Diversity-oriented synthesis approach

Here, we cover several examples that included stereoselective diversity-oriented synthesis approaches. The examples covered in this section are indicative of the growing interest in this area and of the need for developing novel approaches leading to fast access to obtaining natural product-like compounds to be used as small-molecule probes. 

Kopp F et al (2012) A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion. Nat Chem Biol 8 358-365... 

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. 

The term diversity-oriented synthesis (DOS) is relatively new and, as mentioned above, is usually defined as the synthesis of complex, natural product-like molecules using a combinatorial approach and employing the full palette of modern organic reactions. It may be a subject of discussion what exactly qualifies a molecule as being natural product-like [4], and in most cases the similarity to an actual natural product seems reciprocal to the number of synthesized compounds. However, even in less complex cases, the products may be highly substituted polycyclic structures with defined stereochemistry, reminiscent of natural products [19, 20]. In these cases, a moderately complex backbone structure is subsequently modified with a well-established set of selective reactions to introduce 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)). 

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). 

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. 

Abstract In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity. 

From the perspective of diversity-oriented synthesis and the rapid constructirai of complex ring systems, the A C pathway may offer the most promising approach. As an example, an Ugi four-component condensation reaction was used as the key step to constmct 146 (Scheme 39). Conversion of 140 to the corresponding diazoimide 146 followed by rhodium(II)-catalyzed intramolecular dipolar cycloaddition then afforded the hexacyclic product 147 in 57% yield (two steps) in a highly stereocontrolled manner. 

In this chapter, we address two complimentary approaches to componnd collection development namely, Diversity Oriented Synthesis (DOS) and Biology Oriented Synthesis (BIOS). For additional, very well-validated approaches snch as fragment-based design and the application of in silico methods to develop compound libraries the reader is referred to different chapters in this book and to authoritative reviews. " ... 

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