Homoserine derivatives for the preparation of base-stable nucleopeptide analogues

Summary Covalently linked peptide-oligonucleotide hybrids are good candidates for antisense or anti-gene therapeutics. The use of homoserine as the linking amino acid allows nucleopeptide analogues with a base-stable amino acid-nucleoside phosphate diester linkage to be obtained. Three N^α, O-protected homoserine derivatives (N ^α-Boc-Hse(DMT)-O⁻ HTEA⁺ (I),N ^α-Fmoc-Hse(MMT)-O⁻Hpyr⁺ (II) andN ^α-Phac-Hse(DMT)-O⁻HTEA⁺(III) were prepared after transient silylation,N ^α-acylation, desilylation and protection of the hydroxyl group. The first can be placed at any position in the peptide sequence, while the other two must be placed at theN-terminus to afford nucleopeptides with the N-terminal amine group free or permanently blocked, respectively.