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Synthesis 2006(20): 3397-3404  
DOI: 10.1055/s-2006-950214
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Versatile Strategy for the Solid-Phase Synthesis of Penicillin Derivatives: Efficient Preparation of 2β-Methyl Substituted Penams as β-Lactamase Inhibitor Analogues

Dora B. Boggián, Ernesto G. Mata*
Instituto de Química Orgánica de Síntesis (CONICET - UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
Fax: +54(341)4370477; e-Mail: mata@iquios.gov.ar;
Further Information

Publication History

Received 12 May 2006
Publication Date:
21 August 2006 (online)

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Abstract

A convenient solid-phase method for the synthesis of 2β-methyl substituted penicillins using commercially available resins is described. Functionalization of Merrifield and Wang resin bound penam derivatives was performed by penicillin sulfoxide rearrangement and the products were released from the supports under mild conditions. The utility of this methodology has been demonstrated by synthesizing a small library of penicillin derivatives in moderate to very good overall isolated yields for the multistep synthetic sequence.

Key words

solid-phase synthesis - combinatorial chemistry - penicillins - rearrangement - sulfoxides

    References

  • 1 Kidwai M. Sapra P. Bhushan KR. Curr. Med. Chem.  1999,  6:  195 
    Google Scholar
  • 2a Neu HC. Science  1992,  257:  1064 
    CrossrefGoogle Scholar
  • 2b Davies J. Science  1994,  264:  375 
    CrossrefGoogle Scholar
  • 3 Bush K. Curr. Pharm. Des.  1999,  5:  839 
    Google Scholar
  • 4a Mascaretti OA. Boschetti CE. Danelon GO. Mata EG. Roveri OA. Curr. Med. Chem.  1995,  1:  441 
    Google Scholar
  • 4b Mascaretti OA. Danelon GO. Setti EL. Laborde M. Mata EG. Curr. Pharm. Des.  1999,  5:  939 
    Google Scholar
  • 4c Maiti SN. Phillips OA. Micetich RG. Livermore DM. Curr. Med. Chem.  1998,  5:  441 
    Google Scholar
  • 5 Micetich RG. Maiti SN. Spevak P. Hall TW. Yamabe S. Ishida N. Tanaka M. Yamazaki T. Nakai A. Ogawa K. J. Med. Chem.  1987,  30:  1469 
    CrossrefGoogle Scholar
  • 6 Iman Z. Nyda K. Avi Y. Int. J. Pharm.  1997,  153:  115 
    CrossrefGoogle Scholar
  • For reports on biologically active 2β-substituted penam derivatives, see:
  • 7a Richter HGF. Angehrn P. Hubschwerlen C. Kania M. Page MGP. Specklin J.-L. Winkler FK. J. Med. Chem.  1996,  39:  3712 
    CrossrefGoogle Scholar
  • 7b Danelon GO. Mata EG. Mascaretti OA. Girardini J. Marro M. Roveri OA. Bioorg. Med. Chem. Lett.  1995,  5:  2037 
    CrossrefGoogle Scholar
  • 7c Danelon GO. Mascaretti OA. Radice M. Power P. Calcagno ML. Mata EG. Gutkind G. J. Antimicrob. Chemother.  1998,  41:  313 
    CrossrefGoogle Scholar
  • 7d Reddy NAV. Setti EL. Phillips OA. Czajkowski DP. Atwal H. Atchison K. Micetich RG. Maiti SN. J. Antibiot.  1997,  50:  276 
    CrossrefGoogle Scholar
  • 7e Czajkowski DP. Reddy AVN. Setti EL. Phillips OA. Micetich RG. Kunugita C. Maiti SN. Bioorg. Med. Chem. Lett.  1997,  7:  11 
    CrossrefGoogle Scholar
  • 7f Buynak JD. Rao AS. Doppalapudi VR. Adam G. Petersen PJ. Nidamarthy D. Bioorg. Med. Chem. Lett.  1999,  9:  1997 
    CrossrefGoogle Scholar
  • 7g Phillips OA. Reddy AVN. Setti EL. Spevak P. Czajkowski DP. Atwal H. Salama S. Micetich RG. Maiti SN. Bioorg. Med. Chem.  2005,  13:  2847 
    CrossrefGoogle Scholar
  • 8a Boschetti CE. Mata EG. Mascaretti OA. Cricco JA. Coux G. Roveri OA. Bioorg. Med. Chem. Lett.  1995,  5:  2033 
    CrossrefGoogle Scholar
  • 8b Boschetti CE. Mata EG. Mascaretti OA. Cricco JA. Coux G. Lodeyro A. Roveri OA. J. Braz. Chem. Soc.  1996,  7:  285 
    CrossrefGoogle Scholar
  • 9a Seneci P. Solid-Phase Synthesis and Combinatorial Technologies   Wiley; New York: 2000. 
    Google Scholar
  • 9b Obrecht D. Villalgordo JM. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries   Elsevier Science Ltd.; New York: 1998. 
    Google Scholar
  • 9c Solid-Phase Organic Synthesis   Burgess K. Wiley; New York: 2000. 
    Google Scholar
  • 9d Solid-Phase Organic Synthesis   Czarnik AW. Wiley; New York: 2001. 
    Google Scholar
  • 9e Dörwald FZ. Organic Synthesis on Solid Phase: Supports, Linkers, Reactions   Wiley-VCH; Weinheim: 2002.  2nd Ed.
    Google Scholar
  • For reviews on solid-phase synthesis of β-lactams, see:
  • 10a Mata EG. Curr. Pharm. Design  1999,  5:  955 
    Google Scholar
  • 10b Laborde MA. Mata EG. Mini-Rev. Med. Chem.  2006,  6:  107 
    Google Scholar
  • For solid-phase synthesis of 3,4-disubstituted β-lactams, see:
  • 11a Delpiccolo CML. Mata EG. Tetrahedron: Asymmetry  2002,  13:  905 
    CrossrefGoogle Scholar
  • 11b Delpiccolo CML. Fraga MA. Mata EG. J. Comb. Chem.  2003,  5:  208 
    CrossrefGoogle Scholar
  • 11c Delpiccolo CML. Mata EG. Tetrahedron Lett.  2004,  45:  4085 
    CrossrefGoogle Scholar
  • 11d Delpiccolo CML. Méndez L. Fraga MA. Mata EG. J. Comb. Chem.  2005,  7:  331 
    CrossrefGoogle Scholar
  • 12 For a short publication of part of this work, see: Delpiccolo CML. Mata EG. Tetrahedron: Asymmetry  1999,  10:  3893 
    CrossrefGoogle Scholar
  • 13 Beebe X. Schore NE. Kurth MJ. J. Org. Chem.  1995,  60:  4196 
    CrossrefGoogle Scholar
  • 14 Stewart JM. Young JD. Solid Phase Peptide Synthesis   Pierce Chemical Company; Rockford: 1984.  p.38 
    Google Scholar
  • 15a Mata EG. Tetrahedron Lett.  1997,  38:  6335 
    CrossrefGoogle Scholar
  • 15b Ma S. Duan D. Shi Z. Org. Lett.  2000,  2:  1419 
    CrossrefGoogle Scholar
  • 15c Cironi P. Manzanares I. Albericio F. Alvarez M. Org. Lett.  2003,  5:  2959 
    CrossrefGoogle Scholar
  • 15d Marfil M. Albericio F. Alvarez M. Tetrahedron  2004,  60:  8659 
    CrossrefGoogle Scholar
  • 15e Cironi P. Cuevas C. Albericio F. Alvarez M. Tetrahedron  2004,  60:  8669 
    CrossrefGoogle Scholar
  • 15f Olsen CA. Parera N. Albericio F. Alvarez M. Tetrahedron Lett.  2005,  46:  2041 
    CrossrefGoogle Scholar
  • 16 Kamiya T. Tevaji T. Hashimoto M. Nakaguchi O. Oku T. Tetrahedron Lett.  1973,  3001 
    CrossrefGoogle Scholar
  • 17 Giralt E. Rizo J. Pedroso E. Tetrahedron  1984,  40:  4141 
    CrossrefGoogle Scholar
  • 18 Formation of these 2β-(heterocyclyl)thiomethyl derivatives had not been previously reported in solution chemistry under similar conditions, see: Gottstein WJ. Haynes UJ. McGregor DN. J. Med. Chem.  1985,  28:  518 
    CrossrefGoogle Scholar
  • 19 Alpegiani M. Giudici F. Perrone E. Borghi D. Tetrahedron Lett.  1990,  31:  3509 
    CrossrefGoogle Scholar
  • 20a Hecker SC. Cho I.-S. Glinka TW. Zhang ZJ. Prince ME. Lee VJ. Christensen BG. Boggs A. Chamberland S. Malouin F. Parr TR. Annamalai T. Blais J. Bond EL. Case L. Chan C. Crase J. Frith R. Griffith D. Harford L. Liu N. Ludwikow M. Mathias K. Rea D. Williams R. J. Antibiot.  1998,  51:  722 
    CrossrefGoogle Scholar
  • 20b Yamazaki H. Tsuchida Y. Satoh H. Kawashima S. Hanaki H. Hiramatsu K. J. Antibiot.  2000,  53:  546 
    CrossrefGoogle Scholar
  • 21 Aswapokee N. Neu HC. J. Antibiot.  1978,  31:  123 
    Google Scholar
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Oxidation of resin-bound 2β-(heterocyclyl)thiomethyl penicillins to the corresponding sulfones was not carried out; however, this reaction is expected to be difficult to achieve due to the presence of two or more sulfur atoms in the molecule.