Download PDF
Synthesis 2009(1): 33-42  
DOI: 10.1055/s-0028-1083259
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Discoveries from the Abyss: The Abyssomicins and Their Total Synthesis

K. C. Nicolaou*a,b, Scott T. Harrisona, Jason S. Chena
a Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
b Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Fax: +1(858)7842469; e-Mail: kcn@scripps.edu;
Further Information

Publication History

Received 3 September 2008
Publication Date:
12 December 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

Abyssomicin C is a recently discovered antibiotic with promising antibacterial activity, high structural complexity, and a novel mechanism of action. We give an account of our abyssomicin campaign and some of the discoveries that were borne of our total synthesis efforts, including a new Lewis acid templated Diels-Alder­ reaction, the previously undescribed atrop-abyssomicin C, a facile Brønsted acid-catalyzed isomerization of abyssomicin C, and clarification of the likely biosynthetic origin of abyssomicin D.

1 Introduction

2 Retrosynthetic Analysis

3 Initial Forays

4 A Novel Diels-Alder Reaction and Process Development

5 Fragment Coupling and Ring-Closing Metathesis Studies

6 The Structures of the Abyssomicins: Implications for Their Synthesis, Biosynthesis, and Biological Activity

7 Conclusion

Key words

antibiotics - atropisomerism - Diels-Alder reactions - metathesis - total synthesis

    References

  • 1a Riedlinger J. Reicke A. Zähner H. Krismer B. Bull AT. Maldonado LA. Ward AC. Goodfellow M. Bister B. Bischoff D. Süssmuth RD. Fiedler H.-P. J. Antibiot.  2004,  57:  271 
    Google Scholar
  • 1b Bister B. Bischoff D. Ströbele M. Riedlinger J. Riecke A. Wolter F. Bull AT. Zähner H. Fiedler H.-P. Süssmuth RD. Angew. Chem. Int. Ed.  2004,  43:  2574 
    Google Scholar
  • 2 Walsh CT. Liu J. Rusnak F. Sakaitani M. Chem. Rev.  1990,  90:  1105 
    CrossrefGoogle Scholar
  • 3 Zapf CW. Harrison BA. Drahl C. Sorensen EJ. Angew. Chem. Int. Ed.  2005,  44:  6533 
    CrossrefGoogle Scholar
  • For selected reviews on the Diels-Alder reaction and its applications to total synthesis, see:
  • 4a Corey EJ. Angew. Chem. Int. Ed.  2002,  41:  1650 
    Google Scholar
  • 4b Nicolaou KC. Snyder SA. Montagnon T. Vassilikogiannakis G. Angew. Chem. Int. Ed.  2002,  41:  1668 
    Google Scholar
  • 5 Snider BB. Zou Y. Org. Lett.  2005,  7:  4939 
    CrossrefPubMedGoogle Scholar
  • 6 Couladouros EA. Bouzas EA. Magos AD. Tetrahedron  2006,  62:  5272 
    CrossrefGoogle Scholar
  • 7a Rath J.-P. Eipert M. Kinast S. Maier ME. Synlett  2005,  314 
    Google Scholar
  • 7b Rath J.-P. Kinast S. Maier ME. Org. Lett.  2005,  7:  3089 
    Google Scholar
  • 8 Zografos AL. Yiotakis A. Georgiadis D. Org. Lett.  2005,  7:  4515 
    CrossrefGoogle Scholar
  • 9a Nicolaou KC. Harrison ST. Angew. Chem. Int. Ed.  2006,  45:  3256 
    Google Scholar
  • 9b Nicolaou KC. Harrison ST. J. Am. Chem. Soc.  2007,  129:  429 
    Google Scholar
  • For examples of similar Dieckmann condensation reactions, see:
  • 10a Roush WR. Reilly ML. Koyama K. Brown BB. J. Org. Chem.  1997,  62:  8708 
    Google Scholar
  • 10b Takeda K. Shibata Y. Sagawa Y. Urahata M. Funaki K. Hori K. Sasahara H. Yoshii E. J. Org. Chem.  1985,  50:  4673 
    Google Scholar
  • 11 For a review on metathesis reactions in total synthesis, see: Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4490 
    Google Scholar
  • 12 Ward DE. Abaee MS. Org. Lett.  2000,  2:  3937 
    CrossrefGoogle Scholar
  • 13a Evans JM. Kallmerten J. Synlett  1992,  269 
    Google Scholar
  • 13b

    This catalyst was recommended to us by Professor K. B. Sharpless.

  • 14 Ward DE. Souweha MS. Org. Lett.  2005,  7:  3533 
    CrossrefGoogle Scholar
  • 15 Corey EJ. Helal CJ. Angew. Chem. Int. Ed.  1998,  37:  1986 
    CrossrefPubMedGoogle Scholar
  • 16 Prusov E. Röhm H. Maier ME. Org. Lett.  2006,  8:  1025 
    CrossrefPubMedGoogle Scholar
  • 17 Takeda K. Kawanishi E. Nakamura H. Yoshii E. Tetrahedron Lett.  1991,  32:  4925 
    CrossrefGoogle Scholar
  • 18a Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett.  1999,  1:  953 
    Google Scholar
  • 18b Trnka TM. Morgan JP. Sanford MS. Wilhelm TE. Scholl M. Choi T.-L. Ding S. Day MW. Grubbs RH. J. Am. Chem. Soc.  2003,  125:  2546 
    Google Scholar
  • 19 Hong SH. Sanders DP. Lee CW. Grubbs RH. J. Am. Chem. Soc.  2005,  127:  17160 
    Google Scholar
  • For selected examples of other stable atropisomers in strained medium-sized rings lacking obvious steric barriers, see:
  • 22a Shea KJ. Gilman JW. Haffner CD. Dougherty TK. J. Am. Chem. Soc.  1986,  108:  4953 
    Google Scholar
  • 22b Anastasiou D. Campi EM. Chaouk H. Jackson WR. Tetrahedron  1992,  48:  7467 
    Google Scholar
  • 23 Keller S. Nicholson G. Drahl C. Sorensen EJ. Fiedler H.-P. Süssmuth RD. J. Antibiot.  2007,  60:  391 
    CrossrefGoogle Scholar
  • 24 Keller S. Schadt HS. Ortel I. Süssmuth RD. Angew. Chem. Int. Ed.  2007,  46:  8284 
    CrossrefGoogle Scholar
20

In ref. 9b, we disclosed that isomerization between 1 and 1a occurs at 180 ˚C in 1,2-dichlorobenzene. However, it is not clear whether this is occurring thermally or mediated by trace amounts of HCl released by the solvent at elevated temperature.

21

The identity of iso-abyssomicin C was later confirmed; personal communication with Professor E. J. Sorensen.