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. (dn‐Alkyl)diphenylsulfonium salts prepared from the corresponding nondeuterated forms using inexpensive and abundant D2O as the deuterium source with a base, were used as electrophilic alkylating reagents. Additionally, these deuterated sulfonium salts were efficiently transformed into dn‐alkyl halides and a dn‐alkyl azide as coupling reagents and a dn‐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.

Single Electron Transfer Reductive Deuteration of Acyl Chlorides for the Synthesis of Deuterated Alcohols with a High Deuterium Atom Economy

“…Deuterated compounds have long been recognized for their widespread applications, serving as internal standards in liquid chromatography–mass spectrometry (LC–MS) analysis, − unique probes in the fields of metabolism and toxicology studies, , and powerful tools for investigating chemical reaction mechanisms. , Recently, deuterium-labeled drugs have gained significant interest because site-specific deuteration offers an opportunity to improve pharmacokinetic profiles, reduce toxicity, and strengthen chiral centers prone to racemization . Following the approval of the United States Food and Drug Administration (FDA) of deutetrabenazine in 2017, an increasing number of deuterated drugs have entered clinical trials. − However, the high costs associated with deuterated compounds, stemming from the low deuterium atom economy of current synthetic methodologies available, pose a significant impediment to their widespread utilization in cost-sensitive fields, such as agrochemicals. , …”