The Project


Research Axis #1: Molecular Diversity via Direct Functionalization

Objective: speed up the synthesis of drug candidates for structure-activity studies and devise new synthetic protocoles to rapidly convert a molecule into a large panel of biologically relevant derivatives, including regioisomeric and enantiopure compounds.

Research topics:

  • late-stage diversification of advanced molecules
  • remote functionalization using transient directing groups synthesis of chiral aliphatic motifs via asymmetric C-H activation

ESR: Dehang Yin
PI: Dr. J. Wencel-Delord
Host institution: CNRS / Unistra
Secondments: AstraZeneca, Syngenta

The aim of the project is to develop new chiral ligands promoting highly stereo-discriminant metalation of small alkane motifs of interest for the industrial partners. The attention will be focused on direct enantioselective functionalization of scaffolds bearing cycloalkane motifs. Once functionalization of simple substrates is achieved, the newly developed catalytic systems will be used, in collaboration with AstraZeneca and Syngenta, for late stage functionalization drug- and agrochemical-like molecules.

PI: Prof. F. Schoenebeck; AI: Dr I. Funes-Ardoiz
Host institution: RWTH
Secondments: AstraZeneca, Syngenta

The project focuses on the fundamental modelling and mechanistic studies on transient templates for remote C-H activation, from both a synthetic and computational point of view. In close collaboration with Janis Zakis (ESR 13), [ESR 3]’s aim is to model a template prompt to in-situ install on a substrate via imine formation and direct C-H activation at meta position, then re-optimizing said template following experimental results of Janis Zakis (ESR 13); identify key parameters controlling remote C-H activation and design a library of transient templates for meta- and para- functionalization.

In addition, collaboration with Nanditha Narayanan (ESR 5) aims at investigating the methylation procedure with state-of-the art computational methods.

ESR: Nanditha Narayanan
PI: Prof. M. Schnürch
Host institution: TUWien
Secondment: Boehringer-Ingelheim
This project focuses on the selective exploitation of DG for C-H functionalization, through careful optimization of the reaction conditions. An orthogonal set of reaction conditions for direct C-H functionalization in presence of multiple functional groups will be developed and exploited in complex and biologically relevant molecules. Nanditha will initially focus on a set of frequently applied DGs and develop selective reaction conditions, focusing on using abundant 3d-metals, first in intermolecular and then in intramolecular competition experiments of model substrates.

PI: Dr. M. J. Johansson
Host institution: AstraZeneca

Secondments: UGOE, IST

This project aims to discover new synthetic transformations for chemo-selective C-H functionalization, using earth abundant catalysts, with a focus on commercial drugs or drug-like motifs.

Late stage functionalization will be achieved using a specific coordinating moiety inherently present in a scaffold, and employing known literature protocole: couplings (e.g. arylation, acetoxylation, halogenation, etc.) will be performed to access a large library of analogues. High throughput experimentation will be performed to identify suitable catalytic systems. The biological activity along with physical, chemical and DMPK properties of newly accessed derivatives will be assessed.

ESR:  Janis Zakis
PI: Dr. T. Šmejkal
Host institution: Syngenta
Secondments: RWTH, UZH

Novel catalytic methodologies will be developed using innovative (asymmetric) C-H activation strategies, including transient Directing Group (DG) approach. In close collaboration with [ESR 3], Janis works on the design of transient DGs (in-situ temporarily installed on a substrate to allow metalation at meta-position); the elucidation of key parameters governing regioselectivity of such transformations; the meta-selective functionalization, followed by recovery of a transient DG; the design of a library of several transient meta- and para-directing auxiliaries; the development of a protocol compatible with 3d metals (in collaboration with [ESR 9]); and the application of the developed catalytic systems for rapid exploration of the chemical space enabling biological screen and structure-activity Relationships.