Tethering Approach

Caspase 1 (Table 1, entry 4) Another protease screened using fragments is caspase 1. Using a tethering approach (described earlier) active sub-site binders were identified and then linked to produce a sub-micromolar inhibitor 24. Further optimisation by rigidifying the linker produced a ligand-efficient nanomolar inhibitor 25 [38]. 

The tethering approach has been applied extensively toward the development of Zr-based polymerization catalysts [32]. A silica-anchored Zr(lV) cyclopentadienyl heterogeneous catalyst has been developed by immobilization of the organometal-Hc precursor pZr(NMe)3 on mesoporous sihca previously adequately silylated by chlorodimethyline-3-ylsilane. The catalyst, which can polymerize ethylene after... 

Tethering approaches with Si(OEt)Me2 substituents on the ring, appropriate for both solid state sol-gel chemistry toward Zr-functionalized support and for solution chemistry toward analogous zirconium silsesquioxanes, exist [39]. 

Higher adducts of Cjq can also be synthesized regiospecifically using this tether approach. For example, a clipping reaction sequence leads to the tetrakisadduct 87 with an all-ds-2 addition pahern along an equatorial belt (Scheme 10.18) [29]. 

In combination with the range of standard transformations of alcohols, alkenes, and vinylsulfides, these silicon-tethered additions of functionalized radicals offer a versatile and stereoselective approach to amino alcohol synthesis. Whereas vinyl and 2-oxoethyl radicals have not yet been demonstrated as competent participants in the various intermolecular additions reported in the literature, the temporary tether approach allows such functionalized fragments to be installed in an efficient and stereoselective manner. Synthesis of the aminosugar daunosamine from achiral precursors shows how this concept, employing hydrazone radical acceptors, can be merged with asymmetric catalysis to achieve practical synthetic advances. 

The preparation of branched-chain sugars by intramolecular C-C bond formation is based on the tether approach. The radical donor may either be generated on a tether and cyclize onto an unsaturated sugar acceptor or, alternatively, the radical donor can be generated on the sugar template which cyclizes onto a tethered radical acceptor. 

Perhaps the greatest drawback with this tethering approach is the relatively poor yield in the formation of the triene IMDA precursor 1, although the reaction was not optimized. Fortin and co-workers have reported an improved procedure for the efficient formation of unsymmetrical di-ferf-butylsilyl acetals using Bu2Si(Cl)OTf, which is readily prepared from the corresponding chlorosilane [7]. Successive incorporation of the die-nophile and diene is possible by exploiting the different reactivity of silyl trifiates and chlorides towards nucleophilic substitution (Scheme 10-3). 

Figure 3.2 Tethering approaches to cyclise and replace amide function with aminoheterocycles.

Figure 5.16 Identification of Aurora kinase inhibitors applying a bis-thiol extender to the tethering approach.

The application of the RCM approach to create a range of cyclic silyl ethers successfully expands the scope of reactions utilizing the temporary sihcon tether approach, and the novel concept of heteroatom activation of the sihcon from the coupling substrate itself Thus, in cases where homoallylic alcohols or mediumsized rings are the desired products, the aforementioned methods offer a facile and direct route for their synthesis. 

Regioselectivity can usually be reliably obtained when two of the alkyne partners are tethered. A Cp RuCl(cod)-catalyzed intermolecular cyclotrimerization of three different monoalkynes could be performed by an in situ-tethering approach with the formation of a temporal C-B-O linkage from alkynylboronates and propargyl alcohols [13-15] [Eq. (9)]. The resultant arylboronates could not be isolated and were further converted to substituted biaryls via the Suzuki-Miyaura coupling or into a sequential one-pot process [14], or to phtalides via a palladium-catalyzed carbonylation [15]. 

With the above points in mind, Sinay s group developed a direet approach to C-linked disaccharides employing a temporary silicon tether approach to graft the... 

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