Sequence dependence of aspartimide formation during 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis |
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| Authors: | Janelle L Lauer Cynthia G Fields and Gregg B Fields |
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| Institution: | (1) Department of Laboratory Medicine and Pathology, University of Minnesota, Box 107, 55455 Minneapolis, MN, U.S.A.;(2) Biomedical Engineering Center, University of Minnesota, Box 107, 55455 Minneapolis, MN, U.S.A.;(3) Department of Biochemistry, University of Minnesota, Box 107, 55455 Minneapolis, MN, U.S.A. |
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| Abstract: | Summary We have examined the sequence dependence of aspartimide formation during Fmoc-based solid-phase synthesis of the peptide Val-Lys-Asp-X-Tyr-Ile. The extent of aspartimide formation and subsequent conversion to the  - or  -piperidide was characterized and quantitated by analytical reversed-phase high-performance liquid chromatography and fast atom bombardment mass spectrometry. Aspartimide formation occurred for X=Arg(Pmc), Asn(Trt), Asp(OtBu), Cys(Acm), Gly, Ser, Thr and Thr(tBu). No single approach was found that could inhibit this side reaction for all sequences. The most effective combinations, in general, for minimization of aspartimide formation were (i) tert-butyl side-chain protection of aspartate, piperidine for removal of the Fmoc group, and either 1-hydroxybenzotriazole or 2,4-dinitrophenol as an additive to the piperidine solution; or (ii) 1-adamantyl side-chain protection of aspartate and 1,8-diazabicyclo5.4.0]undec-7-ene for removal of the Fmoc group. |
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| Keywords: | Aspartimide Fmoc solid-phase peptide synthesis Piperidides Side reactions |
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