9-fluorenylmethyloxycarbonyl protected peptides

One of the most important limitations in the use of these diamino acids is the need of an additional orthogonal protection for the amino groups. Using the t-butoxycarbonyl/benzyl (Boc/Bzl) strategy of solid-phase peptide synthesis, this additional orthogonality can be easily provided by a base-labile protecting group such as the 9-fluorenylmethyloxycarbonyl... 

Standard amino acid protecting groups that were used routinely in BOC-peptide synthesis. For Lys the -nitrogen has the potential to cyclize. We sometimes protect this with the fluorenylmethyloxycarbonyl (FMOC) protecting group. 

Glycopeptides are more difficult to synthesize than the conventional peptides, because common protection-deprotection reactions used in the peptide synthesis can cause serious problems to the protective groups used for carbohydrates. Many of these problems have been solved by recent technical innovations [21]. The combination of 9-fluorenylmethyloxycarbonyl (Fmoc) group for N-protection and pentafluo-rophenyl (PFP) group as the activating group for the carboxylic acid allows GlcNAc-Asn... 

This is the reason why peptide chemists, to decrease the problems of purification prefer for long peptides to use protecting groups (tert-butyloxycarbonyl (t-Boc), benzyloxycarbonyl (Z), fluorenylmethyloxycarbonyl (FMOC).) and classical reagents such as T.B.T.U. (0-lH-benzotriazol-l-yl)-l,l,3,3-tetramethyl uronium tetrafluoroborate), B.O.P.(benzotriazol-l-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate and so on in polar solvents such as N,N-dimethylformamide or N-methylpyrrolidone. But this solvents are not compatible with the acidic deprotection reagents such as trifluoroacetic acid and... 

The use of 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one (Dhbt-OH, 19d) as an additive in peptide synthesis by either the carbodiimide or active ester method, and the preparation of such esters from 9-Fluorenylmethyloxycarbonyl (Fmoc)-protected amino acids and a method to prepare analogues of Dhbt-OH have been reviewed up to 1992 in CHEC-II(1996). Always crucial is the conservation of optical purity of the amino acid building blocks in amide or peptide synthesis, and addition of 19d is effective in conserving this optical purity. Both the formation of active esters from 19d and the suppression of racemization by 19d are regarded as due to the nucleophilic character of its anion <1970CB2024> see also Section 9.01.4.2. 

Several important peptide-protecting groups such as 9-fluorenylmethyloxycarbonyl, benzyl, 4-nitrobenzyl, 2,2,2-trichloroethyl, and acetonyl (eq 23) can be removed by TBAF under mild conditions. 

In order to design syntheses of complex peptides containing several functional side chains, it is necessary to have a variety of methods of protection and deblocking at disposal. Therefore, it was a major step forward when in addition to reduction and acidolysis deprotection with weak bases, under mild conditions, became a practical possibility. The 9-fluorenylmethyloxycarbonyl (Fmoc) group (Carpino and Han 1970) is removed from the amino group by proton abstraction with secondary amines. A carbamoic add is generated, that, in turn, loses carbon dioxide and affords the free amine ... 

A class of zinc ion (Zn2+) sensors, which utilized an unnatural amino acid that included the chelation-sensitive fluorophore, 8-hydroxy-4-(Af,Af-dimethylsulfonamido)-2-methylquinoline (sulfonamido oxine (Sox), Figure 1.3a), provided inspiration for a second class of kinase activity sensors [12-14]. The Sox amino acid was prepared via asymmetric synthesis and converted to the fluorenylmethyloxycarbonyl (Fmoc)-protected derivative and incorporated via SPPS into a peptide containing a proline-mediated fi-turn sequence [13]. The fl-turn was flanked by both Zn-chelating amino acids and the Sox fluorophore (Figure 1.3b). In this case, the fi-turn was included to provide preorganization... 

Fig. 3. A mild two-dimensional orthogonal protection scheme for solid-phase synthesis. Temporary -amino protection is provided by the 9-fluorenylmethyloxycarbonyl (Fmoc) group, removed by a base-catalyzed elimination mechanism, typically with piperidine. Permanent tert-bulyl-based side-chain-protecting groups and the p-alkoxybenzyl (PAB) ester handle linkage are both cleaved by treatment with TFA to 5deld the free peptide acid at the end of the synthesis. Details in text.

Miscellaneous. Fluoride ion from anhydrous TBAF undergoes nucleophilic displacement of tosylates, halides, and aryl nitro compounds to give fluorinated products. When used with N-Bromosuccinimide, bromofluorination products are obtained. Several important peptide-protecting groups such as 9-fluorenylmethyloxycarbonyl, benzyl, 4-nitrobenzyl, 2,2,2-trichloroethyl, and acetonyl (eq 23) can be removed by TBAF under mild conditions. 

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