Multifunctional Linker Strategies

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

Since safety-catch means the activation of the linker prior to cleavage, such a system can be applied for monodirectional, such as traceless linkers, or multifunctional linkers [9] as well as for cleavage-cyclization strategies. Table 16.1 gives an overview of the safety-catch linker types known to date. Slight differences... 

As the linker units described above have become ever more elaborate and sophisticated, they have evolved into multifunctional (or diversity) linker units. Multifunctional linker imits use the cleavage step in solid-phase organic synthesis for incorporation of additional diversity into compound libraries, and the main classes of such linker units wiU be discussed in this section, along with representative cleavage strategies. 

Beyond RCM and CM strategies, Craig has reported cleavage using Diels-Alder reactions (Scheme 1.16). ° [4 + 2] Cycloaddition (with concomitant aromatization) of the o-quinodimethane precursor (52) with dimethylacetylene dicarboxylate (DMAD), trichlor-oacetonitrile, and benzoquinone provided dimethyl naphthalene-2,3-dicarboxylate (53), 3-(trichloromethyl)isoquinoline (54), and 2,3-naphthoquinone (55), respectively. The diverse products from a single polymer-supported intermediate, such as the bismuth linkers discussed previously, make Craig s multifunctional linker unit attractive for approaches toward diversity-oriented synthesis. 

Besides heterocyclic synthesis, the sulfone linker unit has also been applied to the preparation of a variety of other substrates. " " " " The diverse cleavage strategies that can be applied to cleave substrates from sulfone linkers make them a versatile multifunctional linker. This together with the simple purification process, compared to solution-phase synthesis, adds to the potential of sulfone chemistry being applied to solid-phase synthesis. 

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 independent, noninteracting behaviors of these two modes of self-assembly allowed for the creation of a self-assembled, multifunctional, reversible, cross-linked material in one self-assembly step. This simultaneous self-assembly strategy, based on the results outlined above, allows the creation of a fully functionalized, cross-linked systems. Simultaneous addition of a small metal-complexing molecule such as pyridine, along with a hydrogen-bonding cross-linker such as... 

By varying the electrophile, this class of linker can also be utilized in a multifunctional approach. In its simplest form, this has involved halogenation. For example, cleavage strategies for leaving bromine (Table 1.16, Entry 3)2 2,283 (Table 1.16,... 

In general, thioester Unkers can be called multifunctional as carboxylic ester linkers. They are discussed within this work because cleavage strategies and products differ only slightly from those of esters, hi fact, thioester linkers disclose possibilities where ester linkers traditionally fail. 

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