The dioxanone approach to (2S,3R)-2-C-methylerythritol 4-phosphate and 2,4-cyclodiphosphate, and various MEP analogues

The Journal of Organic Chemistry
Chandraiah LagisettiRobert M Coates

Abstract

Efficient syntheses of the non-mevalonate pathway intermediates 2-C-methylerythritol 4-phosphate (MEP) and 2-C-methylerythritol 2,4-cyclodiphosphate (ME-2,4-cycloPP), as well as the parent tetrol 2-C-methylerythritol, in enantiopure form from (2S,4R)-cis-2-phenyl-4-tert-butyldimethylsilyloxy-1,3-dioxan-5-one are reported. The 2S configuration of the C-methyl group was installed by highly axial-face selective addition of CH3MgBr (20:1) to the chiral dioxanone carbonyl group. Primary selective mono-phosphorylation and 2,4-bis-phosphorylation, followed by desilation and hydrogenolysis to the free mono- and diphosphates, and, in the latter case, cyclization to form the eight-membered phosphoryl anhydride, afforded MEP and ME-2,4-cycloPP in good yields. The C2 epimeric analogues, 2-C-methylthreitol and its 4-phosphate, were accessed by LiAlH4 reduction of the cis,cis epoxide of (2S,4R)-4-tert-butyldimethylsilyloxymethyl-5-methylene-2-phenyl-1,3-dioxane, primary-selective phosphorylation, and cleavage of the silyl, benzylidene, and benzyl protecting groups. Regioselective cleavage of the acetal ring of 1,3-benzylidene 2-C-methylerythritol silyl ether by ozonolysis afforded a 1,2,3-triol 3-monobenzoate intermediate that was converted ...Continue Reading

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Citations

Jun 5, 2012·The Journal of Biological Chemistry·Pei-Lin YuJianbo Yue
Jul 20, 2016·Proceedings of the National Academy of Sciences of the United States of America·Geoffrey BennKatayoon Dehesh
Jul 11, 2009·The Journal of Organic Chemistry·Tony V RobinsonEdward R T Tiekink

Related Concepts

4-dioxanone
methyl-erythritol-4-phosphate
2-C-methyl-D-erythritol 2,4-cyclodiphosphate
Dioxanes
Erythritol
Molecular Stereochemistry
Sugar Phosphates

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