Aminomethyl-based linkers

Coupling of 4-(4-hydroxymethyl-3-methoxyphenoxy)-butyric acid (HMPB, for synthesis of peptide acids) or p-[(R S)-a-[l- (9H- fluorenyl- methoxyform-amido]- 2,4- dimethoxybenzyl] - phenoxyacetic acid (modified Rink linker, for synthesis of carboxamide peptides) linkers to MBHA resin For Fmoc chemistry several types of solid supports are available, which include hydroxymethyl-based, aminomethyl-based, and trityl chloride resins. We describe the use of the MBHA resin. In this case the respective linker (to achieve peptide acid or amide) is coupled to the resin and first amino acid is then coupled to the linker. Attachment of the linker to the resin is a reaction between the carboxyl-group of the linker and amino-group of the MBHA resin. Commercially available resins with linkers already attached could also be used. 

The properties of the various linker-derivatized resins used in Fmoc SPPS have already been discussed and were summarized in Chapter 2, Table 2. For the purpose of selecting the appropriate procedure for attachment of the first residue, these can be conveniently separated into three categories on the basis of their reactive functional groups (hydrox5methyl-, trityl chloride-, and aminomethyl-based resins) the mostly commonly used are listed in Table 1. 

A different, pivaloylglycol-based photolabile hnker 1.26 (83) was prepared with a complex, eight-step procedure from dihydroxyacetone dimer and aminomethyl Ten-tagel resin the linker was used to support and to further elaborate carboxylic acids. The photolytic release at 320 nm of elaborated acids compared favorably with more assessed o-nitrobenzyl linkers. 

The most common resins for SPPS are based on polystyrene (PS), typically with 1 % cross-linking. A starting point for the production of many other resins is provided by chloromethyl-polystyrene (Merrifield resin), made either by chloromethylation of polystyrene or, better, by copolymerization to direcdy incorporate the chloromethyl moiety. Another important base resin is aminomethyl-polystyrene. Although chloromethyl-polystyrene can be used for Boc-SPPS, in by far most cases a dedicated linker (handle) is inserted between the base resin and the first amino acid. 

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