Fmoc protection

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). ... 

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... 

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... 

An Fmoc protecting group can be removed from an amino acid by treatment with the amine base piperidine. Propose a mechanism. 

At this stage of the synthesis, it was convenient to protect the secondary amino function in 56 as the base-labile FMOC derivative22 through the use of the corresponding chloroformate (96% yield). In the planning phase, the selection of an FMOC protecting... 

The completion of the total synthesis only requires a few deprotection steps. It was gratifying to find that the final deprotections could be conducted smoothly and without compromising the newly introduced and potentially labile trisulfide residue. In particular, exposure of intermediate 101 to the action of HF pyridine results in the cleavage of all five triethylsilyl ethers, providing 102 in 90% yield (Scheme 23). Finally, hydrolytic cleavage of the ethylene ketal with aqueous para-toluenesulfonic acid in THF, followed by removal of the FMOC protecting group with diethylamine furnishes calicheamicin y (1) (see Scheme 24). Synthetic calicheami-cin y, produced in this manner, exhibited physical and spectroscopic properties identical to those of an authentic sample. 

Investigation of the microwave-assisted attachment of Fmoc-protected amino acids onto 2-chlorotrityl chloride resin indicated higher loadings and increased rates compared to standard room temperature procedures [146]. In this comparative study standard procedures yielded 0.37 mmol/g loading after 1 hour, whereas at 110 °C using microwave dielectric heating, a similar result (0.38 mmol/g) was obtained after only 15 min (Fig. 7). 

Specifically, the carboxylates of N -Fmoc-protected (and side chain-protected) N-substituted glycines were activated and then coupled to the secondary amino... 

R. M.J. Solid-phase syntheses of peptoids using Fmoc-protected N-substituted glycines The synthesis of (retro) peptoids of leu-enkephalin and substance P. Euro. J. Chem. 1998, 4, 1570-1580. 

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. 

Urge, L., Otvos Jr., L., Lang, E., Wroblewski, K., Laczko, I., and Hollosi, M. (1992) Fmoc-protected, glycosylated asparagines potentially useful as reagents in the solid-phase synthesis of N-glycopeptides. Carbohydr. Res. 235, 83-93. 

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

A more recent publication by Weigand and Pelka has disclosed a polymer-bound Buchwald-Hartwig amination [40], Activated, electron-deficient aryl halides were coupled with conventional PS Rink resin under microwave irradiation. Subsequent acidic cleavage afforded the desired aryl amines in moderate to good yields (Scheme 7.22). Commercially available Fmoc-protected Rink amide resin was suspended in 20% piperidine/N,N-dimethylformamide at room temperature for 30 min to achieve deprotection. After washing and drying, the resin was placed in a silylated microwave vessel and suspended in dimethoxyethane (DME)/tert-butanol... 

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

The earliest published example of microwave-assisted SPOS involved diisopropyl-carbodiimide (DlC)-mediated solid-phase peptide couplings [24], Numerous Fmoc-protected amino acids and peptide fragments were coupled with glycine-preloaded polystyrene Wang resin (PS-Wang) in DMF, using either the symmetric anhydride or preformed N-hydroxybenzotriazole active esters (HOBt) as precursors (Scheme 12.1). 

The SPSS following this route is illustrated in Scheme 5. In the first step, Fmoc-protected glycine is attached to a trityl-derived hydroxyl... 

Here we observe Pbf cleavage from Fmoc-protected arginine under typical conditions, which proceeds as a (pseudo) first order process. Mass spectra from t = 0 and t = 10 min appear in Fig. 2. The reaction took 20 min to go to completion. 

A total of 36 MicroTubes ( 42 pmol / MicroTube) were sorted into three vials (note 9). MicroTubes in each vial were treated at room temperature with Fmoc-protected amino acids (2,5.4 mmol, 10 equiv note 10), DIEA (1.75 mL, 10.08 mmol, 20 Eq.), and HATU (1.91 g, 5.04mmol, 10 Eq.) in DCM (24mL) for 24h. After the supernatant was removed by aspiration, the MicroTubes were then washed three times with DMF, DCM, MeOH, and DCM. The MicroTubes were dried under vacuum overnight. IR 1657 cm-1 (CONHR note 11). 

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 - ). 

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... 

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