Acid-labile handles for Fmoc solid-phase synthesis of peptide N-alkylamides

Summary By analogy to established methodology for the preparation of C-terminal peptide amides by 9-fluorenylmethyl-oxycarbonyl (Fmoc) chemistry, in conjunction with the acidolyzable 5-(4-Fmoc-aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL, 1) handle, the present paper reports on 5-(4-(N-Fmoc-N-alkyl)aminomethyl-3,5-dimethoxyphenoxy)valeric acid (R)PAL, 2] handles that can be used for synthesis of peptide N-alkylamides. The key step in the preparation of these handles was the NaBH₃CN-mediated reductive amination (60 to 85% yields; R=CH₃, CH₃CH₂, C₆H₅CH₂CH₂, 4-NO₂C₆H₅) of 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid (4), an aldehyde precursor to PAL. The (R)PAL handles (2a and b) were applied to the preparation of LHRH analogues. After anchoring of handles to PEG-PS supports, peptide chain assemblies were carried out, and treatments with TFA-thioanisolephenol-1,2-ethanedithiol (87:5:5:3) for 90 min at 25 °C, followed by aqueous workups, provided the expected products in excellent yields and purities as supported by HPLC and mass spectrometric characterization.Taken in part from the Ph.D. Thesis of M.F. Songster, University of Minnesota, 1996. Preliminary reports of this work were presented at the 14th American Peptide Symposium, Columbus, OH, June 18–23, 1995 (poster P047), and at the Fourth International Symposium on Solid Phase Synthesis and Combinatorial Chemical Libraries, Edinburgh, Scotland, UK, September 12–16, 1995.