Deprotection 9-fluorenylmethoxycarbonyl

Krausz el al. have synthesised two series of amino acid porphyrinylsugar derivatives (Fig. 5). One of them involves the coupling of adequate glycoporphyrin derivatives, prepared by pyrrole/aldehyde condensation methodology, with 9-fluorenylmethoxycarbonyl-L-alanine (Fmoc-L-alanine) to give the tri-, di-, and mono-alanine glycoporphyrin derivatives 54—57 after the deprotection step the other series (58) involves a glucosylamino acid moiety instead of the alanine in their preparation.21,44... 

To overcome these difficulties in the selective deprotection and chain extension, several carboxyl-protecting groups, namely, allyl (16,32), benzyl (43,44), tert-butyl (42), 2-bromoethyl (45), 2-chloroethyl (45), heptyl (46), 4-nitrophenyl (47,48), and pentafluorophenyl (49) for L-serine/L-threonine have been introduced or applied. Similarly, amino-protecting groups for L-serine/L-threonine that have proved useful for the synthesis of glycopeptides are tm-butyloxycarbonyl (50), 9-fluorenylmethoxycarbonyl (43,44,48), 2-(2-pyridyl)ethoxycarbonyl (51), 2-(4-pyridyl)ethoxycarbonyl (44,52), and 2-triphenylphosphonioethoxycarbonyl (53). Some applications of these groups have been discussed in earlier reviews (7-11). 

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. 

Unfortunately, A-(9-fluorenylmethoxycarbonyl)aziridine-2-carboxylic acid cannot be used in peptide synthesis, since N-deprotection of the respective peptides with secondary amines leads to oxazoline or dehydroamino acid side products. Similarly, N-(tert-butoxy-carbonyl)aziridine-2-carboxylic acid is inappropriate due to the instability of the aziridine moiety to TFA treatment. Attempts to convert A-tritylaziridine-2-carboxylic acid into homogenous and stable active esters as useful intermediates in peptide synthesis leads to positive results only in the case of the pentafluorophenyl ester. 47 Consequently, this active ester seems to be the method of choice for acylating peptides. The related Abhydroxysuc-cinimide and A-3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine ester could not be isolated in pure form and have therefore been used as crude products. 47 Access to 2-carbonylazir-idine peptides is also possible by carbodiimide-mediated coupling. Additionally, alkylamides of A-tritylaziridine-2-carboxylic acid are prepared by the azide method,1 5 yet this method fails in peptide coupling steps. 85 ... 

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. 

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]). 

First described by Kaljuste and Unden [34], the reaction of polymer-bound tryptophan with a variety of aldehydes and ketones under Pictet-Spengler conditions [35] has also been reported by Mayer et al. [36]. The j8-carboline derivatives 5 exhibited significant bioactivity. Following incorporation of 9-fluorenylmethoxycarbonyl (Fmoc)-tryptophan and deprotection, the condensation with an aldehyde or ketone under acidic conditions provided the /3-carbolines in high yield and purity. The same strategy has been published... 

By changing the surface characteristics of the solid support from neutral to acidic, the cleavage of the 9-fluorenylmethoxycarbonyl (Fmoc) group and related protected amines can be achieved in a similar manner. The hydrolytic deprotection of carboxylic acids from their corresponding allyl esters, under dry conditions , has also been reported on montmorillonite KIO clay [86]. 

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. 

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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