscopy and Powder X-ray Diffraction to analyse different MOFs such as UiO-67, MIL-88B and MIL-101 for the application of the new MOF in the base-cataysed isomerization of allylic alcohols. Promising results in racemic and stereospecific versions have been achieved during the evaluation of commercial DBU immobilized on polystyrene in the isomerization of allylic alcohols. A new organic linker functionalized with DBU has been synthesised and will be used for direct synthesis or post-synthetic modification of new MOFs.

• ESR4 - This project will introduce a new Pd-catalysed annulation strategy for the synthesis of polycyclic piperidines that generates low molecular weight functionalised compounds with the potential to generate sp3-rich products in a stereocontrolled manner.

A new approach to linearly fused heterocycles has been developed and almost complete. The diastereoselective reduction of these products may be achieved through the use of NaBH4 or light promoted reduction processes. Preliminary studies on the enantioselective annulation have been disappointing and products have been isolated with low ee. This will be revisited later in the project using better enantioselectivities after investigation of reactions of a catalytically generated dipolar intermediate with acceptor alkenes to improve understanding. Currently, this method is being used to synthesise an advanced intermediate of an alkaloid natural product. A manuscript in in preparation.

• ESR5 - This project will continue investigations on selective transition metal-catalysed halogenation reactions by applying this methodology to the synthesis of highly substituted α-haloketones and the development of an enantioselective version by using chiral halogenating reagents, chiral ion pairs or using transition-metal complexes bearing chiral ligands.

Optimisation of new methodologies for the synthesis of α-substituted carbonyl compounds has been carried using different electrophiles to understood the reactivity of the isomerization / α-functionalization of allylic alcohols previously developed in the group. Using hypervalent iodine reagents, a methodology is being developed for the synthesis of α-substituted carbonyl compounds from allylic alcohols via umpolung reactivity with different nucleophiles.
To explore enantiospecific variants of this reaction, base-catalyzed isomerization of allylic halides are being carried out. Mechanistic studies as KIE experiments have also been carried out.

• ESR6 - This project applies existing, or new, chiral thioureas, squaramides, and related H-bond donors in combination with achiral, simple Brønsted acids for the asymmetric protonation of enol derivatives in different ways, constituting a powerful strategy that can help make reaction development (discovery) more efficient.

Computational chemistry methodology has been applied to study the alpha-functionalization of enol derivatives in collaboration with the group of Prof. Belén Martín-Matute, where the experimental results are carried out. One manuscript is already under preparation. Experimental efforts have focused on the development of catalytic Pd/Ag processes for the site selective remote C-H functionalization of primary amines, with the intention of exploring the use of H-bonding catalysts (squaramides and thioureas) to develop the asymmetric variant of the process. Future studies will expand the use of these catalysts to other reactions, like the asymmetric protonation of enol derivatives.
CATMEC will offer an excellent and innovative training programme for 6 Early Stage Researchers with complementary, synergistic and multi-disciplinary skills in the scientific fields of synthesis, catalysis and computational studies, within a framework of sustainable chemistry. All ESRs have been jointly enrolled in their home and seconded institutions PhD programme and will follow the standard course of doctoral development with further opportunity to grow their skills and knowledge in non-academic environments offering an aspirational illustration of the opportunities available for young scientists,

The new technologies arising from this EJD have the potential to make a significant impact on the fine chemicals sector by delivering efficient and sustainable methods for the generation of novel small molecules. CATMEC also makes a contribution to the skills shortage in Europe of highly trained chemists.