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Fluorenylmethoxycarbonyl (Fmoc) is a commonly used protecting group in organic synthesis. It is used to protect the amino groups of amino acids during peptide synthesis. The Fmoc protecting group consists of a fluorenyl ring connected to a methoxycarbonyl group. Fluorene is a polycyclic aromatic hydrocarbon that is fluorescent when impure and has a molecular formula of C13H10. The fluorenyl ring provides stability by protecting the amino group from unwanted reactions during peptide synthesis. The methoxycarbonyl group acts as a linker between the fluorenyl ring and the amino group, allowing easy removal of the Fmoc group if necessary.
The Fmoc group is an alkali-sensitive protective group that can be removed in concentrated ammonia water of piperidine, ethanolamine, cyclohexylamine, 1,4-dioxane, pyridone or dioxane-methanol/NaOH solution (4M) and 50% dichloromethane solution. Under weak base conditions such as sodium carbonate or sodium bicarbonate, Fmoc-Cl or Fmoc-OSu is generally used to introduce the Fmoc protecting group. Compared with Fmoc-Cl, the reaction conditions of Fmoc-OSu are easier to control and have fewer side reactions. The Fmoc protecting group is particularly stable under acidic conditions but very sensitive to alkaline conditions. Therefore, it is often used with acid-sensitive protecting groups BOC or CBZ to protect amino acids containing reactive side chain groups. Fmoc has strong UV absorption and can be detected through UV absorption, which brings a lot of convenience to the automatic peptide synthesis of the instrument. Fmoc is compatible with a variety of solvents and reagents, can be used in a variety of carriers and activation methods, and has high mechanical stability. Therefore, Fomc-amino acids are widely used in peptide synthesis.
Fmoc protected amino acids are typically used to introduce an Fmoc protecting group onto the amino group of the amino acid. These amino acids have an Fmoc group attached to their amino group, which protects them from unwanted reactions. The Fmoc group can be removed using a weak acid such as piperidine, which cleaves the Fmoc group from the amino acid, leaving the free amino group available for further reactions.
The general Fmoc-protected amino acids synthesis step is to add the amino acids to a mixed solution of water and sodium bicarbonate with stirring and cool the resulting solution to 5°C, then slowly add Fmoc-OSu or Fmoc-Cl. After the resulting mixture is kept at 0°C for 1h, and then heat to room temperature for one night. Then water is added and the aqueous layer is extracted twice with EtOAc. The organic layer is back extracted with saturated sodium bicarbonate solution twice. The combined aqueous layer is acidified to pH 1 with 10% hydrochloric acid and then extracted with EtOAc for 3 times. The combined organic layers are dried (sodium sulfate) and concentrated in vacuo and the resulting residue could be purified by flash chromatography (SiO).
The amino acid must be compatible with the Fmoc protective group in order to use the Fmoc approach. Certain amino acids pair less well or experience adverse responses when combined with Fmoc. The amino acids that have been demonstrated to react well and selectively with Fmoc groups are frequently utilized in Fmoc-based peptide synthesis. The side chains of amino acids with favorable Fmoc reactions are typically less prone to unintended reactions or disruptions of the Fmoc deprotection phase. Alanine, glutamic acid, lysine, arginine, histidine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, cysteine, serine, threonine, valine, leucine, isoleucine, and aspartic acid are some of these amino acids.
Throughout the coupling and deprotection phases of peptide synthesis, the Fmoc group inhibits undesirable side reactions. Using a base like piperidine, the Fmoc group is easily removed in mild circumstances, selectively deprotecting the amino group without disrupting other functional groups on the side chain of the amino acid. Fmoc-amino acids' compatibility with automated peptide synthesizers is one of the main benefits of employing them in peptide synthesis. Through automated coupling and deprotection procedures, these synthesizers can quickly build peptides, making complicated peptide synthesis effective and repeatable. Fmoc-amino acids are easily accessible for use in peptide synthesis applications since they are also sold commercially in a range of derivative forms.
Peptides are created on a solid support using solid-phase peptide synthesis (SPPS), where amino acids are added one at a time to a peptide chain that is continuously developing. Because the Fmoc protective group is easily removed in mildly acidic environments without causing peptide chain damage, it is perfect for SPPS. The amino acid's Fmoc group shields it against unfavorable side effects that could arise during the coupling and deprotection processes. Because of its stability, amino groups can be selectively deprotected, resulting in a peptide that is built effectively and under control. Moreover, mild circumstances make it simple to remove the Fmoc group, facilitating quick peptide synthesis without the need for harsh chemicals or lengthy reaction periods.
The liquid phase peptide synthesis process also makes extensive use of Fmoc protecting groups. Peptides are manufactured using this approach not on a solid support, but in solution. Solution-phase peptide synthesis can benefit greatly from the flexibility of Fmoc protecting group removal, which can be achieved with weak acids in solution. However, Fmoc-amino acids are not appropriate for every application involving peptide synthesis. For instance, different protective groups can be needed for peptides containing sensitive amino acid residues like histidine or cysteine in order to avoid undesirable side effects. Moreover, Fmoc-amino acids could not work well with some peptide sequences or modifications, including phosphorylation or glycosylation, which call for specific coupling and deprotection techniques.
Anti-corrosion: Fmoc-glycine can be used to prepare a glycine derivative corrosion inhibitor. Through the amidation reaction, Fmoc-protecting groups and hydrophobic long chains are connected to the glycine molecule through heteroatoms (N, O or unsaturated bonds). It can adsorb on the metal with the biphenyl ring containing π electrons, and the hydrophobic long chain blocks water molecules, so that it forms a protective film on the steel surface to achieve the purpose of anticorrosion.
Therapeutic and antibacterial: Some studies have found that several Fmoc-amino acids have extensive anti-inflammatory activity. In vitro studies, Fmoc-modified amino acids blocked the recruitment of neutrophils to the site of inflammatory injury and inhibited T-cell activation instead of traditionally inhibiting lipid metabolism enzymes or increasing circulating levels of endogenous glucocorticoids. Therefore Fmoc-amino acid may be a valuable therapeutic agent for inflammatory diseases
Biocatalysis: Fmoc-amino acid modified molecular assembly has the characteristics of fast assembly, outstanding stability and easy modification, so it has effective catalytic performance.
Drug delivery: Fmoc has strong hydrophobicity and the ease of peptide sequence modification. The Fmoc-amino acids modified assembly can play a dual role of encapsulation and functionalization in the drug delivery of organisms.
