New Strategies for an Efficient Removal of the 9-Fluorenylmethoxycarbonyl (Fmoc) Protecting Group in the Peptide Synthesis

Leggio, Antonella; Liguori, Angelo; Napoli, Anna; Siciliano, Carlo; Sindona, Giovanni

doi:10.1002/(sici)1099-0690(200002)2000:4<573::aid-ejoc573>3.0.co;2-i

Cited by 26 publications

(24 citation statements)

References 8 publications

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“…In addition, intramolecular aminolysis and other side reactions occurred, similar to those reported in the literature [25,26]. To solve this problem, potassium fluoride (KF) was selected as the cleavage reagent [27,28]. In the mixture of DMF and THF containing KF, the de-protection was completed quantitatively in a few hours at room temperature in the presence of TEA.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

Li¹,

Song²,

Oie³

et al. 2017

Med chem (Los Angeles)

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The progress in oral absorption of protein and peptide drugs has been hampered by the difficulty in transporting larger molecules across the gastrointestinal membrane. We are reporting here a study of the design and synthesis of cholic acid-peptide conjugates for peptide drug delivery through gastrointestinal track mediated by bile acid transporter. As principal samples, three small cholic acid-peptide conjugates containing a biodegradable ester bond via threonine linker have been synthesized. In order to introduce ester bond between cholic acid and peptides, conventional solid phase synthesis is not practicable, thus solution phase was employed. The threonine moiety was chosen to introduce a hydroxyl group, on which an ester bond can be formed with different peptides. The threonine moiety also provides the necessary negative charge adjacent to the C24 position as required for transport recognizing by the bile acid transporter in the ilue epicell. The synthetic process was based on DCC chemistry. By using catalytic amounts of N-hydroxysuccinimide the procedure for amide coupling was simplified and shortened while maintaining high efficiency. Esterification using ethyl acetate in the presence of triethylamine selectively introduced an ester bond at the C27 position giving higher yield with no protection on other three hydroxyls. The work also demonstrated that in solution phase synthesis of these peptide conjugates fluoride ion (F -) was more efficient than piperidine to cleave Fmoc from the amino group.Cell culture experiment showed the efficiencies of transporting of the conjugates and the dissociation of the conjugates detected by HPLC, suggesting that the cholic acid conjugates linked by degradable ester bond can be used as bigger molecule drugs delivering template. Further study would be designed by using more different linkers that would be also biodegradable bonds, such as thioester and so forth.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

Li¹,

Song²,

Oie³

et al. 2017

Med chem (Los Angeles)

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“…The action of AlCl 3 on the substrate N ‐Fmoc‐protected 5 causes the partial removal of the Fmoc group. The interaction between the Lewis acid AlCl 3 and the urethanic function of 5 produces a highly reactive electrophilic species, which turns into dibenzofulvene .…”

Section: Resultsmentioning

confidence: 99%

Lewis acid catalysed methylation of N‐(9H‐fluoren‐9‐yl)methanesulfonyl (Fms) protected lipophilic α‐amino acid methyl esters

Leggio

Alò

Belsito

et al. 2015

Journal of Peptide Science

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This work reports an efficient Lewis acid catalysed N-methylation procedure of lipophilic α-amino acid methyl esters in solution phase. The developed methodology involves the use of the reagent system AlCl3/diazomethane as methylating agent and α-amino acid methyl esters protected on the amino function with the (9H-fluoren-9-yl)methanesulfonyl (Fms) group. The removal of Fms protecting group is achieved under the same conditions to those used for Fmoc removal. Thus the Fms group can be interchangeable with the Fmoc group in the synthesis of N-methylated peptides using standard Fmoc-based strategies. Finally, the absence of racemization during the methylation reaction and the removal of Fms group were demonstrated by synthesising a pair of diastereomeric dipeptides.

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“…The N-Fmoc amino acid and peptide nitrones obtained could be used as chiral frame for the preparation of long-chain modified peptides by the removal of the Fmoc protecting group. [7] …”

Section: Introductionmentioning

confidence: 99%

Synthesis of Chiral Nitrones from N‐Fmoc Amino Acids and N‐Fmoc Dipeptides

Gioia

Leggio

Pera

et al. 2004

Synthetic Communications

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In this work is presented a synthetic procedure for the preparation of chiral nitrones from N-Fmoc protected amino acids and dipeptides. The nitrone functional group can replace the carboxyl unit of amino acid and peptide systems and can be inserted into the peptide chain. The introduction of the 1,3-dipole in peptide segments can improve the solubility and the stability toward enzymatic degradation.

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New Strategies for an Efficient Removal of the 9-Fluorenylmethoxycarbonyl (Fmoc) Protecting Group in the Peptide Synthesis

Cited by 26 publications

References 8 publications

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

Lewis acid catalysed methylation of N‐(9H‐fluoren‐9‐yl)methanesulfonyl (Fms) protected lipophilic α‐amino acid methyl esters

Synthesis of Chiral Nitrones from N‐Fmoc Amino Acids and N‐Fmoc Dipeptides

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