Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

TLDR

The most frequently used reactions are amide bond formation, Suzuki‑Miyaura coupling, and SNAr reactions, driven by reagent availability, chemoselectivity, and delivery pressure. The study aims to encourage the integration of new synthetic methods and novel library design. The authors performed a comparative analysis of reactions used in medicinal chemistry in 2014, 1984, and in natural product total synthesis. The analysis found that none of the most common reactions were discovered in the last 20 years, only Suzuki‑Miyaura and Buchwald‑Hartwig emerged in the 1980s–1990s, indicating a high impact threshold for new reactions, and that reliance on these reactions overpopulates certain molecular shapes while excluding others, as shown by PMI plots.

Abstract

An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.