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

A simple and efficient one-pot procedure that enables rapid access to orthogonally protected N,N 0 -diam- inoalkylated basic amino acid building blocks fully com- patible with standard Boc and Fmoc solid-phase peptide synthesis is reported. Described synthetic approach includes double reductive alkylation of N a -protected dia- mino acids with N-protected amino aldehydes in the pres- ence 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 indo- licidin analogue in which the lysine residue was substituted with the synthetic derivative N a -(9H-fluorenyl-9-methox- ycarbonyl)-N b ,N b0 -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.