Thieme Chemistry Journals Awardees – Where Are They Now? Improved Fmoc Deprotection Methods for the Synthesis of 
Thioamide-Containing Peptides and Proteins

Szantai‐Kis, D. Miklos; Walters, Chris; Barrett, Taylor M.; Hoang, Eileen M.; Petersson, E. James

doi:10.1055/s-0036-1589027

Cited by 25 publications

(35 citation statements)

References 18 publications

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“…[29] Use of DBU was shown to be particularly beneficial for the assembly of thioamide peptides, with lower levels of epimerization being observed compared with the use of piperidine. [30] Caution is especially advised when using DBU for the synthesis of sensitive Asp-containing sequences, with reports of aspartimide formation being a major issue. [26,31,32] This problem has been the subject of much investigation given it is an inherent problem with base-mediated Fmoc deprotection.…”

Section: N a -Fmoc Deprotection -The Early Studiesmentioning

confidence: 99%

The 9-Fluorenylmethoxycarbonyl (Fmoc) Group in Chemical Peptide Synthesis – Its Past, Present, and Future

Li¹,

O'Brien-Simpson²,

Hossain³

et al. 2020

Aust. J. Chem.

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The chemical formation of the peptide bond has long fascinated and challenged organic chemists. It requires not only the activation of the carboxyl group of an amino acid but also the protection of the N a -amino group. The more than a century of continuous development of ever-improved protecting group chemistry has been married to dramatic advances in the chemical synthesis of peptides that, itself, was substantially enhanced by the development of solid-phase peptide synthesis by R. B. Merrifield in the 1960s. While the latter technology has continued to undergo further refinement and improvement in both its chemistry and automation, the development of the base-labile 9-fluorenylmethoxycarbonyl (Fmoc) group and its integration into current synthesis methods is considered a major landmark in the history of the chemical synthesis of peptides. The many beneficial attributes of the Fmoc group, which have yet to be surpassed by any other N a -protecting group, allow very rapid and highly efficient synthesis of peptides, including ones of significant size and complexity, making it an even more valuable resource for research in the post-genomic world. This review charts the development and use of this N a -protecting group and its adaptation to address the need for more green chemical peptide synthesis processes.

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Section: N a -Fmoc Deprotection -The Early Studiesmentioning

confidence: 99%

The 9-Fluorenylmethoxycarbonyl (Fmoc) Group in Chemical Peptide Synthesis – Its Past, Present, and Future

Li¹,

O'Brien-Simpson²,

Hossain³

et al. 2020

Aust. J. Chem.

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“…[18][19][20][21][22][23] However, despite these exciting utilities, the synthesis of thioamidated peptides and protein stays a difficult task that continues to be addressed by several groups, including ours. [24][25][26][27][28] In particular, the enhanced nucleophilicity of C═S is responsible for the spontaneous fragmentation of thioamidated peptides and proteins when subjected to acidolytic removal of protecting groups via an Edman-type mechanism. 29 Additionally, the lower pK a of the H α (~3 pK a units less than in oxoamide) in thionated amino acids 26,27 increases their susceptibility to epimerization on treatment with bases for Fmoc-deprotection during solid-phase peptide synthesis (SPPS).…”

Section: Introductionmentioning

confidence: 99%

“…[24][25][26][27][28] In particular, the enhanced nucleophilicity of C═S is responsible for the spontaneous fragmentation of thioamidated peptides and proteins when subjected to acidolytic removal of protecting groups via an Edman-type mechanism. 29 Additionally, the lower pK a of the H α (~3 pK a units less than in oxoamide) in thionated amino acids 26,27 increases their susceptibility to epimerization on treatment with bases for Fmoc-deprotection during solid-phase peptide synthesis (SPPS). 30,31 The most successful method for synthesizing thioamidated peptides employs the use of thioacylating reagents 32-34 over thionating reagents.…”

Section: Introductionmentioning

confidence: 99%

Convenient synthesis of thioamidated peptides and proteins

Khatri

Bhat

Chatterjee

2020

Journal of Peptide Science

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The unique physicochemical properties of a thioamide bond, which is an ideal isostere of an amide bond, have not been fully exploited because of the tedious synthesis of thionated amino acid building blocks. Here, we report a purification‐free and highly efficient synthesis of thiobenzotriazolides of Fmoc‐protected and orthogonally protected 20 naturally occurring amino acids including asparagine, glutamine, and histidine. The near‐quantitative conversion to the respective thioamidated peptides on solid support demonstrates the robustness of the synthetic route. Furthermore, the unaltered incorporation efficiency of thiobenzotriazolides from their stock solution till 48 h suggests their compatibility toward automated peptide synthesis. Finally, utilizing an optimized cocktail of 2% DBU + 5% piperazine for fast Fmoc‐deprotection, we report the synthesis of a thioamidated Pin1 WW domain and thioamidated GB1 directly on solid support.

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“…16,17 Unfortunately, the stereochemical integrity of the resulting peptide is at risk because the α-C of the thioamide is susceptible to deprotonation and epimerization during Fmoc-deprotection of the N-terminal amine. [18][19][20] The stereochemical integrity of the thioamide amino acid therefore further degrades during subsequent coupling and Fmoc-deprotection of subsequent amino acids. 21 This limitation in stereochemical stability constrains the peptide sequence space in which thioamide probes can be implemented.…”

Section: Introductionmentioning

confidence: 99%

Deprotection Strategies for Thioimidates During Fmoc Solid-Phase Peptide Synthesis: A Safe Route to Thioamides

Camacho¹,

Nguyen²,

Turner³

et al. 2019

Preprint

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Thioamides are important biophysical probes of peptide folding, but are prone to α-C epimerization during Fmoc solid-phase peptide synthesis. The stereochemical integrity of thioamide-containing peptides can be dramatically improved by protecting the thioamide as a thioimidate during synthesis. A drawback of this approach, however, is that once synthesis of the peptide is complete, regeneration of the thioamide requires the toxic, corrosive, and flammable gas H2S. This work examines several approaches to supplant H2S as a deprotection reagent in favor of a safer and more convenient alternative. Ultimately, a new application of the 4-azidobenzyl protecting group to thioamides was found to provide the most suitable means of both protection of α-C stereochemistry and conversion back to thioamide.

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Thieme Chemistry Journals Awardees – Where Are They Now? Improved Fmoc Deprotection Methods for the Synthesis of Thioamide-Containing Peptides and Proteins

Cited by 25 publications

References 18 publications

The 9-Fluorenylmethoxycarbonyl (Fmoc) Group in Chemical Peptide Synthesis – Its Past, Present, and Future

The 9-Fluorenylmethoxycarbonyl (Fmoc) Group in Chemical Peptide Synthesis – Its Past, Present, and Future

Convenient synthesis of thioamidated peptides and proteins

Deprotection Strategies for Thioimidates During Fmoc Solid-Phase Peptide Synthesis: A Safe Route to Thioamides

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