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Aldrich, Jane V.; Vigil‐Cruz, Sandra C.

doi:10.1023/a:1008871528559

Cited by 4 publications

(5 citation statements)

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“…The synthesis reagents and amino acid derivatives used in our laboratory have been previously described [13]. Fmoc-D-Asp(OA1) and Fmoc-Dap(Aloc) were obtained from SNPE North America; other amino acid derivatives were obtained from Bachem, Novabiochem or PerSeptive Biosystems.…”

Section: Methodsmentioning

confidence: 99%

“…The dynorphin A-(6-11)NH2 C-terminal sequence was prepared on a Biosearch 9500 peptide synthesizer using the standard Fmoc/DIC+HOBt synthetic protocol with a fourfold excess of amino acids as previously described [13] on either a PAL, PAL-PEG or TentaGel resin (substitutions ranging from 0.14 to 0.23 mequiv/g). The novel amino acids, Fmoc-D-Asp(OA1) and Fmoc-Dap(Aloc), were coupled using a twofold excess relative to the resin (in contrast to the standard four fold excess) in the presence of HOBt in a mixed solvent of DMF/DCM (3.7:1) for 4 h. The N-terminal sequence of the peptide was assembled on either the Biosearch 9500 (PerSeptive Biosystems) (experiments 1 and 2) or on a small scale (experiment 3) on the Symphony Multiple Peptide Synthesizer (Protein Technologies) using a coupling protocol (DIC/HOBt) similar to that used on the Biosearch instrument.…”

Section: Solid-phase Peptide Synthesismentioning

confidence: 99%

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Unexpected aspartimude formation during coupling reactions using Asp(OAl) in solid-phase peptide synthesis

Vigil‐Cruz

Aldrich

1999

Lett Pept Sci

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Succinimide ring closure is a well-documented side reaction in the synthesis of certain Asp-containing peptides. This side reaction is typically acid-or base-catalyzed, and its occurrence during coupling reactions has not been previously noted. This unforeseen manifestation of aspartimide formation was detected while exploring a new strategy for side-chain to side-chain lactam formation on a solid support to synthesize cyclo[D-Asp2,DapS]dynorphin A-(1-11) amide. The availability of allyl protecting groups, which provide an additional level of orthogonality in solid-phase peptide synthesis, was very appealing for use in preparing this conformationally constrained analogue. We found that the allyl ester (OA1) was not sufficient protection from this side reaction in this susceptible D-Asp2-Gly 3 sequence. Remarkably, the aspartimide formation appeared to occur during the coupling reaction in the absence of base if excess coupling reagent was present.

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Section: Methodsmentioning

confidence: 99%

Section: Solid-phase Peptide Synthesismentioning

confidence: 99%

Unexpected aspartimude formation during coupling reactions using Asp(OAl) in solid-phase peptide synthesis

Vigil‐Cruz

Aldrich

1999

Lett Pept Sci

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“…A similar trend is also known for Asi formation. 2,4,24 Recently, the OMpe protecting group was surpassed by β-tri-alkylmethyl esters (alkyl = ethyl/propyl/butyl) for Asi suppression. 25 Longer Fmoc cleavage reaction times lead to increasing levels of Asi or of DKP, respectively.…”

Section: Influence Of Asp-carboxy Protecting Groups and Fmoc Deprotmentioning

confidence: 99%

The aspartimide problem persists: Fluorenylmethyloxycarbonyl‐solid‐phase peptide synthesis (Fmoc‐SPPS) chain termination due to formation of N‐terminal piperazine‐2,5‐diones

Samson

Rentsch

Minuth

et al. 2019

Journal of Peptide Science

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Aspartimide (Asi) formation is a notorious side reaction in peptide synthesis that is well characterized and described in literature. In this context, we observed significant amounts of chain termination in Fmoc‐SPPS while synthesizing the N‐terminal Xaa‐Asp‐Yaa motif. This termination was caused by the formation of piperazine‐2,5‐diones. We investigated this side reaction using a linear model peptide and independently synthesizing its piperazine‐2,5‐dione derivative. Nuclear magnetic resonance (NMR) data of the side product present in the crude linear peptide proves that exclusively the six‐membered ring is formed whereas the theoretically conceivable seven‐membered 1,4‐diazepine‐2,5‐dione is not found. We propose a mechanism where nucleophilic attack of the N‐terminal amino function takes place at the α‐carbon of the carbonyl group of the corresponding Asi intermediate. In addition, we systematically investigated the impact of (a) different adjacent amino acid residues, (b) backbone protection, and (c) side chain protection of flanking amino acids. The side reaction is directly related to the Asi intermediate. Hence, hindering or avoiding Asi formation reduces or completely suppresses this side reaction.

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“…Instead, we used stoichiometric ratios of coupling reagent (1.2 equiv) and base (2 equiv). 31 Alternatively Sheppard's Hmb group 32 could be positioned on the preceding alanine residue, although lower yields were observed due to incomplete coupling of the last aspartic acid residue (even with prolonged coupling times), resulting in contamination of the desired product by the tetrapeptide deletion product.…”

Section: Macrocycle Synthesismentioning

confidence: 99%