Diversity-oriented library

A combinatorial natural-product-like and diversity-orientated library of 10 000 benzopyran-based small molecules was constructed by Nicolaou and coworkers [74, 75]. They chose a solid-phase approach and an anchoring strategy that does not limit complexity building operations (Scheme 14.11). They used a polystyrene-based selenyl bromide resin (43) on which substrates can be immobilized by electrophilic cyclization reactions. Here, ortho-prenylated phenol 44 was reacted with the selenyl bromide (43) to form the benzopyran scaffold (45) via a 6-endo-trig cyclization. 

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. 

Lee JS, Kim YK, Vendrell M et al (2009) Diversity-oriented fluorescence library approach for the discovery of sensors and probes. Mol BioSyst 5 411—421... 

As can be seen from the early combinatorial libraries, chemistry, even in the absence of diversity-oriented design, is capable of producing vast numbers of compounds. The... 

Advances in chemical synthesis have enabled considerable sophistication in the construction of diverse compound libraries to probe protein function [61, 62). However, few general techniques exist that can directly assess binding mechanisms and evaluate ligand afEnities in a multiplexed format. To realize the full potential of combinatorial chemistry in the drug discovery process, generic and efficient tools must be applied that combine mixture-based techniques to characterize protein-ligand interactions with the strengths of diversity-oriented chemical synthesis. 

Structural type. Diversity-oriented synthesis is a new strategy for constructing libraries with both skeletal and functional group diversity. 

Zheng, W. and Lampe, J. (2002) Combinatorial optimization approaches to the design of focused, diverse, and target class oriented libraries. Cambridge Healthtech Institute s Sixth Annual Cheminformatics, Philadelphia, PA. 

Schreiber and co-workers have shown that this approach is useful in the preparation of compound libraries. One of their examples is a diversity-oriented synthesis of polycyclic scaffolds through the Perrier reaction followed by the PKR of a glycal template on solid support (Equation (35)). 

Fig. 1.7. Diversity-oriented synthesis (DOS) libraries (reprinted ( adapted or in part ) with permission from Journal of the American Chemical Society. Copyright 2005 American Chemical Society).

The split-and-pool synthesis not only simplifies the complexity of the combinatorial synthetic process, but also offers additional important benefits. To undertake a full range of solid-phase chemical reactions, elaborate reaction conditions are needed for some chemical transformations. These include, but are not limited to, low temperature and inert atmosphere conditions. Parallel synthesis of a thousand compounds requires handling of a thousand reaction vessels. The timely addition of sensitive reagents (e.g., butyl lithium) at low temperature (—78°) under inert atmosphere during parallel synthesis is not a trivial task. It can be done if sophisticated automated synthesizer equipment is designed to handle and tolerate such reaction conditions. Such a synthesis can alternatively be performed easily in a manual fashion using a split-and-pool method that requires only a limited number of reaction vessels. Examples from Nicolaou s17 and Schrei-ber s18,19 laboratories have shown that the split-and-pool method is the methodology of choice for the synthesis of complex and diversity-oriented combinatorial libraries. 

Multicomponent reactions (MCRs) are one-pot processes combining three or more substrates simultaneously [1], MCR processes are of great interest, not only because of their atom economy but also for their application in diversity-oriented synthesis and in preparing libraries for the screening of functional molecules. Catalytic asymmetric multicomponent processes are particularly valuable but demanding and only a few examples have been realized so far. Here we provide an overview of this exciting and rapidly growing area. 

It is critical to this chemical genetic approach to have a library of compounds that have a high probability of being relatively selective otherwise, the ability to interpret the results becomes at least as complex as deciphering highly poly-genetic phenotypes. To address this, diversity-oriented synthesis has been proposed to provide arrays of complex small molecules that are easily synthesized. The natural-product basis for many of the molecules and their complexity are believed to contribute to their cellular potency and selectivity (6). This chemical genetic approach has been applied to identify novel inhibitors of alpha-tubulin and histone deactylation (7). 

Key Words Chemical diversity compound design diversity-oriented synthesis druglike compounds molecular properties natural products rule of five structure-activity relationship target-focused compound libraries. 

Despite this proven record of biological significance there had been some doubts if natural products are suitable and accessible lead structures for combinatorial libraries by solid-phase synthesis. In contrast to the diversity-oriented approach of library design, which is driven by the underlying chemistry of reliable reactions with broad substrate scope [4], natural product... 

Abstract Recent developments in the microwave-assisted synthesis of heterocycles are surveyed with the focus on diversity-oriented multi-component and multi-step one-pot procedures. Both solution- and solid-phase as well as polymer-supported methodologies for the preparation of libraries of heterocycles are reviewed. Advantages of microwave dielectric heating are highlighted by comparison with conventional thermal conditions. 

Rosania et al. [19] have shown this straightforward preparation to be advantageous for the transposition to a diversity-oriented, combinatorial approach to an organelle-targeted fluorescent library. Therefore, the condensation of 9 and 10 (Fig. 5.4) with pyrrolidine as a catalyst was performed in 96-well plates and the dehydration reaction was accelerated by microwave irradiation for 5 min to give 10-90% conversion. The resulting library compounds were analyzed using an LC-MS system with diode-array and fluorescence detectors and a fluorescence plate-reader to determine the absorption and emission maxima and the emission colors. 

In term of diversity-oriented strategies, multicomponent reactions (MCR) represent an attractive and rapid access to libraries of macrocycles inspired by biologically active natural products. Combined with Passerini and Ugi reactions, M-RCM has already shown promising synthetic potential, as illustrated by the pioneering work of Domling and coworkers [46]. Condensation of isocyanide 69 with carboxylic acid 70 in the presence of paraformaldehyde leads to bis-olefin 71, which is subsequently submitted to RCM in the presence of G1 and titanium isopropoxide to give the 22-membered macrocycle 72 (Scheme 2.27). 

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