Natural-product-like molecules

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-... 

The discovery of PKSs has led to the emergence of new horizons for the engineered biosynthesis of complex natural product-like molecules. The goals of this chapter are twofold. First, we will summarize our understanding of these systems at a molecular level, and the techniques that have emerged to dissect and manipulate these systems. Second, we will present selected examples of how PKSs can be engineered to synthesize novel biomolecules, and the pharmacological implications of such manipulation. Hopefully it will become clear that, al-... 

Daniel, M., Stuart, L., Christopher, C., Stuart, W., and Adam, N. 2009. Synthesis of natural-product-like molecules with over eighty distinct scaffolds. Angew. Chem. hit. Ed. Engl. 48 104-109. 

Metathesis cascades have underpinned the synthesis of diverse small molecule libraries.Metathesis is a superb pairing reaction for the build-couple-pair approach first, it can yield many dilferent ring systems and, second, alkenes (and alkynes) are compatible with the many reactions that may be used to connect building blocks. Metathesis has been used to prepare a library of natural product-like molecules (Scheme 1.7). Initially, unsaturated building blocks were attached iteratively to fluorous-tagged linker to yield metathesis precursors 20. Crucially, alternative attachment reactions were used such that the building blocks were connected through bonds that either did, or... 

Scheme 1.7 Synthesis of natural product-like molecules with unprecedented scaffold diversity. Initially, building blocks were added iteratively to a fluorous-tagged linker, with intermediates purified by fluorous-solid phase extraction. Metathesis cascades were used to reprogramme the scaffolds and to release final products from the fluorous-tagged linker. Reagents and conditions. (1) Grubbs first-generation catalyst, 21a 23% 21b 56% (2) fluorous-tagged Hoveyda-Grubbs second-generation eatalyst, 21c 33%.

Kulkarni, B.A. et al.. Combinatorial synthesis of natural product-like molecules using a first-generation spiroketal scaffold, J. Comb. Chem., 4, 56, 2002. 

Cephalotaxines are important alkaloids having antileukemic properties and some of the members of the family are under clinical trial phases for further development. The family of natural products has inspired the synthesis of natural product-like molecules. Riva and coworkers [41] have developed a quick access to the tricyclic core skeleton of cephalotaxines based on a clever combination of Ugi-4-C with two postcondensation palladium-catalyzed transformations carried out in a one-pot manner. Thus, the Ugi-4-C product on palladium-catalyzed amination followed by a second catalyzed intramolecular Heck cyclization under MW assistance of the resulting vinyl pyrrolidine derivative 42 led access to the tricyclic azepine derivative 43 (Scheme 6). It is interesting to note that tire major product of the Heck cyclization was the desired 7-exo isomer. 

Endothall is a structural analogue of cantharidin (Fig. 20). Its mode of action is apparently inhibition of protein phosphatase(s). A struc-ture/activity relationship study demonstrated that the presence of the oxygen bridge and the location of the two carboxylic groups play important roles in the activity of the molecules. The unusual 7-oxabicyclo[2.2.1]heptane ring of endothal is similar to that of cinmethylin, another natural product-like herbicide for which the mode of action has also eluded scientists for many years. 

Macromolecules are very much like the crystalline powder just described. A few polymers, usually biologically-active natural products like enzymes or proteins, have very specific structure, mass, repeat-unit sequence, and conformational architecture. These biopolymers are the exceptions in polymer chemistry, however. Most synthetic polymers or storage biopolymers are collections of molecules with different numbers of repeat units in the molecule. The individual molecules of a polymer sample thus differ in chain length, mass, and size. The molecular weight of a polymer sample is thus a distributed quantity. This variation in molecular weight amongst molecules in a sample has important implications, since, just as in the crystal dimension example, physical and chemical properties of the polymer sample depend on different measures of the molecular weight distribution. 

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... 

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. 

A combinatorial natural-product-like and diversity-orientated library of 10 000 benzopyran-based small molecules was constructed by Nicolaou and coworkers [74, 75]. They chose a solid-phase approach and an anchoring strategy that does not limit complexity building operations (Scheme 14.11). They used a polystyrene-based selenyl bromide resin (43) on which substrates can be immobilized by electrophilic cyclization reactions. Here, ortho-prenylated phenol 44 was reacted with the selenyl bromide (43) to form the benzopyran scaffold (45) via a 6-endo-trig cyclization. 

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...

Without much exaggeration, the last century could be called the century of chemical innovation. Plastics and other synthetically synthesized molecules and materials changed most industrial and consumer markets tremendously by systematically replacing natural products like paper, wood, or cotton and making completely new applications possible. 

Mother nature is a good resource for new molecules over 10000 natural products are isolated each year [ 1 ]. Historically, natural products have provided a good number of leads for the development of new drugs [2], However, since natural products are commonly screened as an extraction mixture, deconvolution of an active component and structural characterization are difficult tasks. In addition, isolation of natural products has a long cycle time and is considered expensive [3], These limitations have prompted efforts to synthesize natural product analogues and natural-product-like compounds for biological screening and quantitative structure-activity relationship (QSAR) studies. 

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