Linkers for Solid-phase Synthesis

Kerstin Knepper, Carmen Gil, and Stefan Brase 6.1.1


Polymers derived from polystyrene have been known since 1839 [1]. However, organic chemists started to regard polymers as valuable tools for organic synthesis only when Merrifield published the first solid-supported peptide synthesis [2]. Since then synthetic methods on polymeric supports have been employed for the preparation of synthetic oligonucleotides, oligosaccharides, and peptides. Particularly in the last decade the use of solid-phase synthesis has become vital in drug discovery. Large numbers of relatively small drug-like molecules with a molecular weight of 500 g mol-1, which are potential new drugs, are readily available using solid-phase synthesis [3, 4].

The required elements of a solid-phase synthesis consist of three structural parts: the polymeric support (resin), a molecule or fragment, which eventually yields the final product, and the linker, which enables a suitable connection between the two parts [5]. Occasionally the linker can be located further from the polymeric support by use of a spacer (Figure 6.1.1).

Solid-phase synthesis always starts by attachment of the building block to the resin. The next step is a reaction which can be either transformation on the attached building block or coupling of another molecule. After this, a washing process enables simple removal of excess reagents or coupling partners. Reiteration of the sequence of reaction and washing is usually feasible. Finally, the compound is released by cleavage from the resin. Major advantages of solid phase organic synthesis (SPOS) are the easy isolation of the molecules at each step by simple filtration and the ease of automation (Figure 6.1.2). The pseudo dilution is also effective, because reactive functional groups are locally separated. The main disadvantages are the extra effort required to develop solid phase routes and limited analytical methods. Recently, however, new analytical methods have been developed, overriding this drawback [6].

Definition: The International Union of Pure and Applied Chemistry (IUPAC) defines a linker as a ''Bifunctional chemical moiety attaching a compound to a solid support or soluble support which can be cleaved to release compounds from a polymeric spacer |. . moleculeor support p l er fragment crk n

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