Library quality

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

Quality/speed To achieve high-quality libraries in an efficient fashion, it is important to have access to appropriate analytical tools and automation. 

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... 

Other methods are more suitable for the purification of medium-large solution-phase libraries vide infra), but if small arrays are prepared and partition between aqueous and organic phases is appUcable, this method rapidly produces good-quality library compounds, either alone or in conjunction with other separation techniques. 

Furthermore, as the pharmacological database becomes populated with diverse biological assays and grows in structural scope, it will act to guide the design of higher-quality libraries that will access the darkest recess of the genome. 

A key assumption for the utility of encoded libraries is that the code is predictive of the structure of the attached compound. Decoding must be unambiguous, and the correct compound must have been produced. Obtaining this assurance presents significant analytical challenges, but it is critical to obtain, as poor quality libraries can lead to significant wasted time in the screening and re-synthesis of spurious hits. 

LeProust, E. M., B. J. Peck, K. Spirin, H. B. McCuen, B. Moore, E. Namsaraev, and M. H. Caruthers. 2010. Synthesis of high-quality libraries of long (ISOmer) oligonucleotides by a novel depurination controlled process. Nucleic Acids Res. 38 2522-40. 

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