傳統(tǒng)C→N肽化學(xué)合成的過程包括$α-$氨基酸的氨基保護(hù)、羧基激活、與肽鏈游離氨基的氨解反應(yīng)以及N-末端去保護(hù)。這種方法因?yàn)閺?qiáng)制使用α保護(hù)基而導(dǎo)致步驟和原子使用效率低下。

隨著肽類藥物市場的迅猛增長，人們迫切需要成本低廉且環(huán)境友好的生產(chǎn)策略。

提出使用未保護(hù)氨基酸的反向肽化學(xué)合成作為理想策略，但60多年來由于嚴(yán)重的外消旋/表里異構(gòu)化問題而未能成功。

本研究通過使用ynamide偶聯(lián)試劑和瞬時保護(hù)策略，成功地解決了N→C肽鏈延長過程中的外消旋/表里異構(gòu)化問題。

實(shí)現(xiàn)了激活、瞬時保護(hù)、氨解和原位去保護(hù)步驟的一鍋合成，有效利用了未保護(hù)氨基酸作為起始物料。

這項(xiàng)研究提出了一種成本效益高、操作簡便且環(huán)境友好的肽類制備新方法。

Peptide therapeutics have experienced a rapid resurgence over the past three decades. While a few peptide drugs are biologically produced, most are manufactured via chemical synthesis. The cycle of prior protection of the amino group of an α-amino acid, activation of its carboxyl group, aminolysis with the free amino group of a growing peptide chain, and deprotection of the N-terminus constitutes the principle of conventional C → N peptide chemical synthesis. The mandatory use of the Nα-protecting group invokes two additional operations for incorporating each amino acid, resulting in poor step- and atom-economy. The burgeoning demand in the peptide therapeutic market necessitates cost-effective and environmentally friendly peptide manufacturing strategies. Inverse peptide chemical synthesis using unprotected amino acids has been proposed as an ideal and appealing strategy. However, it has remained unsuccessful for over 60 years due to severe racemization/epimerization during N → C peptide chain elongation. Herein, this challenge has been successfully addressed by ynamide coupling reagent employing a transient protection strategy. The activation, transient protection, aminolysis, andin situdeprotection were performed in one pot, thus offering a practical peptide chemical synthesis strategy formally using unprotected amino acids as the starting material. Its robustness was exemplified by syntheses of peptide active pharmaceutical ingredients. It is also amenable to fragment condensation and inverse solid-phase peptide synthesis. The compatibility to green solvents further enhances its application potential in large-scale peptide production. This study offered a cost-effective, operational convenient, and environmentally benign approach to peptides.

 過去三十年里，肽類藥物經(jīng)歷了迅速的復(fù)興。雖然少數(shù)肽藥物是通過生物方式生產(chǎn)的，但大多數(shù)是通過化學(xué)合成制造的。α氨基酸的氨基保護(hù)、其羧基激活、與生長中的肽鏈的游離氨基進(jìn)行氨解以及N-末端的去保護(hù)構(gòu)成了傳統(tǒng)C→N肽化學(xué)合成的原理。$Nα-$保護(hù)基的強(qiáng)制使用使得每加入一個氨基酸就需要進(jìn)行兩個額外操作，導(dǎo)致較差的步驟和原子經(jīng)濟(jì)性。肽類藥物市場的迅猛需求促使人們需要成本效益高和環(huán)境友好的肽制造策略。使用未保護(hù)的氨基酸進(jìn)行反向肽化學(xué)合成被提出為一種理想而吸引人的策略。然而，由于N→C肽鏈延長過程中嚴(yán)重的外消旋/表里異構(gòu)化，這一策略60多年來一直未能成功。在這里，通過使用ynamide偶聯(lián)試劑采用瞬時保護(hù)策略，成功地解決了這一挑戰(zhàn)。激活、瞬時保護(hù)、氨解和原位去保護(hù)在一鍋中完成，從而提供了一種實(shí)際上使用未保護(hù)氨基酸作為起始物料的肽化學(xué)合成策略。它的穩(wěn)健性通過肽活性藥物成分的合成得到了體現(xiàn)。它也適用于片段縮合和反向固相肽合成。與綠色溶劑的兼容性進(jìn)一步增強(qiáng)了其在大規(guī)模肽生產(chǎn)中的應(yīng)用潛力。這項(xiàng)研究提供了一種成本效益高、操作便利和環(huán)境友好的肽類制備方法。

使用瞬時保護(hù)氨基酸的反向肽合成
Inverse Peptide Synthesis Using Transient Protected Amino Acids
Tao Liu,Zejun Peng,Manting Lai,Long Hu, andJunfeng Zhao*
Cite this:J. Am. Chem. Soc.2024, 146, 6, 4270–4280
Publication Date:February 5, 2024
https://doi.org/10.1021/jacs.4c00314

JACS | 使用瞬時保護(hù)氨基酸的反向肽合成  Inverse Peptide Synthesis Using Transient Protected Amino Acids Tao Liu,Zejun Peng,Manting Lai,Long Hu, andJunfeng Zhao* Cite this:J. Am. Chem. Soc.2024, 146, 6, 4270–4280 Publication Date:February 5, 2024 https://doi.org/10.1021/jacs.4c00314 Copyright © 2024 American Chemical Society Request reuse permissions