Research Work Plan

ESR1 Project: A Ni-Catalysed Benzannulation to N-Heteroaromatic Boronates (Sheffield)

Aim to i) explore the scope of alkynylboronate cycloadditions with isatoic anhydrides and phthalimides; ii) establish empirical selectivity data relating to the regiochemical insertion of the alkynes in these reactions (regio-chemistry and -selectivity); iii) demonstrate that the products can be exploited in further catalytic cross-coupling processes. The ESR will demonstrate the employment of novel MOF-based Pd catalysts for the cross-coupling of heteroaromatic boronates prepared in this project as part of their Joint Degree Secondment at SU. A further 3-month Industrial Secondment at AstraZeneca will allow the ESR to demonstrate that heteroaromatic boronates prepared here can undergo Suzuki coupling using supported Pd-catalysts under batch and flow regimes to generate novel heterocycle arrays.

ESR2 Project: Computer guided catalyst design for Metal-X Insertion into triple bonds (UPV/EHU)

Aim to i) systematically study by computational means the geometrical and energy features of different metal centres during the insertion step, ii) gather computational data for the influence of different types of ligands on the regioselectivity of the reactions, and iii) check the accuracy of different computational methods and levels to reproduce the experimental results of representative insertion reactions. The ESR will be trained in essential techniques in organic synthesis and computational chemistry, as part of the Joint Degree with the University of Sheffield. A further 3-month Industrial Secondment at Evotec will use DFT methods to build 3D-QSAR models to deliver interesting drug-like molecules.

ESR3 Project: Transition-metal-functionalised metal organic frameworks for tandem catalysis (Stockholm)

Aim to i) synthesise a family of MOFs with different pore sizes that are functionalised with one or two transition metal complexes, ii) characterise the new materials by using different advanced characterization techniques, iii) evaluate the catalytic activity of the new materials in reactions involving the activation or functionalization of C-H bonds leading to C-C and C-X (X = heteroatom) bond-forming reactions and in tandem catalytic reactions, iv) study the mechanisms of the reactions including the study of the role of the MOF. The ESR will demonstrate the suitability of recently developed periodic DFT+D molecular modelling methods for the description of the experimental MOF catalysts synthesized at SU, employing different computational functionals as a way to test and confront the developing DFT+D methods as part of their Joint Degree Secondment at UPV/EHU. The ESR will also gather important information about the effect of pore sizes and transition metals in the efficiency of the projected MOFs, and will apply these theoretical data for the synthesis of improved systems on return to SU. A further 3-month Industrial Secondment at AZ will allow the ESR to evaluate the efficiency of these novel MOFs for conducting catalytic reactions of importance to the fine chemicals industry.

ESR4 Project: A Pd-Catalysed Annulation Strategy to N-Heterocycles (Sheffield)

Aim to i) develop an enantioselective synthesis of functionalised piperidines; ii) explore diastereoselective functionalization reactions of these products; iii) investigate reactions of a catalytically generated dipolar intermediate with acceptor alkenes, expanding the scope of products accessible by this strategy. The ESR will develop a detailed understanding of DFT methods for modelling Pd-pi-allyl complexes bearing phosphoramidite ligands. Empirical data relating to ligand structure and reaction enantioselectivity will be interrogated by theoretical methods in order to devise a model that can be used i) to further improve the efficiency and selectivity of phosphoramidite ligands; ii) identify new ligand types as part of their Joint Degree Secondment at UPV/EHU. A further 3-month Industrial Secondment at Evotec will explore the diastereo- and chemoselective alkene functionalization of spiro- and bicyclic piperidines. Low molecular weight polar fragments will be prepared and their relevance as scaffolds for the synthesis of pharmaceutically relevant intermediates will be assessed.

ESR5 Project: Synthesis of functionalised ketones and related compounds: Enantioselective Synthesis of a-substituted carbonyl compounds (Stockholm)

Aim to i) optimise catalysed tandem isomerization/functionalization reactions of allylic substrates towards the selective synthesis of alpha-substituted ketones and related compounds; ii) explore enantioselective variants using chiral catalyst or substrate control; iii) study the mechanism. The ESR will explore the reactivity of alpha-halocarbonyl compounds and derivatives for the synthesis of heterocyclic molecules as part of their Joint Degree Secondment at USFD. A further 3-month Industrial Secondment at Cambrex will i) perform large scale synthesis of alpha-halocarbonyls and explore the potential of the method to include pharmaceutically relevant substituents; ii) explore the transformation of selected alpha-halocarbonyls into heterocyclic building blocks by condensation with amine donors such as amidines.

ESR6 Project: Asymmetric protonation of enol derivatives

Aim to i) study computationally the optimal conditions for the asymmetric protonation of enol ethers with bifunctional thiourea/catalysts, ii) evaluate experimentally different thioureas, squaramides, and other dual H-bonding compounds as possible catalysts for the asymmetric protonation of enol derivatives iii) develop new H-bonding catalysts with improved features towards the studied reactions. The ESR will evaluate experimentally different thioureas, squaramides, and other dual H-bonding compounds as possible catalysts for the asymmetric protonation of enol derivatives, based on preliminary DFT studies as part of their Joint Degree Secondment at SU. A further 3-month Industrial Secondment at Cambrex will use optimal catalyst systems to prepare enantioenriched heteroaromatic fused ketones, focusing on privileged scaffolds and heterocycles of relevance to CAMBREX programs.