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Mass spectrometry analysis for the determination of side reactions for cyclic peptides prepared from an Fmoc/t}Bu/Dmab protecting group strategy

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Abstract

The Association of Biomolecular Resource Facilities (ABRF) Peptide Synthesis Research Group (PSRG) proposed for their annual study that laboratory members prepare cyclo(Tyr-Glu-Ala-Ala-Arg-DPhe-Pro-Glu-Asp-Asn) according to the following synthetic pathway: (i) side-chain anchoring Fmoc-Asp(OH)-ODmab to a Rink amide resin; (ii) linear assembly; (iii) Dmab and Fmoc removal, respectively; (iv) on-resin cyclization with an uronium-based coupling reagent; (v) final cleavage/deprotection with TFA. Based upon this protocol, a variety of side-products were identified:(i) N-terminal guanidine formation; (ii) C-terminal piperidyl amide formation; and (iii) a novel C-terminal benzyl amide-guanidine derivative that formed due to a chemical reaction between the Dmab protecting group and the uronium-based coupling agent. The elemental composition and subsequent structure determination of this unexpected derivative was established by tandem mass spectrometry, i.e. low energy collision-induced dissociation experiments with fragment mass determination within 5 ppm.

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Authors and Affiliations

  1. School of Pharmacy, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, U.S.A., 502 16 55)

    Katalin F. Medzihradszky

  2. University of Maryland at Baltimore, Baltimore, MD, U.S.A

    Nicholas P. Ambulos

  3. Massachusetts General Hospital, Boston, MA, U.S.A

    Ashok Khatri

  4. University of California, Irvine, CA, U.S.A

    George Osapay

  5. Biotechnology Center, University of Illinois, Urbana, IL, U.S.A

    Henriette A. Remmer

  6. University of Arizona, Tucson, AZ, U.S.A

    Arpad Somogyi

  7. Consensus Pharmaceuticals, Inc, Medford, MA, U.S.A

    Steven A. Kates

Authors
  1. Katalin F. Medzihradszky
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  2. Nicholas P. Ambulos
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  3. Ashok Khatri
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  4. George Osapay
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  5. Henriette A. Remmer
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  6. Arpad Somogyi
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  7. Steven A. Kates
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Medzihradszky, K.F., Ambulos, N.P., Khatri, A. et al. Mass spectrometry analysis for the determination of side reactions for cyclic peptides prepared from an Fmoc/t}Bu/Dmab protecting group strategy. Letters in Peptide Science 8, 1–12 (2001). https://doi.org/10.1023/A:1014209211651

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  • DOI: https://doi.org/10.1023/A:1014209211651

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