Combinatorial chemistry cleavage

F. Guillier, D. Grain and M. Bradley, Linkers and Cleavage Strategies in Solid-phase Organic Synthesis and Combinatorial Chemistry, Chem Rev 100 2091-2157 2000. 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

Of particular interest to combinatorial chemistry is the use of immobilised functionalised boronic acid templates which are capable of further transformations [20]. For instance, an aryl carboxylic acid 50 can be converted into the corresponding amide 51 (Scheme 12), whilst still being attached to the resin. Benzyl amine and butylamine were coupled efficiently to afford (after cleavage) the corresponding amides 52 in high yield (Scheme 12). 

Most of the mass spectrometry applications for combinatorial chemistry will be described in the following sections of this chapter. Here we will give a short overview of MS techniques utilized for the characterization of resin-bound molecules. The majority of publications in this field describe applications of matrix-assisted laser desorption ionization (MALDI), combined with time-of-flight (TOF) detection. The major difference of MS application for analysis of resin-bound molecules from the above-described NMR and IR applications is that analyte should not be covalently bound to solid support prior to mass measurement. Detachment of compound molecules from resin can be done chemically (for example, by bead exposure to TFA vapors) [30,31] or photochemically, such that cleavage, desorption, and ionization of molecules occur simultaneously upon stimulation by laser radiation [32], Since the... 

Combinatorial chemistry can be carried out in solution or on solid support. Most solution combinatorial chemistries are typically limited to one-step reactions, whereas solid-phase chemistries often involve multistep processes that include resin manipulation, washing, drying, cleavage of the products from the resin, etc. 

Key Words Acidolytic cleavage backbone amide linkage bioconjugate chemical ligation combinatorial chemistry handle linker peptide alcohol peptide aldehyde peptide ester peptide thioester protecting group solid support. 

GuilUer F, Orain D, Bradley M. Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem. Rev. 2000 100 2091-2157. 

Flnorous synthesis An approach to solution-phase synthesis that uses highly niiorinated compounds as soluble. supports for combinatorial chemistry. The addition of water nr organic solvents causes a phase separation of the fluorinatcd support for subsequent cleavage of the synthetic target structure. 

Combidex. 5ir Feruiimxiraii Combinatorial chemistry. 26-27. 43-63 analytical techniques in. 51-.52 bogus-coin detection in. 50 carbohydrates in. 47. 47f chromatography in. 51 cleavage reactions in. 49. 61 deconvolution in. 26. 27t. 61 development uf. 43... 

This electrochemical cleavage appeared to be faster (less than 1 mn) than the parent chemical [100] or photochemical [101] processes. These mild and fast conditions should therefore be of particular interest for the synthesis of fragile compounds such as acid labile derivatives. Finally, considering the small amount of products obtained at the cathode interface, this methodology currently seems fully applicable for combinatorial chemistry. 

For combinatorial chemistry applications, high-quality FT-Raman spectra can be obtained directly from resin beads, i.e., no cleavage of the molecules from the polymeric support is necessary. This is shown in Fig. 5, where the spectra of TentaGel S beads coupled via a trityl linker with Fmoc-protected tryptophan and the native aminoethyl TentaGel S beads are overlaid. As expected, significant differences in the spectra occur in the spectral region between 1620 and 1500 cm-1 where aromatic rings show pronounced Raman activity. 

---