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 3 groups in the same molecule. However, less diversification, except for the CD 3 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 D 2 O as an inexpensive deuterium source to introduce CD 3 , CH 3 CD 2 , and ArCH 2 CD 2 groups into drug candidates. This concept summarises recent reviews related to H/D exchange reactions and novel reagents that introduce the CD 3 group, and our newly developed electrophilic d n -alkyl reagents are discussed.