Solid-phase scavengers

Keywords Combinatorial Chemistry m Solid-Phase Synthesis m Solid-Phase Scavenger m Linker m Targeted Library m Small Molecule Libraries... 

Solid-phase scavenger methods are employed with increasing frequency as a prehminary reaction cleanup step in combinatorial chemistry, and have recently become commercially available (Argonaut, Calbiochem-Novabiochem, Varian, Alltech). lilly researchers first reported on this approach, employing sohd supported electrophiles and nucleophiles for reaction purification in acylation and alkylation reactions. Yield and purity values reported were 90-95% and 50-99%, respectively, for a library generated by reductive amination. Parke-Davis researchers achieved the removal of known reaction product impurities by the application of custom synthesized polymer supported reagents, specifically polystyrene-divinylbenzene supported derivatives of methylisocyanate and tm(2-aminomethyl)amine for cleanup of by-products resulting from urea, thiourea,sulfonamide,amide, and pyrazole libraries. 

TFA, CH2CI2, Et3SiH. Other scavengers are not nearly as effective, but when the xanthenyl group is used on a solid phase, more acid is required to get efficient cleavage. 

Bis(indolyl)nitroethanes are obtained readily in 7-10 min in high yields (70-86%) on fine TLC-grade silica gel (5-40 pm) by Michael reaction of 3-(2 -nitrovinyl) indole with indoles. The same reaction reported requires 8-14 h for completion at room temperature [77]. Several functionalized resins have been prepared from Merrifield resin via a MW-assisted procedure that utilized mixed solvent system to facilitate the swelling of resins and coupling with microwaves [78], These resins can function as solid supports or polymeric scavengers in solid phase synthesis. 

In the case of batch processing the scavenger is added to the reaction mixture after completion. For flow-through processing the scavenger is packed into a column (solid-phase extraction, HPLC, etc.) and the reaction mixture is passed through the column until scavenging is complete. 

NA Sole, G Barany. Optimization of solid-phase synthesis of [Ala8]-dynorphin A1 3, (scavenger Reagents B, K, R) J Org Chem 57, 5399, 1992. 

Supported scavengers are reactive species that selectively quench and/or sequester by-products of the reaction or remove any excess starting materials, and are subsequently removed by filtration (Fig. 2.2). These species, which allow hquid-solid phase extraction are also often referred to as sequestering agents or quenching agents . 

Supported reagents have found application in many areas of synthesis including the construction of small peptides, the traditional foundation stone of solid phase synthesis. For example a recent paper describes the preparation of dipeptide p-nitroanilide and phosphonate libraries by supported carbodiimide coupling and scavenger purification (Scheme 2.52) [79]. 

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