Toward the Computational Design of Diastereomeric Resolving Agents:  An Experimental and Computational Study of 1-Phenylethylammonium-2-phenylacetate Derivatives

Abstract

The crystal structures, including two new polymorphs, of three diastereomerically related salt pairs formed by (R)-1-phenylethylammonium (1) with (S&R)-2-phenylpropanoate (2), (S&R)-2-phenylbutyrate (3), and (S&R)-mandelate (4) ions were characterized by low-temperature single crystal or powder X-ray diffraction. Thermal, solubility, and solution calorimetry measurements were used to determine the relative stabilities of the salt pairs and polymorphs. These were qualitatively predicted by lattice energy calculations combining realistic models for the dominant intermolecular electrostatic interactions and ab initio calculations for the ions' conformational energies due to the distortion of their geometries by the crystal packing forces. Crystal structure prediction studies were also performed for the highly polymorphic diastereomeric salt pair (R)-1-phenylethylammonium-(S&R)-2-phenylbutyrate (1-3) in an attempt to predict the separation efficiency without relying on experimental information. This joint experimental and computational investigation provides a stringent test for the reliability of lattice modeling approaches to explain the origins of chiral resolution via diastereomer formation (Pasteurian resolution). The further developments required for the computational screening of single-enantiomer resolving agents to achieve optimal chiral separation are discussed.

A Major Advance in Crystal Structure Prediction

“…The high number of degrees of freedom results in a complex global optimization problem, for which several solution strategies have been put forward. [5][6][7][8][9][10][11] The central part of the approach used herein is a hybrid method, developed by one of the authors (M.A.N. ), for the calculation of lattice energies [12] that combines density functional theory (DFT) simulations using the Vienna Ab initio Simulation Package (VASP) program [13][14][15] with an empirical van der Waals (vdW) correction expressed in terms of a sum over isotropic atom-atom pair potentials.…”

A computationally inspired investigation of the solid forms of (R)‐1‐phenylethylammonium‐(S)‐2‐phenylbutyrate

“…The redetermined experimental structure was lattice energy minimized, as in the original study, 3 by the DMAflex procedure, allowing the five most flexible torsion angles (Scheme 1) as well as the cell parameters and 24 obtained by analysis of the MP2/6-31G(d,p) ab initio charge density, with all other terms represented by an atom-atom intermolecular exp-6 repulsion-dispersion potential with C, N, O, H C (connected to carbon), and H N,O (connected to nitrogen or oxygen) parameters. 25 (These parameters were also used for the hydrate models, as their suitability has been demonstrated for a range of organic hydrates 26 ).…”

“…The efficiency of (R)-1-phenylethylammonium as a resolving agent for the three 2-phenylacetate derivatives (R/S)-2-phenylpropanoate, (R/S)-2-phenylbutyrate, and (R/S)-mandelate was qualitatively predicted 3 by considering the relative lattice energies of the diastereomeric salt pairs. However, the attempt to predict the excellent resolution of (R)-1-phenylethylammonium-(R/S)-2-phenylbutyrate without any experimental input (by predicting the crystal structures of the two diastereomeric salts) failed because the known P4 1 structure 4 of the RS salt was significantly less stable than other hypothetical structures.…”

Separation of Stereoisomeric Mixtures of Nafronyl as a Representative of Compounds Possessing Two Stereogenic Centers By Coupling Crystallization, Diastereoisomeric Conversion and Chromatography

“…[1][2][3][4] This trend emerged as a result of increasing awareness of individual biological properties for opposite enantiomers in racemic drugs. [5][6][7][8] Two approaches can be used to produce single enantiomers, which involve either resolution of racemates or stereoselective synthesis from achiral material. 9 Nevertheless, manufacturing racemates is usually more economical than stereoselective synthesis of enantiomers.…”

“…The latter allows overcoming the problem associated with the yield limitation in chiral resolutions, where unwanted enantiomers are wasted. [8][9][10][11] A number of separation techniques can be used for the optical resolution. Among them chiral chromatography and enantioselective crystallization are considered the most straightforward, economical and easiest to perform on a large scale.…”