Linker strategies

Backes I, Ellman JA. Solid support linker strategies. Curr Opin Chem Biol 1997 1 86. 

Scheme 4.11 Application of the traceless silyl linker strategy.

To our knowledge, only one attempt has been made toward the preparation and use of a fixed glucosyl trichloroacetimidate.9 Takahashi et al. described the synthesis of an attached O-glucosyl trichloroacetimidate and extended the use of the well known traceless silyl linker strategy (Scheme 4.11). 

Morphy RJ, Rankovic Z, Rees DC. A novel linker strategy for solid-phase-synthesis. Tetrahedron Lett 1996 37 3209-3212. 

The design of powerful new linker strategies is crucial to the advancement of technologies used for combinatorial chemistry on polymeric supports. They are usually derived from protecting groups known for solution-phase chemistry [6, 18]. 

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. 

Among the successful linker strategies that are being developed specifically for solid-supported synthesis of small organic molecules, the safety catch principle has become one of the most important approaches. Safety catch linker strategies... 

This total synthesis is the first of three preparations of macrocycles that will be described (epothilone A, zearalenone, and muscone). All feature cycli-zation/release strategies that involve carbon-carbon bond formation.18 These efforts illustrate how the research on supported syntheses of highly complex structures has inspired the use of creative linker strategies for attachment to a solid phase. 

Figure 3.16. Linker strategies for phosphonic acids [202,203], phosphoric acids [204,205], and sulfonic acids [201].

Subsequent cleavage of the resin-bound Diels-Alder adducts employing lithium aluminium hydride (LiAlH4) via a traceless linker strategy afforded the cyclic phenylethy-lamines. Alternatively, selective reduction of the nitro group using tin(II) chloride... 

SCHEME 52. Solid-phase synthetic strategy for 1,4-benzodiazepine derivatives using a germanium linker strategy i) polymer support linkage, ii) solid-phase synthesis, iii) product release... 

Solid supported isoxazolines 40 were prepared starting from a sulfmate-functionalised resin 38. Oxidation of the resin linked cyclobutanols 40, with concomitant cleavage of the sulfone linker, produced isoxazolinocyclobutenones 41 in 34-38% overall yield (4 steps) <02OL741>. A five-step solid phase synthesis of isoxazolino-pyrrole-2-carboxylates that employing the same traceless sulfone linker strategy has also been reported <02JOC6564>. 

The synthesis of the cycUc peptide 2.12 on SP was achieved in excellent yield and purity, demonstrating the flexibiUty of the SPS approach for a complex sequence containing difficult amino acids such as Glu, Asp, and Arg. A new linker strategy suitable for any peptidelike sequence with no problems of stability and able to permit the final modification of the C-terminus was developed. The iterative nature of peptide SPS and the robustness of these oligomeric structures were instrumental in reaching such good-quality results that are easily amenable to automated SPS procedures. 

Merrifleld 1,2,3-triazole resins 183 and 184 were prepared and utilized in the BAL (Backbone Amide Linker) strategy to synthesize amides 185 via sequential reductive aminations, amide couplings, and traceless resin cleavage with trifluoroacetic acid <03OL1753>. 

Fig. 5. A safety-catch linker strategy for cyclic peptide synthesis.

Backbone Amide Linker Strategies for the Solid-Phase Synthesis of C-Terminal Modified Peptides... 

A similar linker strategy has been used by Taddei [36] in a solid-phase approach to 0-lactams. Treatment of immobilized substrates 209 and 212 with Sml2 resulted in smooth reduction and release of 211 and 213 respectively... 

A -Alkyl-A -(/3-keto)amides 1216 have been prepared using a traceless linker strategy starting from resin-bound benzylamines 1215. The ketoamides 1217 released from the resin react with an ammonium salt to afford 1,2,4-trisubstituted imidazoles 1218 in good yields and high purities (Scheme 297) <20000L323>. 

Fig. 10.1-2 Generation of peptide cr-thioesters by Fmoc-based SPPS using sulfonamide safety catch linker resin (a), a masked thioester equivalent incorporated post-SPPS (b), and a masked thioester linker strategy (c).

Guillier, F., Orain, D. and Bradley, M. (2000) Linkers strategies in solid-phase synthesis and combinatmial chemistry. Chem. Rev. 100 2091-2157. 

---