Synthesis and Solid-Phase Application of Suitably Protected gamma-Hydroxyvaline Building Blocks. [J Org Chem] Journal article

Recently, an unexpected modified residue, gamma-hydroxy-d-valine (d-Hyv), was identified within ribosomally expressed polypeptide chains of four conopeptides from the venoms of Conus gladiator and Conus mus. To assemble Hyv-containing peptides, we have explored several routes for the synthesis of appropriately functionalized Hyv building blocks. d-Hyv was produced from d-Val by using a variation of the previously published K2PtCl4/CuCl2 oxidative method. Direct synthesis of Boc- or Cbz-d-Hyv lactone proceeded in low yield; additionally, the lactones are too unreative for solid-phase applications. 9-Borabicyclononane or copper-complexed d-Hyv was prepared and treated with tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf) to produce d-Hyv(O-TBDMS). The most efficient complex disruption was achieved by Chelex 110 resin (Na+ form) treatment of copper-complexed d-Hyv(O-TBDMS). Reaction of d-Hyv(O-TBDMS) with Fmoc-OSu produced Fmoc-d-Hyv(O-TBDMS) in 26% yield from d-Val. The Fmoc-d-Hyv(O-TBDMS) diastereomers were separated by preparative RP-HPLC in 13% yield from d-Val. Fmoc-d-Hyv(O-TBDMS) was used for the synthesis of the conopeptide gld-V* from Conus gladiator. The isolated synthetic and natural products had coincidental mass and NMR spectra. The methodology presented herein will greatly facilitate biological studies of Hyv-containing sequences, such as receptor responses to hydroxylated versus nonhydroxylated conopeptides and the relative susceptibility of proteins to modification by oxidative stress.

J Org Chem