Oriented Synthesis

CHAPTER 9 Biology Oriented Synthesis and Diversity Oriented Synthesis in Compound Collection Development 

In this chapter, we address two complimentary approaches to componnd collection development namely, Diversity Oriented Synthesis (DOS) and Biology Oriented Synthesis (BIOS). For additional, very well-validated approaches snch as fragment-based design and the application of in silico methods to develop compound libraries the reader is referred to different chapters in this book and to authoritative reviews.  

Complexity and diversity are important characteristics of a library or compound collection as the eventual target of a compound in phenotypic screens can be any one of a multitude of diverse and complex proteins inside a cell. Therefore, the overall design of the synthetic pathways in DOS should integrate both complexity and diversity. Structural complexity can, for instance, be generated in DOS through the use of tandem or domino reactions, processes involving a pair of 

DOS takes its origins from combinatorial chemistry efforts that mainly employed increasingly sophisticated organic transformations. These efforts began with a 

FIGURE 9.1 Comparison of TOS and DOS. (Reproduced, with permission from The Thomson Corporation from Thomas, G. L., Wyatt, E. E., Spring, D. R. Enriching chemical space with diversity-oriented synthesis. Curr. Opin. Drug Discov. Dev. 2006), 9(6), 700-712. Copyright 2005, The Thomson Corporation.) 

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On the other hand, it has also become clear that a materials-oriented synthesis of conjugated poly(phenylene)s cannot narrow its attention to properties of molecules only in solution, but has to include aspects of processing and supramolecu-lar ordering as well. The rigid-rod character of PPPs therefore suggests the use of chain stiffness as a structure-forming principle in the design of supramolecular motifs. 

The total synthesis of palytoxin (1) is a landmark scientific achievement. It not only extended the frontiers of target-oriented synthesis in terms of the size and complexity of the molecules, but also led to new discoveries and developments in the areas of synthetic methodology and conformational analysis. Among the most useful synthetic developments to emerge from this synthesis include the refinement of the NiCh/CrC -mediated coupling reaction between iodoolefins and aldehydes, the improvements and modifications of Suzuki s palladium-catalyzed diene synthesis, and the synthesis of A-acyl vinylogous ureas. 

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. 

Wessjohann LA, Ruijter E (2005) Strategies for Total and Diversity-Oriented Synthesis of Natural Product(-Like) Macrocycles. 243 137-184 Wiesler U-M,Weil T, Mullen K (2001) Nanosized Polyphenylene Dendrimers.212 1-40 Williams P, see Chhabra SR (2005) 240 279-315... 

Scheme 4.7 An example diversity-oriented synthesis strategy (taken from reference [48]).

An example diversity-oriented synthesis strategy as shown in Scheme 4.14 illustrates how complex targets can be quickly synthesized from smaller molecules via combinations of... 

Scheme 4.14 Schreiber diversity-oriented synthesis plan (2000). (a) MeOH/THF, heat (57%) (b) 2KN(SiMe3)2, 2 CH2=CH2 Br (89%) (c) Grubbs catalyst (59%) (d) HF, pyridine (95%).

Table 4.14 Summary of reaction metrics and synthesis tree parameters for divers (DOS) plan example ranked according to overall kernel (maximum) RME. iity-oriented synthesis ...

The term biology-oriented synthesis (BIOS) [45] has been used to describe the design of compound libraries based on biologically relevant chemical space [46]. The areas in protein structures that participate in productive protein-ligand interactions have been, for the most part, already defined by natural products and drugs. Thus libraries inspired by natural products and other bioactive molecules are expected to have a higher probability of biologically activity than randomly synthesized molecules [47,48]. 

L. D. S. Yadav, V. P. Srivastava, V. K. Rai, and R. Patel, Diversity oriented synthesis of fused-ring 1, 3-oxazines from carbohydrates as biorenewable feedstocks, Tetrahedron, 64 (2008) 4246-4253. 

Currently, these reactions are typically conducted with Rh(l) or Ir catalysts. The Pauson-Khand-type reaction of allenynes has also witnessed important developments, especially in its applications to natural products synthesis.388 Brummond s group has been very productive in both areas. Duality in the reaction of allenynes is shown below. In the context of diversity-oriented synthesis, simply changing the reaction conditions gives versatile heterocycles in high yields (Scheme 116).389... 

In this review, an attempt is made to exhaustively catalog the rapidly growing subset of metal-catalyzed reductive C-C bond formations comprising the hydrometallative and hydrogenative carbocyclization of 7t-unsaturated substrates, and application of these methods in target-oriented synthesis. Content is organized on the basis of reaction... 

For a review on asymmetric catalysis in target-oriented synthesis, see A. H. Hoveyda, Stimulating Topics in Organic Chemistry (Eds. F. Vogtle, J. F. Stoddart, M. Shibasaki), Wiley-... 

Hoveyda in his essay on asymmetric catalysis in target-oriented synthesis (p 145). The concept of catalysis-based total synthesis, in which a series of catalytic enantioselective reactions are employed in combination with other catalytic reactions, is emerging as the desirable way to make complex natural products and medidnally-important target compounds. 

There are few transformations that can, in a single stroke, provide the structural and stereochemical complexities that are attained through a Diels-Alder cydoaddition. It is little surprise then that numerous studies have appeared in the past decade that aim to develop a catalytic asymmetric Diels-Alder process. It is only in a few instances, however, that these catalytic asymmetric protocols have been applied to target-oriented synthesis. Several impres-... 

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