Library syntheses

Combinatorial chemistry has played an increasing role in drug discovery. Wacker et al. extended the Madelung indole process successfully to solid phase library synthesis for the preparation of 2,3-disubstituted indoles. A number of examples follow in the table. 

Tetrasubstituted thiophenes obtained by the Gewald reaction serve as templates for structural diversification and semi-automated library synthesis. Thiophene 31, prepared from 3-ketoester 29 and t-butylcyanoacetate 30, could be selectively derivatized at three of the four substituents to maximize library diversity. This procedure represents an improvement over previously published methods for utilizing 1,3-dicarbonyl compounds in the Gewald reaction. 

Centerpieces of combinatorial concepts include the synthesis of compound libraries instead of the preparation of single target compounds. Library synthesis is supplemented by approaches to optimize the diversity of a compound collection (diversity-oriented synthesis) and by efforts to create powerful interfaces between combinatorial synthesis and bioassays. 

Dolle RE (2002) Comprehensive survey of combinatorial library synthesis. J Comb Chem 4(5) 369-418... 

Wang linker, mimic 297 Wang resin, phthalimide library synthesis 103... 

Armstrong, R.W., Combs, A.R, Tempest, P.A., Brown, S.D., Keating, T.A. (1996) Multiple-Component Condensation Strategies for Combinatorial Library Synthesis. Accounts of Chemical Research, 29, 123-131. 

Tietze, L.F. Lieb, M.E. (1998) Domino Reactions for Library Synthesis of Small Molecules in Combinatorial Chemistry. Current Opinion in Chemical Biology, 2, 363-371. 

The Leznoff acetal linker 69 was used to anchor an aldehyde to the solid support and following a series of reactions, the aldehyde was released by acidic cleavage [78]. An application of this resin was demonstrated for a biaryl aldehyde library synthesis which incorporated a Suzuki-Miyaura reaction (Scheme 37) [79]. Cleavage was effected by a solution of 3 M HC1... 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

Dolle, R. E., Comprehensive survey of combinatorial library synthesis 2000, J. Comb. Chem. 2001, 3, 477-517. 

There have been numerous efforts in library synthesis to develop compounds with central nervous system (CNS) activity [37]. Most recently, a QSAR model has been developed based on the activity of 2500 compounds against 180 assays using proprietary 3D pharmacophore descriptors [38]. The model successfully predicted 83% of a test... 

Kobayashi, S. Combinatorial Library Synthesis Using Polymer-supported Catalysts. In Combinatorial Chemistry, Fenniri, H., Ed., Oxford University Press Oxford, U.K., 2000 pp 421-432. 

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

In a separate study, Ohberg and Westman applied the same PS-DMAP in a one-pot microwave-induced base-catalyzed reaction of N-aryl and N-alkyl amino acids (or esters) and thioisocyanates for the library synthesis of thiohydantoins (Scheme 7.115) [136]. Thiohydantoins are of interest due to their ease of preparation and the range of biological properties associated with this heterocyclic ring system. The use of PS-DMAP as the base in this reaction gave slightly lower yields compared to when triethylamine (TEA) was used, but it resulted in a cleaner reaction mixture and an easier purification procedure. Cyclizations of a number of N-substituted... 

Parlow JJ, Devraj RV, South MS (1999) Solution-phase chemical library synthesis using polymer-assisted purification techniques. Curr Opin Chem Biol 3 320-336... 

The resin-bound trienes 83 (Scheme 11) were prepared in a similar fashion to the solution-phase studies (Sect. 2.2.2) and underwent tandem RCM resin-cleavage to liberate four macrolactones 84a,b and 85a,b in a combined yield of 52%. Although, as expected, a large amount of initiator 3 was required to effect this transformation, the procedure constituted a novel and efficient route to the epothilones which paved the way for the generation of a library of epothilone analogs. The library synthesis was achieved using the recently developed SMAR-I9 microreactors (SMART=single or multiple addressable radiofrequency tag) [25] (Scheme 12). 

Drug Discovery Chemical library synthesis Purity and identity determination Yes Low... 

These ligands can be used to reduce a wide variety of carbon-carbon unsaturations, and have the advantage that their simple preparation can be used for rapid ligand library synthesis and screening [314, 318, 319, 330, 331]. 

Fig. 36.6 Phosphoramidite library synthesis and screening protocol. (Reproduced by permission of the American Chemical Society from [36].)...

In this review we have chosen to focus on strategies for designing the templates and scaffolds used in library synthesis. Equally important is the selection of building blocks for library preparation. A number of powerful computational methods have been developed to select the minimal set of building blocks that maxi-... 

Some new synthetic approaches to tetrazolodiazines have recently been reported. Thus, a multi-step variation of the cyclization method discussed in Table 9 has been elaborated <2005S2597> with the aim of library synthesis. 

Our library synthesis was carried out with a set of 27 tube-shaped solid phase synthesis support, called MicroTubes. These supports are prepared by radiation grafting of polystyrene ( — 350 pmol) onto polypropylene tubes, chemically functionalizing the polystyrene with aminomethyl groups to afford about 55 imol of amine per tube, inserting a reusable Rf ID tag into each tube, and heat-sealing the tube ends to prevent loss of the tag. The chemical conversion of all 36 aminomethyl tubes was carried out simultaneously using standard procedures with rink amide linker, each with —46 pmol of available amine per tube.1 2... 

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