Fmoc/Acyl protecting groups in the synthesis of polyamide (peptide) nucleic acid monomers

Abstract

The chemical synthesis of polyamide (peptide) nucleic acid (PNA) monomers 22–25 has been accomplished using Fmoc [N-(2-aminoethyl)glycine backbone], anisoyl (adenine), 4-tert-butylbenzoyl (cytosine) and isobutyryl/diphenylcarbamoyl (guanine) protecting-group combinations, thus allowing oligomer synthesis on both peptide and oligonucleotide synthesizers. An alternative method for the preparation of (N  ⁶-anisoyladenin-9-yl)acetic acid 7 is described using partial hydrolysis of a dianisoylated derivative. Different methods were studied for guanine alkylation including (a) Mitsunobu reaction; (b) low-temperature, sodium hydride- and (c) N,N-diisopropylethylamine-mediated alkylation reactions to give preferentially N  ⁹-substituted derivatives. Empirical rules are proposed for differentiating N  ⁹/N  ⁷-substituted guanines based on their ¹³C NMR chemical-shift differences.