Solid-phase scavenger reagents

SCHEME 3.4. Total synthesis of (+)-plicainine using solid-phase reagents and scavengers. 

Recently, a novel method for the synthesis of a library of substituted prolines with microwave technology [95] has been described. In the first step, 1 equivalent of an amine is added to 1.1 equivalents of an aldehyde in 1,2-dichloroethane (DCE), with subsequent irradiation at 180 °C for 2 min. In the second step, 0.85 equivalents of the maleimide are added and the resulting solution is heated at 180 °C for an additional 5 min. This methodology allowed the production of a solution-phase library of 800 compounds with a crude purity between 65 and 82% (Scheme 9.45). The compounds were purified by solid-supported reagent scavenging to afford the final products with a purity between 90 and 98% and in 79-85 % yield [96]. 

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 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]. 

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. 

The versatility of cyclohexane- 1,3-dione functionalised resins has been illustrated by their syntiietic application as both capture and release reagents and resin scavengers. In addition, CHD resins show considerable potential for further use as linkers in several other solid-phase applications. 

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). 

When reacting two substrates in solution (solution phase) to form a desired product (Ri-E1-Nu-R2 in Fig. 1), a resin with the desired characteristics (solid phase) is utilized to trap undesired material. A scavenging resin, usually added upon reacting of the substrates, interacts with the undesired reagent, thus forming a chemically modified new resin. Upon simple filtration, this resin is separated from the reaction mixture providing (in some cases clean) product without further purification being necessary. 

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. 

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