Preparation of orthogonally protected (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of polo-box domain-binding peptides |
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Authors: | Fa Liu Jung-Eun Park Terrence R Burke Jr |
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Institution: | a Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NCI-Frederick, PO Box B, Bldg. 376 Boyles St., Frederick, MD 2170, USA b Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA |
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Abstract: | Reported herein is the first stereoselective synthesis of (2S,3R)-4-bis-(tert-butyloxy)phosphinyl]-2-(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid (N-Fmoc, O,O-(bis-(tert-butyl))-Pmab), 4] as a hydrolytically-stable phosphothreonine mimetic bearing orthogonal protection compatible with standard solid-phase protocols. The synthetic approach used employs Evans' oxazolidinone for chiral induction. Also presented is the application of 4 in the solid-phase synthesis of polo-like kinase 1 (Plk1) polo box domain (PBD)-binding peptides. These Pmab-containing peptides retain PBD binding efficacy similar to a parent pThr containing peptide. Reagent 4 should be a highly useful reagent for the preparation of signal transduction-directed peptides. |
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