Utilization of N,N,N′,N′-Tetramethylfluoroformamidinium Hexafluorophosphate (TFFH) in Peptide and Organic Synthesis (original) (raw)
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Synthesis of peptides employing 9-fluorenylmethyl chloroformate as a coupling agent
Letters in Peptide Science, 2003
The synthesis of peptides employing 9-fluorenylmethyl chloroformate (Fmoc-Cl) as a coupling agent has been described. The method is simple, efficient and rapid. All the peptides have been obtained in good yield (70–95%). Furthermore, both the1H NMR and the HPLC studies on Fmoc-Phg-Phe-OMe and Fmoc-D-Phg-Phe-OMe revealed that the coupling is free from racemization.
The Journal of Organic Chemistry, 2006
S-2 1. General Procedure for the Buchwald-Hartwig Cyclization Reaction. rac-BINAP (40 mol%) was added to HPLC grade acetonitirle (1.5x10-3 M) solvent and solution refluxed for 30 min. Allowed to room temperature and the palladium acetate (30 mol%) was added and stirred for 15 min, followed by acyclic peptide (500 mg) and finally the base Cs 2 CO 3 (4eq) were added. The resulting reaction mixture was stirred at 100 o C for 15 h. After this period of stirring, the solvent was removed under reduced pressure, and the residue was subsequently purified by column chromatography. 2. General Procedure for the Buchwald-Hartwig Cyclization Reaction. rac-BINAP (40 mol%) was added to HPLC grade acetonitirle (1.5x10-3 M) solvent and solution refluxed for 30 min. Allowed to room temperature and the palladium acetate (30 mol%) was added and stirred for 15 min, followed by acyclic peptide (500 mg) and finally the base t BuOK (2eq) were added. The resulting reaction mixture was stirred at 100 o C for 15 h. After this period of stirring, the solvent was removed under reduced pressure, and the residue was subsequently purified by column chromatography. 3. General Procedure for peptide coupling. (a) To a stirred solution of the TFA salt of C-protected peptide in CH 2 Cl 2 (5 mL/mmol) at 0 o (ice-bath) under N 2 was treated successively with Et 3 N (5 equiv), HOBt (1.2 equiv), a solution of the Boc-protected amino acid (1 equiv) in CH 2 Cl 2 (2.5 mL/mmol), and EDC (1.2 equiv). The mixture was allowed to warm to r.t., and stirring was continued for 15 h. The mixture was diluted with CH 2 Cl 2 and washed with 10% aq. citric acid, aq. saturated NaHCO 3 , H 2 O and saturated NaCl solution. The organic phase was dried (Na 2 SO 4), evaporated, and the residue was purified using flash column chromatography to get the pure material. S-3 (b) To a stirred solution of TFA salt of C-protected peptide in CH 2 Cl 2 (3 mL/mmol) and DMF (2 mL/mmol) at 0 o (ice-bath) under N 2 was treated successively with Et 3 N (5 equiv), HOBt (1.2 equiv), a solution of the Boc-protected amino acid (1 equiv) in CH 2 Cl 2 (2.5 mL/mmol), and EDC (1.2 equiv). The mixture was allowed to warm to r.t., and stirring was continued for 15 h. The residue obtained after the removal of all volatiles was dried under vacuum for 1 h and then stirred in MeOH for 20 min. The white precipitate was collected by filtration and thoroughly washed with MeOH/H 2 O 1:1 mixture. The solid product was dried under high vacuum for several hours. 4. General procedure for Boc deprotection. (a) CF 3 COOH (1.5 mL/mmol) was added to an ice-cold solution of the Boc-protected peptide in CH 2 Cl 2 (5 mL/mmol). The reaction mixture was allowed to warm to r.t. and stirring was continued for 2 h. The mixture was evaporated and the residue dried under high vaccum. The salts with CF 3 COOH were used without further purification and characterization. (b) CF 3 COOH (1.5 mL/mmol) was added to an ice-cold solution of the Boc-protected peptide in CH 2 Cl 2 (5 mL/mmol). The reaction mixture was allowed to warm to r.t. and stirring was continued for 3 h. The mixture was evaporated and the residue dried under high vaccum. Then the residue dissolved in mixture of DCM and DMF solution and basified (PH-8) with Et 3 N. The mixture solution was concentrated to its 1/3 volume and 1:1 Methanol and water solution added. Solid compound was obtained on stirring for 30 min at room temperature. Filtered off and dried under vaccum for 6-10 h.
ACS Sustainable Chemistry & Engineering, 2019
mixture (2 × 3 mL each). A solution of Fmoc-Leu-OH (3 equiv), N,N′-diisopropylcarbodiimide (DIC) (3 equiv), and Oxyma Pure (3 equiv) in the proper mixture, preactivated for 5 min, was charged onto the resin and stirred for 1 h. After the peptide coupling, the resin was washed with DMF, DCM and DMF or mixture, iPrOH, and mixture (2 × 3 mL each). Then, 20% piperidine in DMF or selected mixture was charged on the resin (2 × 3 mL × 15 min). The resin was washed and ready for the subsequent couplings, deprotections, and washings, as reported before, to obtain the pentapeptide. The peptide was cleaved from the resin with trifluoroacetic acid (TFA)/H 2 O/ triisopropylsilane (TIS) (95:2.5:2.5) solution for 2 h at room temperature. The crude was directly analyzed by HPLC-MS. Solid-Phase Synthesis of H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol (Linear Octreotide) in 70:30 Anisole/Dimethyl Carbonate (Method 8). The synthesis was performed in a glass syringe, attached at the bottom to a vacuum source to remove excess of reagents and solvents. The resin (H-Thr(tBu)-ol-2CT-PS 0.6 mmol/g, 500 mg) was washed with 3 mL of Mix C3, 3 mL of iPrOH, and 3 mL of Mix C3. A preactivated solution of Fmoc-Cys(Trt)-OH (3 equiv), DIC (3 equiv), and Oxyma Pure (3 equiv) in Mix C3 (3.3 mL) was charged onto the resin and stirred for 1 h. After the peptide coupling, the resin was washed with 3 mL of Mix C3, 3 mL of iPrOH, and 3 mL of Mix C3. Fmoc removal was performed by adding 2 × 3 mL of 20% piperidine in Mix C3 on the resin, shaking it for 10 min each. After the deprotection, the resin was washed with 4 × 3 mL of Mix C3. The resin was ready for the subsequent couplings, deprotections, and washings, as reported before, to obtain the decapeptide. The final washings were performed with Mix C3 (4 × 3 mL) and iPrOH (3 × 2 mL). The peptide was cleaved from the resin with TFA/TIS/1-dodecanthiol (9 mL/0.7 mL/0.6 mL) solution for 4 h at room temperature. The solution was recovered by filtration. Diisopropyl ether (37 mL) was added dropwise at 0−5°C to the acidic solution until precipitation of peptide was achieved. The resulting mixture was stirred for 1.5 h at 0−5°C. The precipitate was filtered, washed with diisopropyl ether and petroleum ether, and dried under vacuum, affording an off-white solid. The crude was analyzed by HPLC-MS. For the synthesis with method 1, as a substitution for Mix C3 and iPrOH, DMF and DCM were used. Cyclization of Linear Octreotide. Crude trifluoroacetate linear Octreotide (1 g of a raw synthetic product containing 82.3% or 88.0%
Liebigs Annalen der Chemie, 1988
Condensation of amides of N-(benzyloxycarbony1)-and N-(trifluoroacety1)amino acid with pyruvic and phenylpyruvic acid yields, in the presence of p-toluenesulfonic acid as a catalyst, N-(benzyl-oxycarbony1)-and N-(trifluoroacety1)dehydro dipeptides with C-terminal AAla and APhe, respectively (Table 2 and 3). Synthese von Peptiden mil a,P-Dehydroaminosauren, I.-Synthese von N-(Benzyloxycarbonylb und N-(Trifluoracety1)dipeptiden von Dehydroalanin und Dehydrophenylalanin Die Kondensation von Na-(Benzyloxycarbonyl)-und Na-(Trifluoracetyl)arninosaureamiden mit Brenztrauben-und Phenylbrenztraubensaure in Gegenwart von p-Toluolsulfonsaure als Katalysator fuhrt zu N-(Benzyloxycarbony1)-und N-(Trifluoroacety1)dehydrodipeptiden rnit C-standigem AAla2) bzw. APhe (Tab. 2 und 3). N-protected a,B-dehydroamino acid which, among others, can be synthesized by condensation of carboxamides with a-keto acids3-'), have only a limited value in peptide synthesis. The deprotection of the enamine function is somewhat difficult ') and accompanied by side reaction^'.'^). The nucleophilicity of the deprotected amino group, particulary in APhe'), is diminished as compared with amino groups in common amino a~i d s~*~, * * "~'~'. Basing on the condensation of Z-Gly-NH2 with pyruvic acid which leads to Z-Gly-AAla6' and taking into account the considerable improvement in condensation method of amides with a-keto acids4*", to circumvent the above difficulties we put to trial the condensation of a-keto acids with suitably No-protected amino acid amides". We describe here our experiments, observations, and the obtained dehydro dipeptides. Model compounds were selected in that way to represent a given spectrum of N-protections and side chain residues and in consequence reactivity. W e condensed amides of Z-and TFA-glycine,-L-phenylalanine, and-L-valine (the derivatives of amino acids without side chain and with an aromatic or branched aliphatic one) with pyruvic or phenylpyruvic acid which both possess different chemical reactivity toward amides. Viz., they react in the absence4-" or presence4' of catalysts. Condensations led to Zand TFA-dipeptides with C-terminal AAla or APhe, thus, to peptides having the amino group protecting moieties