Scaffold build-couple-pair approach

Functionalized sugars and amino acids have been used to create unique morpholine scaffolds which were further elaborated to create a second generation of morpholino derivatives following the precepts of the build/couple/pair approach [73]. 

In the build-couple-pair approach to library synthesis, the building blocks are first synthesized from commercial material (build phase), which are then coupled to form a substrate (couple phase) that can further react under certain conditions and pair itself intramolecularly to form the cyclic products depicting the scaffold framework [24]. It is in the last two steps that the domino reaction can intervene to yield a more complex scaffold and with higher ring diversity. 

The build-couple-pair is an extremely powerful and flexible approach for preparing small molecule libraries based on a diverse range of scaffolds. The approach is highly general, and many different reactions have been used to connect ( couple ) building blocks. Variants of the Ugi multi-component reaction are, however, still over-represented amongst the reactions that have been used to connect building blocks. 

A wide range of other reactions have been exploited in the final cyclisation ( pairing ) step in addition to the examples illustrated here, lactamisa-tions, metal-catalysed cyclisations and cycloadditions have, for example, been exploited to yield final product scaffolds. At its most powerful, the build-couple-pair strategy can allow the combinatorial variation of the scaffolds of small molecules. However, a significant challenge will be to identify reactions other than olefin metathesis that have the broad scope and chemoselectivity needed to yield scores of different ring systems. It is certainly possible that the overall approach may, in the future, be used to prepare small molecule libraries based on hundreds, or even thousands, of distinct molecular scaffolds. 

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