Diversity-orientated 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. 

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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