Download PDF
Synthesis 2006(5): 753-755  
DOI: 10.1055/s-2006-926342
SHORTPAPER
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of the Immunosuppressive Agent FTY720

Sanghee Kim*a,b, Hyeseung Leea,b, Minhee Leea,b, Taeho Leeb
a College of Pharmacy, Seoul National University, San 56-1, Shilim Kwanak, Seoul 151-742, Korea
b Natural Products Research Institute, College of Pharmacy, Seoul National University, 28 Yungun, Jongro, Seoul 110-460, Korea
Fax: +82(2)7628322; e-Mail: pennkim@snu.ac.kr;
Further Information

Publication History

Received 1 September 2005
Publication Date:
08 February 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

The concise and practical synthesis of the biologically important FTY720 was achieved employing the palladium-catalyzed Sonogashira coupling reaction as a key step. The commercial tris(hydroxymethyl)aminomethane was converted to alkyne 2 via a three-step synthesis. The coupling reactions of alkyne 2 with aryl iodide 3, followed by subsequent hydrogenation of the internal alkyne and removal of the protecting groups provided FTY720 in high overall yield.

Key words

cross-coupling - synthesis - FTY720 - immunosuppressants - alkynes

    References

  • 1a Adachi K. Kohara T. Nakao N. Arita M. Chiba K. Mishina T. Sasaki S. Fujita T. Bioorg. Med. Chem. Lett.  1995,  5:  853 
    CrossrefPubMedSearch in Google Scholar
  • 1b Kiuchi M. Adachi K. Kohara T. Minoguchi M. Hanano T. Aoki Y. Mishina T. Arita M. Nakao N. Ohtsuki M. Hoshino Y. Teshima K. Chiba K. Sasaki S. Fujita T. J. Med. Chem.  2000,  43:  2946 
    CrossrefPubMedSearch in Google Scholar
  • 1c Fujita T. Inoue K. Yamamoto S. Ikumoto T. Sasaki S. Toyama R. Chiba K. Hoshino Y. Okumoto T. J. Antibiot.  1994,  47:  208 
    CrossrefPubMedSearch in Google Scholar
  • 3a Taha TA. Argraves KM. Obeid LM. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids  2004,  1682:  48 
    CrossrefSearch in Google Scholar
  • 3b Praditpornsilpa K. Avihingsanon Y. Transplant. Proc.  2004,  36:  1228 
    CrossrefSearch in Google Scholar
  • 3c Kahan BD. Transplant. Proc.  2004,  36:  S531 
    CrossrefSearch in Google Scholar
  • 4a Mandala S. Hajdu R. Bergstrom J. Quackenbush E. Xie J. Milligan J. Thornton R. Shei G.-J. Card D. Keohane C. Rosenbach M. Hale J. Lynch CL. Rupprecht K. Parsons W. Rosen H. Science  2002,  296:  346 
    Search in Google Scholar
  • 4b Brinkmann V. Davis MD. Heise CE. Albert R. Cottens S. Hof R. Bruns C. Prieschl E. Baumruker T. Hiestand P. Foster CA. Zollinger M. Lynch KR. Biol. Chem.  2002,  227:  21453 
    Search in Google Scholar
  • 5 Matloubian M. Lo CG. Cinamon G. Lesneski MJ. Xu Y. Brinkmann V. Allende ML. Proia RL. Cyster JG. Nature  2004,  427:  355 
    CrossrefSearch in Google Scholar
  • For previous syntheses of FTY720, see:
  • 6a Durand P. Peralba P. Sierra F. Renaut P. Synthesis  2000,  505 
    Crossref
  • 6b Kalita B. Barua NC. Bezbarua M. Bez G. Synlett  2001,  1411 
    Crossref
  • 6c Seidel G. Laurich D. Fürstner A. J. Org. Chem.  2004,  69:  3950 
    CrossrefSearch in Google Scholar
  • 6d Sugiyama S. Arai S. Kiriyama M. Ishii K. Chem. Pharm. Bull.  2005,  53:  100 ; see also references 1a and 1b
    CrossrefSearch in Google Scholar
  • For recent syntheses of FTY720-related compounds, see:
  • 7a Kiuchi M., Adachi K., Tomatsu A., Chino M., Takeda S., Tanaka Y., Maeda Y., Sato N., Mitsutomi N., Sugahara K., Chiba K.; Bioorg. Med. Chem.; 2005, 13: 425
    Thieme Connect
  • 7b Hale JJ. Yan L. Neway WE. Hajdu R. Bergstrom JD. Milligan JA. Shei G.-J. Chrebet GL. Thornton RA. Card D. Rosenbach M. Rosen H. Mandala S. Bioorg. Med. Chem.  2004,  12:  4803 
    Thieme ConnectSearch in Google Scholar
  • 7c Hale JJ. Neway W. Mills SG. Hajdu R. Keohane CA. Rosenbach M. Milligan J. Shei G.-J. Chrebet G. Bergstrom J. Card D. Koo GC. Koprak SL. Jackson JJ. Rosen H. Mandala S. Bioorg. Med. Chem. Lett.  2004,  14:  3351 
    Thieme ConnectSearch in Google Scholar
  • 7d Hinterding K. Albert R. Cottens S. Tetrahedron Lett.  2002,  43:  8095 
    Thieme ConnectSearch in Google Scholar
  • 7e Hinterding K. Cottens S. Albert R. Zecri F. Buehlmayer P. Spanka C. Brinkmann V. Nussbaumer P. Ettmayer P. Hoegenauer K. Gray N. Pan S. Synthesis  2003,  1667 
    Thieme Connect
  • 8 Ooi H. Ishibashi N. Iwabuchi Y. Ishihara J. Hatakeyama S. J. Org. Chem.  2004,  69:  7765 
    CrossrefPubMedSearch in Google Scholar
  • 9 Lane JW. Halcomb RL. Tetrahedron  2001,  57:  6531 
    CrossrefSearch in Google Scholar
  • 10 Roth GJ. Liepold B. Stephan G. Müller SG. Bestmann HJ. Synthesis  2004,  59 
    Thieme Connect
  • 11 Abe T. Yamaji T. Kitamura T. Bull. Chem. Soc. Jpn.  2003,  23:  2175 
    Search in Google Scholar
  • 12 Sonogashira K. In Handbook of Organopalladium Chemistry for Organic Synthesis   Negishi E. Wiley; New York: 2002.  p.493 
2

See http://www.transplantationschweiz.ch/d/fty720/ for more information.