Fmoc and Methionine Peptide Synthesis

Fmoc is a synthetic amino acid introduced by a chemical modification of a functional group, typically methionine. Its purpose is to obtain chemoselectivity in a chemical reaction by reacting only with carbonyl groups. Solid-phase peptide synthesis involves the assembly of a single peptide chain amino acid at a time, on an insoluble resin support. The process minimizes reaction byproducts, including Fmoc. Standard peptide cleavage conditions are employed to remove the Fmoc group. Generally, peptides containing Fmoc are unstable in 50% TFA and therefore, Boc-Lys(Fmoc)-OH is used to prepare protected peptide fragments for fragment coupling.

Methionine derivatives

Methionine is one of the twenty natural amino acids. It is large and contains a thioether function on its side-chain. Since Methionine is not protected, it may oxidize in the presence of oxygen, causing toxic side-effects. However, Fmoc/tBu Solid Phase Peptide Synthesis protects the N-terminus of Methionine and produces Fmoc-L-Methionine.

Methionine can be replaced with other amino acids. Norleucine is similar in size and polarity, but does not oxidize. These peptide analogs retain biological activity while being easier to isolate. The substitution of oxidizable methionine residues in fmoc increases shelf life by as much as two to three times. This compound is used to synthesize bioactive amino acids in human cells.

The methionine derivatives Fmoc-Sec(Xan) have a bench-stable property and are very stable. However, when not stored at -20 degrees C, they detritilate, which is not practical. In addition, Fmoc-Sec(Xan) was a practical compound. Because it is stable on the bench and yields diselenide peptides with high purity, it was selected as a suitable synthetic template for further studies.

Thermo Scientific has developed a photo-activatable methionine analog. This protein can replace methionine in the primary sequence of proteins during catabolism. It contains diazirine rings, which activate under UV light and form covalent bonds with proteins’ backbones and side chains. Photoactivation of the diazirine-containing proteins allows researchers to study the turnover of nucleosomes genome-wide.

These methionine derivatives are commonly used in Boc synthesis and Fmoc chemistry. However, the methionine residues can be oxidized to sulfoxide during cleavage and dimethylsulfoxide prevents this. Post-cleavage reduction of methionine sulfoxide produces a mixture of reduced and oxidized peptides, so it is important to purify the peptide before using methionine sulfoxide.

Two methionine derivatives are useful in Fmoc chemistry. One is Boc-Tyr(Bzl)-OH, which is useful for medium-sized peptides, while the other is Boc-Tyr(2-BrZ)-OH. The former is acid-stable and is useful for preparing protected peptide fragments for fragment coupling.


Fmoc carbamates are oligopeptides with a fluorenyl protecting group. They are synthesized from the Fmoc peptidyl isocyanates. This method was used to synthesize tri, penta and hexapeptidyl ureas. Piperidine (30%) in DMF was added to the resin. Then, AA and DIEA were sequentially coupled. The reagents were shaken at 22 degC for 45 min.

To remove Fmoc, the reaction is usually carried out in polar solvents like dimethylformamide or N-methylpirrolidone. Using less polar solvents will inhibit Fmoc removal and impair synthesis. The choice of solvents should be dependent on the desired product. The solvent should be suitable for Fmoc removal. It must be polar enough to support the reaction.

The solid phase synthesis process of Fmoc carbamates employs Cys residues protected by t-Bu disulfides. The resulting peptides have three additional b-alanine linker subunits, which differ from cholesterol in their C5 double bond. Moreover, Fmoc carbamates are acid-stable. They have many potential uses. They have many applications in the pharmaceutical industry.

The most common protective group for amino groups in solid phase peptide synthesis is 9-fluorenylmethyloxycarbonyl. It deprotects easily by amines but is relatively stable under acidic conditions. As such, peptide chemists typically use primary amines in this process. Secondary and tertiary amines are less effective. The Fmoc carbamates are only a part of the molecule with the BOC group.


Methionine is one of the 20 naturally occurring amino acids. Its large size and thioether side-chain make it prone to side reactions during synthesis. Because Methionine is largely unprotected, it can be reactive during peptide synthesis. However, when it is used in Fmoc/tBu solid phase peptide synthesis, its N-terminus is protected. Here, we will discuss the reduction mechanisms for the mono and di-oxidized Methionine residues.

Bu4NBr is a powerful acidolytic agent that is capable of reducing methionine sulfoxide in TFA. Bu4NBr is compatible with aromatic amino acids, such as cysteine and lysine. Furthermore, bu4NBr reduces methionine in TFA within a short reaction time, allowing the synthesis of peptides with a high concentration of methionine.

This symmetrical anhydride is compatible with Fmoc amino acids, as they can be used in the solid phase synthesis of methionine-enkephalin. The resulting homogeneous free pentapeptide was obtained in 42% yield. Furthermore, it is stable in storage. As a result, this method offers advantages over the present Fmoc solid phase synthesis.

Crystals of two amino acids were grown. These structures are the first of their kind to be reported for this class of gelators. The calculated pattern is based on experimental fibre X-ray diffraction data and matches the predicted crystal structure of FmocF. It is worth mentioning that FmocF has a tendency to crystallise, and these findings show that this is an advantageous property.

The hydrogen bonded networks in FmocF molecules extend along twofold screw axes parallel to the crystallographic b axis. The predicted pXRD of FmocF is very similar to that of the xerogel data, demonstrating that it is compatible with spherulitic structures. This study has revealed new insights into the mechanism of Fmoc’s chirality.

The hydrogen-bonded network formed by the Fmoc molecules is a two-dimensional network, with hydrogen bonding at the core and bulky Fmoc protecting groups. As a result, the crystal packing of FmocF and FmocY is different than that of the former. In FmocY, dipeptide residues are oriented in an alternating manner to the Fmoc groups.

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