Synthesis of Mono-Boc-2,5-Diketopiperazine: A Key Building Block for Amide and Peptide Synthesis

Diketopiperazine (DKP), a versatile scaffold, is extensively used in the synthesis of complex natural products, bioactive molecules, and smart materials in organic chemistry. Recently, activated DKPs, such as Boc-DKPs, have emerged as key building blocks for peptide elongation in peptide synthesis. In this study, we developed a facile protocol for synthesizing mono-Boc-protected DKPs from readily accessible N-4-methoxybenzyl (N-PMB)-amino acids and amino acid methyl esters. This protocol involved a sequence of reactions encompassing the formation of dipeptides from N-PMB-amino acids and amino acid methyl esters, cyclization of N-PMB-dipeptides to form PMB-DKPs, Boc-protection of PMB-DKPs, and subsequent PMB-deprotection of PMB-DKP-Boc to afford mono-Boc-DKPs. The protocol demonstrated a broad substrate scope, accommodating diverse amino acids with various side chains, affording mono-Boc-DKPs in good yields with excellent stereoselectivities (>20:1 dr). The synthetic utility of mono-Boc-DKPs was showcased in peptide synthesis by synthesizing pentapeptide Boc-l-Tyr(t-Bu)-Gly-l-Phe-Gly-l-Val-OtBu by 2-fold peptide elongation with two mono-Boc-DKPs. Furthermore, we synthesized Leu-enkephalin pentapeptide by reacting cyclo(Boc-l-Tyr(t-Bu)-Gly-) with H-Gly-l-Phe-l-Leu-Ot-Bu, resulting in a good yield and excellent optical purity.