Monomer rehearsal

The term chemical assessment describes the process through which the reaction scheme to arrive at a target molecule is combinatorialized. This process may include the transfer of a reaction from solution onto SP and/or the adaptation of the reaction conditions to the use of many monomers with different reactivities and stabilities for library synthesis. Monomer rehearsal is an accurate check of the reactivity of a monomer set in the synthetic scheme for the buildup of the library so that the unreactive/difficult monomers are removed from the set. A model library is a small set of discretes, or a small pool, that is prepared using the planned synthetic route for the library and is fully characterized by the appropriate analytical tools Only if the results are satisfactory is the library synthesis carried out. Quality control determines the analytical profile of a library as a single entity, but data from each library individual, or a significant percentage of library individuals, are acquired. A library with 80% confirmed pure compounds is a good-quality library, but the 20% of samples that are... 

Figure 5.3 Monomer rehearsal A hypothetical example for reductive amination.

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. 

Monomer rehearsal is identical for SP discrete and pool libraries, but the generally larger dimensions of the latter require the use of more monomers and thus their qualification for the planned reaction scheme. The full analytical characterization of this step will be crucial. Discarding poorly performing monomers and identifying reliable monomers and optimized reaction conditions will guarantee the quality of the... 

M, Mj and M3 monomer representatives give >75% yields and are selected from the monomer rehearsal... 

Figure 7.7 Monomer rehearsal for a hypothetical 125,000-member SP pool library.

Iterative deconvolution selects the pools solely according to the screening results, and no analytical characterizations are performed at any deconvolution stage. This is particularly useful when sophisticated analytical instrumentation is not available. The measured activity is always the sum of each individual contribution. Assuming that the SP assessment studies, the monomer rehearsal, and the model library synthesis... 

Figure 7.43 SP monomer rehearsal for the large, natural products-biased hbrary L12.

Monomer rehearsal was followed by a model library synthesis aimed at confirming the feasibility of mix-and-split synthesis for the selected SP hbrary synthetic scheme and to check for unwanted interactions of rehearsed building blocks at different reaction sites than the ones expected. A series of eight monomer representatives from... 

Monomer rehearsal is strongly influenced by the selection of the phase. The higher flexibility in terms of conditions in solution may allow the successful rehearsal of more monomers, whereas the solid support or the linker may interfere with reactive mono-... 

Figure 8.8 Monomer rehearsal soluition- versus solid-phase fonnats.

Fully automated instruments with low-medium throughput, typically a few hundred compounds per week for one- to three-step synthetic schemes in solutions, are suitable for small, focused libraries where more challenging reaction conditions such as heating, using reactive intermediates, or when inert atmospheres are needed. These instmments are also suitable for intermediate steps in the construction of larger libraries. For example, monomer rehearsal can be performed by reacting a common intermediate with various monomer candidates, and a small model library may be prepared. Even chemistry assessment may be tackled with these instmments. 

Figure 8.17 Synthesis of the solution-phase, discrete spiropyrrrohdine library L5 monomer rehearsal.

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