Synthesis of diketopiperazines with on-resin N-methylation and cyclative release.
Enantiomerically pure N-methylated diketopiperazines (DKP) can be obtained by treating a N-methylated resin-bound dipeptide with 20% piperidine in dimethylformamide via a process known as cyclative release. N-methylated resin-bound dipeptides can be formed from N-methylated precursors or N-methylation can be selectively performed on the resin. When on-resin N-methylation was performed on the C-terminal side of the dipeptide, diastereomers were formed. Yet the cyclative release is shown to be a stereoselective process, as seen using preformed N-methylated amino acids. The procedure was also applied to synthesize the pseudodiketopiperazine cyclo(Phepsi[CH2NH]Leu). When comparing nonmethylated, monomethylated and bismethylated derivatives, we find that N-methylation results in a dramatic increase in solubility.
Brunel
F M
FM
Department of Chemistry and the Institute for Molecular Diversity and Drug Design, University of Louisville, Louisville, KY 40292, USA. brunel@scrips.edu
Spatola
A F
AF
D054659:Diketopiperazines; D015195:Drug Design; D008745:Methylation; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry
D054659:Diketopiperazines; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010879:Piperazines