Crystal structure of (1R,4R)-tert-butyl 3-oxo-2-oxa-5-azabicyclo[2.2.2]octane-5-carboxylate

In the title compound, C11H17NO4, commonly known as N-tert-butoxycarbonyl-5-hydroxy-d-pipecolic acid lactone, the absolute configuration is (1R,4R) due to the enantiomeric purity of the starting material which remains unchanged during the course of the reaction. In the crystal there no intermolecular hydrogen bonds.


S1. Comment
5-Hydroxypipecolic acid is a higher homologue of 4-hydroxyproline, which is found in dates (Witkop & Foltz, 1957). 4-Hydroxyproline is formed by post-translational modification of proline in collagen and is responsible for enhancing its stability. Literature reports the synthesis of 5-hydroxypipecolic acid derivatives (Hoarau et al., 1996;Sun et al., 2008), generally forming diastereomeric mixtures of cis-and trans-5-hydroxypipecolic acids. Therefore such syntheses suffer from disadvantages of separation of the diasteromers making the procedure very tedious. A facile procedure to isolate this amino acid was desirable.
Our previous communication reported the synthesis of a 4-hydroxyproline derivative from an amino acid bearing epoxide . It is reported in this study that the cis-isomer undergoes intramolecular lactonization to tert-butyl-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate, making the isolation from the trans ester highly feasible. Based on this observation it can be expected that cis-5-hydroxypipecolic acids would also undergo in situ intramolecular lactonization. In fact, when a mixture of a cis-and trans-5-hydroxypipecolic acid derivatives was reacted under acidic conditions, the cis-isomer successfully converted to the lactone (I), subsequently readily separated from the remaining trans--isomer. We had previously reported the crystal structure of racemic tert-butyl-3-oxo-2-oxa-5- The title compound (I), commonly known as N-tert-butoxycarbonyl-5-hydroxy-D-pipecolic acid lactone, was derived from a starting product having a cis configuration for both hydroxyl and carboxyl groups, leading to lactone formation ( Fig. 1). The nitrogen atom N1 appears next to the bridge-head atom within the bicyclic ring system. The absolute configuration of the compound was found to be (1R,4R) due to the configuration of the starting material (Fig. 3). The Flack structure parameter (Flack, 1983) determined for (I) [0.1 (7)], although not definitive because of the uncertainty factor, is considered to provide adequate supporting evidence for this configuration. The desired hydrophobic conformer (1R,4R), (I) was easily isolated from hydrophylic (1R,4S)-(4) (Fig. 3). The intramolecular lactonization is possible only in (1R,4R)-(3) isomer due to its configuration. The hydroxyl and the carboxyl groups are in close proximity due to the cis-configuration of (1R,4R)-(3), which leads to the intamolecular lactonization with loss of EtOH. With the (1R,4S)-(4) isomer the hydroxyl and the carboxyl groups are far apart due to the trans-configuration, thus preventing the lactonization. In the crystal there no formal intramolecular hydrogen bonds (Fig. 2).
This work represents the first structural characterization of this (1R,4R)-aza and oxa bicyclic chiral lactone characterized by X-ray analysis.

S2. Experimental
The basic reaction scheme for preparation of the title compound (I) is shown in Fig. 3. To a ice cooled solution of 4 mol/L HCl in 1,4-dioxane (16 mL), a solution of diastereomeric (1) ( 0.97 g, 3.56 mmol) in 0.5 mL of 1,4-dioxane was added.
This reaction mixture was then warmed to room temperature and stirred. After 3 h most of the volatile materials were removed under vacuum resulting in a crude oily mixture. Trituration with diethyl ether followed by decantation resulted in (2) as a foam (0.71 g, 95 %). DIEA (0.89 mL, 5.07 mmol) was added to a solution of (2)

S3. Refinement
All hydrogen atoms were placed in calculated positions (C-H = 0.98-1.00 Å) and allowed to ride, with U iso H = 1.5U eq C(methyl) or 1.2U eq C(methine and methylene). The absolute structure parameter (Flack, 1983) for (I) [0.01 (7)   Crystal packing diagram of the title compound.

Figure 3
Synthetic scheme for the title compound (I). Special details Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. 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.