Compound natural product-like

Both chiral lactones and ketones have been utilized in asymmetric synthesis of bioactive compounds like lipoic acid [175[ and natural products like various insect pheromones [176[. 

The application of chiral auxiliaries is an alternative route to obtain enantiomerically pure compounds. This approach has been frequently used in the total syntheses of natural products like hirsutene [53] and (+)-15-norpentalene [61]. 

Ertl P, Roggo S, Schuffenhauer A. (2008) Natural product-likeness score and its application for prioritization of compound hbraries. J Chem Inf Model 48 68-74. 

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. 

Solid phase DOS of natural product-like molecules in many cases concerns polycyclic compounds, but macrocycles have also been reported [4j. In some cases, it is difficult to draw a line between DOS and simple derivati-... 

Fig. 9 Solid phase DOS of partially "natural product-like" compounds by modification of a tricyclic scaffold...

The utility of the privileged structure concept is illustrated by compound library synthesis based on the indole scaffold and the biologically active compounds resulting from that. The indole scaffold is found in natural products, like for example, the neurotransmitter serotonin (5-hydoxytriptamine, 5-HT) and in well-know drugs, like for example, the... 

The formation of /3-hydroxyselenides through the reaction of a selenium-stabilized carbanion with carbonyl compounds has been extensively used also in the context of natural product synthesis. The phenylselenoalkyllithium compound 115 was reacted with aldehyde 116 to afford /3-hydroxyselenide 117. In a radical cyclization cascade the tricyclic molecule 118 was generated in good yields and subsequent transformations led to the synthesis of pentalenene 119 (Scheme 28).1 9 Also other natural products like zizaene and khusimone have been synthesized via a similar route.200... 

After the advent of combinatorial chemistry and its lack of success, it was recognised that the combinatorial libraries lacked diversity. Hence, new approaches were applied to design compounds that allowed the introduction of many points of diversity, such as chiral centres to mimic natural products.6 These libraries are also called natural product-like libraries.7... 

The selection and quality of a screening library with drug-like and lead-like structures is a critical endeavour. The features of drug-like and lead-like structures continue to be better defined, at the same time as the diversity of drug-like and lead-like molecular space continues to be explored and categorised. Other areas of development focus on the discovery of small molecules suitable for modulating protein-protein interactions, with a greater focus on natural product-like compounds. 

Seitz M, Reiser O (2005) Synthetic approaches towards structurally diverse y-butyrolactone natural-product-like compounds. Curr Opin Chem Biol 9 285-292... 

The first part of the chapter covers several examples of stereoselective solution and solid-phase approaches to obtaining natural product analogs. The examples discussed here represent focused strategies to library generation that are based on specific bioactive natural products. These libraries have often served as natural product analogs in searches for better biological responses than those exhibited by the parent natural products. The generation of libraries of natural product-like compounds by solution and solid-phase synthesis methods is discussed in the second half. 

Here, we cover several examples that included stereoselective diversity-oriented synthesis approaches. The examples covered in this section are indicative of the growing interest in this area and of the need for developing novel approaches leading to fast access to obtaining natural product-like compounds to be used as small-molecule probes. 

Fig. 17.13 The use oftetrahydroaminoquinoline and aminoindoline scaffolds in the library generation of natural product-like compounds and in silico testing of these two libraries as small molecule binders to Bcl-2/Bcl-XL...

Arya P, Joseph R, Chou DTH. Toward high-throughput synthesis of complex natural product-like compounds in the genomics and proteomics age. Chem. Biol. 2002 9 145-156. 

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