Problems associated with use of the benzyloxymethyl protecting group for histidines Formaldehyde adducts formed during cleavage by hydrogen fluoride <sup>1</sup>

Mitchell, Mark A.; Runge, Thomas A.; Mathews, W R; Ichhpurani, A. K.; Harn, Nancy K.; Dobrowolski, Paul J.; Eckenrode, F M

doi:10.1111/j.1399-3011.1990.tb01293.x

Cited by 26 publications

(7 citation statements)

References 12 publications

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“…MBom 9 , (Figure ) was most effective, reducing the formation of d ‐Cys to 0.4%. Unfortunately, it is associated with a number of side reactions due to the formaldehyde and methoxybenzyl cation released during cleavage . Complete suppression of these side products was not possible .…”

Section: Introductionmentioning

confidence: 99%

Advances in Fmoc solid‐phase peptide synthesis

Behrendt

White

Offer

2016

Journal of Peptide Science

563

426

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Today, Fmoc SPPS is the method of choice for peptide synthesis. Very‐high‐quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

Advances in Fmoc solid‐phase peptide synthesis

Behrendt

White

Offer

2016

Journal of Peptide Science

563

426

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“…Furthermore, the Bom group is stable to nucleophiles and other conditions used in Boc SPPS but is removed in the final HF cleavage step. However, one molecule of formaldehyde is released during its decomposition which can modify the polypeptide …”

Section: Resultsmentioning

confidence: 99%

A comparison of Boc and Fmoc SPPS strategies for the preparation of C‐terminal peptide α‐thiolesters: NY‐ESO‐1 ³⁹Cys‐⁶⁸Ala‐COSR

Harris

Brimble

2013

Biopolymers

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The synthesis of a polypeptide derived from the cancer testis antigen NY-ESO-1 bearing a C-terminal α-thiolester is described. Employing tert-butyloxycarbonyl solid phase peptide synthesis the thiolester moiety was installed on-resin using a mercaptopropionic acid linker, thereby requiring no post synthetic manipulations and delivering the requisite α-thiolester polypeptide after cleavage from the resin with HF. Several 9-fluorenylmethyloxycarbonyl solid phase peptide synthesis approaches whereby the thiolester was required to be introduced in a post synthesis manner were examined concurrently. These comprised syntheses on two different "safety catch" linkers, an N-alkyl-N-acyl sulphonamide and an N-acyl benzimidazolone wherein the thiolester is generated from an activated precursor. The condensation of a mercaptan with the C-terminal carboxylate in a direct thiolesterification reaction was also examined. When using either of the three 9-fluorenylmethyloxycarbonyl-based approaches, the linear polypeptide could be assembled straightforwardly on the solid phase resin; however, a thiolesterification of the C-terminal carboxyl of the fully side chain protected peptide proved to be the most effective post-assembly method for the installation of the C-terminal thiolester.

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“…Formaldehyde can lead to hydroxymethylated modification of α ‐amino and ε ‐amino groups, although the extent is inconsequential. On the other hand, when a Cys or a Trp residue is located at the N ‐terminus, formaldehyde can react with it to produce a Thz‐peptide or THCar‐peptide, respectively, during isolation from an acidolytic mixture . The methoxybenzyl cation can cause alkylation of susceptible residues such as Cys and Trp .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and application of N^α‐Fmoc‐N^π‐4‐methoxybenzyloxymethylhistidine in solid phase peptide synthesis

Hibino

Miki

Nishiuchi

2012

Journal of Peptide Science

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The 4-methoxybenzyloxymethyl (MBom) group was introduced at the Nπ-position of the histidine (His) residue by using a regioselective procedure, and its utility was examined under standard conditions used for the conventional and the microwave (MW)-assisted solid phase peptide synthesis (SPPS) with 9-fluorenylmethyoxycarbonyl (Fmoc) chemistry. The Nπ-MBom group fulfilling the requirements for the Fmoc strategy was found to prevent side-chain-induced racemization during incorporation of the His residue even in the case of MW-assisted SPPS performed at a high temperature. In particular, the MBom group proved to be a suitable protecting group for the convergent synthesis because it remains attached to the imidazole ring during detachment of the protected His-containing peptide segments from acid-sensitive linkers by treatment with a weak acid such as 1% trifluoroacetic acid in dichloromethane. We also demonstrated the facile synthesis of Fmoc-His(π-MBom)-OH with the aid of purification procedure by crystallization to effectively remove the undesired τ-isomer without resorting to silica gel column chromatography. This means that the present synthetic procedure can be used for large-scale production without any obstacles.

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Problems associated with use of the benzyloxymethyl protecting group for histidines Formaldehyde adducts formed during cleavage by hydrogen fluoride ¹

Cited by 26 publications

References 12 publications

Advances in Fmoc solid‐phase peptide synthesis

Advances in Fmoc solid‐phase peptide synthesis

A comparison of Boc and Fmoc SPPS strategies for the preparation of C‐terminal peptide α‐thiolesters: NY‐ESO‐1 ³⁹Cys‐⁶⁸Ala‐COSR

Synthesis and application of N^α‐Fmoc‐N^π‐4‐methoxybenzyloxymethylhistidine in solid phase peptide synthesis

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Problems associated with use of the benzyloxymethyl protecting group for histidines Formaldehyde adducts formed during cleavage by hydrogen fluoride 1

Cited by 26 publications

References 12 publications

Advances in Fmoc solid‐phase peptide synthesis

Advances in Fmoc solid‐phase peptide synthesis

A comparison of Boc and Fmoc SPPS strategies for the preparation of C‐terminal peptide α‐thiolesters: NY‐ESO‐1 39Cys‐68Ala‐COSR

Synthesis and application of Nα‐Fmoc‐Nπ‐4‐methoxybenzyloxymethylhistidine in solid phase peptide synthesis

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Product

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Problems associated with use of the benzyloxymethyl protecting group for histidines Formaldehyde adducts formed during cleavage by hydrogen fluoride ¹

A comparison of Boc and Fmoc SPPS strategies for the preparation of C‐terminal peptide α‐thiolesters: NY‐ESO‐1 ³⁹Cys‐⁶⁸Ala‐COSR

Synthesis and application of N^α‐Fmoc‐N^π‐4‐methoxybenzyloxymethylhistidine in solid phase peptide synthesis