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

Suvratha Krishnamurthy; Venkataprasad Jalli; Tarun Chand Vagvala; Tetsuji Moriguchi; Akihiko Tsuge

doi:10.1107/S2056989015010476

. 2015 Jun 6;71(Pt 7):o449–o450. doi: 10.1107/S2056989015010476

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

Suvratha Krishnamurthy ^a,^*, Venkataprasad Jalli ^a, Tarun Chand Vagvala ^b, Tetsuji Moriguchi ^a, Akihiko Tsuge ^a

PMCID: PMC4518923 PMID: 26279901

Abstract

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.

Keywords: crystal structure; (1R,4R)- aza-oxa bicyclic chiral lactone

Related literature

For background information on 5-hydroxypipecolic acid and related compounds, see: Witkop & Foltz (1957 ▸); Hoarau et al. (1996 ▸); Sun et al. (2008 ▸). For the synthesis of a related compound, see: Krishnamurthy et al. (2014 ▸). For crystal structures of related lactones, see: (1S,4S) conformer, racemic mixture, Moriguchi, Krishnamurthy, Arai & Tsuge (2014 ▸); Moriguchi, Krishnamurthy, Arai, Matsumoto et al. (2014 ▸). graphic file with name e-71-0o449-scheme1.jpg

Experimental

Crystal data

C₁₁H₁₇NO₄
M _r = 227.26
Orthorhombic,
a = 9.6472 (4) Å
b = 9.7084 (4) Å
c = 12.2323 (5) Å
V = 1145.66 (8) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 90 K
0.45 × 0.40 × 0.40 mm

Data collection

Bruker APEX2 KY CCD diffractometer
Absorption correction: multi-scan SADABS (Bruker, 2009 ▸) T _min = 0.870, T _max = 0.961
13518 measured reflections
2791 independent reflections
2728 reflections with I > 2σ(I)
R _int = 0.021

Refinement

R[F ² > 2σ(F ²)] = 0.030
wR(F ²) = 0.081
S = 1.03
2791 reflections
148 parameters
H-atom parameters constrained
Δρ_max = 0.24 e Å⁻³
Δρ_min = −0.27 e Å⁻³
Absolute structure: Flack (1983 ▸), 2933 Friedel pairs
Absolute structure parameter: 0.1 (7)

Data collection: APEX2 (Bruker,2009 ▸); cell refinement: SAINT (Bruker, 2009 ▸); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▸); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▸); molecular graphics: SHELXTL (Sheldrick, 2008 ▸); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S2056989015010476/zs2333sup1.cif

e-71-0o449-sup1.cif^{(21.5KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989015010476/zs2333Isup2.hkl

e-71-0o449-Isup2.hkl^{(137.1KB, hkl)}

Click here for additional data file.^{(4.7KB, cml)}

Supporting information file. DOI: 10.1107/S2056989015010476/zs2333Isup3.cml

Click here for additional data file.^{(1.2MB, tif)}

. DOI: 10.1107/S2056989015010476/zs2333fig1.tif

Molecular configuration and atom numbering scheme for the title compound with displacement ellipsoids drawn at the 50% probability level. Hydrogen atoms are omitted for clarity.

Click here for additional data file.^{(2.2MB, tif)}

. DOI: 10.1107/S2056989015010476/zs2333fig2.tif

Crystal packing diagram of the title compound.

Click here for additional data file.^{(20.8KB, tif)}

. DOI: 10.1107/S2056989015010476/zs2333fig3.tif

Synthetic scheme for the title compound (I).

CCDC reference: 1062075

Additional supporting information: crystallographic information; 3D view; checkCIF report

Acknowledgments

We are grateful to the Center for Instrumental Analysis, Kyushu Institute of Technology (KITCIA), for high-resolution mass and ¹H NMR spectra and X-ray analysis.

supplementary crystallographic information

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 (Krishnamurthy et al. 2014). 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-azabicyclo[2.2.2]octane-5-carboxylate (Moriguchi, Krishnamurthy, Arai, Tsuge et al., 2014) and (1S,4S)-tert-butyl 3-oxo-2-oxa-5-azabicyclo[2.2.2]octane-5-carboxylate (Moriguchi, Krishnamurthy, Arai, & Tsuge, 2014). Herein we would like to report the crystal structure of enantiomerically pure (1R,4R)-tert-butyl- 3-oxo-2-oxa-5-azabicyclo[2.2.2]octane-5-carboxylate, C₁₁H₁₇N O₄, (I).

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) ( 0.71 g, 3.38 mmol) in DMF (13 mL) and stirred at 50 °C. After 6 h the solution was warmed to room temperature, followed by addition of Boc₂O (3.96 g, 18.1 mmol), additional DIEA (0.3 mL, 1.69 mmol) and stirred at room temperature for 18 h. The DMF was evaporated and the crude mixture was subsequently washed with 10% aqueous citric acid, 4% aqueous NaHCO₃, brine, dried (MgSO₄), filtered and evaporated to obtain an oil. The crude product was purified by silica gel column chromatography with (CHCl₃/MeOH, 100:0 to 98:2, v/v) to yield (1R,4R), (I) (0.18 g, 23%) as a white solid. Single crystals were obtained by vapour diffusion method at room temperature, i.e., hexane vapour was allowed to diffuse into an EtOAc (0.5 ml) solution of (1R,4R), (I) at room temperature. Single crystals suitable for analysis were obtained after a week.

¹H NMR 4.61-4.82 (2H, m), 3.63 (1H, m), 3.45 (1H, m), 2.22 (1H, br s), 2.11 (1H, m), 2.00 (1H, m), 1.80 (1H, m), 1.47 (9H, s); MS (FAB m/z): 228 (74), 190 (44), 172 (100), 137 (50), 128 (68), 55 (47). HRMS(FAB) calcd for C₁₁H₁₈N₁O₄ [M + H]⁺ 228.12358, found 228.1243