A facile and effective synthesis of lipophilic 2,6-diketopiperazine analogues

Adamantane and cyclooctane lipophilic 2,6-diketopiperazines (2,6-DKPs) have been prepared by a simple and effective method, including the synthesis of the corresponding iminodiacetic amido-ester derivatives and their intramolecular cyclization. In this method, the key step of the imide formation was accomplished by a novel base-induced cyclization protocol, which involved the treatment of amido-ester 2,6-DKP precursors with potassium bis(trimethylsilyl)amide. Moreover, the cyclization methodology used allowed the synthesis of the respective 1-functionalized 2,6-DKPs in one pot and in excellent yields when the same primary amido-esters were treated with the previous base and the intermediate potassium imidate salts were then reacted with the electrophile benzyl bromoacetate. Hydrogenolysis of the benzyl 2,6-diketopiperazine acetates afforded the respective carboxylic acids, which constitute versatile intermediates in the synthesis of peptidomimetics and other bioactive molecules concerning our pharmacological studies.

Graphical abstractAdamantane and cyclooctane lipophilic 2,6-diketopiperazines (2,6-DKPs) have been prepared by a simple and effective method, including the synthesis of the corresponding iminodiacetic amido-ester derivatives 7-9 and their transformation either into 1-unsubstituted 2,6-DKPs 10-12, by a novel base-induced cyclization protocol in a quantitative yield of isolated products (route A), or into the respective 1-functionalized 2,6-DKPs 13-15 (route B), in one pot and in excellent yields.Download full-size image