Amino Acids

, Volume 44, Issue 2, pp 321–333 | Cite as

Direct access to side chain N,N′-diaminoalkylated derivatives of basic amino acids suitable for solid-phase peptide synthesis

  • Jean-Philippe Pitteloud
  • Nina Bionda
  • Predrag CudicEmail author
Original Article


A simple and efficient one-pot procedure that enables rapid access to orthogonally protected N,N′-diaminoalkylated basic amino acid building blocks fully compatible with standard Boc and Fmoc solid-phase peptide synthesis is reported. Described synthetic approach includes double reductive alkylation of N α-protected diamino acids with N-protected amino aldehydes in the presence of sodium cyanoborohydride. This approach allows preparation of symmetrical, as well as unsymmetrical, basic amino acid derivatives with branched side-chains that can be further modified, enhancing their synthetic utility. The suitability of the synthesized branched basic amino acid building blocks for use in standard solid-phase peptide synthesis has been demonstrated by synthesis of an indolicidin analogue in which the lysine residue was substituted with the synthetic derivative N α -(9H-fluorenyl-9-methoxycarbonyl)-N β ,N β -bis[2-(tert-butoxycarbonylamino)ethyl]-l-2,3-diaminopropionic acid. This substitution resulted in an analogue with more ordered secondary structure in 2,2,2-trifluoroethanol and enhanced antibacterial activity without altering hemolytic activity.

Graphical abstract


N-alkylation Reductive amination One-pot procedure Branched basic amino acids Solid-phase peptide synthesis Indolicidin 



Acetic acid








Cationic antimicrobial peptide




Circular dichroism


Cell-penetrating peptide






Ethyl acetate




Formic acid


High-performance liquid chromatography




Matrix-assisted laser desorption ionization time of flight mass spectrometry


Multiantigen peptide system






Minimal inhibitory concentration




Nuclear magnetic resonance


Phosphate buffered saline


Solid-phase peptide synthesis


Trifluoroacetic acid






Thin-layer chromatography


Retention time





We acknowledge support of the N,N′-diaminoalkylated basic amino acid building blocks work described herein by the Torrey Pines Institute for Molecular Studies (TPIMS) start-up fund to P.C. We are especially thankful to Dr. Stanislaw F. Wnuk and Yong Liang from Florida International University for their assistance with NMR experiments. Also, we thank our colleague Dr. Mare Cudic for helpful comments and Ms. Karen Gottwald for editing the text.

Supplementary material

726_2012_1336_MOESM1_ESM.pdf (4.8 mb)
Supplementary material 1 (PDF 4941 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Jean-Philippe Pitteloud
    • 1
  • Nina Bionda
    • 1
    • 2
  • Predrag Cudic
    • 1
    Email author
  1. 1.Torrey Pines Institute for Molecular StudiesPort St. LucieUSA
  2. 2.Department of Chemistry and BiochemistryFlorida Atlantic UniversityBoca RatonUSA

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