Nε-carbonyl> Derivatives of Tri-L-lysine and Tetra-L-lysine as Potential Intermediates in the Block Polymer Synthesis of Macromolecular Drug Conjugates

Article abstract of DOI:10.1021/jo00284a031

Tri-L-lysine and tetra-L-lysine derivatives were synthesized with N^ε-<<2-(trimethylsilyl)ethoxy>carbonyl>(N^ε-Teoc) protecting groups an all the lysines, or on all but the N-terminal lysine, and with N^α-(tert-butyloxycarbonyl) (N^α-Boc) or N^α-(9-fluorenylmethyloxycarbonyl) (N^α-Fmoc) groups on the N-terminal lysines.Treatment of the Boc/Teoc peptides with p-toluenesulfonic or 2,4,6-trimethylbenzenesulfonic acid led to Boc cleavage with Teoc retention only when the Teoc/Boc ratio was 1:1 or 2:1.In contrast, treatment of the Fmoc/Teoc peptides with liquid ammonia in a sealed vessel cleaved the Fmoc group without significant loss of Teoc groups even when the Fmoc/Teoc ratio was 3:1, showing that Fmoc and Teoc groups provide more selectivity than the Boc and Teoc combination.N^α-Fmoc and N^ε-Teoc groups were both stable under catalytic hydrogenolysis conditions.This made it possible to prepare N^α-Fmoc-tri-L-lysine and N^α-Fmoc-tetra-L-lysine derivatives with N^ε-Teoc groups on all but the N-terminal lysine and demonstrated that the triad Fmoc/Cbz/Teoc is superior to Boc/Cbz/Teoc in peptide synthesis involving the orthogonal protection strategy.