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

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 CD groups in the same molecule. However, less diversification, except for the CD group, is a problem for future medicinal chemistry. Recently, we developed various deuterated alkyl (d-alkyl) sulfonium salts based on the H/D exchange reaction of the corresponding hydrogen form using DO as an inexpensive deuterium source to introduce CD, CHCD, and ArCHCD groups into drug candidates. This concept summarises recent reviews related to H/D exchange reactions and novel reagents that introduce the CD group, and our newly developed electrophilic d-alkyl reagents are discussed.