9-Fluorenylmethoxycarbonyl group peptide synthesis

For a review of the use of Fmoc protection in peptide synthesis, see E. Atherton and R. C. Sheppard, The Fluorenylmethoxycarbonyl Amino Protecting Group, in The... 

JD Wade, J Bedford, RC Sheppard, GW Tregear. DBU as an V -deprotecting reagent for the fluorenylmethoxycarbonyl group in continuous flow solid-phase peptide synthesis. Pept Res 4, 194, 1991. 

Scheme 15 Synthesis of Tyrosine 0-Sulfate Peptides with the 9-Fluorenylmethoxycarbonyl Group for Temporary N"-Protection 421...

The 9-fluorenylmethoxycarbonyl group, developed by Carpino and co-workers in 1972 [257], has become one of the most widely used protective groups for aliphatic or aromatic amines in solid-phase synthesis. For solid-phase peptide synthesis in particular, this protective group plays an important role [258] (Section 16.1). The Fmoc group is not well suited for liquid-phase synthesis because non-volatile side products are formed during deprotection. 

The 9-fluorenylmethoxycarbonyl group is another distinguished contribution from the Carpino laboratory198199 to the solution-phase synthesis of peptides and latterly it has been adapted to solid-phase peptide synthesis too.200 The Fmoc group is exceptionally stable towards acid thus, carboxylic acids can be converted to acid chlorides with thionyl chloride201 or terf-butyl esters using sulfuric acid and isobutene.202 Furthermore, Fmoc groups are unscathed by HBr in... 

The 9-fluorenylmethyl group, in the guise of the 9-fluorenylmethoxycarbonyl or Fmoc group, is the keystone in modern solid-phase peptide synthesis and we will examine its enormous influence in section 8.3.5. The great virtues of the 9-fluorenylmethyl group have also been adapted to the protection of carboxylic acids as 9-fluorenylmethyl esters (see section 6.5.3). Bodanszky and Bednarek realised the opportunity for extending the principle of 9-fluorenylmethyl activation, the aromaticity of the fluorenyl anion, to the protection of cysteine in peptide synthesis. 9-Fluorenylmethyl thioethers are stable towards iodine and acidic conditions, including HF, but they easily eliminate on treatment with piperidine or DBU. 

Solid-phase peptide synthesis. The combination of the base-labile N-a-fluorenylmethoxycarbonyl (Fmoc) amino acids and the acid-labile /-butyl protecting group is valuable for solid-phase peptide synthesis, particularly with polar resins. Intermediate Fmoc-peptide resins are deprotected with 20% piperidine or 5% piperazine in DMF. Six amino acid groups can be added per day without difficulty. This new strategy was used for synthesis of human /3-endorphin (31 residues), with 29 residues added as the anhydrides of Fmoc-amino acids. The last residue was the N-a-Boc derivative of 0-/-butyltyrosine. The peptide resin was cleaved with anhydrous CF3COOH. The overall yield of isolated polypeptide was 41 %. This method does not require vigorous acidic conditions. 

The application of additives was investigated in order to suppress or diminish side reactions (A-acyl urea formation and racemization). Al-Hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HoBt), and ethyl l-hydroxy-lH-l,2,3-triazole-4-carboxylate are potential additives in the DCC-based coupling synthesis. Solid-phase peptide synthesis (SPPS) is a variant of the linear (stepwise) coupling of amino acids in the C N direction using two major protection groups Boc/Bzl (iert-butoxycarbonyl/benzyl) and Fmoc/tBu (/9-fluorenylmethoxycarbonyl/ieri-butyl). The synthetic scheme for peptides on a polymer (Atherton and Sheppard, 1989 Fields, 1997) is illustrated in Figure 8.1. 

A range of base-labile N-terminal protecting groups was therefore investigated for application in solid phase peptide synthesis (S). Carpino s 9-fluorenylmethoxycarbonyl (Fmoc) group (10) soon proved to be quite... 

In a variation of the Merrifield solid-phase peptide synthesis, the amino group is protected by a fluorenylmethoxycarbonyl (FMOC) group. This protecting group is removed by treatment with a weak base such as the secondary amine piperidine. Write a balanced equation and propose a mechanism for this deprotection. 

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