Abstract
Cross-coupling reactions have played a critical role enabling the rapid expansion of structure–activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in the pharmaceutical industry, becoming one of the most used approaches from Lead Generation to Lead Optimization. In this mini-review, we present an overview of cross-coupling reaction applications to medicinal chemistry efforts, in particular the Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions as a remarkable resource for the generation of carbon–carbon and carbon–heteroatom bonds. To further appreciate the impact of this methodology, the authors discuss some recent examples of clinical candidates that utilize key cross-coupling reactions in their large-scale synthetic process. Looking into future opportunities, the authors highlight the versatility of the cross-coupling reactions towards new chemical modalities like DNA-encoded libraries (DELs), new generation of peptides and cyclopeptides, allosteric modulators, and proteolysis targeting chimera (PROTAC) approaches.
Highlights
Cross-coupling reactions have made an impressive impact in medicinal chemistry, and drug discovery and development for more than two decades
Due to its bench high reactivity, palladium was considered the preferred metal for cross-coupling reactions, and is stability and high reactivity, palladium was considered the preferred metal for cross-coupling utilized reactions, in a routine basis across medicinal chemistry therapeutic areas. chemistry therapeutic areas
Palladium cross-couplingreactions reactions have a profound impact thediscovery drug discovery phase, the rapid functionalization of key precursors and exploration of structure–activity relationships (SAR), as we have reviewed several cases enabling the rapid functionalization of key precursors and exploration of SAR, as we have reviewed in previous sections
Summary
Cross-coupling reactions have made an impressive impact in medicinal chemistry, and drug discovery and development for more than two decades. We want to highlight the impactful applications of cross-coupling reactions in medicinal chemistry with a few recent examples from the field, with an emphasis on the Suzuki–Miyaura and Buchwald–Hartwig methodologies due to their versatility to generate carbon–carbon and carbon–heteroatom bonds and their prevalence as Molecules 2020, 25, 3493; doi:10.3390/molecules25153493 www.mdpi.com/journal/molecules. To its bench stability and that other organometallic reagents could be used instead of Due. Due to its bench high reactivity, palladium was considered the preferred metal for cross-coupling reactions, and is stability and high reactivity, palladium was considered the preferred metal for cross-coupling utilized reactions, in a routine basis across medicinal chemistry therapeutic areas. Due to its bench high reactivity, palladium was considered the preferred metal for cross-coupling reactions, and is stability and high reactivity, palladium was considered the preferred metal for cross-coupling utilized reactions, in a routine basis across medicinal chemistry therapeutic areas. chemistry therapeutic areas
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