吡咯烷
哌啶
溶剂
化学
组合化学
肽
肽合成
有机化学
三氟乙酸
生物化学
作者
Peter H. G. Egelund,Sandip V. Jadhav,Vincent Martin,Henrik Johansson,Franziska Richner,Sebastian T. Le Quement,Frank Dettner,Carolin Lechner,Ralph Schoenleber,Daniel Sejer Pedersen
出处
期刊:ACS Sustainable Chemistry & Engineering
[American Chemical Society]
日期:2021-10-25
卷期号:9 (42): 14202-14215
被引量:5
标识
DOI:10.1021/acssuschemeng.1c04770
摘要
Green binary solvent mixtures with a polarity and viscosity close to that of DMF perform similarly in solid-phase peptide synthesis (SPPS). However, while coupling reactions readily proceed in solvents of significantly lower polarity than that of DMF, a high solvent polarity is essential for Fmoc-removal using piperidine, which limits the options for green SPPS solvents. Herein, we report our efforts to expand the available solvent polarity space for green SPPS. We identified pyrrolidine as an efficient base to enable Fmoc-removal in less polar solvent mixtures that also favor coupling reactions, such as dimethyl sulfoxide/ethyl acetate (1:9) and N-butylpyrrolidone/1,3-dioxolane (2:8 and 4:6). Employing less polar binary solvent mixtures in combination with pyrrolidine gave crude peptide purities comparable to or better than for DMF with piperidine in the SPPS of challenging peptide targets. An evaluation of base-dependent side reactions such as diketopiperazine (DKP) and aspartimide formation showed increased side-product formation when using pyrrolidine on DKP- and aspartimide-prone sequences. However, the scaled-up syntheses (5 and 7.5 mmol, respectively) of the peptide therapeutics dasiglucagon (29-mer) and bivalirudin (20-mer) gave good crude peptide purities and purity profiles amenable to SPPS optimization. Pyrrolidine therefore represents a useful alternative to piperidine for Fmoc-removal in an expanded solvent space for green SPPS.
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