Amide-based linker

Tab. 3.4 Overview of some ester- amide-based linkers.

Resin-bound amides generally need to be activated to make them susceptible to saponification under acceptably mild reaction conditions [114] (Table 3.5). Particularly elegant are those linkers that allow this activation to be realized as the final synthetic step before cleavage (safety-catch linkers [115-117]). The activation of some amide-based safety-catch linkers is outlined in Figure 3.9. 

Figure 3.9. Activation and nucleophilic cleavage of amide-based safety-catch linkers [118,119].

When the resin-leaving group is a secondary amide or similar derivative, 3-dialkoxybenzyl-based linkers are sufficiently electron rich to allow product release... 

A wide range of benzhydryl-based linkers bearing additional electron-donating functionalities has also been developed for Fmoc SPPS of peptide amides, the most popular of which are the eponymous Rink amide (7) [13] and Knorr linkers 24 [65]. Primary amides prepared on this resin can be cleaved with TFA in the same manner as previously described for the PAL linker. 

Diacid-based linkers, such as the succinic linker 21, have been described to prepare alcohols. The procedure involves the esterification of the starting alcohol with succinic anhydride and DMAP to yield the hemiester that is anchored to an amino containing-resin by means of an amide bond. The bound alcohol is then elaborated and finally released with a nucleophile. Oligosaccharides have been assembled following this approach and released with aqueous ammonia or sodium methoxide in methanol-dioxane [73, 74]. Peptide alcohols have also been prepared with the succinic linker on BHA resin and released by treatment with NH3 in MeOH for 72-96h or hydrazine in DMF for 24h [75]. Similarly, hydroquinone-0,0 -diacetic acid (linker 22) has been used to link nucleosides to polystyrene or CPG supports. Cleavage of oligonucleotides was carried out with aqueous ammonia [76]. Other diacids with a similar function have also been described [77]. 

Figure 1. (a) Ammonolysis/aminolysis of resin-bound esters, (b) Synthesis of peptidyl amides and peptidyl Aralkyl amides using amine-based linkers. 

Another multifunctional amide-containing linker has also been published recently by Abell et al. [180]. The synthesis of the new anthracenyl-based linker 168 involves again four synthetic steps in solution phase that can be conducted in 53% overall yield. Different to the other linker strategies is the attachment to the resin because the linker core and the substrate are connected in solution phase and are afterwards linked to a maleimide-polystyrene resin. To prove the utility of the new resin, N- and 0-nucleophiles were added to give amides 171, esters 170 and carboxylic acids 169 (Scheme 26). 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

Aryl hydrazide linker 38 stable to both acid and base was utilized in SPPS [46], Treatment of the resin with a copper(II) catalyst in the presence of a base and nucleophile gave the corresponding acid, amide, or ester (Scheme 13). 

Contrary to an alkoxy benzene scaffold, secondary amides were generated via novel aldehyde linker 43 based upon an indole scaffold (Scheme 15) [52]. The indole resin was prepared from indole-3-carboxy-aldehyde in two steps and reacted with amines under reductive conditions to generate resin-bound secondary amines. Treatment of the resin with... 

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