As a step toward green Fmoc solid-phase peptide synthesis (SPPS), we explored the compatibility of the green bases morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and NaOH with the green solvent anisole as a replacement for the traditionally used hazardous piperidine in N,N-dimethylformamide (DMF) for the Fmoc removal step. Green Fmoc cleavage protocols were optimized for the Fmoc-Ala-NH-Rink resin model and subsequently verified for other Fmoc-amino acids. Only Gly required a modified NaOH-based protocol with the addition of 5 % water. Furthermore, we evaluated the effects of basic treatment on the notorious aspartimide formation as an undesired side product of SPPS. We also introduced a new green solvent mixture, anisole/dimethyl sulfoxide (DMSO) (4:1) for acylation step, which did not cause racemization. The applicability of these new green protocols was shown during SPPS of the pentapeptides Leu-enkephalin and Aib-enkephalin using polystyrene (PS)-based resins. Additionally, we identified the new sequence-dependent side products that formed after treatment with NaOH in anisole/ethanol (EtOH) (1:1).

作为迈向绿色 Fmoc 固相肽合成 (SPPS) 的一步，我们探索了绿色碱吗啉、1,8-二氮杂双环 [5.4.0] undec-7-ene (DBU) 和 NaOH 与绿色溶剂苯甲醚的相容性作为N,N 中传统使用的危险哌啶的替代品-二甲基甲酰胺 (DMF) 用于 Fmoc 去除步骤。Green Fmoc 裂解方案针对 Fmoc-Ala-NH-Rink 树脂模型进行了优化，随后针对其他 Fmoc-氨基酸进行了验证。只有 Gly 需要添加 5% 水的基于 NaOH 的改进方案。此外，我们评估了基础处理对臭名昭著的天冬氨酸形成的影响，作为 SPPS 的不良副产品。我们还引入了一种新的绿色溶剂混合物，苯甲醚/二甲基亚砜 (DMSO) (4:1) 用于酰化步骤，它不会引起外消旋。在使用聚苯乙烯 (PS) 基树脂对五肽 Leu-脑啡肽和 Aib-脑啡肽进行 SPPS 期间显示了这些新的绿色方案的适用性。此外，我们确定了在苯甲醚/乙醇 (EtOH) (1:1) 中用 NaOH 处理后形成的新的序列依赖性副产物。