Department of Pharmacology & Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
Department of Chemistry & Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Org Lett. 2024 Oct 18;26(41):8961-8966. doi: 10.1021/acs.orglett.4c03493. Epub 2024 Oct 7.
We report a general approach for efficient deuteration of the metabolically labile α-C-H bonds of widespread amides and amines. Temporarily masking the secondary amine group as a carbamate allows an unprecedented photoredox hydrogen atom transfer-promoted α-carbamyl radical formation for efficient H/D exchange with DO. The mild protocol delivers structurally diverse α-deuterated secondary amines including "privileged" piperidine and piperazine structures highly regioselectively with excellent levels of deuterium incorporation (≤100%). Furthermore, we successfully implemented the strategy for α-deuteration of amides, lactams, and ureas with high regioselectivity and high levels of D incorporation. Finally, the observed efficient deuteration of secondary alcohol moieties in late-stage modification of complex amine-containing pharmaceuticals allows for the development of a viable method for efficient α-deuteration of the important functionality.
我们报告了一种通用的方法，可有效地对广泛存在的酰胺和胺的代谢不稳定的α-C-H 键进行氘代。暂时将仲胺基团掩蔽为氨基甲酸酯，可使前所未有的光还原氢原子转移促进α-氨甲酰基自由基形成，从而与 DO 进行有效的 H/D 交换。该温和的方案提供了结构多样的α-氘代仲胺，包括“特权”哌啶和哌嗪结构，具有高区域选择性和优异的氘掺入水平（≤100%）。此外，我们成功地将该策略用于酰胺、内酰胺和脲的α-氘代，具有高区域选择性和高氘掺入水平。最后，观察到在复杂含胺药物的后期修饰中仲醇部分的有效氘代，为有效α-氘代重要官能团的方法的发展提供了可能。
