Abstract
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 a=9.6402(10) Å, b=9.7026(10) Å, c=12.2155(12) Å, Dcalc=1.3194 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.
Highlights
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 [1, 2]
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 3-oxo-2-oxa-5azabicyclo[2.2.2]octane-5-carboxylate, which was readily separated from the remaining trans isomer by washing the organic layer with an alkaline solution
The positive fast atom bombardment (FAB) mass spectrum (MS) and high-resolution FAB mass spectrum of the compound were obtained on a JEOL JMS-SX102A spectrometer using nitrobenzyl alcohol (NBA) as the matrix and dichloromethane (DCM) as the solvent
Summary
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]. 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. We reported the crystal structure of “racemic” tert-butyl 3-oxo-2-oxa5-azabicyclo[2.2.1]heptane-5-carboxylate prepared using an alternative synthetic pathway [8]. Based on these previous results, it was expected that cis5-hydroxypipecolic acids would undergo intramolecular lactonization, while the corresponding trans isomers would not. 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 3-oxo-2-oxa-5azabicyclo[2.2.2]octane-5-carboxylate, which was readily separated from the remaining trans isomer by washing the organic layer with an alkaline solution. A crystal structure analysis was performed to determine the exact chiral structure of the molecule, and the results were compared to those for a crystal of the “racemic” compound reported previously [8]
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