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Synthesis of N-Fmoc 3-(4-(di-(tert- butyl)phosphonomethyl)phenyl)pipecolic acid as a conformationally constrained phosphotyrosyl mimetic suitably protected for peptide synthesis

  1. Author:
    Liu, D. G.
    Wang, X. Z.
    Gao, Y.
    Li, B. H.
    Yang, D.
    Burke, T. R.

  2. Author Address

    NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA Univ Michigan, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA Burke TR NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA
    1. Year: 2002
  2. Journal: Tetrahedron
    1. 58
    2. 52
    3. Pages: 10423-10428
  4. Type of Article: Article
  1. Abstract:

    Phosphonomethylphenylalanine (Pmp, 2) has shown wide utility as a hydrolytically stable phosphtyrosyl (pTyr, 1) mimetic, particularly in Src homology 2 (SH2) domain-binding peptides. (2S,3R)-3-(4-(phosphonomethyl)phenyl)pipecolic acid (3) represents a variant of Pmp having phi and chi(1) torsion angles constrained through incorporation into the piperidinyl ring structure contained within pipecolic acid. Reported herein is the enantioselective preparation of 3, in an orthogonally protected form (4) suitable for use in peptide synthesis. Stereochemistries at both the 2- and 3-positions are derived inductively from a single chiral center provided by the commercially available Evans chiral auxiliary, (4S)-4-benzyl- 1,3-oxazolidin-2-one. Incorporation of 4 into a Grb2 SH2 domain-directed tripeptide (18) showed that Grb2 SH2 domain- binding affinity was reduced relative to the parent Pmp- containing tripeptide (19). Although conformational constraint did not enhance affinity in this case, novel amino acid analogue 4 may serve as a useful tool for the induction of defined phosphotyrosyl geometry in peptides directed at other signal transduction targets. (C) 2002 Elsevier Science Ltd. All rights reserved.

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