Synthesis of Combinatorial Libraries

A tabular literature survey with about 650 entries listing all dihydropyrimidine derivatives of type 14 prepared via three-component Biginelli reactions up to the year 2001 has been published [7]. 

Since the experimental conditions for the traditional Biginelli reaction are quite straightforward, small libraries of DHPMs are readily accessible by parallel synthesis. Along these lines the generation of a 140-member single compound DHPM library by combination of 25 aldehydes, 6 ureas/thioureas, and 7 acetoacetates or acetoamides under standard reaction conditions has been reported [123, 124]. More rapid approaches make use of microwave-enhanced solution-phase protocols [88, 89, 125]. Apart from these conventional solution-phase methods, it is also possible to employ polymer-supported reagents to aid in the purification and workup protocol. Polymer-assisted solution-phase chemistry using polymer-supported 

E = ester, acyl, amide, nitro, nitrile, phosphono X = O, S, NR 

Lewis acid (Yb-(III)-reagent supported on Amberlyst 15) in combination with polymer-supported urea scavenging resins (Amberlyst 15 and Ambersep 900 OH) permits a rapid parallel Biginelli synthesis with a simple and efficient purification strategy [126]. 

There are alternative solid-phase protocols described in the literature for the generation of DHPMs, not via the classical three-component Biginelli approach but through related modifications [129-131]. Furthermore, there have been reports de- 

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Substructure searches provide another method of searching for available starting materials. They arc used primarily for planning the synthesis of combinatorial libraries. After the target compound has been dissected into a set of suitable precursors, substructure searches can provide for each of them a series of representatives of a certain class of compounds, Siibsti ucturc searches enable the user to specify attributes such as open sites or atom lists at certain positions of the structure. Figure 10.3-38 shows the possible specification elements for the query in a substructure search. 

Parallel processing of synthetic operations has been one of the cornerstones in combinatorial chemistry for years [1-6]. In the parallel synthesis of combinatorial libraries, compounds are synthesized using ordered arrays of spatially separated reaction vessels adhering to the traditional one vessel-one compound philosophy. The defined location of the compound in the array provides the structure of the compound. A commonly used format for parallel synthesis is the 96-well microtiter plate, and today combinatorial libraries comprising hundreds to thousands of compounds can be synthesized by parallel synthesis, often in an automated fashion [6]. 

D. L. Boger, C. M. Tarby, P. L Myers, L H. Caporale, Generalized Dipeptidomimetic Template Solution Phase Parallel Synthesis of Combinatorial Libraries , J. Am Chem. Soc. 1996,118,2109. 

Adaptation of new synthetic methods for the solid-phase synthesis of combinatorial libraries. 

Adaptation of New Synthetic Methods for the Solid-phase Synthesis of Combinatorial Libraries... 

The observed differences create a basis for a rational selection of building blocks for synthesis of combinatorial libraries enriched in target-specific motifs. The quantitative structure-activity discrimination function found at this stage of our study can be used for effective search of reactive monomers possessing the desired physicochemical and spatial parameters. 

Parlow, J. J. The Use of Anion Exchange Resins for the Synthesis of Combinatorial Libraries Containing Aryl and Heteroaryl Ethers, Tetrahedron Lett. 1996, 37, 5257. 

Combinatorial chemistry has moved from specially centralized laboratories, often equipped with multimillion-dollar robots, onto the bench of individual medicinal chemists. This change in direction requires the availability of personal chemistry tools that are simple to operate, easy to arrange in the laboratory, and reasonably priced. Such instruments are now available for the effective synthesis of combinatorial libraries. The Encore synthesizer represents a simple and efficient personal chemistry tool that allows the execution of directed split-and-pool combinatorial synthesis. The current version of the Encore synthesizer is designed for solid-phase synthesis on SynPhase Lanterns however, it can be modified for synthesis on alternative solid supports such as resin plugs from Polymer Laboratories (e.g., StratoSpheres Plugs). 

Fig. 12. Parallel synthesis of combinatorial libraries of heterocycles via resin-bound...

Recent literature contains a multitude of examples of synthetic organic methodologies which have been optimized and applied to the solid-phase synthesis of combinatorial libraries [2]. In fact, the production of a number of these libraries has been realized on such systems as the Multipin SPOC [8], the DIVERSOMER [9] and the OntoBLOCK [10], All three apparatuses allow the automated production of spatially dispersed combinatorial libraries and facilitate the isolation, identification, screening and archiving of single compounds in distinct physical locations which are crucial factors during lead discovery and optimization. 

Parlow JJ, The use of anion exchange resins for the synthesis of combinatorial libraries containing aryl and heteroaryl ethers, Tetrahedron Lett., 37 5257-5260,... 

Seneci P, Sizemore C, Islam K, Kocis P, Combinatorial chemistry and natural products, Teicoplanin aglycone as a molecular scaffold for solid phase synthesis of combinatorial libraries, Tetrahedron Lett., 37 6319-6322, 1996. 

A short overview of synthetic strategies that are currently used in combinatorial chemistry is important to get a better understanding of how to characterize a combinatorial library in the most efficient way. Figure 10.3 presents different strategies for synthesis of combinatorial libraries on an example of a library with three points of randomization (X, Y, Z), three building blocks in each randomization (XI, X2, X3, Yl, Y2, etc., correspondingly), and total complexity of 27 compounds. 

FIGURE 10.3 Different strategies for synthesis of combinatorial libraries. Dotted arrows indicate the step of resin split or combination solid arrows indicate a chemical reaction step. 

Parallel synthesis of combinatorial libraries is a synthetic sequence where the assembly of library is performed using an ordered array of spatially separated reaction vessels under the same reaction conditions. In sequential synthesis, the general reaction conditions can be modified for each building block combination according to the reactivity of the reagents in each reaction vessel. Parallel synthesis can be carried out with both conventional and MAOS and either in solid-phase or solntion-phase synthesis. 

In the synthesis of combinatorial libraries, there is a raft of tactical issues that need to be tackled. Will the library be made of mixtures or discrete compounds Prepared by solid-phase or solution-phase Screened in solution or attached to beads What level of purification and characterization is needed Will hits be identified by deconvolution, encoding techniques, or other means These are aU crucial operational aspects of combinatorial chemistry but it is equally important not to concentrate on them to the extent of missing the big picture. At the end of the day, neither a biological assay nor a medicinal chemist care how a compound was made. It is vital, though, that the tactical decisions do not prevent one from making the right compounds. Combinatorial synthesis is a means to an end, not an end in itself. 

M. Braban, L. Pop, X. Willard and D. Horvath, Reactivity prediction models applied to the selection of novel candidate building blocks for high-throughput organic synthesis of combinatorial libraries, J. Chem. Inf. Comp. Sci., 1999, 39(6), 1119. 

The appeal of cyclic peptides as a rich source of biologically active molecules makes the synthesis of combinatorial libraries of these compounds desirable. However, few avenues for the synthesis of large arrays of cyclic peptides exist. This is primarily caused by the difficult orthogonal deprotection requirements, which require a careful choice of synthetic strategy. For example, if a solution-phase head-to-tail cyclization is undertaken (15) (Fig. 2A), the peptide must be purified at each step of the synthesis (i.e., after synthesis of the linear, cyclized protected and after deprotection) (see Note 1). 

A similar approach utilizing cellulose paper (27,28) (originally developed for DNA synthesis [29J), was later modified by using a printer to label individual pieces of synthetic support (30). Cotton, as the most pure form of cellulose, was found to be a convenient support for parallel synthesis as well (31-34), and was used for the synthesis of combinatorial libraries with guaranteed uniform representation of each structure (35). 

Saneii, H. H. and Shannon, J. D. (1994) Fully automated solid phase synthesis of combinatorial libraries on the peptide librarian. In Innovation and Perspectives in Solid Phase Synthesis (Epton, R., ed.), Intercept, Andover, UK, pp. 335-338. 

This chapter provides a manual for a laboratory-hased short course to introduce the common techniques of solid-phase peptide synthesis (SPPS). The course provides students the opportunity to design and manually synthesize analogs of glutathione using relatively simple equipment available in any unsophisticated laboratory. The manual provides compact protocols for both the different steps of SPPS and the final cleavage of peptides from resin supports. We also introduce a simple method for the synthesis of combinatorial libraries of glutathione analogs that is suitable for those relatively unfamiliar with the field of peptide chemistry. 

In the study of the structure-activity relationships of the epothilones, solid-phase synthesis of combinatorial libraries has been used to probe regions of the molecule important to retention of inq>rovement of activityThe combinatorial approach, using an active natural product as the central scaffold, can also be applied to the generation of large numbers of analogs for structure-activity studies, the so-called parallel synthetic approach. ... 

One of the advantages of this method is the commercial availability of the above devices. The HiTOPS device has been used in the synthesis of combinatorial libraries of piper-azinedionesl l for the development of highly selective inhibitors of collagenase-1. 

DL Boger, CM Tarby, PL Myers, LH Caporale. Generalized dipeptidomimetic template solution phase parallel synthesis of combinatorial libraries. J Am Chem Soc 118 2109-2110, 1996. 

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