Trifluoroacetic acid cleavage reactions

Then another N-protected amino acid is coupled to the free amino group of the polymer-bound substrate using the dicyclohexylcarbodiimide activation or the active ester method. The N-deblocking and coupling steps are repeated until the desired sequence is formed. Finally the resin-peptide bond is split by a suitable acid cleavage reaction with HBr—AcOH, trifluoroacetic acid or HF. This results in a simultaneous N-deblocking and deprotection of most of the side-chain functionalities. 

CF3CO2H. Colourless liquid, b.p. 72-5 C, fumes in air. Trifluoroacetic acid is the most important halogen-substituted acetic acid. It is a very strong acid (pK = o y) and used extensively for acid catalysed reactions, especially ester cleavage in peptide synthesis. 

The original procedure for the trifluoroacetylation of amino acids used trifluoroacetic anhydride [Acetic acid, trifluoro-, anhydride].4 This reagent, although inexpensive and readily available, has certain disadvantages it is a highly reactive compound and thus has caused undesired reactions such as the cleavage of amide or peptide bonds,5 unsymmetrical anhydrides are formed between the newly formed A-trifluoroacetylamino acids and the by-product trifluoroacetic acid, and excess trifluoroacetic anhydride has caused racemization of asymmetric centers. 

The preparation of purine derivatives substituted at the C-2 position via amine displacement of a halogen is known as a difficult reaction step requiring several days of reaction time. However, Al-Obeidi and coworkers have recently prepared 2,6,9-trisubstituted purines on soUd-phase by employing a synthetic route in which the critical step was performed with microwave irradiation (Fig. 37) [62]. PS resin-bound 2-iodosubstituted purine was treated with diethanolamine or propanolamine in NMP with microwave irradiation at 200 °C for 30 min. Trifluoroacetic acid-mediated cleavage resulted in the 2-amino substituted purines in 45-59% yields and 77-89% purities. 

The best results in the imidazole synthesis were obtained by microwave-assisted reaction of an eightfold excess of the polymer-supported isonitrile suspended in 1,2-dimethoxyethane (DME) with the appropriate amines. Cleavage with 50% trifluoroacetic acid in dichloromethane afforded the desired heterocyclic scaffolds in moderate yields. 

Utilizing the novel syringaldehyde resin, smooth release from the support could be achieved upon microwave heating of a suspension of the resin-bound pyridinones in trifluoroacetic acid/dichloromethane (5 95) at 120 °C for just 10 min. The very mild cleavage conditions for this new linker, as well as its stability towards various reaction conditions and its easy accessibility, make it highly suitable for ongoing pyrazinone chemistry. 

To the product of the previous reaction are added DMF (7.0 mL) and DBU (1.6 mL). After shaking for 15 h, the resin is extensively washed with DMF, dichloromethane and methanol (note 7). Cleavage from the support is effected by treatment with 50% trifluoroacetic acid in dichloromethane (6.0 mL) for 1 h. Concentration of the filtrate yields 273 mg (80%) of the title compound as an oil (85% pure by HPLC, 254 nm), which crystallizes upon addition of methanol (2.0 mL). Filtration and drying yields 82 mg (24%) of slightly yellow crystals, 93% pure by HPLC (254 nm note 8). 

A phosphitylation procedure was carried out in THF using tetrazole as the activator subsequent oxidation was performed by TBHP in THF (steps a and b). Simultaneous cleavage of 2-cyanoethyl and Fmoc groups was achieved by DBU in dichloromethane solution (step c). Finally the tert-butyl group was removed under acidic conditions by trifluoroacetic acid (TFA). In phosphitylation reactions leading to the phosphopeptides, symmetrically protected phosphoroamidites have formerly been used [53]. 

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