| We have studied the mechanism of a C-terminal peptide elongation using a 2-aminophenol auxiliary. An amino acid can be coupled using the phenol handle of a peptide 2-hydroxyphenylamide, and then inserted into the peptide-auxiliary amide to provide an extension of the C-terminus. The mechanism of the rearrangement was elucidated using kinetic analysis of isomerization and crossover experiments. The evidence is all consistent with a 5-exo-trig intramolecular transacylation to form a high-energy imide intermediate, followed by opening of the imide by the free amine to give the linear peptide. The rearrangement conditions are compatible with the Boc/benzyl protection strategy for peptide synthesis, and rearrangement can be affected in 30--90% yield. Finally, the 2-aminophenol auxiliary can be selectively removed by acylation with a benzoyl group and subsequent treatment with isopropanol and weak base to yield the peptide isopropyl ester.; We have synthesized differentially protected 3,7-diamino-3,7-dimethyl-1,5-diazabicyclo[4.3.0]non-5-ene caps as alpha-helix nucleators to be covalently attached to the C-terminus of a peptide. The overall synthesis is 15 steps, with 11 steps in the longest linear sequence. The overall yield for the Cbz/Boc protected cap is 1.4% from benzaldehyde dimethyl acetal, and 0.6% for the Cbz/Teoc protected cap. We have explored the mechanism of a late-stage Curtius rearrangement in which neighboring group participation occurs between the 3- and 7- positions, as well as enhanced nucleophilicity of a 3-carbamate towards electrophilic attack. The synthesis of new Fmoc-protected thioacylation reagents as well as silyl-protected amino acids is also presented. |
