Download PDF
Synlett 2011(6): 826-830  
DOI: 10.1055/s-0030-1259913
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of the Selective Neuronal Nitric Oxide Synthase (nNOS) Inhibitor 5,6-Dibromo-2′-demethylaplysinopsin

Emily M. Boyd, Jonathan Sperry*
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand
e-Mail: j.sperry@auckland.ac.nz;
Further Information

Publication History

Received 7 January 2011
Publication Date:
15 March 2011 (online)

    Permissions and Reprints All articles of this category

Abstract

The first synthesis of the selective neuronal nitric oxide synthase (nNOS) inhibitor 5,6-dibromo-2′-demethylaplysinopsin is described. The rare 5,6-dibromoindole moiety was constructed using a previously unused dibromination of an indole-3-carboxylate, the product of which was verified by X-ray crystallography. It was discovered the natural product was characterised as its trifluoroacetate salt in the isolation report.

Key words

5,6-dibromoindole - aplysinopsin - neuronal nitric oxide synthase (nNOS) - heterocycle

    References and Notes

  • 1a Ishikura M. Yamada K. Abe T. Nat. Prod. Rep.  2010,  27:  1630 
    Google Scholar
  • 1b Ishikura M. Yamada K. Nat. Prod. Rep.  2009,  26:  803 
    Google Scholar
  • 1c Higuchi K. Kawasaki T. Nat. Prod. Rep.  2007,  24:  843 
    Google Scholar
  • 1d Kawasaki T. Higuchi K. Nat. Prod. Rep.  2005,  22:  761 
    Google Scholar
  • 1e Somei M. Yamada F. Nat. Prod. Rep.  2005,  22:  73 
    Google Scholar
  • 2 Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 
    CrossrefPubMedGoogle Scholar
  • 3a Van Lear GE. Morton GO. Fulmor W. Tetrahedron Lett.  1973,  299 
    Google Scholar
  • 3b Djura P. Stierle DB. Sullivan B. Faulkner DJ. Arnold E. Clardy J. J. Org. Chem.  1980,  45:  1435 
    Google Scholar
  • 3c Kochanowska A. Rao KV. Childress S. El-Alfy A. Matsumoto RR. Kelly M. Stewart GS. Sufka KJ. Hamann MT. J. Nat. Prod.  2008,  71:  186 
    Google Scholar
  • 4 Tasdemir D. Bugni TS. Mangalindan GC. Concepción GP. Harper MK. Ireland CM. Z. Naturforsch., C  2002,  57:  914 
    Google Scholar
  • 5 Lee N.-K. Fenical W. Lindquist N. J. Nat. Prod.  1997,  60:  697 
    CrossrefGoogle Scholar
  • 6a Reyes F. Fernández R. Rodríguez A. Francesh A. Taboada S. Ávila C. Cuevas C. Tetrahedron  2008,  64:  5119 
    Google Scholar
  • 6b Šíša M. Pla D. Altuna M. Francesch A. Cuevas C. Albericio F. Álvarez M. J. Med. Chem.  2009,  52:  6217 
    Google Scholar
  • 6c

    A semi-synthesis of aplycyanin F (7) has been achieved by acetylation (Ac2O, py) of aplycyanin E (6); see ref. 6a.

  • 7 Gompel M. Leost M. de Kier Joffe EB. Puricelli L. Franco LH. Palermo J. Meijer L. Bioorg. Med. Chem. Lett.  2004,  14:  1703 
    CrossrefGoogle Scholar
  • 8a Appleton DR. Page MJ. Lambert G. Berridge MV. Copp BR. J. Org. Chem.  2002,  67:  5402 
    Google Scholar
  • 8b Appleton DR. Copp BR. Tetrahedron Lett.  2003,  44:  8963 
    Google Scholar
  • 9 Aoki S. Ye Y. Higuchi K. Takashima A. Tanaka Y. Kitagawa I. Kobayashi M. Chem. Pharm. Bull.  2001,  49:  1372 
    CrossrefGoogle Scholar
  • 10a Uehara T. Nakamura T. Yao D. Shi ZQ. Gu Z. Ma Y. Masliah E. Nomura Y. Lipton SA. Nature (London)  2006,  441:  513 
    Google Scholar
  • 10b Chung KK. Thomas B. Li X. Pletnikova O. Troncoso JC. Marsh L. Dawson VL. Dawson TM. Science  2004,  304:  1328 
    Google Scholar
  • 10c Cho DH. Nakamura T. Fang J. Cieplak P. Godzik A. Gu Z. Lipton SA. Science  2009,  324:  102 
    Google Scholar
  • 10d Hantraye P. Brouillet E. Ferrante R. Palfi S. Dolan R. Matthews RT. Beal MF. Nature Med.  1996,  2:  1017 
    Google Scholar
  • 11a Calabrese V. Mancuso C. Calvani M. Rizzarelli E. Butterfield DA. Stella AM. Nature Rev. Neurosci.  2007,  8:  766 
    Google Scholar
  • 11b Contestabile A. Monti B. Contestabile A. Ciani E. Curr. Med. Chem.  2003,  10:  2147 
    Google Scholar
  • 11c Estevez AG. Jordan J. Ann. N. Y. Acad. Sci.  2002,  962:  207 
    Google Scholar
  • 12a Ferriero DM. Holtzman DM. Black SM. Sheldon RA. Neurobiol. Dis.  1996,  3:  64 
    Google Scholar
  • 12b Tan S. Bose R. Derrick M. Free Radical Biol. Med.  2001,  30:  1045 
    Google Scholar
  • 12c Derrick M. Drobyshevsky A. Ji X. Tan SA. Stroke  2007,  38:  731 
    Google Scholar
  • 12d Derrick M. Luo NL. Bregman JC. Jilling T. Ji X. Fisher K. Gladson CL. Beardsley DJ. Murdoch G. Back SA. Tan S. J. Neurosci.  2004,  24:  24 
    Google Scholar
  • 13 Huang Z. Huang PL. Panahian N. Dalkara T. Fishman MC. Moskowitz MA. Science  1994,  265:  1883 
    CrossrefGoogle Scholar
  • For two excellent reviews covering the chemistry and biology of the aplysinopsin alkaloids, see:
  • 14a Stanovnik B. Svete J. Mini-Rev. Org. Chem.  2005,  2:  211 
    Google Scholar
  • 14b Bialonska D. Zjawiony JK. Mar. Drugs  2009,  7:  116 
    Google Scholar
  • 15a Da Settimo A. Saettone MF. Nannipieri E. Barili P. Gazz. Chim. Ital.  1967,  97:  1304 
    Google Scholar
  • 15b Da Settimo A. Primofiore G. Ferrarini PL. Franzone JS. Cirillo R. Cravanzola C. Eur. J. Med. Chem.  1983,  18:  261 
    Google Scholar
  • 16a Miki Y. Umemoto M. Nakamura M. Hibino H. Ohkita N. Kato A. Aoki Y. Heterocycles  2006,  68:  1893 
    Google Scholar
  • 16b Buszek KR. Luo D. Kondrashov M. Brown N. VanderVelde D. Org Lett.  2007,  9:  4135 
    Google Scholar
  • 16c Brown N. Luo D. VanderVelde D. Yang S. Brassfield A. Buszek KR. Tetrahedron Lett.  2009,  50:  63 
    Google Scholar
  • 17 Majima R. Kotake M. Ber.  1930,  63:  2237 
    Google Scholar
  • 18a Leggetter BE. Brown RK. Can. J. Chem.  1960,  38:  1467 
    Google Scholar
  • 18b Da Settimo A. Antonio SV. Primofiore G. Biagi G. Veneziano C. Gazz. Chim. Ital.  1977,  107:  367 
    Google Scholar
  • 21 Roué N. Bergman J. Tetrahedron  1999,  55:  14729 
    CrossrefGoogle Scholar
  • 22 Kenyon GL. Rowley GL. J. Am. Chem. Soc.  1971,  93:  5552 
    CrossrefGoogle Scholar
  • 23a Djura P. Faulkner DJ. J. Org. Chem.  1980,  45:  735 
    Google Scholar
  • 23b Guella G. Mancini I. Zibrowius H. Pietra F. Helv. Chim. Acta  1988,  71:  773 
    Google Scholar
  • 23c Guella G. Mancini I. Zibrowius H. Pietra F. Helv. Chim. Acta  1989,  72:  1444 
    Google Scholar
  • 24 Reddy YT. Sekhar KR. Sasi N. Reddy NP. Freeman ML. Crooks PA. Bioorg. Med. Chem. Lett.  2010,  20:  600 
    CrossrefGoogle Scholar
  • 25a Schuisky P. Twistel W. Grivas S. Heterocycles  1998,  48:  1431 
    Google Scholar
  • 25b Grivas S. Schuisky P. Heterocycles  1998,  48:  1575 
    Google Scholar
  • 27 Burke CP. Swingle MR. Honkanen RE. Boger DL. J. Org. Chem.  2010,  75:  7505 
    CrossrefGoogle Scholar
19

Crystallographic data (reference number CCDC 804778) can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge, CB21EZ, UK; fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk].

20

5,6-Dibromoindole-3-carbaldehyde is a side product (5% yield) obtained from treating indole-3-carbaldehyde with bromine in the presence of iron; see ref. 15a.

26

See Supporting Information for full details.