Synthesis of a Diketopiperazine: The Key Structure of the Norgeamide

Overview

Objectives/Goals In early 2006, scientists discovered the Norgeamide; a natural product found in a marine-derived fungus. The Norgeamide has shown some interesting biological activity, such as potential treatments for certain cancers, implying that its synthesis could be of help to the medical world. The natural product itself is extremely scarce in nature and needs to be chemically synthesized. The noregeamide is stereochemically challenging, due to the selective oxidation at the 2-position of the proline, making it difficult for scientists to synthesize. The purpose of this project is to synthesize the key intermediate of the Norgeamide; a diketopiperazine structure. Methods/Materials Starting from commercially available cis-3-hydroxy-L-proline, an esterification reaction resulted in an ethyl ester. This ethyl ester was then coupled with Fmoc protected L-Phenylalanine to result in a dipeptide. Finally, the structure was cyclized to give the hydroxy diketopiperazine intermediate whose structure was confirmed by a single crystal X-ray structure analysis. This compound was dehydrated under Mitsunobu conditions to give the diketopiperazine structure. Results All reactions were carried out with fairly high yields and gave an overall yield of about 41%. Each structure constructed after every reaction was confirmed by structural elucidation techniques such as various NMRs, HPLC, LC-MS, and X-Ray Diffraction. The final product has been achieved and is now an available key intermediate for the construction of the Norgeamide. Conclusions/Discussion The final diketopiperazine 7 has been constructed and is now ready for N-acyliminium ion chemistry to introduce the hydroxyl/methoxyl functionality at the bridge carbon. The scheme for the synthesis was developed through the use of retrosynthetic analysis. This route is general and applicable to the construction of diketopiperazines carrying various substituents at the 4-position. This can be achieved by using suitable amino acids in place of phenylalanine. This synthetic approach could find utility in the total synthesis of norgeamides A and B.