Download PDF
Synthesis 2006(22): 3747-3789  
DOI: 10.1055/s-2006-950332
REVIEW
© Georg Thieme Verlag Stuttgart · New York

The Synthesis of Cryptophycins

Stefan Eißler, Arvydas Stoncius, Markus Nahrwold, Norbert Sewald*
Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany
Fax: +49(521)1068094; e-Mail: norbert.sewald@uni-bielefeld.de;
Further Information

Publication History

Received 16 May 2006
Publication Date:
20 October 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

Nature provides a huge reservoir of highly diverse chemical compounds with interesting biological properties. Secondary metabolites continue to represent promising candidates for therapeutic applications and drugs are very often based on natural pro­ducts. Frequently, the total synthesis of such compounds is a real challenge, and this also drives the development of new synthetic methodology.

This review article focuses on the biochemistry and chemistry of cryptophycins, a class of 16-membered macrocyclic depsipeptides. The first representative was isolated more than 15 years ago from cyanobacteria. With respect to structure, the class can be subdivided into two structural categories, containing either an epoxide or an alkene moiety. The bioactivity of cryptophycins is based on their ability to interact with tubulin. They display considerable tumour-selective cytotoxicity both against multidrug-resistant tumour cell lines and solid tumours implanted in mice. Consequently, cryptophycin derivatives are considered as potential antitumour drugs.

Despite the fact that the cryptophycins were discovered only recently, several different synthetic approaches have already been published. In addition to information on the synthesis of the subunits A-D, strategies for both their assembly and the macrocyclisation are compiled in this review.

  • 1 Structural and Biological Features of Cryptophycins

  • 1.1 The Cryptophycins: A Short History

  • 1.2 Structural Features

  • 1.3 Tubulin as a Drug Target

  • 1.4 Biological Activity of Cryptophycins

  • 1.5 Structure-Activity Relationship

  • 2 Synthesis of the Building Blocks

  • 2.1 Syntheses of Unit A with Two Stereogenic Centres

  • 2.2 Syntheses of Unit A with Four Stereogenic Centres

  • 2.3 Units B, C, and D

  • 3 Coupling of Units and Cyclisation

  • 3.1 Cyclisation between Units C and B

  • 3.2 Cyclisation between Units A and B

  • 3.3 Horner-Wadsworth-Emmons Reaction and Ring-Closing Metathesis

  • 3.4 Other Cyclisation Methods

  • 4 Epoxidation

  • 4.1 m-Chloroperoxybenzoic Acid

  • 4.2 Dimethyldioxirane

  • 4.3 Diol-Epoxide Conversion

  • 4.4 Halohydrins

  • 5 Reactions of Cryptophycins

  • 6 Conclusion and Outlook

Key words

drugs - medicinal chemistry - natural products - peptides - total synthesis