Parallel Syntheses of Individual Compounds

After a few frenzied years of development in combinatorial chemistry, there is now a clearly identifiable trend away from the synthesis of complex 

The advantages of SynPhase crowns over conventional solid-phase syntheses on resin beads are as follows  

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). 

SynPhase crowns may be used to perform large numbers of optimization reactions in parallel. This library of reaction conditions may be analyzed by assaying product purities after cleavage from the solid phase using high-throughput techniques such as HPLC and ESMS. Overall, this approach can greatly reduce the time required for this critical step of compound library development. 

Consideration of reaction mechanisms helps reduce the number of reaction variables, but trial and error still plays a large part in optimization processes. Large numbers of reactions therefore are required to fully optimize chemistries. In our experience, one variable for which the optimal 

---

The two synthetic approaches described above became especially popular with the expansion of automated synthetic platforms, which provide the opportunity for parallel synthesis of hundreds and thousands of organic compounds per day. Due to relatively large amounts of synthesized compounds (milligram scale), almost any analytical method can be used for characterization of products of parallel synthesis. The major analytical challenge associated with the libraries of individual compounds is to keep up with the high productivity of the automated synthetic platforms. 

A number of different solid supports and uniquely designed reaction vessels are adopted for the parallel synthesis of organic compound libraries. The yields of the individual compounds synthesized vary widely from nanomoles to millimoles. Unlike split-pool synthesis, which requires a solid support, parallel synthesis can be done either on solid phase or in solution. 

The traditional and established way of conducting chemical transformations employs one reaction vessel for each compound synthesized. To prepare 50 different acetamides, 50 reaction vessels are needed, one for each amide. When synthesis of 50 amides is performed at the same time, this approach is referred to as a parallel synthesis. It is, of course, always desirable to simplify the process by reducing the number of vessels used in the synthesis. However, it is not feasible just to mix 50 amines into one reaction vessel and acetylate the mixture of amines because the isolation of 50 amides from the resultant reaction mixture could be complicated and time consuming. Simple separation of individual components was made possible by Merrifield s solid-phase synthesis.1 Solid support-bound substrates can... 

Although combinatorial libraries were originally synthesized as mixtures, today most libraries are prepared in parallel as discrete compounds and then screened individually in microtiter plates of 96-well, 384-well, or 1536-well formats. To facilitate subsequent structure-activity analyses and to assure the validity of the screening results, many laboratories verify the structure and purity of each compound before high-throughput screening. Semi-preparative HPLC has become the most... 

---