Amine-protecting group strategies

Scheme 6.1 Common AG amine-protecting group strategies.

The ability of [18]crown-6 derivatives to complex primary alkylammonium ions has been elegantly exploited in the protection of primary amines (80CC300). In the presence of primary amines, secondary amines can be acylated selectively by adding [18]crown-6 and a proton source. This strategy has obvious advantages over normal amine protecting groups which require a deprotection step. 

It appears also that, for the synthesis of large libraries, there are few reactions that fulfil these prerequisites. Among the reactions that proved to have wide applicability, amide bond formations and peptide-like protecting group strategies can be found. In a general way all amine functionalization reactions are usually effective and lead to stable structures (i.e. sulfonamide, carbamate, urea, thiourea formation, reductive amination and nucleophilic substitution). Moreover, for any of these reactions the suitable linker can be easily selected from various literature sources. 

Alcohols (eq 20) and amines (eq 21) react with silanes in the presence of Wilkinson s catalyst to give the silylated compounds and, presumably, hydrogen. These reactions are useful in protecting group strategies. 

There are basically two strategies for this. The first one is the attachment of whole and commercially available polyamines like spermine or their appropriate derivatives to solid phase. This mostly requires protection of the polyamine and at least one tedious chromatographic step before linking it to the solid support. All earlier examples in the literatme go back on this approach and they mostly adopt protection group strategies for tri- and tetra-aza-polyamines, which have already been established in solution phase. The differentiation between primary and secondary amines is a crucial factor. Depending on the type of resin (see Table 1) and the chosen substrate, the crosslinking reactions of symmetrical molecules must also be taken into account as these can decrease the overall yield and pmity of the final products. 

An example that starts the synthesis of polyamine toxins from a central amino group is shown in Scheme 13 [229,230]. The backbone is elongated by alternate coupling of benzyl-protected amines and bromides. Due to the protection group strategy consisting of orthogonal Boc- (128), benzyl- (138), and phthalimides (137) it is possible to synthesize polyamines from center to tail. Unfortunately, after three alkylation steps the overall yield is only 30%, which drops the overall yield to 10-30%. 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

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