Download PDF
Synlett 2008(7): 958-962  
DOI: 10.1055/s-2008-1072653
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Influence of Fluoroalkyl-Group Electronegativity on Stereocontrol in the Synthesis of Ψ[CH(RF)NH]Gly Peptides

Serena Bigottia, Alessandro Volonterio*a, Matteo Zanda*b
a Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘G. Natta’ del Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy
e-Mail: alessandro.volonterio@polimi.it;
b C.N.R-Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘A. Quilico’, via Mancinelli 7, 20131 Milano, Italy
Fax: +39(02)23993080; e-Mail: matteo.zanda@polimi.it;
Further Information

Publication History

Received 19 January 2008
Publication Date:
28 March 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

New peptidomimetics featuring CH(RF)NH units, having different degree of fluorination, as peptide-bond surrogates have been synthesized. The key step in the synthesis consists of a stereoselective aza-Michael addition of chiral α-amino acid esters to β-fluoroalkyl-α-nitroethenes. The diastereoselection of the process was influenced by the electronegativity, rather than by the steric bulk, of the fluorinated residue RF in β-position of the nitroalkene acceptors. Replacement of a single F atom of RF by a hydrogen or methyl group brings about a dramatic drop of stereocontrol, whereas Br, Cl, and CF3, albeit bulkier than F, provide poorer results in terms of stereocontrol.

Key words

peptidomimetics - fluorine - electronegativity - peptide bond surrogate - fluoroalkyl

    References and Notes

  • 1a Olson GL. Bolin DR. Bonner MP. Bös 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:  3039 
    CrossrefGoogle Scholar
  • 1b Gante J. Angew. Chem., Int. Ed. Engl.  1994,  33:  1699 
    CrossrefGoogle Scholar
  • 1c Leung D. Abbenante G. Fairlie DP. J. Med. Chem.  2000,  43:  305 
    CrossrefGoogle Scholar
  • 2 Fauchère J.-L. Thurieau C. Adv. Drug Res.  1992,  23:  127 
    Google Scholar
  • 3 Spatola AF. In Chemistry and Biochemistry of Amino Acids, Peptides and Proteins   Vol. 7:  Weinstein B. Marcel Dekker; New York: 1983.  p.267-357  
    Google Scholar
  • 4a Morley JS. Hennessey TD. Payne JW. Biochem. Soc. Trans.  1983,  11:  798 
    CrossrefGoogle Scholar
  • 4b Smith AB. Hirschmann R. Pasternak A. Guzman MC. Yokoyama A. Sprengeler PA. Darke PL. Emini EA. Schleif WA. J. Am. Chem. Soc.  1995,  117:  11113 
    CrossrefGoogle Scholar
  • 5 For a review on the trifluoethylamine unit, see: Sani M. Volonterio A. Zanda M. ChemMedChem  2007,  2:  1693 
    CrossrefGoogle Scholar
  • 6 Volonterio A. Bellosta S. Bravin F. Bellucci MC. Bruché L. Colombo G. Malpezzi L. Mazzini S. Meille SV. Meli M. Ramirez de Arellano C. Zanda M. Chem. Eur. J.  2003,  9:  4510 ; and references cited therein
    CrossrefGoogle Scholar
  • 7 Molteni M. Volonterio A. Zanda M. Org. Lett.  2003,  5:  3887 
    CrossrefGoogle Scholar
  • 8a Black WC. Bayly CI. Davies DE. Desmarais S. Falgueyret J.-P. Léger S. Li CS. Massé F. McKay DJ. Palmer JT. Percival MD. Robichaud J. Tsou N. Zamboni R. Bioorg. Med. Chem. Lett.  2005,  15:  4741 
    CrossrefGoogle Scholar
  • 8b Li CS. Deschenes D. Desmarais S. Falgueyret J.-P. Gauthier JY. Kimmel DB. Léger S. Massé F. McGrath ME. McKay DJ. Percival MD. Riendeau D. Rodan SB. Thérien M. Truong V.-L. Wesolowski G. Zamboni R. Black WC. Bioorg. Med. Chem. Lett.  2006,  16:  1985 
    CrossrefGoogle Scholar
  • 8c Black WC. Percival MD. ChemBioChem  2006,  7:  1525 
    CrossrefGoogle Scholar
  • 9a For the electronegativities, see: Carey FA. Sundberg RJ. Advanced Organic Chemistry   3th ed.:  New York; Plenum Press: 1990. 
    Google Scholar
  • 9b For the Bondi volume values, see: Banks RE. Talow JC. Smart BE. Organofluorine Chemistry: Principles and Commercial Applications   Plenum Press; New York: 1994. 
    Google Scholar
  • 10 For a recent analysis of this issue, see: Müller K. Faeh C. Diederich F. Science  2007,  317:  1881 
    CrossrefPubMedGoogle Scholar
  • 11 Nitroalkene 2 was prepared starting from a commercially available aqueous solution of fluoral hydrate, whereas nitroalkenes 3-7 were synthetized from fluoroacetaldehyde hemiacetals prepared by reduction of the corresponding esters: Molteni M. Consonni R. Giovenzana T. Malpezzi L. Zanda M. J. Fluorine Chem.  2006,  127:  901 
    CrossrefGoogle Scholar
  • 13 For a recent mechanistic investigation on a related Michael reaction involving fluorinated acrylamide acceptors: Fustero S. Chiva G. Piera J. Volonterio A. Zanda M. Gonzalez J. Ramallal AM. Chem. Eur. J.  2007,  13:  8530 
    CrossrefGoogle Scholar
12

The stereochemistry of the diastereoisomers was assessed by X-ray diffraction of a Michael adduct and on the basis of their spectroscopic and analytical features. Full details will be given in a full paper.