A discovery tool at work: the unexpected properties of a two-carbon residue

We report the very easy preparation of novel peptides 6a–n as represented by CF3CH2(l)Phe(l)IleOtBu (6a), a prospective antitumor compound. Peptides such as 6a are directly obtained via standard chemistry from a novel class of amino acids, Nα-trifluoroethyl amino acids 4. In fact, unexpectedly, the Nα-1,1,1-trifluoroethyl substitution completely deactivates the α-nitrogen. That is, compounds 4 behave exactly like Nα-protected amino acids, and take part in standard peptide synthesis accordingly. Representative compounds 4a–c are prepared by reaction of commercial amino acid t-butyl esters 2a–c with 1 eq iodonium salt 1 in dichloromethane/water at 22°C in 1 h or less. The reaction is promoted by NaHCO3 (1.5 eq). The intermediate Nα-1,1,1-trifluoroethyl t-butyl esters 3a–c are hydrolyzed and separated from coproducts at the same time by treatment with aqueous HCl at 22°C. Evaporation of the acid extracts provides analytically pure 4a–c in 78–98% yields.