Date Published: November 01, 2019
Publisher: International Union of Crystallography
Author(s): Ai Wang, Ulli Englert.
The light-atom compound (2S)-methyl (Z)-5-(2-tert-butoxy-1-cyano-2-oxoethylidene)pyrrolidine-2-carboxylate is an enantiopure coordination partner for cations. Despite its only minor resonant scattering, the absolute structure was determined by a combination of diffraction, CD spectroscopy and theoretical calculations.
Pyrrolidine derivatives have found applications as potential ligands, as organic intermediates and in medicinal chemistry. They can inhibit the activity of over-expressed protein tyrosine phosphatases (PTPs) of cancer cells and may be employed as anticancer drugs (IC50 value is 3.65 ± 0.08 µM) (Chen et al., 2017 ▸). By forming imine or enamine intermediates with aldehydes and ketones, chiral monopyrrolidine derivatives have been widely used in asymmetric catalysis, and alkylation and acylation reactions of aldehydes and ketones have been achieved (Jensen et al., 2012 ▸). We report here the absolute configuration of the chiral pyrrolidine derivative (2S)-methyl (Z)-5-(2-tert-butoxy-1-cyano-2-oxoethylidene)pyrrolidine-2-carboxylate, (1) (Scheme 1). The compound has been synthesized and spectroscopically characterized by Pfaltz and co-workers (Pfaltz et al., 1977 ▸; Fritschi et al., 1988 ▸; Pfaltz, 1993 ▸); retention of the configuration at C1 may be assumed. No studies in medicinal chemistry have been conducted on (1), but a closely related compound was investigated, i.e. methyl 5-[1-cyano-2-oxo-2-(2,3,4-trimethoxyphenyl)ethylidene]prolinate was screened by the National Cancer Institution, USA, against 60 human tumour cell lines and showed moderate cell-growth inhibition at 10 µM concentration for renal cancer and leukemia (Ghinet et al., 2012 ▸). To the best of our knowledge, the structure of (1) has never been investigated and its absolute configuration has not been confirmed. Our assignment relies on a combination of diffraction experiments, experimental circular dichroism (CD) spectroscopy and theoretical calculations of these spectra. We will show that diffraction results, albeit with only a modest contribution of resonant scattering, and CD spectroscopy agree in their assignment of the absolute structure, whereas a diffraction experiment without relevant anomalous dispersion remains inconclusive.
The absolute structure of (1) could reliably be assigned as S, despite the limited contribution of resonant scattering; a low-temperature diffraction experiment with Cu Kα radiation resulted in consistent values for the commonly applied enantiopol parameters. Their final standard uncertainties are still rather high, but our assignment is in agreement with the expected retention at the stereocentre of the starting material and could be further corroborated by the match between experimentally observed and theoretically calculated CD spectra. The associated Cotton effect was well reproduced by our TDDFT calculations, thus confirming that our methodology was suitable. We hope to use enantiopure (1) in future experiments as a ditopic ligand with the additional possibility to transfer central chirality from the ligand to its coordination complexes (Wang et al., 2015 ▸).