Stereoselective synthesis of a phosphonate pThr mimetic via palladium-catalyzed γ-C(sp3)–H activation for peptide preparation?

Organic & Biomolecular Chemistry Pub Date: 2019-01-08 DOI: 10.1039/C8OB02999G

Abstract

We report a facile synthetic strategy toward CH2-substituted phosphothreonine mimetics. Herein, inexpensive valine with a directing group was converted into homothreonine via palladium-catalyzed γ-methyl C(sp3)–H bond activation, followed by construction of a phosphorus–carbon bond via the well-developed Appel reaction and Michaelis–Becker reaction with a total yield of 30%. Furthermore, the derived mimetic was applied for solid-phase synthesis of two phosphopeptide inhibitors. This efficient synthesis provides a chance to prepare not only phosphopeptides but also phosphoproteins resistant to phosphatases.

Graphical abstract: Stereoselective synthesis of a phosphonate pThr mimetic via palladium-catalyzed γ-C(sp3)–H activation for peptide preparation
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