Tris[(6S)-6-hydroxy-4-epi-shikimic acid] monohydrate: an enantiomerically pure hydroxylated shikimic acid derived from methyl shikimate

The title compound, 3C7H10O6·H2O, is the enantiomerically pure product of a multi-step synthesis from the enantiomerically pure natural shikimic acid. The asymmetric unit contains three molecules of the acid and one molecule of water. The cyclohexene rings of the acids have half-chair conformations. The carboxylate, the four hydroxide groups and the additional water molecule form a complex three-dimensional hydrogen-bonding network.


Comment
The title compound is a enantiomerically pure, highly substituted polyhydroxylated cyclohexane derived from the natural shikimic acid. Polyfunctionalized shikimic acid derivatives, e.g. the drug oseltamivir (tamiflu) lately have become well known as drugs repressing the symptoms of bird flu. Furthermore, the 4-epi-shikimic acid skeleton is present in numerous natural products with interesting biological properties, one example is the (6S)-6-chloro derivative (pericosine A), an antitumour agent from Periconia byssoid (Usami et al., 2006). Synthetic efforts to new and efficient structural modifications of the shikimate skeleton are thus of current and high relevance.
The asymmetric unit contains three molecules of the acid and one molecule water. All three independent acid molecules have the same half chair conformation (Fig. 1). Two molecules of the acid form hydrogen bonded carboxylic acid dimers, which are connected to double layers by hydrogen bonds (Fig. 3). The third molecule of the acid and the water molecule form a second layer structure (Fig. 4). These two different layer structures are connected via additional hydrogen bonds, forming a three dimmensional network (Fig. 5).

Experimental
By means of a 7-step synthetic procedure (Fig. 2), the acetal 2 was synthesized starting from enantiomerically pure shikimic acid (Griesbeck et al., 2007) by a sequence of 1) esterification (methanol, camphorsulfonic acid), 2) acetalization (dimethoxypropane, camphorsulfonic acid), 3) trifluoromethanesulfonate formation (trifluoromethanesulfonic anhydride, pyridine), 4) dehydration (caesium carbonate, dimethylformamide), 5) singlet oxygenation (rose bengal, visible light, oxygen atmosphere, tetrachloromethane), 6) reduction (potassium iodide, water-acetic acid), and 7) saponification of the methyl ester(lithium hydroxide, water). The acetal 2 was hydrolyzed by the following procedure: To a solution of 60 mg (0.26 mmol) of 2 in 2.5 ml of water and 2.5 ml of methanol was added 2 drops of concentrated HCl under vigorous stirring at room temperature. The reaction mixture was stirred overnight and the solvent evaporated under reduced pressure. The residue was repeatedly dissolved in ethanol and the solvent evaporated to give 45 mg (91%) of the title compound 1 as a colorless product. Recrystallization from ethanol resulted in fine colorless needles, m.p. 140-141°C.

Refinement
Crystals of 1 are monoclinic; space group P2 1 was chosen as the acid component used was enantiopure sikimic acid and the absolute structure was set by reference to the known chirality of the enantiopure acid employed. 1.00 Å and U iso (H) = 1.2U eq (C) for CH, C-H = 0.95 Å and U iso (H) = 1.2U eq (C) for C=CH.     Two connected Layers.

Tris[(6S)-6-hydroxy-4-epi-shikimic acid] monohydrate
Crystal data Refinement. Refinement of F 2 against all reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on all data will be even larger.