Ramakrishna Isai, Boateng Alex, Hattori Tomohiro, Nakagai Kozue, Kawase Masae, Ogata Shinichi, Yamamoto Hisashi
Peptide Research Center, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan.
J Org Chem. 2025 Mar 28;90(12):4357-4364. doi: 10.1021/acs.joc.5c00097. Epub 2025 Mar 17.
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.
二酮哌嗪（DKP）是一种通用的骨架，在有机化学中广泛用于合成复杂的天然产物、生物活性分子和智能材料。最近，活化的DKP，如Boc-DKP，已成为肽合成中肽链延伸的关键构建块。在本研究中，我们开发了一种简便的方法，可从易于获得的N-4-甲氧基苄基（N-PMB）-氨基酸和氨基酸甲酯合成单Boc保护的DKP。该方法包括一系列反应，包括由N-PMB-氨基酸和氨基酸甲酯形成二肽、将N-PMB-二肽环化形成PMB-DKP、对PMB-DKP进行Boc保护以及随后对PMB-DKP-Boc进行PMB脱保护以得到单Boc-DKP。该方法展示了广泛的底物范围，能够容纳具有各种侧链的不同氨基酸，以良好的产率和优异的立体选择性（>20:1 dr）得到单Boc-DKP。通过用两个单Boc-DKP进行两倍肽链延伸合成五肽Boc-l-Tyr（t-Bu）-Gly-l-Phe-Gly-l-Val-OtBu，展示了单Boc-DKP在肽合成中的合成效用。此外，我们通过使环（Boc-l-Tyr（t-Bu）-Gly-）与H-Gly-l-Phe-l-Leu-Ot-Bu反应合成了亮脑啡肽五肽，产率良好且光学纯度优异。
