化学
烷基
硫
杂原子
试剂
动力学同位素效应
合成子
亲核细胞
氘
电泳剂
烷氧基
组合化学
立体化学
药物化学
有机化学
盐(化学)
量子力学
催化作用
物理
作者
Kazuho Ban,Katsuhiko Imai,Shuki Oyama,Jin Tokunaga,Yûji Ikeda,Hiromasa Uchiyama,Kazunori Kadota,Yuichi Tozuka,Shuji Akai,Yoshinari Sawama
标识
DOI:10.1002/anie.202311058
摘要
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 D2 O 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.
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