Total Synthesis of Biologically Active Gamma-Pyrones

Summary

Principal Investigator: Dirk Trauner
Abstract: Total syntheses of the immunosuppressants SNF4435 C and D as well as the antibiotics spectinabilin and N-acetyl aureothamine are proposed. These highly unsaturated polypropionates were isolated from various strains of Streptomyces sp. Furthermore, synthetic approaches towards the molluscan polypropionates photodeoxytridachione and crispatene as well as the fungal immunosuppressants candelalide A and B are presented. All natural products feature a terminal gamma-pyrone moiety as a common structural motif. Polyenes consisting of an array of conjugated trisubstituted double bonds have been used as synthetic precursors of the complex polypropionates. The stereoselective assembly of these structures will be further investigated. Preliminary studies have shown that the core bicyclo[4.2.0]octadiene core of SNF4435 compounds can be formed using a highly stereoselective tandem Stille cross-coupling / electrocyclization cascade. A novel Lewis-acid catalyzed cyclization leading to the bicyclo[3.1.0]hexane core of photodeoxytridachione and crispatene has also been developed. The proposed total syntheses provide an opportunity to investigate asymmetric electrocyclization reactions. As opposed to cycloadditions and sigmatropic rearrangements, this class of pericyclic reactions has not yet succumbed to asymmetric catalysis. In a further contribution to synthetic methodology, new approaches towards gamma-pyrones are proposed. The significance of the gamma-pyrone moiety for the biological activity of the natural products will be explored. The biological mode of action of SNF4435C and D remains presently unknown. The natural products do not suppress IL-2 production, distinguishing them from FK506 or cyclosporin A. Our synthetic material and derivatives thereof will be used to isolate binding proteins and gain further insight into of the mechanism of these promising new lead compounds for drug development.
Funding Period: 2003-05-02 - 2008-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Biosynthetic and biomimetic electrocyclizations
    Christopher M Beaudry
    Department of Chemistry, University of California, Berkeley, 94720 1460, USA
    Chem Rev 105:4757-78. 2005
  2. ncbi Total synthesis of (-)-archazolid B
    Paul A Roethle
    Department of Chemistry, University of California, Berkeley, Berkeley, California 94720 1460, USA
    J Am Chem Soc 129:8960-1. 2007
  3. ncbi Biomimetic synthesis of the shimalactones
    Vladimir Sofiyev
    Department of Chemistry, University of California Berkeley, Berkeley, California 94720 1460, USA
    Org Lett 10:149-52. 2008
  4. ncbi Stereoselective synthesis of cyercene A and the placidenes
    Guangxin Liang
    Center for New Directions in Organic Synthesis, Department of Chemistry, University of California Berkeley, Berkeley, CA 94720 USA
    Org Lett 7:819-21. 2005
  5. ncbi Photochemical origin of the immunosuppressive SNF4435C/D and formation of orinocin through "polyene splicing"
    Markus Muller
    Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena, Germany
    Angew Chem Int Ed Engl 45:7835-8. 2006
  6. ncbi Photosensitized conversion of 9,10-deoxytridachione to photodeoxytridachione
    Daniel R Zuidema
    Department of Chemistry, Wake Forest University, Winston Salem, North Carolina 27109, USA
    Org Lett 7:4959-62. 2005
  7. ncbi Total synthesis of (-)-SNF4435 C and (+)-SNF4435 D
    Christopher M Beaudry
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    Org Lett 7:4475-7. 2005
  8. ncbi Biomimetic synthesis of elysiapyrones A and B
    Jennifer E Barbarow
    Department of Chemistry, University of California, Berkeley, 94720, USA
    Org Lett 7:2901-3. 2005
  9. ncbi Stereoselective syntheses of the bioactive polypropionates aureothin, N-acetylaureothamine, and aureonitrile
    Guangxin Liang
    Department of Chemistry, University of California, Berkeley, 94720, USA
    Org Lett 7:2837-9. 2005
  10. ncbi Mining the tetraene manifold: total synthesis of complex pyrones from Placobranchus ocellatus
    Aubry K Miller
    Department of Chemistry, University of California, Berkeley, CA 94720 1460, USA
    Angew Chem Int Ed Engl 44:4602-6. 2005

Detail Information

Publications10

  1. ncbi Biosynthetic and biomimetic electrocyclizations
    Christopher M Beaudry
    Department of Chemistry, University of California, Berkeley, 94720 1460, USA
    Chem Rev 105:4757-78. 2005
  2. ncbi Total synthesis of (-)-archazolid B
    Paul A Roethle
    Department of Chemistry, University of California, Berkeley, Berkeley, California 94720 1460, USA
    J Am Chem Soc 129:8960-1. 2007
  3. ncbi Biomimetic synthesis of the shimalactones
    Vladimir Sofiyev
    Department of Chemistry, University of California Berkeley, Berkeley, California 94720 1460, USA
    Org Lett 10:149-52. 2008
    ..2.1]heptane and bicyclo[4.2.0]octadiene, respectively. The synthesis is convergent and void of protecting groups...
  4. ncbi Stereoselective synthesis of cyercene A and the placidenes
    Guangxin Liang
    Center for New Directions in Organic Synthesis, Department of Chemistry, University of California Berkeley, Berkeley, CA 94720 USA
    Org Lett 7:819-21. 2005
    ..Two key iodovinyl pyrone building blocks were coupled to appropriately selected vinyl stannanes to assemble the highly substituted polyene side chains of the natural products. [structure: see text]..
  5. ncbi Photochemical origin of the immunosuppressive SNF4435C/D and formation of orinocin through "polyene splicing"
    Markus Muller
    Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena, Germany
    Angew Chem Int Ed Engl 45:7835-8. 2006
  6. ncbi Photosensitized conversion of 9,10-deoxytridachione to photodeoxytridachione
    Daniel R Zuidema
    Department of Chemistry, Wake Forest University, Winston Salem, North Carolina 27109, USA
    Org Lett 7:4959-62. 2005
    ..The results show that some, and perhaps all, of the photoreactions of 9,10-deoxytridachione occur through a triplet excited state. The mechanistic and biosynthetic implications of these results are discussed...
  7. ncbi Total synthesis of (-)-SNF4435 C and (+)-SNF4435 D
    Christopher M Beaudry
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    Org Lett 7:4475-7. 2005
    ..The synthetic pathway features a stereo- and regioselective [3,3]-sigmatropic rearrangement as well as a high-yielding Stille coupling/8pi-6pi electrocyclization cascade...
  8. ncbi Biomimetic synthesis of elysiapyrones A and B
    Jennifer E Barbarow
    Department of Chemistry, University of California, Berkeley, 94720, USA
    Org Lett 7:2901-3. 2005
    ..reaction: see text] The total synthesis of bicyclo[4.2.0]octane natural products elysiapyrones A and B is described...
  9. ncbi Stereoselective syntheses of the bioactive polypropionates aureothin, N-acetylaureothamine, and aureonitrile
    Guangxin Liang
    Department of Chemistry, University of California, Berkeley, 94720, USA
    Org Lett 7:2837-9. 2005
    ..reaction: see text] Concise total syntheses of the bioactive polypropionates aureothin, N-acetylaureothamine, and aureonitrile are described...
  10. ncbi Mining the tetraene manifold: total synthesis of complex pyrones from Placobranchus ocellatus
    Aubry K Miller
    Department of Chemistry, University of California, Berkeley, CA 94720 1460, USA
    Angew Chem Int Ed Engl 44:4602-6. 2005