REM linker

Here, we envisage building the benzimidazole scaffold directly onto the linker and, by analogy with a regular tertiary amine synthesis on the REM linker, we can quaternize the resin-bound benzimidazole compounds by reaction with reactive bromides. The quaternary salt can then be liberated by a Hofmann elimination reaction upon treatment with base. 

The hydroxymethyl resin-supported regenerated Michael (REM) linker 1.38 (96), has been used to support secondary amines during elaboration followed by release as tertiary amines by classical Hoffman elimination [DIEA/(diisopropyl ethylamine)-DMF at rt over 18 h] of the resin-bound quaternary ammonium salt. 

Figure 15.14 Preparation of tertiary amines with the REM linker, based on the Hofmann elimination reaction.

Figure 15.15 Sulfone-based resins. Resins 25-27 are used as alternatives to REM linkers. Resin 28 is based on the safety-catch principle while resins 29 and 30 were used to synthesize peptides.

A traceless linker for anchoring secondary amines has been developed [123,124] and is referred to as the REM linker 21 (regenerated after cleavage, functionalized by Michael addition). Tertiary amines can be prepared on this support by conversion to a resin-bound quaternary ammonium salt followed by cleavage by base-induced Hofmann elimination [125]. The analogous vinyl sulfone resin 2m can also be used to anchor secondary amines and is stable to a greater range of reactants [126,127]. 

The REM-linker can also be regarded as a safety-catch linker (Figure 1.7.7, entry c). Activation of polymer-bound 6 was achieved by alkylation to form 7. Subsequent treatment with DIEA resulted in formation of the cleaved tertiary amines... 

Two major changes to the double-linker resin used in development were introduced a modification to the REM-type linker itself and the inclusion of tags for chemical encoding. The new resin/linker is easily made from commercially available reagents. In our hands, the use of PEG-PS-based resins works best for the scheme, which does call for both organic and aqueous reaction conditions. We have previously reported the use of an unencoded version of this route.2... 

Typical nucleophilically cleavable linkers are the REM resin linker 86 [75] (polymer-bound benzyl acrylate regenerated Michael acceptor) and the Dde group 87 (ADCC (4-Acetyl-3,5-dioxo-l-methylcyclohexane carboxylic acid) anchor) [76], which are linkers for tertiary and primary amines, respectively (Figure 6.1.7). 

TRAM linker by Belshaw et al. [45] and the REM resin by Morphy et al. [46] should be mentioned here, as they are built on a quaternization strategy of amines as activation step and subsequent (3-elimination by basic treatment as well. While the REM resin releases tertiary amines from the solid support, the use of the TRAM linker yields Michael acceptors. 

A 1,2,3-triazole-based solid-phase click linker was developed with an aldehyde functionality or a regenerative Michael acceptor (REM) functionality (Figure 11.1). In addition, a chiral pyrrolidine catalyst was grafted to the resin with a 1,2,3-triazole linker, enabling enantioselective Michael addition of ketones to nitroolefins... 

Using Resin-Bound Vinyl Sulfone. Resin-bound vinyl sulfones have also been used as an alternative sulfone linker unit since they have been shown to be stable to a wider range of conditions compared to the REM benzyl ester system. The vinyl sulfone group reacts efficiently with nucleophilic substrates, such as secondary amines, via conjugate addition. Quaternization of the resin-bound tertiary amine followed by subsequent deamination provided the respective tertiary amine and the regenerated resin-bound vinyl sulfone (Scheme 12.4). 

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