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 b y CF3CH2(L)Phe(L)UeOtBu (6a), a prospective antitumor compound. Peptides su ch as 6a are directly obtained via standard chemistry from a novel class of amino acids, N-alpha-trifluoroethyl amino acids 4. In fact, unexpectedly, the N-alpha-1,1,1-trifluoroethyl substitution completely deactivates the al pha -nitrogen. That is, compounds 4 behave exactly like N-alpha-protected a mino acids, and take part in standard peptide synthesis accordingly. Repres entative 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 degreesC in 1 h or less. The reaction is promoted by NaHCO3 (1.5 eq). The intermediate N-alpha-1,1,1-trifluoroethyl t-butyl esters 3a-c are hydrolyze d and separated from coproducts at the same time by treatment with aqueous HCl at 22 degreesC. Evaporation of the acid extracts provides analytically pure 4a-c in 78-98% yields. (C) 2001 Elsevier Science B.V. All rights reser ved.