Solution-Phase Discrete Libraries

1 Design and Synthesis of Solution-Phase Discrete Libraries 

The design of a library that is project dependent and identical for both solution and solid phases, involves the identification of a suitable structural motif together with its randomization points, which are available for generation of diversity (Fig. 8.6, top) and the overall definition of library size. A retrosynthetic study follows in which a reasonable synthetic route in solution is determined, while work on SP requires the choice of a suitable support and of a linker as well (Fig. 8.6, bottom). 

The next phase for SP is the validation of the selected route in solution. It is useful to check the outcome of the reaction on several compounds to uncover potential weaknesses. This step is obviously redundant in the solution phase, because it corresponds to the following chemical assessment step, even though the synthesis of a few more fully characterized discretes may be desirable (Fig. 8.7, top). Typically, the assessment of the chemistry in solution takes several weeks to check a few representative monomers with different reactivities in order to discard unsuitable monomer 

The optimized reaction conditions to make the same library in solution or on SP differ significantly in most examples because of the influence exerted by the heterogeneous support (see Chapter 1), which may lead to different purities and yields of the final compounds. When the chemistry assessment, either in solution or on solid phase, does not give satisfactory results after having exploited all the reasonable experimental conditions, the other phase should at least be considered before abandoning the library synthesis. 

Potential representative monomers are then selected from commercially available compounds or from internal collections, possibly through the application of computational methods to select only the most significant examples, and the chemistry is rehearsed using these. The process is identical both in SP and in solution, but the support makes monitoring of the reactions, the precise determination of yields and purities of the reaction products, and the structure and the quantity of impurities more difficult and time consuming in the SP (Fig. 8.8). If the proper analytical equipment and expertise for working in SP are not available, the selection or rejection of a monomer candidate may be more difficult, less accurate, or even wrong. 

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SYNTHETIC ORGANIC LIBRARIES SOLUTION-PHASE LIBRARIES 8.2 SOLUTION-PHASE DISCRETE LIBRARIES... 

SOLUTION-PHASE DISCRETE LIBRARIES SOLUTION-PHASE... 

Figure 8.31 Synthesis and purification of the solution-phase discrete libraries L15-L17 using the polymer supported catalyst 8.53.

Figure 8.10 Synthesis of the solution-phase, discrete aminoglucopyranoside library LI.

Figure 8.11 Synthetic scheme to the solution-phase, discrete thiohydantoin library L2.

Figure 8.14 Synthesis of a cyclopropane-based monomer subset for the solution-phase, discrete triazine library L3.

Figure 8.16 Synthesis of the solution-phase, discrete spirop)TTolidine library L5 from a subset of the solution-phase chalcone library L5.

Figure 9.8 Synthesis of the solution-phase discrete chalcone library LI.

Figure 9.13 Solution-phase discrete polycyclic libraries L9-L10 obtained from the solution-...

Figure 9.24 Structures of the known opioid antagonists 9.54-9.56 and of the solution-phase discrete focused library L16 inspired by their structures.

Figure 9.26 Monomer sets M1-M2 used in the synthesis of the solution-phase discrete focused piperidine library L16.

TABLE 9.1 K-Opioid Inhibition of Active Individuals from Screening of the Solution-Phase Discrete Focused Piperidine Library L16... 

TABLE 9.5 Hydrosilylation Kinetics for the Individuals from the Solution-Phase Discrete Catalytic System Library L21 ... 

Figure 9.38 Mono- (L22) and diphosphine (L23) solution-phase discrete ligand libraries for the catalyzed Heck reaction of the labeled substrate 9.92 with supported 9.93.

TABLE 9.6 Ligands from Solution-Phase Discrete Mono- and Diphosphine Libraries L22 and L23 for the Catalyzed Heck Reaction of Labeled Substrate 9.92 with Supported 9.93 Screening Results... 

Figure 11.17 Synthesis of the solution-phase, discrete copolymer library of soluble supports L13 and structures of monomers used for its synthesis.

A convenient procedure for the solution phase preparation of a 2-aminothiazole combinatorial library has been reported. The Hantzch synthesis of 2-aminothiazoles has been adapted to allow the ready solution phase preparation of libraries of discrete 2-aminothiazoles <96BMC1409>. 

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