From Process Chemistry to Methodology Development in Metal-Mediated Chemistry and Catalysis

Our research interests focus on development of new methods for the synthesis and use of sulfur-containing compounds, such as thioesters and thioethers. They constitute valuable synthetic intermediates and target compounds for material chemistry and pharmaceutical applications. Our aim is to develop efficient transformations employing non-precious metals as homogeneous catalysts. We have demonstrated the usefulness of thioesters in cross coupling reactions with arylzinc reagents to generate ketones. A defined nickel complex was employed as catalyst and a series of functionalized ketones was successfully obtained. The scope was later expanded to the coupling of thioesters with more reactive organomanganese reagents upon iron catalysis. Furthermore, we developed nickel-catalyzed coupling reactions of challenging aryl chlorides with thiols, whereby max. TOF of 800 h-1 was achieved. A broad scope of substrates containing various functional groups and heterocyclic motifs was successfully converted. Further systematic studies of couplings of sterically hindered aliphatic thiols with a broad range of electrophiles, including ortho-substituted triflates, were conducted.

Discovery Process Chemistry (DPC) is an emerging intersectoral space that is characterized by the development of new chemical reactions or syntheses that enable the efficient elucidation of structure-activity relationships (SARs) and structure-property relationships (SPRs) as well as a rapid transition to process development. Drug discovery and development are accelerated by such efforts and this has led chemists in academia and industry alike to place an increasing importance on these aims. In this seminar, we explore recent advances in DPC and the impact that it can have on SAR/SPR interrogation and downstream drug development efforts.

The direct transfer of a reactive nucleophilic CH2X unit into an existing linkage enables the formal introduction of the moiety with the precisely defined degree of functionalization. Upon the fine tuning of the reaction conditions governing the transformation, the initial homologation event can serve as the manifold for triggering unusual rearrangement sequences leading to complex architectures through a unique synthetic operation. The direct – full chemoselective - conversion of a ketone into the homologated all-carbon quaternary aldehyde (via a), the telescoped homologation of imine-surrogates to quaternary aziridines (via b) and bis-trifluoromethyl-β-diketiminates (via c) will illustrate these unprecedented concepts. Additionally, the homologation of disulfides and thiosulfonates will furnish symmetrical (via d) and unsymmetrical oxothio- and dithio-acetals (via e). The one-step mono-fluoromethylation of carbon electrophiles with extremely labile fluoromethyllithium reagents will provide a novel entry to valuable fluorinated building-blocks without the needing of using protecting elements for fluoro-containing carbanions (via f). Finally, the development of homologation strategies not relying on the use of external C1-sources will be discussed.