Solid supports handling

As an extension to thep-carboxybenzenesulfonamide safety-catch linker [43,44], alkanesulfonamide handle 37 was developed [45]. This linker tethers carboxylic acids to the solid support to give an acylated sulfonamide which is stable to both basic and acidic conditions (Scheme 12). Products were released by treatment with iodoacetonitrile followed by the addition of a nucleophile. 

Dihydropyran (DHP) linker 45 is a common handle that couples an alcohol to a solid support with subsequent release upon mild TFA conditions (Fig. 12) [54]. An alternative approach is to prepare an active carbonate linker. TV,TV -Disuccinimidyl carbonate (DSC), a valuable reagent for converting hydroxymethyl-based supports to their corresponding carbonates, was reacted with 4-hydroxymethylpolystyrene 46 and 4-nitrobenzamido (Nbb) 47 resins to anchor alcohols and phenols (Scheme 17) [55]. The final products were released from the solid support by HF and photolysis, respectively. 

The utility of such reagents in the oxidation processes is compromised due to their inherent toxicity, cumbersome preparation, potential danger in handling of metal complexes, difficulties encountered in product isolation and waste disposal problems. Immobilization of metallic reagents on solid supports has circumvented some of these drawbacks and provided an attractive alternative in organic synthesis because of the selectivity and associated ease of manipulation. Further, the localization of metals on the mineral oxide surfaces reduces the possibility of their leaching into the environment. 

The simplest technique is the use of the 96-well collection plate format (analogous to the format used in SPE) in conjunction with a liquid handling robotic system it follows the same principle as bulk scale LLE. However, immobilization of the aqueous plasma sample on an inert solid support medium packed in a cartridge or in the individual wells of a 96-well plate and percolating a water-immiscible organic solvent to extract the analyte from this medium evoked significant enthusiasm from the pharmaceutical industry. 

The preparation of solid-supported selenium resins and their application as linkers and reagents for sohd-phase synthesis have heen described [121, 122]. These reagents have proven to be useful for applications in sohd-phase and combinatorial synthesis because of their versatility and ease of handling. 

The PNA chain was linked to the peptide spacer glutamic acid-(y-tert-butyl ester)-(fi-aminohexanoic acid)-(fi-aminohexanoic acid) (Glu [OtBuj-fiAhx-fiAhx) via an enzymatically cleavable Glu-Lys handle. The Glu [OtBuj-fiAhx-fiAhx spacer was coupled to the amino-functionalized membrane by standard Fmoc-Chemistry. Then the membranes were mounted in an ASP 222 Automated SPOT Robot and a grid of the desired format was dispensed at each position. The free amino groups outside the spotted areas were capped and further chain elongation was performed with Fmoc-protected PNA monomers to synthesize the desired PNA oligomers (18). After completion of the synthesis, the PNA oligomers were cleaved from the solid support by incubation with bovine trypsin solution in ammonium bicarbonate at 37 °C for 3 h. 

Among the electrophilic handles proposed for head-to-tail and side-chain-to-tail cyclization of peptides on solid support by intrachain aminolysis with concurrent detachment of the product from the resin in the protected form (see Section 6.8.3.1.3), generally the oxime resin (also called Kaiser resin)1364 365 and a thioester resin[363l are recommended (see Scheme 14). In addition to the classical head-to-tail cyclization,[3431 the oxime resin is used for side-chain cyclizations as well as for the synthesis of multicyclic peptides vide infra). Due to its dual functions, the oxime resin can be employed only with Boc/Bzl chemistry it is not compatible with Fmoc/tBu chemistry where the basic N -deprotection leads to free amino groups and thus to premature cyclization reactions. To avoid this premature cleavage of the... 

Concerns over toxicity have also been raised for the Cinchona alkaloids, which have been described as dangerous to handle and highly toxic by Federsel [59], who recommended linkage to a solid support as a means of preventing toxic effects. At the present time, there is no indication of what effect the many substituents that have been linked to the quinudidine nitrogen in Cinchona alkaloids could have on toxicity and, until this problem is solved, they will be viewed with caution by industry. 

The handling advantages of this type of solid support for carrying out multiple parallel syntheses mean that libraries involving tens to hundreds of compounds are conveniently prepared. The use of tagging techniques expands the potential library size into the thousands (see Section 6.4). 

Formation of piperazine-2,5-diones from dipeptide esters containing Pro or other N-alkyl amino acids has also been observed during SPPS. The dipeptides most prone to cyclization are those that contain a C-terminal Pro or other IV-alkyl amino acids connected via an ester bond to a sterically unhindered handle.1171-1781 Scheme 33 depicts the formation of piperazine-2,5-diones 81 from dipeptides 80 in which the IV-alkyl amino acid is connected via a benzyl ester to the solid support. 

Recent developments in reaction techniques which include handling of air-sensitive and moisture-sensitive compounds new chromatographic procedures phase transfer catalysis and solid support reagents. 

Organometallic complex catalysts have been removed from reaction mixtures with solid-supported phosphines as well as other ligands to facilitate reagent handling and product purification. Alternatively, Leadbeater28... 

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