Synthesis diversity-oriented

Diversity-oriented synthesis Biology-oriented synthesis Diverted total synthesis 

FIGURE 15.4 Characteristic features of the strategies used for hbrary design of biologically active compounds. 

Diversity-oriented synthesis (DOS) has been defined by Schreiber as the opposite to target-oriented synthesis (TOS) 

SCHEME 15.18 The concept of Build/Couple/Pair strategy in DOS. 

In order to access greater structural diversity as available from standard library synthesis with a common scaffold, efforts have been focused on diversity-oriented synthesis (DOS) from a common starting point [64]. Usually, a single common scaffold defines a library. The stereochemistry of this scaffold is often kept constant, and the molecular framework is the same within a library as well [65]. In addition, compounds with a higher structural complexity [66] similar to the complexity of many natural products would be desirable [67]. 

The field should still be considered in its infancy [46] and DOS libraries are usually small [69]. It is up for discussion if the DOS concept still refers to the preparation of single libraries or rather sets of libraries, as not all final compounds will be prepared in a truly parallel fashion [70]. For example, the synthesis of two different types of tetracyclic products from a common precursor is 

3 Generation of New Screening Compounds l09 Diversity-oriented synthesis 

If the effort of finding suitable templates and synthetic routes is greater than the synergistic advantage the concept presents, it may be more efficient to design sets of libraries instead, which in the best case would not share any part of the synthetic scheme at all. An intermediate approach would be to design and synthesize libraries from libraries, that is, the design of several compound libraries in parallel and interdependent fashion in order to increase structural diversity [72]. 

Kieron M. G. O Connell, Warren R. J. D Galloway, Brett M. Ibbeson, Albert Isidro-Llobet, Cornelius J. O Connor, and David R. Spring 

The ability of small molecules to interact with biological macromolecules such as proteins in a selective, often reversible, and dose-dependent manner, and to exert specific effects, has led to them being regarded as powerful tools for the study of biological systems. The use of small molecules in this manner to selectively perturb biological function underpins the whole of medicinal chemistry as well as forming the basis for the field of chemical genetics.  

Solid-Phase Organic Synthesis Concepts, Strategies, and Applications, First Edition. Edited by Patrick H. Toy and Yulin Lam. 

With the advent of combinatorial chemistry in the 1990s, their came the use of split-pool techniques that, when combined with advances in automation, made possible the efficient synthesis of literally millions of compounds. These libraries, however, were generally made up of broadly similar structures, with any variation between molecules resulting from appendage alteration of building blocks assembled around a common scaffold. Libraries of this sort have had limited success in the discovery of novel biologically active agents, a fact that is mainly attributed to the relative lack of diversity within the libraries. Therefore, it is believed that the quality, in terms of structural complexity and diversity, of these libraries is as important, if not more so, than the number of the compounds synthesized.  

Many proprietary and commercially available libraries are synthesized in this combinatorial fashion and so suffer from these limitations. Another criticism of these libraries is that they may be too heavily biased toward certain predefined criteria such as the Lipinski rule of 5. ° These rules for bioavailability have proved very useful in drug discovery however, they may be unnecessarily limiting when it comes to the discovery of ligands for novel biological targets such as protein-protein interactions. Despite these limitations, many of the principles of combinatorial chemistry are shared by DOS. 

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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%).

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... 

Rev. 1996, 96, 555-560 for a new one-bead, one-stock solution technology platform, see (b) An Alkylsilyl-Tethered, High-Capacity Solid Support Amenable to Diversity-Oriented Synthesis for One-... 

Strategies for Total and Diversity-Oriented Synthesis of Natural Product(-Like) Macrocycles... 

Keywords Macrocycles Natural products Diversity-oriented synthesis ... 

Burkholderia cepacia lipase (Amano PS) 2,2 -Bis(diphenylphosphino)-1,1 -binaphthyl Candida antarctica lipase B Diversity-oriented synthesis... 

Aldol reactions have also been used as a means of macrocychzation in total synthesis and were quite successful in some cases. However, over a broader spectrum of substrates, the results are unpredictable at best and yields and stereochemical outcome vary greatly. The predominant reasons are difficulties in selective enolate formation in multi-carbonyl compounds, competing and equilibrating retro-aldolizations—especially with polyketides, which often possess several aldol moieties—and intermolecular instead of intramolecular reaction preference. Whereas most of these drawbacks may be overcome, substrate-independent stereocontrol plays a crucial role. At least one new stereocenter is formed during a macroaldolization, and because of the folding constraints involved, its configuration cannot be adequately predicted. Therefore, this can be useful in special cases but with the current possibilities is not the method of choice for a general diversity-oriented synthesis. 

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. 

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

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