Highly efficient enantioselective synthesis of 1,3-disubstituted 2,5-diketopiperazine derivatives via microwave irradiation

Abstract

Chiral 2,5-diketopiperazine (2,5-DKP) derivatives have a broad range of biological activities in the medicinal field. The synthetic protocols of 1,3-disubstituted 2,5-DKPs via base-catalyzed cyclization of chloroacetamide have been reported. However, there are several drawbacks, such as an overly long reaction time, low to moderate yield, and racemization of the products. The sequence modified herein of 1,3-disubstituted 2,5-DKPs involves microwave-assisted cyclization. It increases yields and reduces reaction time. Furthermore, employing N-PMB protection prevents racemization, which frequently occurs in the base-catalyzed cyclization reaction. Consequently, the rapid synthetic method of enantiomerically pure 1,3-disubstituted 2,5-DKPs via microwave reaction was established successfully.

GRAPHICAL ABSTRACT

The key step of the synthetic method

Keywords:

• Chiral
• 1,3-disubstituted 2,5-diketopiperazine (DKP)
• DKP cyclization
• enantiomer
• microwave
• p-methoxybenzyl (PMB) protection

Additional information

Funding

All authors were supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [No. 2016R1D1A1B04932654], and the Ministry of Trade, Industry & Energy, and the Korean Institute for Advancement of Technology through the industrial infrastructure program for fundamental technologies [No. 2014M3A9A9073847] in Korea.