Solid phase supported scavengers

The purification problem in the solution-phase synthesis of combinatorial libraries is addressed in various ways. For example, for a multistep synthesis polymer-bound reagents could be used [72-75]. A complementary approach uses scavenger, such as a solid-phase-supported electrophile or nucleophile, to remove unreacted starting material after the synthesis has taken place [76-79],... 

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. 

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]. 

The use of scavenger resins in solution-phase synthesis illustrates a type of procedure that is actually a hybrid between solution-phase and solid-phase methods. The first step of this procedure is clearly a form of solution-phase synthesis since the reactions take place totally within a dissolved state with no solid support provided for any of the reactants. The separation stage of the process occurs only after products have become attached to solid supports—the scavenger resins—from which they may or may not then be removed. 

Note 3 Use of the term resin to describe the polymer beads used in solid-phase synthesis and as polymer supports, catalysts, reagents, and scavengers is also discouraged. 

It should be highlighted that in some cases the distinction between a traditional solid-phase synthesis and a process involving solid-supported reagents is often difficult. The reader is advised to refer also to the chapter on the integration of microwave-assisted synthesis with solid supported reagents and scavengers (Chapter 6). 

Thus, gel-type polystyrene-sulfonyl-hydrazide resin 20, which originally was developed for carbonyl scavenging applications [30] can also serve as a linker for carbonyl compounds in solid phase synthesis and gives access to support-bound sulfonyl hydrazones 21 (Scheme 8)... 

Two complementary procedures have been developed for alkylation of secondary amines [11] - both of which involve the use an excess of amine to drive the reaction to completion. The remaining amine was removed from the required tertiary amine using a polymer supported isocyanate 5 as a nucleophilic scavenger (under thermodynamic control) (Table 1 entry 2). The use of this amine scavenger has subsequently been applied in the purification of urea-based libraries prepared by solid-phase organic synthesis [12],... 

Possible use of supported reagents-scavenger Simultaneous reaction and filtration Byproducts are retained on the solid phase ... 

Combined with expedient purification techniques (e.g., scavengers, reagents on solid support, and solid phase extraction techniques) [ 14], microwave-assisted synthesis is leading the way towards genuine high-throughput chemistry that will hopefully ease the chemistry-related bottleneck in the drug development process. 

Dahmen S, Braese S, The first stable diazonium ion on solid support— Investigations on stability and usage as linker and scavenger in solid-phase organic synthesis, Angew. Chem. Int. Ed., 39 3681-3683, 2000. 

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