Linkers types

As the pioneering development of Merrifield [21] and Wang [22] are based on the benzyl linker type, this type represents the starting point of modern linker development. 

Ester and amide moieties are, apart from being used in the benzyl and allyl linker-type, are also suitable for attachment of building blocks (Figure 6.1.6). 

The first traceless linkers for arenes were silyl linkers. This linker type was used in the synthesis of a benzodiazepine library, a milestone in the solid-phase synthesis of small organic molecules (Scheme 6.1.9). Synthesis of the linker involves lithium-halogen exchange and, after chlorosilane attachment, coupling with an... 

Boronates have been used in a variety of linker types either as linkers for diols [42] or as precursors for metal-mediated cleavage. A boronic acid ester, which contains an aryl iodide moiety attached by an appropriate tether, can act as an intramolecular arylation agent. A polymer-bound precursor furnished a macrocydic constrained / -tum peptide mimic via biaryl coupling, leading to cleavage [43] (Scheme 6.1.10). 

In particular, cleavage of substrates from a solid support by use of palladium-promoted or -catalyzed reactions has some advantages over other cleavage methods. Because most protecting groups and functionalities are resistant toward palladium complexes, selective surgical removal is frequently possible. In addition, intermediate 7z>allyl- and er-aryl-palladium complexes can be used in principle for further derivatization with the use of appropriate linker types. 

In recent years different types of new linker have emerged (Table 6.1.7). For the synthesis of small molecules on solid supports, in particular, the design of a new anchoring group might be essential for success of the synthesis. Linker, cleavage conditions, and functional groups are selected for each other. The decision to use one specific linker type must, therefore, be balanced with the need of the library synthesized. 

Linker Type Number of Sub -Clusters Number of examples tiV (LI) v (L2)... 

The three residue linker between two strands (E-L3-E) has a single major cluster (Table II). The side chain conformation of the second linker residue is mostly g. The third linker residue is mostly Gly for this linker type. Few of the representatives from this cluster ate shown in Figure 6. The remarkable similarity between the backbone conformations of the three residue linkers of H-L3-H (second sub-cluster) and E-L3-E is obvious (Figure 6). The carbonyl oxygen is pointing outwards and the side chain of L2 also points outwards, in both the linkers. 

Lee KY, Rowley JA, Eiselt P, Moy EM, Bouhadir KH, and Mooney DJ. Controlling mechanical and swelling properties of alginate hydrogels independently hy cross-linker type and cross-linking density. Macromolecules 2000 33 4291 294. 

Homometallic systems (i.e. (U02f"" only) with a single linker type. 

Tables 14.1 and 14.2 show the comparative ease of cleavage of common linker types and leaving groups encountered in solid phase synthesis. By taking into account the relative positions of linker and leaving groups within these tables, the...

Table 14.1 Common linker types ordered by stability of incipient carbocation. 

Translated to solid phase chemistry, this would mean the careful selection of the appropriate linkage of the substrates to the solid support. An ever increasing number of various linker types is now available, most of them used very successfully in the synthesis of complex molecules on solid supports [4-7]. 

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... 

Safety-Catch and Traceless Linkers in Solid Phase Organic Synthesis Table 16.1 Overview of safety-catch linker types. 

Besides the benzyl hydrazide linker 44, Wieland et al. introduced a 2,2-diphenyl-2-hydroxyethyl-ester derived resin [58], This linker type can be activated by acid-catalyzed dehydration (aq. TFA) to give the reactive enol ester 51, which affords amides 53 upon treatment with amines (Scheme 16.12). 

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