Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery
Kazuho Ban, Keisuke Imai, Shuki Oyama, Jin Tokunaga, Yui Ikeda, Hiromasa Uchiyama, Kazunori Kadota, Yuichi Tozuka, Shuji Akai, Yoshinari Sawama
Abstract
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 D 2 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‐( d 2 ‐ethoxy)flavone. The present concept for the synthesis of deuterated reagents and the first demonstration of a KIE in a d 2 ‐ethoxy group will contribute to drug discovery research based on deuterium chemistry.