Study and development on the hydroxamation of natural resinic acids: synthesis and computational studies

The hydroxamic acid moiety is part of many bioactive molecules, including several clinical drugs, which can be constructed through, generally, the parent carboxylic acid and a source of hydroxylamine by a variety of methods. Hydroxamic acids compose an remarkable group of N-hydroxy amides with high capacity to chelate certain transition metal ions such as Fe(III), considered siderophores in Nature, and Ni(II), for instance.

During a synthetic program towards the derivatization of natural resinic acids, it was decided to prepare some corresponding hydroxamic acid derivatives with potential biological activity for further studies. There are few reports on hydroxamate-derived terpenoids. It was predicted that adding a hydroxamic acid moiety to the carbon skeleton could enhance the antiproliferative activities or other pharmacological properties, as it occurs in other terpenoid compounds.

In this communication, we describe the several issues that we faced in this generally straightforward conversion. Generally, the carboxylic group needs to be activated towards coupling with hydroxylamine. We screened several methods and realized that the desired conversion is difficult in this kind of substrates. After extensive testing, we propose a new protocol via a phosphate intermediate for better results than standard procedures. A basic computational study on the mechanism of this transformation was also carried out to support our experimental results.