Scaffold-oriented synthesis

Schreiber and co-workers have shown that this approach is useful in the preparation of compound libraries. One of their examples is a diversity-oriented synthesis of polycyclic scaffolds through the Perrier reaction followed by the PKR of a glycal template on solid support (Equation (35)). 

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... 

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. 

Scheme 2 Diversity-oriented synthesis of highly complex scaffolds via Ugi-5C CR followed by ROM/RCM cyclizations and Diels-Alder reactions...

Attempts to extend this work to the keto-oxime substrate 54 derived from D-glucosamine with an JV-phthalimido group resulted in the formation of a completely different product (Scheme 40). In this case, cyclization was initiated by reduction of the phthalimido carbonyl group to its corresponding ketyl radical anion followed by cyclization onto the ketone, providing an a-hydroxylactam 55 which was proposed to be a potentially useful scaffold for diversity-oriented synthesis. 

A new approach termed Biology Oriented Synthesis (BIOS) has been developed recently by Waldmann et alf This approach is based on the structural similarity between small bioactive molecules on the one side and their receptors, that is proteins, on the other side as well as on the complementarity of both. BIOS employs compound classes from biologically relevant regions of chemical space, for example natural product or drug space, to select scaffolds as starting points for the design and synthesis of small focused libraries with limited diversity. In this respect BIOS provides a conceptual alternative to other approaches... 

Galanthamine is a natural alkaloid and a potent acetylcholinesterase inhibitor. Recognizing the potential to access this rigid polycyclic core through a biomimetic oxidative coupling/Michael addition, Shair and coworkers developed a highly efficient diversity-oriented synthesis based on this scaffold (Scheme 21.16) [96]. A library of 2527 compounds was prepared on the aforementioned macrobeads... 

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.) ...

Another relevant library-building concept that also emerged from the diversity of natural products assumes that such molecular scaffolds primarily hold the biological activity, and the side chains and functional groups only modify or fine-tune the interaction. Therefore, a new term was introduced by the Schreiber group, skeletal diversity (Kwon, Park, and Schreiber, 2002). Instead of increasing the overall structural diversity or dissimilarity, skeletal diversity is required in libraries involved in chemical genetics which can only be achieved by diversity-oriented synthesis (DOS) (Arya et al., 2005 Tan, 2005). 

Biology-Oriented Synthesis Biology-oriented s)mthesis (BIOS) is a synthetic design approach, which aims to expand the chemical space around scaffolds of natural origin. 

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. 

A flexible diversity-oriented synthesis (DOS) approach to a collection of tricyclic sultams is depicted in Scheme 2.21 [13f. The functionalized sultam scaffolds 52 and 55 embedding oxanorbornene units are readily derived by intramolecular Diels-Alder (IMDA) reactions. Domino ROM/RCM/CM transformations of these substrates using the Grubbs catalyst 2 with a set of co-olefins 53 gave rise to the desired heterocyclic systems 54 and 56, respectively, in good to very good yields. Interestingly, only one of the two epimers 55 participated in the RRM process. 

Scheme 14.8 Spring s diversity-oriented synthesis of polycyclic scaffolds via domino depro-tection/double conjugate addition/Dieckmann condensation.

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