Scaffold diversity

Combinatorial Synthesis of Natural Product-Based Libraries 

FIGURE 2.2 The biosynthesis of terpenoids provides an excellent example of achieving skeletal diversity. The single precnrsor famesyl pyrophosphate gives rise to all sesquiterpenoids. Only five of the many known sesquiterpenoid ring skeletons are Ulnstrated here. 

---

Fig. 17 Selected examples for scaffold diversity obtained by the trisubstituted oxazole MCR followed by intramolecular tandem processes...

Grabowski, ., Baringhaus, . -H., Schneider, G. (2008) Scaffold diversity of natural products inspiration for combinatorial library design. Nat Prod Rep 25, 892-904. 

Todorov, N. P., Dean, R. M. (1997) Evaluation of a method for controlling molecular scaffold diversity in de novo ligand design. J Comput Aided Mol Des 11, 175-192. 

Viewing secondary metabolites from a chemical perspective, the scaffold diversity and polyfunctional features offer significant potential to generate random libraries for screening purposes. The structural status of a compound on this level is, therefore, a transition state with the goal to become a hit or a lead for further development (Table 7.2). Various automatic chromatographic separation techniques and modern spectroscopic methodologies can... 

Contributions by R. Joseph and P. Arya as well as M. A. Koch and H. Waldmann focus on synthetic aspects towards lead structures originating from natural product-derived scaffolds. R. Joseph and P. Arya refer to two complementary approaches, the synthetic access to focussed libraries around bioactive natural product cores, and diversity-oriented synthesis aiming at 3D scaffold diversity for hit generation, respectively. On the other hand, M. A. Koch and H. Waldmann emphasise the correlation of natural product-based library concepts with structural features of targeted protein domains, thus strengthening the privileged structure concept from a bioorganic viewpoint. 

Abstract In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity. 

Keywords Complexity Diversity oriented synthesis Multicomponent reactions Scaffold diversity Synthesis... 

Novel Multicomponent Strategies Towards Scaffold Diversity.107... 

Molecular complexity (generally found in natural products) seems to be extremely important to obtain an optimal perturbation function and specificity of action of the chemical modulators on their protein targets [2, 9]. The goal of achieving molecular diversity can be divided in three different diversity elements (a) appendage diversity (combinatorial chemistry), (b) stereochemical diversity, and most importantly (c) scaffold diversity (Fig. 2) [2]. 

Finally, scaffold diversity (Fig. 2c), probably the most important element of diversity, is the generation of a collection of products with different molecular skeletons (scaffolds). This can, for example, be realized by changing the reagents added to a common substrate (reagent-based approach) or by transforming a collection of substrates having suitable preencoded skeletal information with similar reaction conditions (substrate-based approach) [2, 10]. 

As already became clear from the previous examples, MCRs are ideal to obtain complex products in an easy way. However, DOS also requires molecular diversity (appendage, stereochemical and scaffold diversity), which can also be accomplished using MCRs. 

Regarding scaffold diversity it is evident that any single MCR does not lead to multiple scaffolds, since ideally, three or more components combine to form a single product (one of the criteria for MCRs). As a result several research groups have introduced scaffold diversity by combining MCRs with cychzation reactions, as illustrated in Fig. 5 [40, 41]. 

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]. 

Fig. 5 The generation of scaffold diversity, by combining MCRs with cyclization reactions ...

Scheme 4 The intro(ductioii of scaffold diversity by the Ugi-4CR (couple) and follow-up cyclization reactions (pair)...

From the previous examples it is clear that scaffold diversity can be achieved using MCRs and post condensation cyclizations. However, during the last decade much work has also been devoted to obtain scaffold diversity by using MCR strategies exclusively. Besides scaffold diversity, this has also lead to the development of a number of novel MCRs. These new multicomponent design strategies, to achieve scaffold diversity, can be divided into four main approaches ... 

The SRR strategy (Fig. 6), a phrase first introduced by Ganem, involves the development of new MCRs by systematic assessment of the mechanistic or functional role of each component in a known MCR [55]. In this method one reactant (C) is substituted for reactant (D) that displays a similar chemical reactivity mode required for condensation with A and B. By incorporation of an additional reactivity or functionality into D, the resulting MCR might be directed to a different outcome, leading to scaffold diversity [55]. 

Fig. 6 Schematic representation of the single reactant replacement (SRR) strategy to scaffold diversity...

The second MCR development strategy leading to scaffold diversity involves MRS (Fig. 7), which is closely related to SRR but involves a versatile reactive intermediate that is generated from substrates A, B, and C by an initial MCR. This intermediate is then reacted in situ with a range of final differentiating components (D, E and F) to yield a diverse set of scaffolds. 

One striking example is the use of 1-azadiene 92 as intermediate to scaffold diversity which is generated in situ from a phosphonate 89, a nitrile 90 and an aldehyde 91 via a 3CR involving a Homer-Wadsworth-Emmons (HWE) reaction (Scheme 9) [77, 78]. 

In summary, MRS have proven to be extremely useful for the fast generation of scaffold diversity. It can be argued that these example belong to the SRR strategy. However, since the intermediate is formed by a MCR, we have divided this as a... 

In conclusion, the CBD approach makes it possible to obtain scaffold diversity starting from the same reaction inputs by adapting the temperature, reaction promoter or solvent. 

In 2009, our group demonstrated that the MCR strategy can also be used to obtain complexity as well as scaffold diversity (Scheme 17) [103]. The strategy is based on the abovementioned 3CR to 2//-2-imidazolines (reacting an isocyano ester, aldehyde or ketone and an amine) that shows extraordinary FG and solvent compatibility [96]. By incorporation of a second orthogonally reactive group in one of the starting materials, this MCR can be coupled to a second MCR. 

The possibility of obtaining scaffold diversity by the MCR strategy has been further demonstrated using the M-(cyanomethyl)amide 3CR [60] (discussed earlier) as the primary MCR [103]. By applying the primary a-isocyano amide derivative of 176, this MCR could be connected to the Passerini, the Ugi and the Ugi Smiles [106, 107] MCRs resulting in various new scaffolds. 

Diversity-oriented synthesis of small molecules is a great challenge for synthetic organic chemists. DOS requires the development of new methodologies that generate scaffold diversity in addition to appendage and stereochemical diversity. 

W.H.B. Sauer and M.K. Schwarz, Size doesn t matter scaffold diversity, shape diversity and biological activity of combinatorial libraries, Chimia, 2003, 57(5), 276. 

Commercial screening libraries Range from low scaffold diversity (e.g., combinatorial libraries) to high diversity. 100s to > 100 K Used widely in academia. 21... 

Nielsen, T. E., Meldal, M. Solid-Phase Intramolecular N-Acyliminium Pictet-Spengler Reactions as Crossroads to Scaffold Diversity. J. Org. Chem. 2004, 69, 3765-3773. 

---