疏水性硅基标签辅助的肽醇液相合成

doi:10.6023/cjoc202503021

摘要/Abstract

开发了一种新型疏水性硅基标签((氯亚甲基)双(1,4-亚苯基))双(氧))双(叔丁基二甲基硅烷)(CBTBS), 用于辅助液相合成肽醇. 通过采用环境友好型溶剂乙酸乙酯(EA)替代具有生殖毒性的N,N-二甲基甲酰胺(DMF), 并使用3-巯基-1-丙烷磺酸钠(Mps)与1,8-二氮杂二环十一碳-7-烯(DBU)的协同脱保护体系(取代传统受管制的哌啶试剂). 该策略不仅能够高效且便捷地去除富烯加成物等副产物, 还实现了Gramicidin A片段的高效合成(粗品收率>80%). 与传统固相合成相比, 该方法的过程质量强度(PMI)大幅降低, 为肽醇的绿色合成开辟了一条高效、可持续的新途径.

关键词: 疏水性硅基标签, 肽醇, 液相合成, 绿色

This study presents the development of a novel hydrophobic silicon-based tag, ((chloromethylene)bis(1,4-phen- ylene))bis(oxy))bis(tert-butyldimethylsilane) [CBTBS], for facilitating the liquid-phase synthesis of peptide alcohols. By replacing the reproductive-toxic solvent N,N-dimethylformamide (DMF) with the environmentally friendly ethyl acetate (EA) and implementing a synergistic deprotection system using sodium 3-mercapto-1-propanesulfonate (Mps) and 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU) (substituting the traditionally regulated piperidine reagent), this strategy enables efficient and convenient removal of byproducts such as fulvene adducts. Additionally, it achieves high-efficiency synthesis of the Gramicidin A fragment with a crude yield exceeding 80%. Compared with conventional solid-phase synthesis, this method significantly reduces the process mass intensity (PMI), thereby providing an efficient and sustainable new pathway for the green synthesis of peptide alcohols.

Key words: hydrophobic silica-based tag, peptide alcohol, liquid phase synthesis, green

引用此文

程蓉, 钱伊依, 徐元强, 苏贤斌. 疏水性硅基标签辅助的肽醇液相合成[J]. 有机化学, 2025, 45(12): 4433-4442.

Rong Cheng, Yiyi Qian, Yuanqiang Xu, Xianbin Su. Liquid-Phase Synthesis of Peptide Alcohol Assisted by a Hydrophobic Silica-Based Tag[J]. Chinese Journal of Organic Chemistry, 2025, 45(12): 4433-4442.

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图/表 11

图式1. 传统固相合成肽醇及疏水性硅基标签CBTBS

Scheme 1. Traditional solid-phase synthesis of peptidols and hydrophobic silicon-based tag CBTBS

图式2. CBTBS的合成以及接入第一个氨基醇

Scheme 2. Synthesis of CBTBS and coupling of the first amino alcohol

图式3. Fmoc脱保护及副产物的去除

Scheme 3. Fmoc deprotection and by-product removal

Reagent	DBF/Fulvene adduct^a	Washing solvent	Removal rate^b/%	Yield^c/%
Piperidine	6∶94	HCl aq	100	89
Pyrrolidine	16∶84	HCl aq	100	76
DBU/Mps	>99	K₂CO₃ aq	100	98

表1. 哌啶、四氢吡咯和Mps捕获DBF的效果对比

Table 1. Comparison of DBF capture performance among piperidine, pyrrolidine and Mps

Reagent (mmol)	DBU/mmol	DMSO/EA (volume ratio)	DBF/Fulvene adduct^a	Washing solvent	Removal rate^b/%	Yield^c/%
Mps (5)	3	1∶1	>99	K₂CO₃ (aq.)	100	98
Mps (5)	1	1∶1	>99	K₂CO₃ (aq.)	100	98
Mps (5)	1	3∶7	>99	K₂CO₃ (aq.)	100	98
Mps (5)	1	2∶8	>99	K₂CO₃ (aq.)	100	98
Mps (2)	1	2∶8	>99	K₂CO₃ (aq.)	100	98

表2. Fmoc脱保护反应条件优化

Table 2. Optimization of Fmoc deprotection reaction conditions

图1. 偶联模板反应

Figure 1. Coupling template reaction

Entry	Coupling reagent (mmol)	Conversion^a/%	Yield^b/%
1	HATU (1.5)	100	93
2	DIC (1.5)	100	90
3	EDC•HCl (1.5)	100	98
4	EDC•HCl (1.1)	100	98
5	EDC•HCl (1.0)	96	92

表3. 缩合试剂的选择

Table 3. Selection of condensing reagents

图式4. 标签辅助液相合成Gramicidin A片段

Scheme 4. Tag-assisted liquid phase synthesis of Gramicidin A fragment

SPPS		Tag-assisted LPPS
Material	Dosage/kg	Material	Dosage/kg
CTC Resin (1 mmol/g)	1.00	CBTBS	0.46
Fmoc-AA-OH	8.32	Fmoc-AA-OH	2.74
Coupling reagent	5.47	Coupling reagent	1.09
DMF	64.23	EA	2.71
Piperidine	5.89	DBU/Mps	3.08

表4. 合成Gramicidin A片段物料消耗对比

Table 4. Comparison of material consumption for synthesizing Gramicidin A fragment

Synthetic method	Purity (HPLC)/%	Yield/%
SPPS	70	95
Tag-assisted LPPS	65	80

表5. SPPS和Tag-assisted LPPS合成Gramicidin A片段的收率与纯度对比

Table 5. Comparison of yield and purity in Gramicidin A fragment synthesis: SPPS vs Tag-assisted LPPS

图2. SPPS与Tag-assisted LPPS合成1 mol Gramicidin A片段的PMI对比

Figure 2. Comparison of PMI of 1 mol Gramicidin A fragment synthesized by SPPS and Tag-assisted LPPS

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