The title compound (2S, 5S)-tert-butyl 3-oxo-2-oxa-5-azabicyclo[2.2.2]octane-5-carboxylate was synthesized as a chiral cyclic amino acid ester from the corresponding cis- and trans-5-hydroxypipecolic acid ethyl esters via an intramolecular lactonization reaction without using chiral catalyst or enzyme and without separation by chiral column chromatography. The chiral compound was characterized using 1H NMR spectroscopy and high-resolution mass spectrometry. Its exact structure was then determined via single crystal X-ray diffraction analysis of a single crystal obtained after recrystallization of the compound from ethyl acetate/diethyl ether. The crystal was found to be of the orthorhombic space group P212121 (No. 19, noncentrosymmetric, chiral) with ？？, ？？, ？？, 4？g/cm3, and a Flack parameter of 0.0(5) at 90？K. The compound has a bicyclo[2.2.2]octane structure comprised of lactone and piperidine groups. 1. Introduction Hydroxypipecolic acid (5-hydroxy-2-piperidinecarboxylic acid) is a six-membered homologue of 4-hydroxyproline found in some natural plants, such as date and acacia trees, whereas 4-hydroxyproline is found in animals (collagen) [1, 2]. Several hydroxypipecolic acid derivatives have been synthesized via intramolecular reactions of precursors functionalized with epoxide groups [3–5]. However, a diastereomeric mixture of cis- and trans-5-hydroxymethylpipecolic acids has generally been obtained, and in some cases, the formation of undesired 5-hydroxymethylprolines has also been noted [4–6]. Because the intramolecular reaction of epoxide precursors suffers from the formation of stereo- and regioisomers, a straightforward method for the preparation, isolation, and characterization of the pure single enantiomers of hydroxypipecolic acid and derivatives of this rare amino acid is required. Previously, we synthesized a 4-hydroxyproline derivative from an amino acid bearing an epoxide . During this study, we observed that the cis isomer underwent intramolecular lactonization. In addition, we reported the crystal structure of “racemic” tert-butyl 3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate prepared using an alternative synthetic pathway . Based on these previous results, it was expected that cis-5-hydroxypipecolic acids would also undergo intramolecular lactonization, while the corresponding trans isomers would not. Indeed, when a mixture of a cis- and trans-5-hydroxypipecolic acid derivative was reacted under acidic conditions, the cis isomer was successfully converted to the lactone (2S, 5S)-tert-butyl
D. Scarpi, L. Bartali, A. Casini, and E. G. Occhiato, “Complementary and stereodivergent approaches to the synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids from enantiopure hydroxylated lactams,” European Journal of Organic Chemistry, vol. 2013, no. 7, pp. 1306–1317, 2013.
J. A. Hodges and R. T. Raines, “Stereoelectronic and steric effects in the collagen triple helix: toward a code for strand association,” Journal of the American Chemical Society, vol. 127, no. 45, pp. 15923–15932, 2005.
S. Hoarau, J. L. Fauchère, L. Pappalardo, M. L. Roumestant, and P. Viallefont, “Synthesis of enantiomerically pure (2R,5S)- and (2R,5R)-5-hydroxypipecolic acid from glycinate Schiff bases,” Tetrahedron Asymmetry, vol. 7, no. 9, pp. 2585–2593, 1996.
D. S. Kemp and T. P. Curran, “Stereoselective decarboxylation of a geminal dicarboxylic acid. Synthesis of cis-5-(hydroxymethyl)-D-proline derivatives,” Journal of Organic Chemistry, vol. 51, no. 12, pp. 2377–2378, 1986.
S. Krishnamurthy, T. Arai, K. Nakanishi, and N. Nishino, “Epoxy amino acids produced from allylglycines intramolecularly cyclised to yield four stereoisomers of 4-hydroxyproline derivatives,” RSC Advances, vol. 4, no. 5, pp. 2482–2490, 2014.
T. Moriguchi, S. Krishnamurthy, T. Arai et al., “Synthesis and molecular structure of tert-butyl 3-oxo-2-oxa-5-azabicyclo[2.2.2]octane-5-carboxylate,” Journal of Crystallography, vol. 2014, Article ID 645079, 6 pages, 2014.