PAL linker

Benzhydryl- (phenylbenzyl) and 4-methylbenzhydrylamine resins (see Section 5.18) are available for preparing primary amides, using Boc/Bzl chemistry. 4-Methylben-zhydrylamine, Rink amide, Sieber amide and dhnethoxytritylamine resins and the linkers PAL and XAL (see Section 5.20) are available for preparing primary amides, using Fmoc/tBu chemistry. Secondary amides can be synthesized by making use of AJ-alkyl-Sieber or ALalkyl-PAL linkers. 

To assess the versatility of this reaction on solid support, several heterocyclic carboxylic acids were coupled to the PS-PEG resin (PAL linker). Applying the... 

Ding et al.15 captured a number of dichloroheterocyclic scaffolds, where one chloro atom is prone to nucleophilic aromatic substitution onto resin-bound amine nucleophiles, as shown in Fig. 1. They found the PAL linker... 

Scheme 6.1.3. Backbone amide linkage using the PAL linker.

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. 

Solid-phase synthesis was initiated by coupling 5-(4-formyl-3,5-dimethoxyphenyloxy)valeric acid (PAL linker, 0 cf. Chapter 1.7) to amine derivatised crowns using diisopropylcarbodiimide hydroxybenzotriazole in DMF to give 79. Subsequent reductive alkylation of 78 by means of triacetoxyborohydride in DMF containing 1% of AcOH led to the desired central template linked to the solid support 80 as depicted in Scheme 4.1.16. 

Systematic modifications of these linker-resins by substitution with electron-donating substituents have resulted in the generation of numerous linker-resins with increased acid sensitivity. Notably, the 4-(2, 4 -dimethoxyphenylamino-methyl)phenoxy derivatized (Rink) resin 1 (7), which is cleavable by 95% v/v TFA, and the 5-(2-fluorenylmethoxycarbonylaminomethyl-3,5-dimethoxy)-phenoxyvaleric acid (PAL) linker 2 (8) addolysed by 75% v/v TFA. 

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