Skeletal diversity approaches

FIGURE 9.6 A skeletal diversity approach in small molecules library synthesis. 

Developing synthetic routes that provide skeletal diversity with multiple core scaffolds or backbone structures is an area of particular current interest. Several approaches to generating such multiscaffold libraries have been advanced. In one straightforward strategy, Schultz synthesized a 45 140-member library from multiple heterocyclic scaffolds, each having a set of functional groups in common [39]. The scaffolds were coupled as building blocks, which were then... 

The Diels-Alder reaction is particularly useful in DOS. Figure 1.4 shows two applications where natural product-like libraries with high skeletal diversity were obtained in two consecutive steps. The approach... 

Comer, E., Rohan, E., Deng, L., and Porco, J.A. (2007) An approach to skeletal diversity using functional group pairing of multifunctional scaffolds. Org. Lett, 9, 2123-2126. 

A number of examples such as 1,3-dioxanes, macrolactones, °° ring-containing biaryls, ° spirooxindoles, alkaloid-like compounds, and polycyclic compounds from the Schreiber group illustrate this approach to natural product-like libraries (see Chapter 11). An early example converted shikimic acid into intermediate tetracyclic y-butyrolactones, which were then functionalized around the core structure (see Chapter 11, Subsection 11.10.2). y-Butyrolactones, found in about 10% of all natural products and which exhibit a broad range of biological activities, are a key element in a number of recent natural product-like compounds. A more recent example, inspired by the rich skeletal diversity of indole alkaloids, utilized the rhodium(II)-catalyzed consecutive cyclization-cycloaddition reactions developed by Padwa and coworkers (Scheme 1.4). A stereocontrolled tandem reaction utilizing the versatile scaffold allowed for multiple modes of intramolecular reactions. 

Attanasi, O. A., Bartoccini, S., Favi, G., Giorgi, G., Pemilli, F. R., and Santeusanio, S. (2012a). Powerful approach to heterocyclic skeletal diversity by sequential three-component reaction of amines, isothiocyanates, and 1,2-diaza-l,3-dienes. J. Org. Chem., 77, 1161-1167. 

B. Maiti, CM. Sun, Novel approach towards the synthesis of skeletally diverse benzimidazole-pyrrolo[l,2-a]quinoxaline by Sf Ar/ Pictet-Spengler reaction under focused microwave irradiation. New J. Chem. 35 (2011) 1385-1396. 

Finally, scaffold diversity (Fig. 2c), probably the most important element of diversity, is the generation of a collection of products with different molecular skeletons (scaffolds). This can, for example, be realized by changing the reagents added to a common substrate (reagent-based approach) or by transforming a collection of substrates having suitable preencoded skeletal information with similar reaction conditions (substrate-based approach) [2, 10]. 

Schreiber and coworkers recently described a synthetic strategy using o elements, functionality that encodes skeletal information that can be transformed into products with different skeletons. The diversity-oriented synthetic approach, aimed at understanding the function of proteins has taken root in a number of laboratories around the world. DOS develops on what combinatorial chemistry initially sought to achieve. As previously indicated, DOS as a combinatorial approach to parallel synthesis expands the array diversity by increasing the number of stereoisomers per array and varying the number of core scaffolds per array. 

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