Synthesis of Solid-Phase Discrete Libraries

2 High-Throughput Organic Synthesis Manual, SemiAutomated and Automated Devices 

The main purpose of parallel high-throughput organic synthesis (HTOS) is, as already mentioned in Chapter 4, to prepare focused libraries of discrete compounds that can be used to assess a fast, preliminary stmcture-activity relationship for a specific target. The components of these libraries may vary in number from tens to thousands of compounds therefore different instrumentation and expertise are required depending on the library size. 

These instmments are engineered to a high degree of complexity and allow the reliable control of the multiple operations and reaction conditions encountered in the automated synthesis protocol. This topic has been extensively covered in some recent reviews (30-40), and we will limit our discussion of automated SP discrete synthesizers to the implications of their use for the synthesis of small organic molecules on SP. 

The synthesis of a library of discretes in SP makes extensive use of anal54 ical tools to check the validity of the synthetic route and to monitor the reaction course for each library individual. Every reaction vessel contains a single entity with the possible presence of side products that can be fuUy characterized at any step in the synthesis. We will briefly review the most useful analytical techniques that can be employed for the SP discrete library synthesis. For a detailed description of each technique the reader is referred to Sections 1.3 and 1.4 and to the references cited therein. 

The exact nature of the monomer rehearsal of the hbrary strongly depends on the size of the library. For example, if the planned library is small, the preparation of a few target comp)ounds may suffice, while the number of comp)ounds prepared during rehearsal may be larger when the discrete hbrary is made by thousands of components. In both cases these comp)ounds are prepared with the same procedure that will be used for the hbrary S5mthesis, and thus the same steps wih be present in both the monomer rehearsal and the final hbrary synthesis. This step is cmcial to rule out monomers that perform poorly and to determine the optimized reaction conditions. 

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