Liquid-Phase Synthesis of Peptide Alcohol Assisted by a Hydrophobic Silica-Based Tag

doi:10.6023/cjoc202503021

Abstract

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

Cite this article

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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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

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

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

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

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

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