PDF herunterladen
Synthesis 2010(2): 221-232  
DOI: 10.1055/s-0029-1217125
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Traceless, Solid-Supported Synthesis of β-Turn Mimetics Based on the Hexahydropyrazino[1,2-a]pyrazine-1,2-dione Scaffold

Adam Mieczkowskia, Wiktor Koźmińskia, Janusz Jurczak*a,b
a Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Fax: +48(22)8225996; e-Mail: jjurczak@chem.uw.edu.pl;
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Weitere Informationen

Publikationsverlauf

Received 27 July 2009
Publikationsdatum:
13. November 2009 (online)

   Lizenzen und Reprints Alle Artikel dieser Rubrik
Preview

Abstract

The solid-supported synthesis of a library of β-turn mimetics based on the three-component Petasis condensation and 2,5-diketopiperazine formation is reported. The eight-step sequence starts from optically pure (S)-piperazine-2-carboxylic acid dihydrochloride, which is first converted into an orthogonally protected, resin-bound amino derivative. The subsequent transformations lead to compounds having the common hexahydropyrazino[1,2-a]pyrazine-1,2-dione core and diverse side chains, which mimic the β-turn structure. This synthetic route includes protection of the initial amino acid with two different protecting groups, followed by attachment to the Wang resin using the Mitsunobu reaction, deprotection of the β-nitrogen atom, then Petasis reaction, amidation, deprotection of the α-nitrogen atom, coupling with a Boc-protected α-amino acid, cleavage of the Boc group, and the cyclizative cleavage from the resin, resulting in the requested bicyclic products obtained in good yields and having good to moderate purities. Six different boronic acids, four amines, and nine α-amino acids were applied to this synthetic route, to explore the efficiency and limitations of the described method.

Key words

solid-phase synthesis - cyclizative cleavage - multicomponent reactions - β-turn mimetics

    References

  • 1a Fu X. Zeng L.-M. Su J.-Y. Pais M. J. Nat. Prod.  1997,  60:  695 
    Suche in Google Scholar
  • 1b Fu X. Ferreira MLG. Schmitz FJ. Kelly-Borges M. J. Nat. Prod.  1998,  61:  1226 
    Suche in Google Scholar
  • 2a Kanoh K. Kohno S. Asari T. Harada T. Katada J. Muramatsu M. Kawashima H. Sekiya H. Uno I. Bioorg. Med. Chem. Lett.  1997,  7:  2847 
    Suche in Google Scholar
  • 2b Kanoh K. Kohno S. Katada J. Takahashi J. Uno I. Hayashi Y. Bioorg. Med. Chem.  1999,  7:  1471 
    Suche in Google Scholar
  • 3 Donkor IO. Sanders ML. Bioorg. Med. Chem. Lett.  2001,  11:  2647 
    CrossrefSuche in Google Scholar
  • 4 Clark B. Capon JR. Lancey E. Tennant S. Gill JH. J. Nat. Prod.  2005,  68:  1661 
    CrossrefSuche in Google Scholar
  • 5 Cui CB. Kakeya H. Osada H. Tetrahedron  1996,  52:  12651 
    CrossrefSuche in Google Scholar
  • 6a Shiono Y. Akiyama K. Hayashi H. Biosci., Biotechnol., Biochem.  2000,  64:  103 
    Suche in Google Scholar
  • 6b Shiono Y. Akiyama K. Hayashi H. Biosci., Biotechnol., Biochem.  2000,  64:  1519 
    Suche in Google Scholar
  • 6c Hayashi H. Furutsuka K. Shiono Y. J. Nat. Prod.  1999,  62:  315 
    Suche in Google Scholar
  • 6d Hayashi H. Fujiwara T. Murao S. Arai M. Agric. Biol. Chem.  1991,  55:  3143 
    Suche in Google Scholar
  • 6e Hayashi H. Takiuchi K. Murao S. Arai M. Agric. Biol. Chem.  1989,  53:  461 
    Suche in Google Scholar
  • 7 Wyatt PG. Allen MJ. Borthwick AD. Davies DE. Exall AM. Hatley RJD. Irving WR. Livermore DG. Miller ND. Nerozzi F. Sollis SL. Bioorg. Med. Chem. Lett.  2005,  15:  2579 
    CrossrefSuche in Google Scholar
  • 8 Boger DL. Fink BE. Hendrick MP. Bioorg. Med. Chem. Lett.  2000,  10:  1019 
    CrossrefSuche in Google Scholar
  • 9 Szardenings AK. Antonenko V. Cambell DA. DeFrancisko N. Ida S. Shi L. Sharkov N. Tien D. Wang Y. Navre M. J. Med. Chem.  1999,  42:  1348 
    CrossrefSuche in Google Scholar
  • 10 Prakash KRC. Tang Y. Kozikowski AP. Flippen-Anderson JL. Knoblach SM. Faden AI. Bioorg. Med. Chem.  2002,  10:  3043 
    CrossrefSuche in Google Scholar
  • For examples see:
  • 11a Suat KK. Seettharama DSJ. Curr. Pharm. Des.  2003,  9:  1209 
    Suche in Google Scholar
  • 11b Monfardini C. Canziani G. Plugariu C. Kieber-Emmons T. Godillot PA. Kwah J. Bajgier J. Chaiken I. Williams WV. Curr. Pharm. Des.  2004,  8:  2185 
    Suche in Google Scholar
  • 11c Perez de Vega MJ. Martin-Martinez M. Genzales-Muniz R. Curr. Top. Med. Chem.  2007,  7:  33 
    Suche in Google Scholar
  • 11d Kocis P. Campbell JB. Sparks RB. Wildonger R. In High-Throughput Synthesis   Sucholeiki I. Marcel-Dekker; New York: 2001.  p.65-83  
  • 11e Souers AJ. Ellman JA. Tetrahedron  2001,  57:  7431 
    Suche in Google Scholar
  • 11f Burgess K. Acc. Chem. Res.  2001,  34:  826 
    Suche in Google Scholar
  • 11g Cochran AG. Curr. Opin. Chem. Biol.  2001,  5:  654 
    Suche in Google Scholar
  • 11h Zhao L. Chmielewski J. Curr. Opin. Struct. Biol.  2005,  15:  31 
    Suche in Google Scholar
  • 11i Tyndall JDA. Pfeiffer B. Abenante G. Fairlie DP. Chem. Rev.  2005,  105:  793 
    Suche in Google Scholar
  • 11j Olson GL. Bolin DR. Bonner MP. Bos M. Cook CM. Fry DC. Graves BJ. Hatada M. Hill DE. Kahn M. Madison VS. Rusiecki VK. Sarabu R. Sepinwall J. Vincent GP. Voss ME. J. Med. Chem.  1993,  36:  3041 
    Suche in Google Scholar
  • 11k Golebiowski A. Klopfenstein SR. Portlock DE. Curr. Opin. Drug Discov. Devel.  2001,  4:  428 
    Suche in Google Scholar
  • 12a Golebiowski A. Klopfenstein SR. Shao X. Chen JJ. Colson A.-O. Grieb AL. Russell AF. Org. Lett.  2000,  2:  2615 
    Suche in Google Scholar
  • 12b Golebiowski A. Klopfenstein SR. Chen JJ. Shao X. Tetrahedron Lett.  2000,  41:  4841 
    Suche in Google Scholar
  • 12c Golebiowski A. Jozwik J. Klopfenstein SR. Colson A.-O. Grieb AL. Russell AF. Rastogi VL. Diven CF. Portlock DE. Chen JJ. J. Comb. Chem.  2002,  4:  584 
    Suche in Google Scholar
  • 13a Smith GG. Sivakua T. J. Org. Chem.  1983,  48:  627 
    Suche in Google Scholar
  • 13b Yokoyama Y. Hikawa H. Murakami Y. J. Chem. Soc., Perkin Trans. 1  2001,  1431 
  • 14a Bisang C. Weber C. Robinson JA. Helv. Chim. Acta  1996,  79:  1825 
    Suche in Google Scholar
  • 14b Beeli R. Steger M. Linden A. Robinson JA. Helv. Chim. Acta  1996,  79:  2235 
    Suche in Google Scholar