Iridium-catalyzed α-selective deuteration of alcohols

The research group of Hiroshi Naka, associate professor at the Graduate School of Pharmaceutical Sciences, Kyoto University, Taro Udagawa, assistant professor at Gifu University, and Kyoko Maekawa, professor at Doshisha Women's University, has developed an efficient method to exchange hydrogen contained in complex alcohols such as drugs with deuterium. 

Heavy drugs bear deuterium atoms in their active pharmaceutical ingredient and have higher stability towards metabolism in the body as compared with non-deuterated analogs. Accordingly, there are growing expectations for their clinical application as excellent drugs that are effective longer at lower doses and have fewer side effects. Because the position is susceptible to cleavage by metabolism, the carbon−hydrogen bond at the α-position of the hydroxy group in pharmaceutical molecules is an attractive target site for deuteration. However, it has been challenging to synthesize pharmaceutical molecules deuterated only at the α-position of the hydroxy group.

To address this problem, the research group revealed that iridium complex catalysts with functional nitrogen-containing ligands efficiently deuterate a wide range of complex alcohols such as pharmaceuticals using heavy water. Unlike conventional methods, the α-position of the hydroxy group can be preferentially deuterated without being affected by coordinating functional groups contained in the pharmaceuticals. This method has also enabled the efficient deuteration of several drugs and natural products.

The establishment of this direct deuteration technology for complex alcohols has made it possible to introduce deuterium directly into a wide variety of alcohols, including pharmaceuticals. This has dramatically expanded the possibility of creating durable organic molecules without compromising their original properties.

The research results were published online in Chemical Science on July 20, 2022.