Traceless Linker Systems

Braese S, Enders D, Koebberling J, Avemaria F, A surprising solid-phase effect development of a recyclable traceless linker system for reactions on solid support, Angew. Chem., Int. Ed., 37 3413-3415, 1998. 

The condensation reaction of immobilized ester enolates with imines has been reported to give (3-lactam resins in good yields and high diastereomeric excess (Scheme 49), [133]. Traceless cleavage from the linker system yielded the desired (3-lactams. 

An anchor for traceless linking might also have a safety-catch function or be suitable for multifunctional cleavage. Linker systems enable the introduction of certain atoms or molecule fragments and will play an important role in the development of diverse organic substance libraries. It is important to point out that the final diversity is achieved on cleavage, and not in an additional solution phase re-... 

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 principle of this linker is based on an oxidative cleavage of aryl hydrazides, and it has been successfully used in the synthesis of peptides [144]. The linker system is stable under acidic and basic conditions, and may be modified as shown for 126 so as to allow the synthesis of combinatorial compounds 127 in a traceless manner, as outlined in Scheme 60 [145]. 

This linker system is based on the principle that triazenes can be efficiently generated by reactions of diazonium salts with amines. Under basic conditions, these triazenes are stable, but they can be cleaved under mildly acidic conditions to regenerate a diazonium salt and an amine. Based on this system, originally pubhshed by Moore and Tour [151, 152], two different hnkers have been developed. In the so-called T1 variant (Scheme 63), a secondary amine is created on the sohd support and reacted with a diazonium salt to yield the triazene 136. After the synthetic manipulations leading to 137, the triazene is cleaved, resulting in the formation of the initial support and the desired product [153]. Besides the traceless cleavage from the support, the diazonium salt formed as intermediate during the... 

In contrast to Si and Ge linkages (traceless linkers) of the aryl ring to the resin where electron-rich aromatic ring systems favor rapid cleavage, the reductive cleavage of arylsulfonates works well with electron-poor aromatic rings. 

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... 

Takahashi, T. et al., Nucleophilic substitutions on Multipin systems linked with a traceless linker, Synlett, 1261, 1998. 

Within the course of reaction or upon workup, the template is mostly cleaved off. Since the template is usually not recognized as such in the product, these systems should be named traceless templates. This naming is in analogy to the corresponding linker systems in solid-phase synthesis [4-6]. 

Hughes exploited a polymer-bound phosphonium-salt as a traceless linker for the synthesis of alkyl, alkenyl and heteroaryl products [263]. The linker system 383 was prepared from commercially available resin-bound triph-enylphosphine and nitrobenzyl bromide with following reduction of the nitro group and acylation. 

After removal of the protecting group (PG) from 134, the system was amenable to the oxidation/nucleophilic substitution process. Since this hnker represents a reversal of the original phenylhydrazide hnker, the traceless part stayed on the sohd support and the desired compound 135 was released. The utility of the linker was demonstrated in the synthesis of mono-ketopiperazines resulting from a cyclative cleavage. 

Wagner and coworkers developed a traceless sulfur-based linker by applying the chemistry of benzylsulfonium salts [90]. Various benzyl bromides were attached to a thiol linker synthesized in four steps starting from Merrifield resin. Reaction of the resulting resin 96 with triethyloxonium tetrafluoroborate gave the solid supported sulfonium salt 97, which could be cleaved by reaction with boronic acids to afford biphenylmethyl derivatives 98 (Scheme 16.23). The alkylation can be regarded as an activation step and the linker as a safety-catch system. 

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