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Synthesis and Solid-Phase Application of Suitably Protected Gamma-Hydroxyvaline Building Blocks

Synthesis and Solid-Phase Application of Suitably Protected Gamma-Hydroxyvaline Building Blocks

Mare Cudic, Frank Marí, Gregg B Fields

J Org Chem. 2007 Jul 20;72(15):5581-6.

PMID: 17583956

Abstract:

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 unreactive 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP69739340	tert-Butyldimethylsilyl trifluoromethanesulfonate		69739-34-0	Price

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