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

  • Ludger A. WessjohannEmail author
  • Eelco Ruijter
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 243)


Numerous biologically active macrocycles, including antibiotic, antifungal, and antitumor compounds, have been isolated from natural sources. In recent years the number of such structures has steadily increased, predominantly by polyketide- and peptide-derived compounds from various microorganisms. Macrocycles can combine the right amount of rigidity and flexibility and often exhibit unrivalled activity, thereby deviating from the current paradigm that medicinally active compounds should be small, nitrogen-rich heterocycles. Their challenging structures and intriguing activities have motivated organic chemists to find synthetic access to these compounds. Total synthesis plays a crucial role in the medicinal chemistry efforts towards macrocycles of already defined activity, as well as in the development of new and selective macrocyclization reactions. For lead discovery purposes, however, isolation or classical total synthesis may lack structural variability or prove to be too time consuming and impractical. A more rapid solution may be provided by diversity-oriented synthesis (DOS) of natural product-like molecules. A compromise between total synthesis and combinatorial chemistry, DOS concerns molecules displaying sufficient molecular complexity to resemble natural products, but features a more straightforward synthesis, thus allowing introduction of significant structural diversity. A brief review of flexible macrocyclization strategies and applications of DOS is given, as well as an overview of contributions to total and diversity-oriented synthesis of macrocycles from our laboratory.


Macrocycles Natural products Diversity-oriented synthesis Multi component reactions 

List of Abbreviations


Burkholderia cepacia lipase (Amano PS)




Candida antarctica lipase B


Diversity-oriented synthesis






O-(7-Azabenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate


Multi component reaction


Multiple Multicomponent Macrocyolization including Bifunctional Building Blocks


Sodium hexamethyldisilazide


(Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate


Ring-closing metathesis


Recombinant pig liver esterase


Tris(dimethylamino)sulfonium difluorotrimethylsilicate


(= TBDMS) tert-Butyldimethylsilyl


Ugi four component reaction


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Authors and Affiliations

  1. 1.Leibniz-Institute of Plant BiochemistryHalle (Saale)Germany

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