Compound libraries stereochemical diversity

The diversity of chemical libraries may derive from the high substitutional, stereochemical and scaffold diversity of its members. Combinatorial chemistry is focused on the synthesis of chemical libraries with only high substitutional diversity. In general, combinatorial syntheses exploit a rather limited palette of chemical transformations to vary the substitution of library members. The synthesis of compound libraries with high substitutional diversity is described in Section 1.2.1. 

Varying the configuration of library members is more challenging, but has been hugely facilitated by the many reliable asymmetric transformations that have been developed in the past 30 years. In many cases, the high enantio-selectivity of these transformations can dominate over substrate-based dia-stereoselectivity, and allow the configuration of compounds to be varied systematically. The synthesis of a compound library with both high substitutional and stereochemical diversity is described in Section 1.2.2. 

Synthesis of Compound Libraries with High Stereochemical Diversity... 

Spiroketals consist of a ring with an endocyclic oxygen that could be a furanose or pyranose, whereas chromans and isochromans need a pyranose as core structure to which a benzene is attached. Such an approach is particularly attractive since about half of the anticipated molecules are directly derived from a natural carbon source. In addition, the sugar commonly bears several residues such as hydroxyl groups that are available in different stereoisomers paving the way for a facile access to a plethora of structurally similar, but stereochemically diverse compounds. Such a strategy is ideally suited for the development and generation of compound libraries. 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

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