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

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• 作者：Mare Cudic ; Frank Marí ; Gregg B. Fields
• 刊名：Journal of Organic Chemistry
• 出版年：2007
• 出版时间：July 20, 2007
• 年：2007
• 卷：72
• 期：15
• 页码：5581 - 5586
• 全文大小：103K
• 年卷期：v.72,no.15(July 20, 2007)
• ISSN：1520-6904

文摘

Recently, an unexpected modified residue, -hydroxy-D-valine (D-Hyv), was identified within ribosomallyexpressed 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 appropriatelyfunctionalized Hyv building blocks. D-Hyv was produced from D-Val by using a variation of the previouslypublished K₂PtCl₄/CuCl₂ oxidative method. Direct synthesis of Boc- or Cbz-D-Hyv lactone proceeded inlow yield; additionally, the lactones are too unreative for solid-phase applications. 9-Borabicyclononaneor 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 byChelex 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 methodologypresented herein will greatly facilitate biological studies of Hyv-containing sequences, such as receptorresponses to hydroxylated versus nonhydroxylated conopeptides and the relative susceptibility of proteinsto modification by oxidative stress.