Linker multifunctional cleavage

Triazenes are disguised diazonium ions which can be released under very mild acidic conditions. Inspired by the use of triazenes in natural product synthesis by Nicolaou et al. [127] and the pioneering work of Moore et al. [128, 129] and Tour et al. [130] in the synthesis of triazenes on a solid support and the final detachment to give iodoarenes, a whole set of triazene-based linkers has been developed (Tab. 3.10) [131]. The arene diazonium salts generated from the triazene linkers offer diverse opportunities for multifunctional cleavage. Two linkers based on tria-... 

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. 

Examples for multifunctional cleavage are given by the use of sulfone-, silyl- or triazene-linkers [202]. Wagner et al. for example used a cleavage Suzuki reaction on a sulfonium-linker (105) (Scheme 3.8) [206]. 

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-... 

Triazene Linker Units. Owing to their multifunctionality and high stability, triazene linker units have become the most versatile diversity linker units reported to date. Initial reports of triazene linker units appeared in the mid-1990s from the groups of both Moore " and Tour. Inspired by this work, the chemistry has been refined by Erase, whose T1 and T2 triazene linker units have now been extensively developed for multifunctional cleavage. 

Scheme 1.8. Multifunctional cleavage from Kamogawa s hydrazone linker.

Building on the many examples of thioether linker units, larger numbers of linker units have been reported that utilize the related reactivity profiles of selenium and tellurium compo-nents to achieve multifunctional cleavage. Such linkers tend to be straight-... 

Finally, silicon-nitrogen bonds are also labile in the presence of electrophiles, and this concept has been used by Komatsu in development of a silylimine linker (Table 1.16, Entries 12-14). Multifunctional cleavage was achieved with a range of electrophiles. For example, treatment with TFA left a hydrogen residual at the point of attachment (Table 1.16, Entry 12), while benzoyl (Table 1.16, Entry 13) and allyl (Table 1.16, Entry 14) groups were introduced by cleavage with benzoyl chloride and allyl iodide, respectively. 

In 1995, the group of Ley showed the utility of a simple ester linker 25 for multifunctional cleavage [59]. While reductive cleavage has always been performed with DIBAL-H and acidic cleavage with TFA, nucleophilic cleavage... 

Scheme 51 Multifunctional cleavage from the hydrazone linker...

Scheme 54 Multifunctional cleavage from the phosphonium linker hy Hughes...

Scheme 89 Multifunctional cleavage from selenium linkers...

Scheme 105 Multifunctional cleavage of boronic ester linkers...

SCHEME 3.24. Multifunctional cleavage of sugars from a sulfur linker. 

One limitation of monofunctional linkers is that they provide only one type of compound in a library. However, the so-called multifunctional linkers offer the important opportunity to incorporate additional diversity upon cleavage. In this case, the number of new functionalities (Fig. 1, type I) can multiply the number of compounds produced (Fig. 2). 

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. 

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,... 

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. 

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