Synthesis of novel protected Nα(ω‐thioalkyl) amino acid building units and their incorporation in backbone cyclic disulfide and thioetheric bridged peptides

Abstract: General methods for the preparation of protected N^α(ω‐thioalkyl) amino acids building units for backbone cyclization using reductive alkylation and on‐resin preparation are described. The synthesis of non‐Gly Fmoc‐protected S‐functionalized N‐alkylated amino acids is based on the reaction of readily prepared protected ω‐thio aldehyde with the appropriate amino acid. Preparation of Fmoc‐protected S‐functionalized N‐alkylated Gly building units was carried out using two methods: reaction of glyoxylic acid with Acm‐thioalkylamine and an on‐resin reaction of bromoacetyl resin with Trt‐thioalkylamines. Three model peptides were prepared using these building units. The GlyS2 building unit was incorporated into a backbone cyclic analog of somatostatin that contains a disulfide bridge. Formation of the disulfide bridge was performed by on‐resin oxidation using I₂ or Tl(CF₃COO^–)₃. Both methods resulted in the desired product in a high degree of purity in the crude. The AspS3 building unit was also successfully incorporated into a model peptide. In addition, the in situ generation of sulfur containing Gly building units was demonstrated on a Substance P backbone cyclic analog containing a thioether bridge.