Protection phenylacetamide

Penicillin acylase catalyzes the hydrolysis of phenylacetamides and has been used in peptide synthesis for the cleavage of protecting groups [46—47]. In linker (40) developed by Flitsch et al. [41—42] (Scheme 10.8) the group -XR represents the alcohol or amine group of the target molecule. Hydrolysis of the phenylaceta-... 

From the aforementioned, it should be evident that the amino group is one of the most reactive functionalities towards dioxirane oxidation consequently, to achieve a chemo-selective oxidation of a multi-functionalized substrate that possesses an amino group, the latter must be protected. This may be accomplished by masking the amino substituent in the form of its ammonium salt ", or BF3 complex ", even better as an amide functionality (iV-phenylacetamide resists TFD oxidation at room temperature""). This will reduce sufficiently the oxidative reactivity of the amino group, such that another less reactive group may be selectively oxidized" ... 

Phenylacetamides, to protect amines, 354 p-0-Phenylacetate esters, to protect alcohols, %... 

Enzymatic protecting-group techniques have recently been usedb in the synthesis of phosphopeptides, in which the phenylacetanoide group is removed from the respective phenylacetyl amides by means of PGA. In the course of the ensuing enzymatic transformations only the phenylacetamide-blocking group is attacked. The peptide bonds, the C-terminal ester, and the phosphates remain intact (Scheme 6). More importantly, the reaction conditions are so mild that no trace of P-elimination is observed. ... 

Proteases, such as thermitase,papain,f " l and subtilisinf have been employed for the deprotection of tert-butyl and methyl esters from various glycopeptides. More interestingly, the C-terminus of a nucleopeptide methyl ester 8 was deprotected selectively and in very high yield by papain.l Neither the acetate, the N-terminal urethane, the allyl phosphate, nor the phenylacetamide protection of the nucleobase were attacked (Scheme 17). 

For the N-terminal deprotection of peptides, the enzyme penicillin G acylase from E. coli has been applied. This attacks phenylacetic acid (PhAc) amides and esters but does not hydrolyze peptide bonds [12-14,25]. The danger of a competitive cleavage of the peptide backbone at an undesired site, which always exists when proteases like trypsin and chymotrypsin are used, is overcome by using the acylase. The penicillin G acylase accepts a broad range of protected dipeptides (27) as substrates, and selectively liberates the N-terminal amino group under almost neutral conditions (pH 7-8, room temperature), leaving the peptide bonds as well as the C-terminal methyl-, allyl-, benzyl-, and tert-butyl ester unaffected (Fig. 8) [25a,bj. On the other hand, the phenylacetamide... 

The application of the non-urethane PhAc blocking group results in ca. 6% racemization during the construction of the phenylacetamido-protected dipeptides by chemical activation of the phenylacetamido amino acids. This disadvantage can be overcome by forming the peptide bonds enzymatically, e.g. with trypsin [26,27], chymotrypsin [26,28], or carboxypeptidase Y [26,29]. An interesting example is the biocatalyzed synthesis of leucine-enkephalin tert-butyl ester [25e], in which phenylacetamides are introduced and cleaved by means of penicillin G acylase, and the elongation of the peptide chain is carried out with papain or a-chymotrypsin. 

Aromatic amines are often protected by acetylation before chlorosulfonation because reaction of the resultant acetanilides reduces decomposition of the product. An important example is the chlorosulfonation of acetanilide N-phenylacetamide, 344) to form 4-(acetamido)benzenesulfonyl chloride (A-acetyl-sulfanilyl chloride, 345) (Equation 109). Smiles and Stewart reported that the synthesis went in excellent yield (80%) by treatment of acetanilide 344 with the reagent (five equivalents) at 60 °C for 2 hours. The reaction is of considerable... 

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