Protecting chemoselective amine group

Benzyl groups are one way of protecting secondary amines against strong bases that might depro-tonate them. But it is the nucleophilicity of amines that usually poses problems of chemoselectivity, rather than the acidity of their NH groups, and we come back to ways of protecting them from electrophiles when we deal with the synthesis of peptides in Chapter 25. 

A complex of copper ions was used for the chemoselective preparation of the 6, 3-di-NHBoc derivative of kanamycin A (29) from the parent AG (6) in 72% yield (Scheme 6.3b) [43]. Another example for selective amine-protecting group manipulations on the scaffold of the pseudo-trisaccharide scaffold of the AG sisomicin (13) is demonstrated in Scheme 6.3c. Three amine groups of sisomicin (13) were selectively protected using the NH-trifluoroacetamide and NH-Boc groups. The 6 -aminomethylene of the free base form of 13 was selectively... 

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

Checking for chemoselectivity problems, we might suspect that the amine could be alkylated twice by the very reactive a-bromoketone 74 so it might be better to protect the nitrogen atom with a benzyl group. This can be removed by catalytic hydrogenation. In the laboratory, it proved better to brominate 73 in neutral rather than acidic solution so the final scheme becomes ... 

N- and O-benzyl groups are among the most useful protective groups in synthetic organic chemistry and the method of choice for their removal is catalytic hydrogenolysis [37]. Recently the most important reaction conditions were identified [38] Usually 5-20% Pd/C the best solvents are alcoholic solvents or acetic acid acids promote debenzylation, whereas amines can both promote and hinder hydrogenolysis. Chemoselectivity can mainly be influenced by modifying the classical Pd/C catalysts. 

The development of chemoselective reactions to give a native peptide bond at the site of hgation allows the synthesis of proteins with little or no modification to the covalent structure. A native structure at the ligation site is often desirable in the middle of protein structural domains (amino acid 60-120). The challenge of this approach is to form an amide bond chemoselectively in the presence of free amine side chains (Lys) and carboxylate side chains (Glu/Asp). Ideally, no protecting groups should be used for any of the amino acid side chains as they limit peptide solubility and require additional deprotection steps that can severely reduce the yield and convenience of the synthesis. 

Protection of unhindered amines. The chemoselectivity of the reagent is Nhown by the exclusive Boc-derivatization of the CH2NH2 group in the presence of several other CHNH2 pendants in an amino sugar. 

Deprotection of Amines and Ethers. Catalytic NIS in MeOH has been shown to be a chemoselective catalyst for the deprotection of alkyl TBDMS ethers selectively over phenyl TBDMS ethers. A method for the deprotection of dibenzylamino groups selectively to either the monobenzylamine or directly to the amine has also been developed. In the case of carbohydrates containing multiple protecting groups, as in eq 24, NIS in the presence of TEMPO provided the monobenzylamine in excellent yield. Excess NIS under slightly modified conditions could be used to afford the amine in modest yield. The process is not restricted to carbohydrates but does require the presence of a nearby alcohol or alkoxy substituent to work, as for the amine in eq 25. It should also be noted that the benzyloxy group in this example remained intact. 

For a hydrocarbon substrate which does contain tertiary and secondary C—H bonds, a better chemoselectivity is observed with 5 mol% of Rh2[(S)-nttl]4- For instance, a 12 1 ratio is obtained for the C—H amination of adamantane leading to 58% of Troc-protected 1-adamantanamine, compared to 3 1 if Rh2(tpa)4 is used (Scheme 5.9). The protecting group is easy to cleave using Zn in acetic acid and amantadine hydrochloride is then isolated in quantitative yields [77]. 

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