Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery

Abstract

The pharmacokinetics of pharmaceutical drugs can be improved by replacing C-H bonds with the more stable C-D bonds at the α-position to heteroatoms, which is a typical metabolic site for cytochrome P450 enzymes. However, the application of deuterated synthons is limited. Herein, we established a novel concept for preparing deuterated reagents for the successful synthesis of complex drug skeletons with deuterium atoms at the α-position to heteroatoms. (d_n -Alkyl)diphenylsulfonium salts prepared from the corresponding nondeuterated forms using inexpensive and abundant D₂ O as the deuterium source with a base, were used as electrophilic alkylating reagents. Additionally, these deuterated sulfonium salts were efficiently transformed into d_n -alkyl halides and a d_n -alkyl azide as coupling reagents and a d_n -alkyl amine as a nucleophile. Furthermore, liver microsomal metabolism studies revealed deuterium kinetic isotope effects (KIE) in 7-(d₂ -ethoxy)flavone. The present concept for the synthesis of deuterated reagents and the first demonstration of a KIE in a d₂ -ethoxy group will contribute to drug discovery research based on deuterium chemistry.

Keywords: Alkylation; Deuteration; Heavy Drugs; Kinetic Isotope Effect; Sulfonium Salts.