Natural product-like

Twenty-four years before its detection in nature PEA was first synthesized in 1876 (56) by reducing phenylacetaldehyde [122-78-1] with sodium amalgam. Then, in 1900, it was independently identified in otto of rose (57) and rose water (58). Subsequently, PEA has been identified in numerous flower oils such as ylang-ylang, narcissus, hyacinth, lily, neroH, and geranium as well as various other natural products like tea, tobacco, orange juice, beer, cigarette smoke, etc. 

The high chemoselectivity for the Baeyer-Villiger process was utilized in the synthetic elaboration of another hetero-bicyclic substrate. The biooxidation only provides the expected unsaturated lactone in a desymmetrization reaction without compromising the olefin functionality. The biotransformation product was then converted to pivotal intermediates for C-nucleosides like showdomycin, tetrahydro-furan natural products like kumausyne, and goniofufurone analogs in subsequent chemical operations (Scheme 9.17) [161]. 

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[. 

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... 

Soldi AM. Libraries from natural product-like scaffolds. Curr Opin Chem Biol 2004 8 281-6. 

The hydroxy groups in natural products like, for example, the macrolide antibiotics erythromycin, 1"1 and desmycosin, 2001 2011 as well as the 3-(hydroxymethyl)-2- or 3-cephems 2021 and derivatives of the amino sugar garamin 2031 have been converted into the carbamate function with CDI and amines. In the case of aminoglycoside antibiotics of the sisomicin series, thiocarbamates or dithiocarbamates have been prepared from alcohols or thiols using ImCSIm and amines.12041... 

Although a few other acyclic examples of stereospecific isomerisation of hexatrienes are known, specially in the field of natural product like steroid chemistry, the commonest reactions of this type are in cyclic hexatrienes. Cyclooctatriene and cyclooctatetraene are systems in which the electrocyclic reaction goes very readily and they show an interesting trend. 

Twenty chapters cover such new and exciting developments as metal-catalyzed synthesis of allenes, strained cyclic allenes, the numerous applications of different metallated allenes in organic synthesis, as well as the many addition and rearrangement reactions of allenes and allene units in natural products like the remarkable enyne-allenes. 

A few thousand years before the word biotechnology was coined, vinegar had been obtained from the bacterial oxidation of the ethanol contained in natural products like wine, cider, or malt. A pure dilute solution of acetic acid can also be made by the same method when aqueous ethanol is the starting material. The net reaction is represented by ... 

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]. 

Scheme 3.32 Prototypical structures for the synthesis of natural product-like libraries.

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. 

Abreu PM, Branco PS. (2003) Natural product-like combinatorial libraries. J Braz Chem Soc 14 675-712. 

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

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...

Also reactions that rapidly create more diversity are sought after. In recent years, more and more multicomponent reactions (MCRs) have been developed and combined with modern synthetic methods such as RCM or Pd couplings to provide rapid access to complex, natural product-like structures in solution. 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

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. 

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. 

Boldi AM. (2004) Libraries from natural products-like scaffolds. Curr. Opin. Chem. Biol. 8 281-286. 

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... 

Beck B, Larbig G, Mejat B, Magnin Lachaux M, Picard A, Herdtweck E, Domling A (2003) Short and diverse route toward complex natural product-like macrocycles. Org Lett 5 1047-1050... 

Cristau P, Vors JP, Zhu JP (2003) Rapid and diverse route to natural product-like biaryl ether containing macrocycles. Tetrahedron 59 7859-7870... 

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