Build/pair strategy

Fig. 7, Build/Pair strategy with Ugi-four-components reactions (Ugi-4CR) and their post-transformations. RCM ring dosure metathesis.

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. ... 

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. 

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. 

Much of the recent work on the use of anodic amide oxidation reactions has focused on the utility of these reactions for functionalizing amino acids and for synthesizing peptide mimetics [13]. For example, in work related to the cyclization strategy outlined in Scheme 3, the anodic amide oxidation reaction has been used to construct a pair of angiotensin-converting enzyme inhibitors [14]. The retrosynthetic analysis for this route is outlined in Scheme 4. In this work, the anodic oxidation reaction was used to functionalize either a proline or a pipercolic add derivative and then the resulting methoxylated amide used to construct the bicyclic core of the desired inhibitor. A similar approach has recently been utilized to construct 6,5-bicyclic lactam building blocks for... 

This strategy culminated in the synthesis of the racemic tricycle 282 as a pair of diastereomers that were separated by chromatography. The cyclopen-tenone 274 served as A-ring building block and the C-ring was synthesized utilizing a Diels-Alder reaction between 279 and 280 as the key step. 

Alternatively to the DNA modifications in the previous two sections where the chromophore was attached to one of the four DNA bases, chromophores can be incorporated as artificial DNA bases substituting a natural base or even a whole base-pair. There is a large number of recently reported syntheses of chromophores as DNA base surrogates, e.g. flavine derivatives [26] and thiazole orange derivatives [42]. Additionally, a variety of phosphoramidites as DNA building blocks for the introduction of fluorophores into DNA are commercially available, e.g. acridine derivatives. Clearly, the synthetic protocols for this kind of DNA modification do not follow a principle strategy which can be applied in a versatile fashion, as is the case for the DNA base modifications mentioned in the previous sections. It is important to point out that in many cases it turned out to be useful to replace the 2 -deoxyribose moiety with acyclic linker systems. This was also the case during our attempts to synthesize ethidium-modified DNA, which will be described here briefly. 

With the enantiomeric pair of 1 in hand, we examined the stereodivergent synthesis of a,a -disubstitued 3-piperidinol alkaloids. The basic strategy we used to prepare the building blocks (I-IV) from (-)-1 is presented in Figure 3. 

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