Boronic-Acid-Accelerated Electrophilic Activation of Unprotected Maltols to N-Substituted Hydroxypyridinones in Water.

Di Ke, Lei Zhang, Xiuwen Zhong, Jiaan Shao, Yongping Yu, Wenteng Chen

Organic letters 2022 Feb 18

filter terms:

3,4-Hydroxypyridinone (3,4-HOPO) is a vital metal-chelating pharmacophore. However, the efficient synthesis has been a long-standing problem in drug development. In this paper, we report an efficient electrophilic activation of unprotected maltols via reversible covalent bonds between boronic acid and 3-hydroxyl/4-carbonyl. This one-pot reaction proceeded well on a gram scale in water with excellent efficiencies up to 97%. Moreover, taking advantage of the covalent interactions via the transient boronate, most of the previously tough amine donors, including sterically hindered amines, aromatic amines, and amino acids and amino alcohols, were well-tolerated. Importantly, the potential of this strategy in the pharmaceutical industry was highlighted with a successful synthesis of 3,4-HOPOs containing iron-chelating active pharmaceutical ingredients on 10 g and kilogram scales.

Citation

Di Ke, Lei Zhang, Xiuwen Zhong, Jiaan Shao, Yongping Yu, Wenteng Chen. Boronic-Acid-Accelerated Electrophilic Activation of Unprotected Maltols to N-Substituted Hydroxypyridinones in Water. Organic letters. 2022 Feb 18;24(6):1263-1267