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

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

Abstract

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.

Keywords

Macrocycles Natural products Diversity-oriented synthesis Multi component reactions 

List of Abbreviations

BCL

Burkholderia cepacia lipase (Amano PS)

BINAP

2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl

CAL-B

Candida antarctica lipase B

DOS

Diversity-oriented synthesis

EDCI

N-Ethyl-N′-(dimethylaminopropyl)carbodiimide·HCl

FDPP

Pentafluorophenyldiphenylphosphinate

HATU

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

MCR

Multi component reaction

MiB

Multiple Multicomponent Macrocyolization including Bifunctional Building Blocks

NaHMDS

Sodium hexamethyldisilazide

PyBOP

(Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate

RCM

Ring-closing metathesis

rPLE

Recombinant pig liver esterase

TAS-F

Tris(dimethylamino)sulfonium difluorotrimethylsilicate

TBS

(= TBDMS) tert-Butyldimethylsilyl

U4CR

Ugi four component reaction

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Authors and Affiliations

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

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