Diversity library, natural product-like

Nicolaou, K.C. Pfefferkom, J.A. Barluenga, S. Roecker, A.J. Cao, G.-Q. (2000C) Natural product-like combinatorial libraries based on privileged structures. 3. The libraries from libraries principle for diversity enhancement of benzopyran libraries. J. Am. Chem. Soc., 122, 968-76. 

After the advent of combinatorial chemistry and its lack of success, it was recognised that the combinatorial libraries lacked diversity. Hence, new approaches were applied to design compounds that allowed the introduction of many points of diversity, such as chiral centres to mimic natural products.6 These libraries are also called natural product-like libraries.7... 

The selection and quality of a screening library with drug-like and lead-like structures is a critical endeavour. The features of drug-like and lead-like structures continue to be better defined, at the same time as the diversity of drug-like and lead-like molecular space continues to be explored and categorised. Other areas of development focus on the discovery of small molecules suitable for modulating protein-protein interactions, with a greater focus on natural product-like compounds. 

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. 

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

The power of furan has long been appreciated in target-oriented synthesis and more recently in diversity-oriented synthesis. Schreiber has made elegant use of the embedded diversity in this heterocycle to build complex, natural product-like libraries <03SCI1613 04JA14095> (Scheme... 

S. Shang, D.S. Tan, Advancing chemistry and biology through diversity-oriented synthesis of natural product-like libraries, Curr. Opin. Chem. Biol. 2005, 9, 248-258. 

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. 

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... 

Metathesis cascades have underpinned the synthesis of diverse small molecule libraries.Metathesis is a superb pairing reaction for the build-couple-pair approach first, it can yield many dilferent ring systems and, second, alkenes (and alkynes) are compatible with the many reactions that may be used to connect building blocks. Metathesis has been used to prepare a library of natural product-like molecules (Scheme 1.7). Initially, unsaturated building blocks were attached iteratively to fluorous-tagged linker to yield metathesis precursors 20. Crucially, alternative attachment reactions were used such that the building blocks were connected through bonds that either did, or... 

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. 

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