Linker concept

The high purity (>95%) of the released product from resin 14 prompted us to investigate the potential of radical release as a traceless linker concept. To our knowledge, thermolytic radical fragmentation of covalent bonds is a mechanism of bond dissociation that has not been exploited so far for linker chemistry and for solid-phase transformations. Cleavage yields, determined by releasing nonvolatile products, were found to be higher than 90%. 

This linker concept was originally introduced by Wieland and co-workers [11] but has been fashioned to suit practical applications by the groups of Semenov, Lowe and Waldmann [12— 14]. The aminolysis has been achieved by treatment of the hydrazide 10 with copper (II) acetate in solutions of the amine in methanol. NBS in pyridine has been employed as an alternative oxidising agent that triggered a cyclative release of cyclopeptide 13 [15]. 

Oxidative Pd insertion into electron-poor aryl sulfonates is a key step in Pd(0)-mediated C-C coupling reactions. This principle has been turned into a traceless linker concept in which phenols are attached via sulfonates to a solid support [107]. The system has been optimized by employing a perfluoroalkylsulfonyl linker that closely resembles the commonly applied inflates (90, Scheme 41). In this respect, the linker acts as a protecting group and as an activating entity. Reductive cleavage of 91 with Pd(0) and formic acid led to arenes 92 [108]. 

The same concept was transferred to the water side and the respective molecules were called hydrophilic linker [47, 48]. However, since the shape of the water molecules and their interactions are quite different from those of oils, hydrophilic linkers are no elongated molecules like the lipophilic linkers. Up to now the hydrophilic linker concept has been tested with alkyl naphtalene sulphonates only. Non-alkylated naphtalene sulphonate is a... 

The fluorenylidene linker concept was also applied to the synthesis of triarylamine segmented polymers via a Hartwig Buchwald reaction [132] (Scheme 48). 

For the solid-phase experiments [115], the commercially available Wang and HMPB-AM resins were chosen due their stability under the applied reaction conditions and an easy cleavage with TFA/DCM mixtures. Moreover, a novel, tailor-made and readily available linker, derived from inexpensive syringaldehyde was designed and proven to be superior to both standard Wang and HMPB-AM resins. For an initial study, as a proof of concept , the Wang linker was mimicked with a 4-methoxybenzyl group at N-1 position of a pyrazinone, and the sequence was evaluated in solution (Scheme 41). 

A further extension to this concept was (dimethylsilyl)propionic acid linker 75 used for the solid-phase synthesis of aryl-containing organic compounds [86], The linker was cleaved smoothly with TFA and has been used for the synthesis of compounds which involved alkylation, acylation, and Mitsunobu reactions. 

The sulfoxide method has been applied to the concept [319,374] of intramolecular aglycone delivery for the formation of [1-mannosidcs by means of a silylene linker. In the original work, the acceptor and a thioglycoside donor were joined by means of a silylene group before the oxidation to the sulfoxide [141]. However, it was later found that the preformed sulfoxide was tolerated by the chemistry for the introduction of the linker [286,375]. The intramolecular aglycone delivery step was shown to function effectively for the transfer of the donor to the 2-, 3- and 6-position of glucopyr-anosides, as exemplified in Scheme 4.64. 

Fig. 1. Concept of molecular imprinting - the non-covalent approach. 1. Self-assembly of template with functional monomers. 2. Polymerization in the presence of a cross-linker. 3. Extraction of the template from the imprinted polymer network. 4. Selective recognition of the template molecule...

The use of sequence information to frame structural, functional, and evolutionary hypotheses represents a major challenge for the postgeno-mic era. Central to an understanding of the evolution of sequence families is the concept of the domain a structurally conserved, genetically mobile unit. When viewed at the three-dimensional level of protein structure, a domain is a compact arrangement of secondary structures connected by linker polypeptides. It usually folds independently and possesses a relatively hydrophobic core (Janin and Chothia, 1985). The importance of domains is that they cannot be divided into smaller units— they represent a fundamental building block that can be used to understand the evolution of proteins. 

The nucleosome is the fundamental repeating structural unit of chromatin. It is composed of two molecules of the core histones H2A, H2B, H3, H4, approximately two superhelical turns of double-stranded DNA, and linker histone HI (H5). In addition to biochemical studies, the existence of the nucleosome was established in electron micrographs (Fig. la) [1,2], and the name nucleosome, coined to incorporate the concept of the spherical nu-bodies [3]. Micrococcal nuclease limit digestion of chromatin established the nucleosome core particle (NCP) as the portion of the nucleosome containing only the core histones surrounded by 1.75 superhelical turns of double-stranded DNA [4,5]. 

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