Fmoc deprotection reaction

Alloc, and racemization does not occur on cleavage. Typical nucleophiles that can be used for the cleavage are amines, water, and alcohols (35). The oxidation sensitivity of the linker does require the coupling reactions, and especially Fmoc deprotecting reactions, to be performed under exclusion of oxygen. 

Sequential acylation reactions were carried out at ambient temperature for 1.5 h using a DMF solution (1.3 mL) of the appropriate A-Fmoc-protected amino acids [Fmoc-Arg/D-Arg(Pmc)-OH, 265 mg Fmoc-Trp/D-Trp(Boc)-OH, 211 mg 0.4 mmol) and then carboxyl activated using TBTU (154 mg, 0.4mmol), HOBt (54mg, 0.4mmol), and DIEA (140pL, 0.8 mmol). Repetitive A"-Fmoc deprotection was achieved using 20% v/v piperidine in DMF (6 min, 2.5 mL min - ). 

After the reaction times given in Scheme 38, the respective couplings were quantitative according to chloranil and the Kaiser ninhydrin test and/or HPLC of small cleavage. The peak area of the crude Fmoc-deprotected dodecapeptide was 90% (HPLC k=214nm). The pure cyclic peptide was obtained in an overall yield of 31%. Cyclosporin O was synthesized by a similar procedure.129 ... 

Fmoc-deprotection After the reaction is complete, wash the membrane three times with DMF for at least 30 s each. For storage, wash the modified membrane at least twice with methanol or ethanol and dry it in the air stream of a fume hood or using a hair dryer without heat. For resumption of synthesis after storage, treat the membrane once with DMF for 20 min (see Note 5). The Fmoc-deprotection is carried out by treatment of the membrane twice with 20% piperidine in DMF for at least 5 min each. 

Examples of off-bead yield estimation that do not require cleavage include reactions where new species are stoichiometrically formed in solution, and their quantification provides an indirect, but accurate, yield estimation of the SPS step. The classical Fmoc deprotection of amines in peptide synthesis is a widely used example. In a typical experimental procedure, the beads are treated with a 20% DMF solution of piperidine at rt for 20 min and the solution is recovered together with the resin washings. The solution is brought to a constant volume (typically 10 mL) by addition of DMF, and the quantitation is carried out by reading the UV absorbance of the piperidine-... 

Figure 2.7 Side reaction of BAL-supported A-Fmoc amino acids during Fmoc deprotection Diketopiperazines 2.15.

Tab. 1 The time for the complete Fmoc deprotection and the time for the condensation reaction of the fragments for the TCR peptides are given. In the left column only the product of the fragment condensation is shown. The fragmentation for the TCR peptides is given in Fig. 2.

The chemical reactivity of aliphatic hydroxy groups is reduced by acylation, but the resulting esters are reactive toward amino groups. Thus, under basic conditions, as commonly used for Fmoc deprotection, an intramolecular O N migration of the acyl residue can occur.b l This O N shift, which produces N-acylated derivatives (Scheme 3), is nearly irreversible and further elongation of the peptide is prevented. The same reaction can occur during acidolytic deprotection of final peptides with TFA via intermediate formation of the tri-fluoroacetyl ester of N-terminal hydroxy amino acids,... 

The Fmoc group lends itself particularly to the solid-phase procedure and is used almost exclusively in this mode. This is because in the deprotection reaction the initially formed dibenzofulvene moiety is efficiently scavenged by the secondary amine, usually piperidine, used for cleavage and is then washed away effectively from the solid support, whereas in solution phase the resulting moieties are not readily removed. However, the group still finds occasional utility in solution phase.t ... 

With the aim of preparing bicydic diketopiperazines as potential P-tum mim-etics [351], a-N-Boc-P-N-Fmoc-optically active diaminopropionic acids were attached to a standard Merrifield s hydroxymethyl resin under Mitsunobu conditions to afford [428]. Fmoc deprotection and subsequent Ugi reaction using, as the car-boxyhc component, optically active 2-bromoaIkyl adds (430), afforded the required intermediates (431). Further standard manipulations of these compounds, indud-ing a cydative deavage, gave rise to the desired bicydic peptidomimetics (432) (Scheme 88). 

The resin was then filtered off and washed vtith CH2CI2 (2x7 mb), DMF (3x7 mb), and CH2CI2 (3x7 mb) to give the desired product 85. The loading level was determined by Fmoc reading (UV-active piperidine-dibenzofulvene adduct) after Fmoc deprotection -with 20% piperidine in DMF (2 + 20 min). In the next step, coupling of Fmoc-amino acids and 2-fluoro-5-nitrobenzoic acid to the previous amino acid was performed under the same reaction conditions, except for the shorter reaction time (24 h). 

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... 

Diketopiperazine formation has long been described as a side reaction in peptide synthesis. It occurs after deprotection or neutralization of the oc-amino group at the dipeptide stage and reduces the overall yield of the synthesis. However, diketopiperazine structures have also been found in natural products with therapeutic properties and hence they have been used as a scaffolds to design new potential drugs [38, 91, 92]. A typical example would be the synthesis of indolyl diketopiperazine alkaloids. Access to these compounds may be achieved by Pictet-Spengler reaction of L-tryptophan bound to hydroxymethylpolystyrene resin with aldehydes. Fmoc amino acids were then coupled and final Fmoc deprotection resulted in cyclative release to yield alkaloids in 50-99% yields (Figure 15.9) [93, 94],... 

Dibenzofulvene (100), which is a byproduct of fluorenylmethoxycarbonyl (FMOC) deprotection in peptide synthesis, undergoes Michael addition reactions with carbanions. Conversion of 100 with the silyl enol ether of cyclohexanone (101) and a desilylation reagent furnishes directly the ketone 102, that now can be subjected to the already described acid mediated intramolecular cyclodehydration procedure followed by aromatization. The product is again a polycyclic fluoranthene (103), that can be considered as a naphtho annelated fluor-ene in this sequence (see Scheme 50 [150]). 

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