Macrocycles, natural product-like

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... 

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

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-... 

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. 

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... 

The Wittig-like reactions are well known for C=C bond formation. An intramolecular process can serve as a ring closure and has been generally employed in the synthesis of numerous macrocyclic natural products [150]. Oishi and coworkers [151] applied this strategy to the synthesis of the aglycone (252) of the antibiotics venturicidins A and B. Thus, as shown in Scheme 84, the aldehyde phosphate 250 was subjected to the modified intramolecular Wittig-Homer condensation with a mild base, yielding the macrocycle 251 in 48% yield. 

Fig. 1 Recently developed routes to natural product-like macrocycle and medium-ring libraries using ring expansion strategies...

Lactones and the macrocyclic lactones, like the y- and 5-lactones, are of importance since these ring systems are found widespread in nature. The simpler substituted lactones are important building blocks in the synthesis of many natural products, e.g. in the fields of antibiotics, anticancer pharmaceuticals, pheromones and prostaglandins to name but a few. 

Kaiser et al. have reported a general entry for the selective synthesis of dimeric macrocycles like cyclostellettamines and for polymeric natural products [41]. It uses the Zincke reaction by which it is possible to control the number of units in a 3-alkylpyridinium polymer. As summarized in Fig. (33), the reaction of the free amine 89 with the Zincke salt 88 gives the dimer 90 (route b) which, after terminal amine deprotection and DNB functionalization at the A-pyridine centre, gives the cyclic dimer, as in the synthesis of cyclostellettamine B. Otherwise, compound 90 furnishes both the protected dimer 91 and the free linear dimer, which, refluxed together in butanol, give the linear tetramer (route c). By the same iterative sequence, the linear octamer was obtained from the tetramer, and from the latter the hexadecamer. 

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