Intramolecular Hydrogen Bonding (PO--H) Stabilizes the Chair Conformation of Six-Membered Ring Phosphates

Six-membered cyclic phosphates (2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes) bearing an internal
protected or unprotected hydroxyl group were designed, synthesized, and studied by NMR and
computational methods. Selective opening of O-isopropylidene-protected 1,2-diols at the primary
site was achieved with either triethylsilane or trimethylallylsilane in the presence of BF3·OEt2.
Applied to 5,6-O-isopropylidenepentofuranosides, this reaction gave rise to the formation of the
corresponding 1,3-diol precursors for the six-membered ring phosphates containing an O-isopropyl
or O-1,1-dimethyl-3-butenyl functional group at C-6. The O-1,1-dimethyl-3-butenyl protecting group
was efficiently removed after the phosphorylation with BF3·OEt2, and the six-membered cyclic
phosphates containing free hydroxyl groups were obtained. A cyclic phosphate with a free hydroxyl
group oriented cis to the phosphoryl group shows a vicinal coupling constant 3JHP that is in
accordance with the chair conformation. This is due to the formation of a seven-membered
intramolecular hydrogen-bonded ring structure that stabilizes the chair conformation. Thus, the
strong tendency of the phenoxy group to be in an axial position is diminished by the internal
hydrogen bonding interaction. Computational studies provided strong support for the experimental
observation.