Synthetic diversity-oriented 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. 

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. 

Most commonly, a commercial library, containing a subset of compounds that matches a desired set of properties (if known), is screened in an initial study. Once hits are obtained and verified, a small library of compounds is synthesized to produce a set of compounds in the same chemical-stmctural space as the original hit stmcture. This process allows for hits with higher potency and elucidates information of the structure-activity relationship within the system of interest. Such synthetic libraries of chemically diverse compounds have been made possible through combinatorial chemistry (52-56) and diversity-oriented synthesis (52). 

Spring, D. R. Diversity-oriented synthesis a challenge for synthetic chemists. Org. Biomol. Chem. 2003,1, 3867—3870. 

Figure 6.28 Some different scaffolds prepared through diversity oriented synthesis (DOS). (Taylor, S. J. et al. Synthetic strategy toward skeletal diversity via solid-supported, otherwise unstable reactive intermediates. Angew. Chem. Int. Ed. Engl. 2004, 43, 1681-1685.) ...

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. 

Diversity-oriented synthesis (DOS) was defined by Schreiber in 2000 [34]. He referred to synthetic processes that contain only a few steps ( 3-5) and are planned with a forward... 

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