G. Alexander Groß

The Eschenmoser coupling reaction under continuous-flow conditions.

Summary The Eschenmoser coupling is a useful carbon–carbon bond forming reaction which has been used in various different synthesis strategies. The reaction proceeds smoothly if S-alkylated ternary thioamides or thiolactames are used. In the case of S-alkylated secondary thioamides or thiolactames, the Eschenmoser coupling needs prolonged reaction times and elevated temperatures to deliver valuable yields. We have used a flow chemistry system to promote the Eschenmoser coupling under enhanced reaction conditions in order to convert the demanding precursors such as S-alkylated secondary thioamides and thiolactames in an efficient way. Under pressurized reaction conditions at about 220 °C, the desired Eschenmoser coupling products were obtained within 70 s residence time. The reaction kinetics was investigated and 15 examples of different building block combinations are given.

Robotic alliance of miniaturized synthesis and screening: A case study for the identification of histone deacetylase inhibitors

Modern drug development in preclinical pharmaceutics is based on two fundamental processes: library synthesis and screening. Usually, synthesis and screening are separated processes that need a compound storage facility as an interface. Unfortunately, compound storage is a complex process and can lead to compound degradation. For this reason, the chemical identities of found screening hits have to be reanalyzed after the biological screening to be confident. Here, we present a robotic facility that combines solid‐phase one‐bead one‐compound synthesis and screening in a unified workflow using miniaturized formats for on‐demand library synthesis. The technical proof of concept was achieved by an exemplary run that combines the solid‐phase synthesis of a hydroxamate library and the subsequent biological screening for different histone deacetylase activities using a homogeneous fluorescence assay. Compound storage and related processing steps were thus omitted in this way. Technical concepts for all necessary steps and their robotic solutions for the integration of both synthesis and screening processes in one overall workflow are shown in detail. As a result, different enzyme selective histone deacetylase inhibitors were identified using the integrated workflow.