Miniaturization of popular reactions from the medicinal chemists’ toolbox for ultrahigh-throughput experimentation

Organopalladium Catalysis as a Proving Ground for Data-Rich Approaches to Reaction Development and Quantitative Predictions

“…While this Perspective showed how organopalladium catalysis has been the proving ground of choice for many data-rich methods, there is nothing inherent about palladium or its reactivity that makes it uniquely suited for these new approaches. Many other reaction classes are well-represented in the chemical literature, and high-throughput experimentation methods are increasingly accessible to many reaction types. , The concepts from the case studies presented here, as well as others from the literature, are applicable to any type of synthetic chemistry. Finally, as remarked throughout, many of the seminal works on data-driven catalysis research are the result of academic/industry collaborations.…”

“…Many other reaction classes are well-represented in the chemical literature, and high-throughput experimentation methods are increasingly accessible to many reaction types. 90,135 The concepts from the case studies presented here, as well as others from the literature, are applicable to any type of synthetic chemistry. Finally, as remarked throughout, many of the seminal works on data-driven catalysis research are the result of academic/industry collaborations.…”

“…Researchers at Merck used a combination of advanced liquid handling automation with rapid UPLC-MS or MALDI-TOF MS analysis to interrogate thousands of Pd-catalyzed C–N coupling reactions in plate-based formats. , Researchers at Pfizer similarly demonstrated a new flow-based HTE platform using Pd-catalyzed Suzuki–Miyaura couplings to run and analyze thousands of examples . In academia, the Cernak group is continuing to push the envelope of ultrahigh throughput methods in array design and execution. − In the area of laboratory automation, the Hein group, in collaboration with Merck and the Aspuru-Guzik and Sigman groups, demonstrated the power of data-dense experimentation in an autonomous optimization of a Pd-catalyzed Suzuki–Miyaura reaction . The Newman group published a user-centered “how-to-HTE” guide on multiwell screening, using a Pd-catalyzed C–N coupling as the prototype reaction .…”

Integrated Direct-to-Biology Platform for the Nanoscale Synthesis and Biological Evaluation of PROTACs

“…This paradigm-shifting publication was the first direct-to-biology process reported and demonstrated how crude assessment of drug-like molecules could accelerate the drug discovery process of kinase inhibitors. Inspired by this work, along with other key advancements in the use of ultraHTE, − we sought to achieve the same throughput but extend biological evaluation to cell-based assays in the context of targeted protein degradation. Janssen recently reported a platform to accelerate PROTAC synthesis with multistep amide coupling chemistry, using scavenging resins to semipurify the reaction mixtures prior to testing, and highlighted how this could be used to assess crucial structure–activity relationships (SAR) in the PROTAC space .…”

Enabling synthesis in fragment-based drug discovery (FBDD): microscale high-throughput optimisation of the medicinal chemist's toolbox reactions

“…To achieve this goal at Astex, we are exploring the use of miniaturised high-throughput experimentation (HTE) to enable rapid multifactorial optimisation of key chemical reactions that are frequently used during F2L. [17][18][19][20][21][22][23][24][25][26][27][28][29][30] Fig. 1 Fragment elaboration occurs along well-defined growth vectors (red arrows) and is often achieved from a pre-functionalised intermediate (e.g., halogenated analogue 1) using palladium-catalysed cross couplings.…”