Deuterated Alkyl Sulfonium Salt Reagents; Importance of H/D Exchange Methods in Drug Discovery

Abstract

Deuterated drugs (heavy drugs) have recently been spotlighted as a new modality for small-molecule drugs because the pharmacokinetics of pharmaceutical drugs can be enhanced by replacing C-H bonds with more stable C-D bonds at metabolic positions. Therefore, deuteration methods for drug candidates are a hot topic in medicinal chemistry. Among them, the H/D exchange reaction (direct transformation of C-H bonds to C-D bonds) is a useful and straightforward method for creating novel deuterated target molecules, and over 20 reviews on the synthetic methods related to H/D exchange reactions have been published in recent years. Although various deuterated drug candidates undergo clinical trials, approved deuterated drugs possess CD₃ groups in the same molecule. However, less diversification, except for the CD₃ group, is a problem for future medicinal chemistry. Recently, we developed various deuterated alkyl (d_n-alkyl) sulfonium salts based on the H/D exchange reaction of the corresponding hydrogen form using D₂O as an inexpensive deuterium source to introduce CD₃, CH₃CD₂, and ArCH₂CD₂ groups into drug candidates. This concept summarises recent reviews related to H/D exchange reactions and novel reagents that introduce the CD₃ group, and our newly developed electrophilic d_n-alkyl reagents are discussed.

Keywords: Alkylation; Deuteration; Heavy drugs; Kinetic isotope effect; Sulfonium salt.