Network Showcase Presentations

Medicinal Chemistry in 2021: Current Trends and Opportunities to Accelerate Drug Discovery

Keynote Speaker Dr. Stefan Schiesser - CATMEC Supervisory Board

Department of Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca.

In this presentation, Stefan will discuss “Current trends to facilitate drug discovery” including:

“Plate chemistry” and ”off-rate screening”;

High throughput experimentation;

Late-stage functionalization;

Biocatalysis;

Prediction of retrosynthesis & reaction condition; and

Artificial intelligence.

De Novo Catalysts' Design towards Effective Anion-binding and Photocatalysis

Keynote Speaker Prof Dr. Olga García Mancheño - CATMEC Advisory Board

Professor of Organic Chemistry, Organisch-Chemisches Institut,

University of Münster

In this presentation, Olga will discuss two main research themes:

1. AB-Catalyst design and Enantioselective Applications

2. Photocatalyst Design and Synthetic Applications

Synthesis of N-Heteroaromatics and Imine Compounds

ESR 1 Kenji Kopf - MSCA-ITN Early Stage Researcher at The University of Sheffield

Nitrogen-containing compounds are common building blocks for the synthesis of organic compounds. Whether the nitrogen atom is located in a heterocycle or as part of an amine functional group, its derivatives are ubiquitous in agrochemicals and pharmaceuticals and they play a role in the constitution of biologically active compounds. This presentation will cover different routes for the synthesis of nitrogen-containing compounds. In the first project we investigated the development of a new and efficient strategy for the stereoselective synthesis of highly functionalised heteroaromatic compounds. This method comprises two different steps. First, an aza Diels-Alder cycloaddition leading to a difluoroboron intermediate. The substituents on the aryl groups provide atropisomerism, and at this stage it is possible to resolve the atropisomers by reacting this intermediate with a chiral ligand.

The second part of this presentation was conducted at Stockholm University. The goal of this project was to study the photocatalytic oxidative coupling of two different amines catalyzed by the MOF PCN-222(M) [M = Co, Ni, Cu, Zn, Pd] In particular, we wanted to identify which metal (M) on the PCN-222 would give the best performance, with a view to developing a protocol that gives high selectivity (cross-condensation vs self-condensation). This would dramatically increase the scope of the reaction, as well as the utility of the process. We also wanted to identify the advantages of using the current method compared to those described in the literature.

A Computational understanding of organocatalysed asymmetric α-functionalisation reactions

ESR 2 Giovanna Zanella - MSCA-ITN Early Stage Researcher at UPV/EHU

Asymmetric catalysis consists in the formation of an asymmetric environment in order to introduce chirality into the product of the reaction. Asymmetric organocatalysis, together with transition metal catalysis and enzymatic transformations, is one of the main approaches used for the enantioselective synthesis of organic compounds.

In this presentation, a synergistic experimental and computational study of asymmetric catalysed α-functionalisation of carbonyl compounds is presented. In particular, the reactivity of α-substituted dienolates and trienolates is examined. The use of a bifunctional Brønsted base/H-bond donor ensures the formation of the product with high enantioselectivity. The computational analysis provides insights on the interactions between the catalyst and the substrates, as well as on the reactivity of the substrates.

DFT Calculations for the Metal-free Isomerization of Polyenol Ethers

ESR 3 Alba Carretero Cerdán - MSCA-ITN Early Stage Researcher at Stockholm University

In 2016 our group described a metal-free protocol for the isomerization of allylic alcohols and ethers using a simple guanidine base (triazabicylodecene, TBD) as catalyst. Our group extended the protocol to other conjugated systems such as dienyl alkyl dienols and ethers. These unsaturated moieties are present in a great number of natural products and pharmaceuticals.

In this presentation, a computational study of conjugated polyenyl ethers is presented. DFT calculations revealed that the reaction followed a [1,3]-proton shift or a direct [1,n]-proton shift. The activation energies involve in the reaction are very similar which suggest that all the possible adducts formed in the reaction are under thermodynamic equilibrium. For that, the product distribution will depend on the relative energy difference between them. A kinetic simulation showed that the reaction goes till the formation of the most thermodynamically stable product and a theoretical study of the Kinetic Isotope Effect (KIE) confirmed that the rate-determining step (RDS) is the deprotonation step.

A Pd-Catalysed [4 + 2] Annulation Strategy to Densely Functionalised N-Heterocycles

ESR 4 Larry Hoteite - MSCA-ITN Early Stage Researcher at the The University of Sheffield

This presentation describes a palladium-catalysed allylation-condensation sequence that allows the synthesis of a library of novel sp3-rich N heterocycles containing orthogonal functionality. The employment of a readily available cyclic carbamate in the presence of a palladium catalyst generates a palladium-stabilised zwitterion, which reacts with a wide range of carbonyl substrates to provide the corresponding α-allylated compounds. These products can be further converted into six-membered N heterocycles through a TFA mediated deprotection-condensation step.

The scope of this methodology to 1-aryl-2-indanones, 1-aryl-2-tetralones, α-fluoro-β-ketoesters and α- trifluoromethylthio-ketones is discussed, and the potential of the final heterocyclic compounds to undergo further derivatisation is demonstrated.

Stereospecific Isomerization of Allylic Halides through Chiral Ion Pairs

ESR 5 Victor García Vázquez - MSCA-ITN Early Stage Researcher at Stockholm University

The base-catalyzed isomerization of allylic alcohols and ethers have been recently reported in our group under metal-free conditions. Importantly, starting from chiral allylic alcohols and ethers, the simple guanidine type base TBD (triazabicyclodecene) showed high levels of chirality transfer. Using this methodology, we have been able to synthesize g-trifluoromethylated ketones and ethers with excellent enantiomeric excesses.

Here we report the applicability of this methodology to other allylic systems. In particular, after developing a regioselective protocol for the synthesis of allylic chlorides, bromides and fluorides, the base-catalyzed isomerization of these substrates has been studied. Remarkably, when the optimized conditions were applied to enantiomerically enriched allylic chlorides, the formation of chiral ion pairs resulted on outstanding levels of chirality transfer.

Computational studies on umpolung strategy reactions

ESR 6 Martin Pauze - MSCA-ITN Early Stage Researcher at UPV/EHU

In this presentation, mechanistic investigations using Density Functional Theory (DFT) on two different experimental organic reactions are presented.

In the first part, the formation of esters in a three-component reaction, namely terminal alkynes with CO2 and organochlorides, is presented. The mechanism has been investigated by DFT. A better comprehension of the reaction is attained. The limitations of the reaction have been explained thanks to the comparison of the different transition state energies.

The second part concerns an umpolung a-functionalization of allylic alcohols in a domino reaction. As a new synthetic method, the mechanism elucidation had not been performed yet. By using DFT studies, an understanding of the mechanism and of the selectivity of the reaction was obtained.

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