Build/Couple/Pair

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]. 

This concept of introducing scaffold diversity by intramolecular cyclizations is nowadays commonly referred to as the build/couple/pair strategy, introduced by Schreiber in 2008 [42]. 

A second, very elegant, example of build/couple/pair strategy in DOS is performed by Schreiber and co-workers (Scheme 5) [51]. This example uses the Petasis reaction of (5)-lactol 42, L-phenylalanine methyl ester (43), and ( )-2-cyclopropylvinylboronic acid (44) as coupling reaction, which is followed by a... 

Products F and G were in turn substrates for subsequent pairing reactions to obtain multicyclic compounds J, N, K, O, and H. Finally, products B, J, and H, which all comprise a diene functionality could be further converted by a subsequent Diels-Alder (DA) reaction with 4-methyl-l,2,4-triazolin-3,5-dione to obtain the highly complex products I, M, and L. This example shows that by applying the build/couple/pair strategy a collection of 15 highly diverse (and complex) scaffolds can be obtained in only three to five steps. ... 

For more examples of the Build/Couple/Pair principle applied in DOS [52-54]. 

Domino Reactions in the Build-Couple-Pair Approach for Library Synthesis... 

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. 

Introducing Scaffold Diversity by Combining Building Blocks the Build-Couple-Pair Strategy... 

The scope of the approach is extremely broad and, indeed, some folding pathways e.g. Scheme 1.4 Section 1.2.3.1) and branching pathways e.g. Scheme 1.5 Section 1.2.3.2) can be considered to exemplify the build-couple-pair strategy. For example, the four component Petasis reaction illustrated in Scheme 1.4 allowed simple building blocks to be combined complementary cyclisation reactions were then use to pair functional groups to yield a diverse range of product scalfolds. 

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... 

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. 

After the build process the diversity potential can be enriched by adding a new fragment with functionalities which offer new pairing combinations with existing functional groups (Couple). An illustration of this Build/Couple/Pair strategy is shown in Fig. 8(57). 

Fig. 8. Build/Couple/Pair strategy to expand 3D shape diversity.

An aldol-based Build/Couple/Pair strategy has recently been applied for the discovery of new histone deacetylase inhibitors (58). 

Marcaurelle LA, Comer E, Dandapani S et al (2010) An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings Discovery of Macrocyclic Histone Deacetylase Inhibitors. J Am Chem Soc 132 16962-16976... 

The above work by Oguri and Schreiber can be considered to be an example of the build/ couple/pair strategy as the initial building blocks A, B, and C must first be built, then coupled to the piperidinone template, and finally the reactive functionality paired inlramolecularly to yield the products. Another example of the build/couple/pair strategy incorporating a folding pathway can be found in the work of Mitchell and Shaw (Scheme 4.6). ... 

A particularly elegant example of the build/couple/pair strategy combined with reagent-based skeletal diversity construction can be found in the solution-phase work carried out by Comer et al. (Scheme A.l) Their strategy involved the synthesis of a number of substituted p-nitrostyrenes and alkylated 1,3-dicarbonyls in the build phase that were then coupled by enantioselective Michael addition of the dicarbonyls to the p-ni-trostyrenes using a cinchona alkaloid-derived organocatalyst to give densely functionalized molecules such as 27 and 28. 

Build/couple/pair strategy - Rich in heteroatoms - Suitable for SAR analysis... 

SCHEME 15.18 The concept of Build/Couple/Pair strategy in DOS. 

SCHEME 15.19 Build/Couple/Pair DOS synthesis using a Petasis 3-CR. 

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