Amine protection -type group

Carbamates are by far the most common type of amine protection used in solid-phase synthesis. Various types of carbamate have been developed that can be cleaved under mild reaction conditions on solid phase. Less well developed, however, are techniques that enable the protection of support-bound amines as carbamates. Protection of amino acids as carbamates (Boc or Fmoc) is usually performed in solution using aqueous base (Schotten-Baumann conditions). These conditions enable the selective protection of amines without simultaneous formation of imides or acylation of hydroxyl groups. Unfortunately, however, Schotten-Baumann conditions are not compatible with insoluble, hydrophobic supports. Other bases and solvents have to be used in order to prepare carbamates on, for example, cross-linked polystyrene, and more side reactions are generally observed than in aqueous solution. 

Various other types of amine protection have been investigated as replacements for the native V-acetyl group in sialyl donors including Boc [54], allyloxycarbonyl [55], 9-fluorenylmethylcarbonyl [55], trichloroacetyl [55], and Cbz [55, 56] groups, but no particular advantages of these systems are apparent at present. 

The latter is known as the elimination-addition mechanism of the nucleophilic aromatic substitution. The high reactivity of aryllithiums precludes the use of several types of functional groups such as aldehydes, ketones, esters, amides, amines, alcohols, phenols, nitro-compounds, carboxylic acids etc. However, properly protected alcohols, phenols or amines can effect the reaction. Various ether protecting groups, e.g. Tr, Me, /-Pr, Bn, 4-MeOBn, are employed in the former instances, whereas A, V-dibenzyl group is convenient for the amine protection. 

As fluorous Cbz-type hnkers are known to be partially deprotected in acidic medium, a base-labile amine-protecting group (19, Scheme 8.4) was developed as an orthogonal alternative. The peptide products were purified by both fluorous HPLC and FSPE [41]. The deprotection of the fluorous tag was carried out using 2% aqueous ammonia, a reagent that would raise concerns in the presence of common carbohydrate-protecting groups such as acetates. 

The main type of hydrolysis reaction is that of halogenoaryl compounds to hydroxyaryl compounds, eg, the aqueous caustic hydrolysis of 0- and /)-chloronitrobenzene derivatives to nitrophenols. Another important reaction is the hydrolysis of A/-acyl derivatives back to the parent arylamine, where the acyl group is frequently used to protect the amine. 

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... 

Problematic functional groups, however, are thioethers and disulfides [28] as well as free amines which poison catalysts of type 1 [4c]. In case of amines this problem is easily solved by choosing either an appropriate protecting group for nitrogen (e.g. amide, sulfonamide, urethane), or simply by protonation since ammonium salts were found to be compatible with 1 [4c]. As will be discussed in Sect. 4, free amines can also be metathesized in supercritical C02 as the reaction medium [7]. 

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