Reducing agents, solid supported

Cross-hnked polyacrylamides are a group of hydrophihc solid supports introduced primarily for preparation of biopolymers (Fig. 4). Unhke PS resins, polyacrylamides have excellent swelling capacity in both protic (water, alcohols) and aprotic (dichloromethane, dimethylformamide) solvents [88]. These beads are stable towards bases, acids, and weak reducing and oxidizing agents [89]. Predictably, conditions under which amide bonds are cleaved (i.e., sodium in liquid ammonia) [90] lead to rapid decomposition of the polymer. 

Another useful strategy is scaffolding. For example, immunoassays employ BSA both as a blocking agent to reduce nonspecific adsorption of other proteins and also as a scaffold. Essentially, BSA is first attached to the solid support and then further derivatized for the coupling of additional capture ligands. MacBeath and Schreiber first formed a monolayer of BSA and then printed proteins on top of the monolayer. In this manner, small proteins were expressed on the surface and not buried by the BSA. 

Few examples of the preparation of hydrazines or hydroxylamines on insoluble supports have been reported (Table 10.17). Hydrazines have been prepared by the reduction of aromatic diazonium salts or /V-nitroso amines (prepared from secondary amines by treatment with tert-butyl nitrite [340]), and by the N-amination of support-bound amines (Entry 3, Table 10.17). The direct reduction of hydrazones with borane to yield hydrazines on solid phase has not been reported, and appears to be difficult because of the ease with which the N-N bond of hydrazines is cleaved by reducing agents [340]. 

The relatively inexpensive and safe sodium borohydride (NaBH4) has been extensively used as a reducing agent because of its compatibility with protic solvents. Varma and coworkers reported a method for the expeditious reduction of aldehydes and ketones that used alumina-supported NaBH4 and proceeded in the solid state accelerated by microwave irradiation (Scheme 7) [50]. The chemoselectivity was apparent from the reduction of frarcs-cinnamaldehyde to afford cinnamyl alcohol. 

The second approach, named many compounds per bead (Fig. 7.3), starts by coupling the solid support in a single reaction vessel with an equimolar mixture of the 100 amines (step a) then the mixture is reduced (step b) and the resin-bound amines are reacted with an equimolar mixture of the 100 acylating agents (step c). The 10,000-member library is obtained as a single 50-g pool of resin, and each bead contains similar quantities of each library individual. A bead has typically 10 " -10 reaction sites, so that each bead will contain an average of lO -lO copies of each library individual. The library synthesis could technically be considered successful if all the monomers react properly and the 10,000 compounds are acmally present, but the identification of positives from this library for any specific application is not feasible. In fact, the cleavage of resin-bound materials produces an equimolar mixture of all the components, whose activity, if any, is the activity of a 10,000-member unresolved mixmre. As a consequence of this major limitation, this SPS approach is not used for library synthesis. 

An interesting safety-catch linker is based on solid-phase-bound 1,2-dihydroqui-noline [192]. The principle is outhned in Scheme 77. The acylated form of the 1,2-dihydroquinoline on the support (167) is stable under basic and acidic conditions as well as towards mild reducing agents. Oxidation leads to aromatization and hence to the activated quinolinium derivative 168, which is prone to nucleophilic displacement, leading to the target compounds 169. 

Solid-Supported Reducing Agents and Their Applications... 

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