Diversity-oriented synthesis libraries

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. 

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

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. 

Diversity-oriented Synthesis of Natural-product-like Libraries... 

Contributions by R. Joseph and P. Arya as well as M. A. Koch and H. Waldmann focus on synthetic aspects towards lead structures originating from natural product-derived scaffolds. R. Joseph and P. Arya refer to two complementary approaches, the synthetic access to focussed libraries around bioactive natural product cores, and diversity-oriented synthesis aiming at 3D scaffold diversity for hit generation, respectively. On the other hand, M. A. Koch and H. Waldmann emphasise the correlation of natural product-based library concepts with structural features of targeted protein domains, thus strengthening the privileged structure concept from a bioorganic viewpoint. 

Diversity-Oriented Synthesis in Prospecting Library Design... 

Chemical Libraries Screening for Biologically Active Small Molecules Diversity-Oriented Synthesis of Small Molecules Reverse Chemical Genetics... 

Angular epoxyquinol library A -Pyrazoline Diversity oriented synthesis (DOS). 244 80 Chemical Methodology and Library Development (CMLD) initiative to develop novel libraries. 18, 19... 

Most commonly, a commercial library, containing a subset of compounds that matches a desired set of properties (if known), is screened in an initial study. Once hits are obtained and verified, a small library of compounds is synthesized to produce a set of compounds in the same chemical-stmctural space as the original hit stmcture. This process allows for hits with higher potency and elucidates information of the structure-activity relationship within the system of interest. Such synthetic libraries of chemically diverse compounds have been made possible through combinatorial chemistry (52-56) and diversity-oriented synthesis (52). 

Kubota, H., Lim, J., Depew, K. M., Schreiber, S. L. Pathway development and pilot library realization in diversity-oriented synthesis. Exploring Perrier and Pauson-Khand reactions on a glycal template. Chem. Biol. 2002, 9, 265-276. 

In the late 1990s, the group led by Schreiber introduced the concept of diversity-oriented synthesis (DOS) [18-20] into the field of organic chemistry. In combination with the split-pool synthesis [21,22] and tagging strategies [23,24], DOS allowed chemists to prepare large collections of structurally diverse small molecules. The library compounds are usually prepared on polymeric beads, and thus each compound contains a common functional group that mediates covalent attachment to the solid surface. 

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