Combinatorial diversity-oriented synthesis

Centerpieces of combinatorial concepts include the synthesis of compound libraries instead of the preparation of single target compounds. Library synthesis is supplemented by approaches to optimize the diversity of a compound collection (diversity-oriented synthesis) and by efforts to create powerful interfaces between combinatorial synthesis and bioassays. 

The term diversity-oriented synthesis (DOS) is relatively new and, as mentioned above, is usually defined as the synthesis of complex, natural product-like molecules using a combinatorial approach and employing the full palette of modern organic reactions. It may be a subject of discussion what exactly qualifies a molecule as being natural product-like [4], and in most cases the similarity to an actual natural product seems reciprocal to the number of synthesized compounds. However, even in less complex cases, the products may be highly substituted polycyclic structures with defined stereochemistry, reminiscent of natural products [19, 20]. In these cases, a moderately complex backbone structure is subsequently modified with a well-established set of selective reactions to introduce diversity. 

Gerencser J, Dorman G, Darvas F (2006) Meldrum s acid in multicomponent reactions applications to combinatorial and diversity-oriented synthesis. QSAR Comb Sci 25 439 48... 

One of the major innovations in combinatorial and medicinal chemistry in recent years aiming at efficient diversity-oriented synthesis has been the implementation of polymer reagents in polymer-assisted solution phase (PASP) synthesis. This contribution will present—following an introduction to the field—a concept of advanced polymer reagents based on reactive intermediates and active reactants that should extend the scope PASP synthesis significantly. Experimental procedures describing preparation and use of the novel polymer reagents are included. 

Diversity-oriented Synthesis of Chromophores by Combinatorial Strategies and Multi-component Reactions"... 

Metathesis is inherently flexible. As a result, this transformation allows, inter alia, for a rapid chemistry-driven evaluation of structure/activity profiles and qualifies for applications in combinatorial and diversity oriented synthesis this is particularly true when combined with suitable post-metathesis transformations exploiting diverse alkene reactivity. 

Muller TJJ (2007) Diversity-oriented synthesis of chromophores by combinatorial strategies and multi-component reactions. In Muller TJJ, Bunz UHF (eds) Functional organic materials. Syntheses, strategies, and applications. Wiley-VCH GmbH KGaA, Weinheim, pp 179-223... 

Fig. 1 Representation of (a) target oriented synthesis (TOS), (b) combinatorial chemistry and (c) diversity oriented synthesis (DOS) in chemical space [2]...

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). 

Borman, S. Rescuing combichem. Diversity-oriented synthesis (DOS) aims to pick up where traditional combinatorial chemistry left off. Chem. Eng. News 2004, S2(40), 32-40. 

Fig. 9.1-3 Early efforts in diversity-oriented synthesis of combinatorial libraries. 

DOS—Diversity-oriented synthesis Synthesis planning from a common set of starting materials to mnltiple target products linked to construction of compound libraries in a combinatorial sense. 

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