Base-induced side reactions in Fmoc-solid phase peptide synthesis: Minimization by use of piperazine as Nα-deprotection reagent

Autor: Mary Macris, Geoffrey W. Tregear, John D. Wade, Marc N. Mathieu
Rok vydání: 2000
Předmět:
Zdroj: Letters in Peptide Science. 7:107-112
ISSN: 1573-3904
0929-5666
DOI: 10.1007/bf02443569
Popis: Base-induced aspartimide (cyclic imide) and subsequent base adduct formation in the Fmoc-solid phase synthesis of sensitive sequences are serious side reactions that are difficult to both anticipate and control. The effect of extended treatment of piperazine as Nα-Fmoc deprotection reagent on two sensitive peptide sequences was examined. For comparison, other bases were also investigated, including piperidine, 1-hydroxypiperidine, tetrabutylammonium fluoride, and 1,8-diazabicyclo[5.4.0]undec-7-ene. The results showed that all bases induced varying degrees of both aspartimide and, in some cases, base adduct formation, although piperazine caused the least side reaction. Use ofN-(2-hydroxy-4-methoxybenzyl) peptide backbone amide protection was confirmed to confer complete protection against side reaction. In the absence of such protection, for all bases, the use of 1-hydroxybenzotriazole as additive had some, but not complete, beneficial effect in further reducing side reaction. Best results were obtained with piperazine containing 0.1M 1-hydroxybenzotriazole indicating that this reagent merits serious consideration for Nα-deprotection in the Fmoc-solid phase synthesis of base-sensitive sequences. A further advantage of this reagent is that it causes little racemisation of resin-bound C-terminal cysteine, an occasionally serious base-mediated problem in Fmoc-solid phase assembly.
Databáze: OpenAIRE
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