Gt. Bourne et al., A backbone linker for BOC-based peptide synthesis and on-resin cyclization: Synthesis of stylostatin 1, J ORG CHEM, 64(9), 1999, pp. 3095-3101
We have developed a new 4-alkoxybenzyl-derived linker that anchors the C-te
rminal amino acid to the resin through the alpha-nitrogen atom. The linker
allows BOC solid-phase peptide assembly and peptide cleavage using standard
HF protocols. This linking strategy provides a versatile on-resin route to
cyclic peptides and avoids the diketopiperazine formation that is prominen
t when using FMOC chemistry on backbone linkers. The linker was prepared by
forming the aryl ether fi om 4-hydroxybenzaldehyde and bromovaleric acid.
Subsequent reductive amination of the aldehyde with an allyl-protected amin
o acid eater and acylation of the resulting secondary amine provided the te
rtiary amide. After linking the amide to the resin, standard BOC SPPS, foll
owed by allyl deprotection, cyclization, and HF cleavage gave cyclic peptid
es in high purity. To exemplify the strategy, the cytotoxic heptapeptide, s
tylostatin 1, was synthesized from two linear precursors. For comparison pu
rposes, the yields of the on-resin and solution-phase cyclization were dete
rmined and found to be dependent upon the linear precursor. This linker tec
hnology provides new solid-phase avenues in accessing libraries of cyclic p
eptides.