Scaffolds natural product-like

Soldi AM. Libraries from natural product-like scaffolds. Curr Opin Chem Biol 2004 8 281-6. 

Fig. 9 Solid phase DOS of partially "natural product-like" compounds by modification of a tricyclic scaffold...

Boldi AM. (2004) Libraries from natural products-like scaffolds. Curr. Opin. Chem. Biol. 8 281-286. 

The utility of the privileged structure concept is illustrated by compound library synthesis based on the indole scaffold and the biologically active compounds resulting from that. The indole scaffold is found in natural products, like for example, the neurotransmitter serotonin (5-hydoxytriptamine, 5-HT) and in well-know drugs, like for example, the... 

Several attempts have also been reported to integrate natural products and combinatorial synthesis, either by using natural products as scaffolds for combinatorial modification or by building libraries of natural product-like... 

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. 

Fig. 17.13 The use oftetrahydroaminoquinoline and aminoindoline scaffolds in the library generation of natural product-like compounds and in silico testing of these two libraries as small molecule binders to Bcl-2/Bcl-XL...

In the preceding section, we have seen the value of natural products in dmg discovery and development. Now that we have a better understanding of the complementarity between natural products and synthetic chemistry, can we design new scaffolds that lean towards the former Compared to classical skeletons favoured by medicinal chemists, the newer natural product-like scaffolds incorporate a high degree of... 

Thus, DOS of natural product-like libraries is a major area of current interest. Library design strategies have been divided into three general categories, according to the degree of structural similarity to natural products [34,35] (a) Libraries based on the core scaffold of an individual natural product,... 

Natural products are generally complex chemical structures, whether they are cyclic peptides like cyclosporin A, or complex diterpenes like paclitaxel. Inspection of the structures that are discussed in Section IV is usually enough to convince any skeptic that few of them would have been discovered without application of natural products chemistry. Recognition of this structural diversity has certainly made an impact on the design of combinatorial strategies, as exemplified by the 2 million plus compound library that was recently assembled by the Schreiber group using natural product-like structures as the initial scaffolds. 

Daniel, M., Stuart, L., Christopher, C., Stuart, W., and Adam, N. 2009. Synthesis of natural-product-like molecules with over eighty distinct scaffolds. Angew. Chem. hit. Ed. Engl. 48 104-109. 

Scheme 1.7 Synthesis of natural product-like molecules with unprecedented scaffold diversity. Initially, building blocks were added iteratively to a fluorous-tagged linker, with intermediates purified by fluorous-solid phase extraction. Metathesis cascades were used to reprogramme the scaffolds and to release final products from the fluorous-tagged linker. Reagents and conditions. (1) Grubbs first-generation catalyst, 21a 23% 21b 56% (2) fluorous-tagged Hoveyda-Grubbs second-generation eatalyst, 21c 33%.

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. 

Kulkarni, B.A. et al.. Combinatorial synthesis of natural product-like molecules using a first-generation spiroketal scaffold, J. Comb. Chem., 4, 56, 2002. 

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