Protecting groups carbobenzyloxy

Improved Catalyst for the Removal of Carbobenzyloxy Protective Groups... 

See K. Humphries, T. Dunn, K. Moebus, B. Chen, Improved Catalyst for the Removal of Carbobenzyloxy Protecting Groups, this issue, Ch. 54. 

One of the first compounds to be introduced to the clinic, aztreonam (40-9), has been produced by total synthesis. Constmction of the chiral azetidone starts with amide formation of L-threonine (40-1) via its acid chloride treatment with ammonia leads to the corresponding amide (40-2). The primary amino group in that product is then protected as its carbobenzyloxy derivative (40-3). Reaction of that product with methanesulfonyl chloride affords the mesylate (40-4). Treatment of that intermediate with the pyridine sulfur trioxide complex leads to the formation of the A -sulfonated amide (40-5). Potassium bicarbonate is sufficiently basic to ionize the very acidic proton on the amide the resulting anion then displaces the adjacent mesylate to form the desired azetidone the product is isolated as its tetrabutyl ammonium salt (40-6). Catalytic hydrogenation over palladium removes the carbobenzyloxy protecting group to afford the free primary amine (40-7). The... 

In order to transform the spirocyclic enone 445 to ( )-elwesine (439) and ( )-epielwesine (449), it was treated with boron trifluoride and dimethylsulfide to cleave the Al-carbobenzyloxy protecting group, and cyclization of the resulting amino enone spontaneously ensued to produce ( )-dihydrooxocrinine (447). Reduction of carbonyl function of 447 with sodium borohydride afforded ( )-3-epielwesine (449), which was converted to ( )-elwesine (439) by inversion of the hydroxyl function at C-3 via a Mitsunobu protocol using diethyl azodicarboxylate, triphenylphosphine, and formic acid. Attempted reduction of 447 directly to 439 by a Meerwein-Ponndorf-Verley reduction or with bulky hydride reagents gave only mixtures of 449 and 439 that were difficult to separate. 

The enone 445 was then converted to ( )-oxocrinine (415) by a sequence that commenced with the bromination of 445 using excess 5,5-dibromo-2,2-di-methyl-4,6-dioxo-l,3-dioxane to provide a mixture of bromo ketones 446. Removal of the jV-carbobenzyloxy protecting group according to the protocol previously detailed gave 448 as a mixture (a-Br (3-Br = 3 1) of diastereomers, but only the a-bromo isomer underwent dehydrobromination on heating with lithium bromide and lithium carbonate in dry DMF to furnish 415. Interestingly, treatment of the (3-bromo derivative of 448 under similar conditions afforded the debrominated product 447 (200). 

Benzyl and carbobenzyloxy protecting groups have been particularly useful in peptide syntheses but hydrogenolyses do not occur under the normal reaction conditions when sulfur containing amino acids are present. This problem was overcome, however, by miming the hydrogenolyses over palladium black in liquid ammonia. In this way complete removal of the benzyl entity from benzyl... 

The resulting 2-benzylthioethylamine could be debenzylated by treatment with sodium in liquid ammonia. However, when 2-benzylthioethylamine was treated with carbobenzyloxy-P-alanine azide (prepared from carbobenzyloxy-P-alanylhydrazide by nitrosation), 2-benzylthio-7V-(carbobenzyloxy-P-alanyl)ethyl-amine formed. Reduction with sodium in liquid ammonia was sufficient to remove both the benzyl and carbobenzyloxy protecting groups and, as noted above, reaction with pantolactone yielded pantetheine. Phosphorylation to the mono- and diphosphates of pantetheine has been effected with the corresponding dibenzylphospho-nates (vide supra, ATP). 

The removal of carbobenzyloxy (Cbz or Z) groups from amines or alcohols is of high interest in the fine chemicals, agricultural and pharmaceutical industry. Palladium on activated carbon is the catalyst of choice for these deprotection reactions. Nitrogen containing modifiers are known to influence the selectivity for certain deprotection reactions. In this paper we show the rate accelerating effect of certain N-containing modifiers on the deprotection of carbobenzyloxy protected amino acids in the presence of palladium on activated carbon catalysts. The experiments show that certain modifiers like pyridine and ethylenediamine increase the reaction rate and therefore shorten the reaction times compared to non-modified palladium catalysts. Triethylamine does not have an influence on the rate of deprotection. 

Figure 1 Removal of carbobenzyloxy (Cbz) groups from protected amino acids.

In the synthesis of the antibiotic L-azatyrosine, the simultaneous removal of the carbobenzyloxy and diphenylethylene protecting groups presented a problem (Scheme 4.47). 

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