Amino-protecting groups

Unprotected amino groups are sites of both nucleophilicity and a weakly acidic hydrogen. If a given reaction cannot proceed in the presence of either of these types of reactivity, a protected derivative must be employed. The masking of nucleophilicity can be accomplished by acylation. The importance of temporarily masking amino-group nucleophilicity in synthesis of polypeptides will be discussed in Chapter 11. 

The most useful protecting group for this purpose is the carbobenzyloxy group. The utility of this group lies in the ease with which it can be removed. Because of the lability of the benzyl C-O bonds towards hydrogenolysis, the amine can be regenerated from a carbobenzyloxy derivative by hydrogenation, which is accompanied by spontaneous decarboxylation  

Tertiary alkoxycarbgnyl groups are also useful for protecting amines. The ease of removal in this case results from the stability of the tertiary carbonium ion. Acidic conditions, such as trifluoroacetic acid, bring about removal of t-butoxycarbonyl 

Phthaloyl and succinoyl derivatives of ammonia are relatively acidic, and the 

Gabriel synthesis of primary amines. More recently, phthalimide has been used in a 

Primary and secondary amino groups are sites of both nucleophilicity and a weakly acidic hydrogen. If a given reaction cannot proceed in the presence of either 

CH302C(CH2)7CHCH(CH2)5CHj0H CHjOjCfCH l HC-----CHtCH lsCHjOH 

Simple amides are satisfactory protecting groups only if the molecule as a whole can resist the vigorous acidic or alkaline conditions required for hydrolytic removal. Phthaloyl groups have been used to protect primary amine centers. The group can be removed hydrolytically or by treatment with hydrazine. The imide carbonyl groups are more reactive than simple amides and the deprotection is completed by an intramolecular cyclization. 

Under some circumstances, it is possible to effect removal of amide groups by selective hydride reduction. Trichloroacetamides are readily cleaved by sodium 

The trifluoroacetyl group also finds some use as a protecting group. Because of the electron-withdrawing effect of the trifluoromethyl group, the 

2 Reviews Concerning AFPro-tection in the Synthesis of a-Amino Aldehydes and Ketories 630 

4 Reviews CorK ming AAFuru -tk nal Groups Pertinent to Their Role as Protecting Groups 631 

5 Reviews Concerning the Synthesis of Natural Guanidine Derivatives 631 

An asterisk in the text indicates that a pertinent review can be found at the end of the chapter. 

Amines are nucleophilic and easily oxidized. Primary and secondary amino groups are also sufficiently acidic that they are deprotonated by many organometallic reagents. If these types of reactivity are problematic, the amino group must be protected. The 

In addition to standard catalytic hydrogenolysis, methods for transfer hydrogenolysis using hydrogen donors such as ammonium formate or formic acid with Pd-C catalyst are available.216 The Cbz group also can be removed by a combination of a Lewis acid and a nucleophile for example, boron trifluoride in conjunction with dimethyl sulfide or ethyl sulfide.217 

The t-butoxycarbonyl (rBoc) group is another valuable amino-protecting group. The removal in this case is done with an acid such as trifluoroacetic acid or /Moluenesulfonic acid.218 r-Butoxycarbonyl groups are introduced by reaction of amines with f-butoxypyrocarbonate or a mixed carbonate-imidate ester known as BOC-ON. 219 

Another carbamate protecting group is 2,2,2-trichloroethyoxycarbonyl, known as Troc. 2,2,2-Trichloroethylcarbamates can be reductively cleaved by zinc.220 

Allyl carbamates also can serve as amino-protecting groups. The allyloxy group is removed by Pd-catalyzed reduction or nucleophilic substitution. These reactions involve formation of the carbamic acid by oxidative addition to the palladium. The allyl-palladium species is reductively cleaved by stannanes,221 phenylsilane,222 formic acid,223 and NaBH4,224 which convert the allyl group to propene. Reagents 

Wiinsch, Methoden der Orgamschen Chemie, Vol. 15, Fourth Edition, Thieme, Stuttgart, 1975. 

There are other Pd-catalyzed procedures for deallylation. Allyl groups attached directly to amine or amide nitrogen can be removed by isomerization and hydrolysis. Catalysts which have been found to be effective include Wilkinson s catalyst/ other rhodium catalysts, and iron pentacarbonyl. 2,2,2-Trichloroethylcarbamates can be reductively cleaved by zinc.  

Simple amides are satisfactory protecting groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

Reduction by NaBH4 in aqueous ethanol is an alternative method for deprotection of phthalimides. This reaction involves formation of an o-hydroxybenzamide in the reduction step. Intramolecular displacement of the amino group follows.  

Beugelmans, L. Neuville, M. Bois-Choussy, J. Chastanet, and J. Zhu, Tetrahedron Lett. 36 3129 (1995). 

SCHEME 3.7 Formation of l,3,4,6-tetra-0-acetyl-2-deoxy-2-phthalimido-D-glucopyranose. 

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Fig. 2. Synthesis of clinically useful monobactams where R = H, CH P is an amino protecting group, and Mes = mesyl is methanesulfonyl.

Fig. 7. Synthesis of monocarbams where P is an amino protecting group and CSI is chlorosulfonyl isocyanate. TFA is trifluoroacetic acid...

Amino-protecting groups include benzyloxycarbonyl (Z) and ten-btitoxy-carbonyl (Boc). 

For a review of the use of Fmoc protection in peptide synthesis, see E. Atherton and R. C. Sheppard, The Fluorenylmethoxycarbonyl Amino Protecting Group, in The... 

The choice of the acyl substituent X for Diels-Alder reactions of l-N-acylamino-l,3-butadicnes depends on the particular synthetic problem. The acyl substituent has a moderate effect on the cycloaddition reactivity of these dienes, and also determines what amine unmasking procedures are required. As a result of their stability and the variety of amine deprotection procedures available, " the diene carbamates are the components of choice in most cases. A particularly attractive aspect of the diene synthesis detailed here is the ability to tailor the amino-protecting group... 

The first version of SPPS to be developed used the t-Boc group as the amino-protecting group. f-Boc can be cleaved with relatively mild acidic treatment and TFA is usually used. The original coupling reagents utilized for SPPS were carbodiimides. In addition to dicyclohexylcarbodiimide (DCCI), N, (V -diisopropylcarbodiimide (DIPCDI) is often used. The mechanism of peptide coupling by carbodiimides was... 

Rosenau, T. Chen, C. L. Habicher, W. D. A vitamin E derivative as a novel extremely advantageous amino-protecting group. J. Org. Chem. 1995, 60, 8120-8121. 

Carbamates by Reaction of Imidazole- or Imidazolium-iV-carboxylates. Introduction of Amino Protecting Groups... 

A variant of this method for the introduction of amino protecting groups into amino acids via the alkoxycarbonylimidazolium salts starts from the more reactive carbonyl-bis(methylimidazolium) salts [105]... 

Some examples for the introduction of amino protecting groups such as 2-(4-nitro-phenyl)ethoxycarbonyl (npeoc) or benzyloxycarbonyl (Z) were already given in the compilation of carbamates produced with imidazolium caiboxylates in Section 4.6.1. 

Analogously to these reactions of imidazolium carboxylates, the introduction of urethane-type amino-protecting groups can be accomplished with the following mesoionic azolides [194]... 

In brief, the use of acetonitrile as solvent and the selection of an appropriate C-5 amino protecting group and reactive promoter system are critical for achieving high a-selectivities and yields in the synthesis of sialosides. 

To overcome these difficulties in the selective deprotection and chain extension, several carboxyl-protecting groups, namely, allyl (16,32), benzyl (43,44), tert-butyl (42), 2-bromoethyl (45), 2-chloroethyl (45), heptyl (46), 4-nitrophenyl (47,48), and pentafluorophenyl (49) for L-serine/L-threonine have been introduced or applied. Similarly, amino-protecting groups for L-serine/L-threonine that have proved useful for the synthesis of glycopeptides are tm-butyloxycarbonyl (50), 9-fluorenylmethoxycarbonyl (43,44,48), 2-(2-pyridyl)ethoxycarbonyl (51), 2-(4-pyridyl)ethoxycarbonyl (44,52), and 2-triphenylphosphonioethoxycarbonyl (53). Some applications of these groups have been discussed in earlier reviews (7-11). 

G Barany, RB Merrifield. A new amino protecting group removable by reduction. 

CGJ Verhardt, GI Tesser. New base-labile amino-protecting groups for peptide synthesis. Rec Trav Chim Pays-Bas 107, 621, 1988. 

H Kuntz, C Unverzagt. The allyloxycarbonyl (Aloe) moiety — conversion of an unsuitable into a valuable amino protecting group for peptide synthesis. Angew Chem Int Edn Engl 23, 436, 1984. 

A Paquet. Introduction of 9-fluorenylmethoxycarbonyl, trichloroethoxycarbonyl, and benzyloxycarbonyl amino protecting groups into O-unprotected hydroxyamino acids using succinimidyl carbonates. Can J Chem 60, 976, 1982. 

P Sieber, B Iselin. Peptide synthesis using the 2-(p-diphenyl)-isopropoxycarbonyl (Dpoc) amino protecting group. Helv Chim Acta 51, 622, 1968. 

E Atherton, RC Sheppard. The fluorenylmethoxycarbonyl amino protecting group, in The Peptides Analysis, Synthesis, Biology, Vol. 9, pp 1-38, Academic Press, New York, 1987. 

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