Over the past decade, there has been a drive toward accessing compounds with greater molecular complexity within the field of medicinal chemistry. Increases in molecular complexity parameter values, such as number of chiral centers and fraction sp3-character, have been correlated to higher success rates for progressing compounds from discovery, through clinical trials, and ultimately to drug approval. In response to this, an explosion of highly enabling methodologies has been developed for robust and modular sp2-sp3 C-C bond formations. However, one area that remains a challenge is the incorporation of 5-membered heterocycles, such as pyrazoles, as substrates in sp2-sp3 coupling methods. This talk will detail several approaches that were explored to access α-pyrazolyl pyrrolidines that were of interest in a legacy medicinal chemistry program. Viable strategies were prioritized based on results from high throughput experimentation, step count and cost considerations. In situ reaction monitoring, as well as overall route optimization, led to highly robust and scalable syntheses of α-pyrazolyl pyrrolidines that reliably provided access to these key substructures.

Strategies toward robust and scalable syntheses of α-pyrazolyl pyrrolidines

ACS Spring Meeting 2021

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