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

The chemical synthesis of polyamide (peptide) nucleic acid (PNA) monomers 2 2-25 has been accomplished using Fmoc [N-(2-aminoethyl)glycine backbone], a nisoyl (adenine), 4-tert-butylbenzoyl (cytosine) and isobutyryl/diphenylcar bamoyl (guanine) protecting-group combinations, thus allowing oligomer synt hesis on both peptide and oligonucleotide synthesizers. An alternative meth od for the preparation of (N-6-anisoyladenin-9-yl)acetic acid 7 is describe d 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. E mpirical rules are proposed for differentiating N-9/N-7-substituted guanine s based on their C-13 NMR chemical-shift differences.