Fmoc group,

Some advantages of the Fmoc protective group are that it has excellent acid stability thus BOC and benzyl-based groups can be removed in its presence. It is readily cleaved, nonhydrolytically, by simple amines, and the protected amine is liberated as its free base. The Fmoc group is generally considered to be stable to hydrogenation conditions, but it has been shown that under some circumstances it can be cleaved with H2/Pd-C, AcOH, MeOH, (t /2 = 3-33 h). ... 

The Fmoc group is cleaved under mild conditions with an amine base to afford the free amine and dibenzofulvene. The approximate half-lives for the. deprotection of Fmoc-ValOH by a variety of amine bases in DMF are as follows ... 

Piperazine attached to a polymer has also been used to cleave the Fmoc group. 

Because of the electron-withdrawing sulfonic acid substituent, cleavage occurs under milder conditions than needed for the Fmoc group (0.1 N NH4OH 1% Na2C03, 45 min). ... 

This is a very important and well tested method for the quantitative determination of loading of Fmoc protected compounds particularly that of Fmoc (fluorenylmethoxycarbonyl) amino acids on solid support. Fmoc groups can... 

Thermitase, pH 7.5, 55°, 50% DMSO, 3-140 min. This method was used to avoid the degradation of base-sensitive side chains during peptide synthesis. The method is compatible with the Fmoc group. ... 

HCl, AcOH, CH2CI2, 5°, 2 h. A t-butyl ether and an Fmoc group were not affected. ... 

Direct conversion of an Fmoc group to a Cbz group KF, TEA, DMF, A-benzyloxycarbonyloxy-5-norbomene-2,3-dicarboximide, 7-12 h, 83-99% yield. ... 

These base-sensitive protective groups were introduced from the chloroformate or azidoformate. They are more sensitive to base than is the Fmoc group. Cleavage times with 0.2 mL of piperidine to 0.1 mmole of urethane in 5 mL of CHCL at It occur as follows Climoc, <10 min Bimoc, <14 h Fmoc, 18 h. °... 

During the cleavage of the Fmoc group with base, dibenzofulvene is liberated and must be scavenged to prevent its reaction with the liberated peptides during... 

The Bsmoc derivative is formed from the chloroformate or the A -hydroxy-succinimide ester. It is cleaved rapidly by a Michael addition with tris(2-aminoethyl)amine at a rate that leaves Fmoc derivatives intact. More hindered bases, such as A -methylcyclohexylamine or diisopropylamine, do not react with the Bsmoc group, but do cleave the Fmoc group, illustrating the importance of steric effects in additions to Michael acceptors. 

K2CO3 is used to remove the Fmoc group instead of the usual amines. 

The details of the solid-phase technique have been improved substantially over the years, but the fundamental idea remains the same. The most commonly used resins at present are either the Wang resin or the PAM (phenyl-acetamidomethyl) resin, and the most commonly used N-protecting group is the fluorenylmethyloxycarbonyl, or Fmoc group, rather than Boc. 

In the Fmoc protection approach, the acid-labile ferf-butyl groups are often used for side-chain protection. The base-labile Fmoc groups can be easily removed during a synthesis using piperidine (Fig. 4). The final global deprotection together with cleavage from the polymeric support is achieved with TFA. 

Another competing cyclisation during peptide synthesis is the formation of aspartimides from aspartic acid residues [15]. This problem is common with the aspartic acid-glycine sequence in the peptide backbone and can take place under both acidic and basic conditions (Fig. 9). In the acid-catalysed aspartimide formation, subsequent hydrolysis of the imide-containing peptide leads to a mixture of the desired peptide and a (3-peptide. The side-chain carboxyl group of this (3-peptide will become a part of the new peptide backbone. In the base-catalysed aspartimide formation, the presence of piperidine used during Fmoc group deprotection results in the formation of peptide piperidines. 

Synthesis of a number of O-glycosides (such as 131 -134) having different chain lengths between amino acids Ax and A10, which are part of interleukin-2, was accomplished by application of the Fmoc group in combination with the rm-butyl ester (77,78). 

Removal of the Fmoc group was achieved by treatment with morpholine-dichloromethane, leaving the allylic anchor and the 0-glyco-... 

Liming and coworkers (56) also used the Fmoc group for temporary amino protection and employed a commercial resin (SASRIN , trademark of Bachem, Switzerland) having a dialkoxybenzyl anchoring group. The synthesized glycopeptide could be cleaved from the resin with 1% trifluoroacetic acid in dichloromethane. 

A thioglycoside was immobilized by the following sequence of reactions. Treatment of the dibutyltin acetal of diol 36 with succinic anhydride afforded 37 in an excellent yield of 85%. Attachment of Fmoc protected glycine to TentaGel hydroxyl resin (38, 0.37 mmol/g resin) under standard conditions followed by removal of the Fmoc group by treatment with piperidine gave polymer 27. Compound 37 was immobilized by amide bond formation with 27 in the presence of... 

FIGURE 5.18 Resins and linkers for synthesis of peptide amides using Fmoc/tBu chemistry. Chain assembly is effected after removal of the Fmoc group. Treatment with CF3C02H releases a peptide amide by cleavage at the NH-CH/CH2 bond. 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

---