Syntheses of All Four Stereoisomers Which Are Conformationally Constrained 1,4-Dioxanyl Analogs of the Antineoplastic Ether Lipid ET-18-OCH3

Article abstract of DOI:10.1021/jo00049a021

The syntheses of each of the four nearly optically pure stereoisomers of <<(5-heptadecyl-1,4-dioxan-2-yl)-methyl>oxy>phosphocholine (2,3,2',3') were performed by two parallel divergent sequences.Phosphocholines 2 and 3 were prepared via the corresponding 5-heptadecyl-2-(hydroxymethyl)-1,4-dioxanes 21 and 23, respectively, from the completely regiospecific mixed-hydride reductions of (1R,4S,5S)-4-heptadecyl-3,6,8-trioxabicyclo<3.2.1>octane (19) and (1R,4R,5S)-4-heptadecyl-3,6,8-trioxabicyclo<3.2.1>octane (20), respectively.The two 4-heptadecyl-3,6,8-trioxabicyclo<3.2.1>octanes 19 and 20 were the two separable products from an intramolecular cyclization reaction.By a parallel divergent sequence from the enantiomeric starting material, 3-O-benzyl-sn-glycerol (16'), the other two diastereomeric <<(5-heptadecyl-1,4-dioxan-2-yl)methyl>oxy>phosphocholines 2' and 3' were prepared.These four monocyclic <<(5-heptadecyl-1,4-dioxan-2-yl)methyl>oxy>phosphocholines (2,3,2',3') are conformationally constrained analogs of the antineoplastic and immunomodulatory ether lipid rac-2-O-methyl-1-O-octadecylglycero-3-phosphocholine (rac-1) (rac-ET-18-OCH3, rac-Edelfosine).