Scaffold diversity synthesis

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

Scaffold Diversity Synthesis with Branching Cascades Strategy... 

Chemical/Biological Evaluation - Branching Cascades Strategy in Scaffold Diversity Synthesis 399... 

Scheme 27.4 Mechanistic insights into diverse cascade directing scaffold diversity synthesis.

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. 

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. 

Ideally, a DOS should address all four of the principal types of structural diversity mentioned previously. However, the ideal synthesis of a structurally diverse small molecule collection is one in which the diversity is achieved in the most efficient manner possible [1]. As alluded to previously, it is the scaffold diversity of the library that is the key parameter in this regard. It is generally acknowledged... 

Towards drugging the undrug-gable enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis. Divers. Oriented Synth., 1, 21-28. 

Scaffold diversity is an important parameter to characterize any compound collection. Organic synthesis is expected to provide efficient approaches to create three-dimensionally complex and structurally diverse small molecules. Branching pathways in DOS is an elegant approach to access scaffold diversity that could lead to small, yet diverse, focused compound libraries. Branching cascades strategy has successfully demonstrated the power and application of cascade or domino reactions in compound collection synthesis to build rapidly complex scaffolds for library synthesis. Further synthesis endeavors toward branching pathways... 

The reagent-based approach or branching pathways in diversity synthesis exploits different functional or reactive sites of a common substrate to yield diverse scaffold... 

Reagent-based and substrate-based approaches can also be combined in a single two-directional synthesis in which different symmetrical substrates can be used under different reaction conditions to achieve predictable scaffold diversity [23]. In an example by Spring et al, two domino reactions were used to synthesize polycyclic alkaloids from a common substrate 147. A Boc-removal/bicyclization process using AlClj as Lewis acid from 147 was used to produce 5-5, 5-6, and 6-6 bicyclic compounds (148-153), and a domino Michael addition/Dieckmann process/Michael addition reaction yielded 6-6-6, 6-6-5 tricyclic compounds (154-156). The 6-5-5 tricyclic scaffold 156 could not be synthesized by means of the same domino... 

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. 

Synthesis of Compound Libraries with High Scaffold Diversity... 

Scheme 1.7 Synthesis of natural product-like molecules with unprecedented scaffold diversity. Initially, building blocks were added iteratively to a fluorous-tagged linker, with intermediates purified by fluorous-solid phase extraction. Metathesis cascades were used to reprogramme the scaffolds and to release final products from the fluorous-tagged linker. Reagents and conditions. (1) Grubbs first-generation catalyst, 21a 23% 21b 56% (2) fluorous-tagged Hoveyda-Grubbs second-generation eatalyst, 21c 33%.

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