Nucleophilic Cleavage of Aryl Esters

Immobilized, highly reactive phenyl esters can be prepared by acylating resin-bound 4-acyl-2-nitrophenol (Entry 4, Table 3.13 [285-288]) or 4-(aminocarbonyl)-2,3,5,6-tetrafluorophenol (Entries 7 and 8, Table 3.13). These esters are similar to oxime esters (see Section 3.3.3.3), and even react with weak nucleophiles such as anilines or alcohols. This type of linker is not, therefore, well suited for long synthetic sequences on insoluble supports, but only for the preparation of simple acid derivatives. Because cleavage yields the unchanged phenol, these resins can be reused several times, which renders this strategy of preparing acid derivatives quite cost-effective. 

Entry Loaded resin Cleavage conditions Product, yield (purity) Ref. 

The preparation of cyclic peptides by intramolecular nucleophilic cleavage of polystyrene-bound 2-nitrophenyl esters has also been reported [287], 

Entry 9 in Table 3.13 is an example of a safety-catch linker, which requires activation by TFA-mediated cleavage of a tert-butyl ether. The unactivated 2-(tm-butoxyj-phenyl esters are cleaved by amines 700 times more slowly than the corresponding 2-hydroxyphenyl esters [289]. A similar linker has been described [290], in which a benzyl ether is used instead of a ferf-butyl ether. Activation of this linker by debenzy-lation was achieved by treatment with HF or HBr/TFA [290]. 

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