Peptide protecting groups

Only one method has been used to prepare various peptidyl diazomethyl ketones. A protected amino acid or peptide acid is activated as the mixed anhydride and reacted with ethereal diazomethane at low temperature. Generally a peptide with the desired sequence is prepared first and then converted into the diazomethyl ketone in the final step of the synthesis. Since the diazomethyl ketone functional group is stable to alkali but unstable to acid, acidic conditions used to deprotect many peptide protecting groups must be avoided. 

In the synthesis of sulfur-free peptides, protecting groups removable by catalytic hydrogenation, such as Arg(N02), Asp(OBzl), or Glu(OBzl), can be used. Boissonnas et al. employed this procedure for the synthesis of bradykinin in 1960,and Arakawa and Bumpus utilized this method in the synthesis of angiotensin II in 1961.0 ... 

F makes an excellent probe to monitor solid phase reactions most solid supports do not contain fluorine, 19F NMR is almost as sensitive as proton NMR, the range of 19F chemical shifts is large, and the resonance can be monitored even when the fluorine atom is quite remote from the site of reaction. The buildup of the peptide chain could be monitored by incorporating 19F into a peptide-protecting group (18). 

Several important peptide-protecting groups such as 9-fluorenylmethyloxycarbonyl, benzyl, 4-nitrobenzyl, 2,2,2-trichloroethyl, and acetonyl (eq 23) can be removed by TBAF under mild conditions. 

In the presence of 10% palladium on charcoal, peptide protecting groups, such as N-benzyloxycarbonyl and benzyl esters, are rapidly removed at room temperature in high yield by the use of cyclohexa-1,4-diene as the hydrogen source for catalytic transfer hydrogenation. ... 

Miscellaneous. Fluoride ion from anhydrous TBAF undergoes nucleophilic displacement of tosylates, halides, and aryl nitro compounds to give fluorinated products. When used with N-Bromosuccinimide, bromofluorination products are obtained. Several important peptide-protecting groups such as 9-fluorenylmethyloxycarbonyl, benzyl, 4-nitrobenzyl, 2,2,2-trichloroethyl, and acetonyl (eq 23) can be removed by TBAF under mild conditions. 

Primary and secondary amines are susceptible to oxidation and replacement reactions involving the N—H bonds. Within the development of peptide synthesis numerous protective groups for N—H bonds have been found (M, Bodanszky, 1976 L.A. Carpino, 1973), and we shall discuss five of the more general methods used involving the reversible formation of... 

In each step of the usual C-to-N peptide synthesis the N-protecting group of the newly coupled amino acid must be selectively removed under conditions that leave all side-chain pro-teaing groups of the peptide intact. The most common protecting groups of side-chains (p. 229) are all stable towards 50% trifluoroacetic acid in dichloromethane, and this reagent is most commonly used for N -deprotection. Only /ert-butyl esters and carbamates ( = Boc) are solvolyzed in this mixture. 

Another protecting group of amines is 1-isopropylallyloxycarbonyl, which can be deprotected by decarboxylation and a /3-elimination reaction of the (tt-l-isopropylallyl)palladium intermediate under neutral conditions, generating CO2 and 4-methyl-1,3-pentadiene. The method can be applied to the amino acid 674 and peptides without racemization[437]. 

To direct the synthesis so that only Phe Gly is formed the ammo group of phe nylalanme and the carboxyl group of glycine must be protected so that they cannot react under the conditions of peptide bond formation We can represent the peptide bond for matron step by the following equation where X and Y are amine and carboxyl protecting groups respectively... 

Carboxyl groups of ammo acids and peptides are normally protected as esters Methyl and ethyl esters are prepared by Fischer esterification Deprotection of methyl and ethyl esters is accomplished by hydrolysis m base Benzyl esters are a popular choice because they can also be removed by hydrogenolysis Thus a synthetic peptide protected at both... 

Several of the ammo acids listed m Table 27 1 bear side chain functional groups which must also be protected during peptide synthesis In most cases protecting groups are available that can be removed by hydrogenolysis... 

The most frequendy used technique to shift the equiUbrium toward peptide synthesis is based on differences in solubiUty of starting materials and products. Introduction of suitable apolar protective groups or increase of ionic strength decreases the product solubiUty to an extent that often allows neady quantitative conversions. Another solubiUty-controUed technique is based on introduction of a water-immiscible solvent to give a two-phase system. Products preferentially partition away from the reaction medium thereby shifting the equiUbrium toward peptide synthesis. 

Many protective groups have been developed for the amino group, including carbamates (>NCO,R), used for the protection of ammo acids in peptide and protein syntheses, and amides (>NCOR). used more widely in syntheses of alkaloids and for the protection of the nitrogen bases adenine, cytosine, and guanine in nucleo-... 

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