Resolution of 2‐chloromandelic acid with (R)‐(+)‐N‐benzyl‐1‐phenylethylamine: chiral discrimination mechanism

Abstract

During the resolution of 2-chloromandelic acid with (R)-(+)-N-benzyl-1-phenylethylamine, the crystals of the less soluble salt were grown, and their structure were determined and presented. The chiral discrimination mechanism was investigated by examining the weak intermolecular interactions (such as hydrogen bond, CH/π, and van der Waals interactions) and molecular packing mode in crystal structure of the less soluble diastereomeric salt. A one-dimensional double-chain hydrogen-bonding network and a "lock-and-key" supramolecular packing mode are disclosed. The investigation demonstrates that hydrophobic layers with corrugated surfaces can fit into the grooves of one another to realize a compact packing, when the molecular structure of resolving agent is much larger than that of the racemate. This "lock-and-key" assembly is recognized to be another characteristic of molecular packing contributing to the chiral discrimination, in addition to the well-known sandwich-like packing by hydrophobic layers with planar boundary surfaces.

Experiment and simulation on kinetic resolution of (R,S)‐2‐chloromandelic acid by enzymatic transesterification

“…Previously, a number of methods have been applied to separate ClMA enantiomers by diastereomeric salt resolution, liquid–liquid extraction, and enantioselective enzymatic hydrolysis of the corresponding nitrile compounds . In addition, some studies had reported that excellent enzyme enantioselectivities could be obtained from esterase‐catalyzed hydrolysis of ( R,S )‐CIMA esters in aqueous or biphasic solutions .…”

Crystal structure of (R)-N-benzyl-1-phenylethanaminium (R)-4-chloromandelate

“…For the resolution of chlorine-substituted mandelic acids, see: He, Gomaa et al (2010); He, Peng et al (2010); Peng et al (2012) Hydrogen-bond geometry (Å , ).…”

“…However, it failed to resolve racemic 2-chloro-mandelic acid. A benzyl functional group was introduced in PEA, leading to a new resolving agent, N-benzyl-phenyl-ethyl-amine-(BPA), which demonstrated a high resolution efficiency in the resolution of 2-chloro-mandelic acid (Peng et al, 2012). In order to obtain insight into the enhanced chiral discrimination ability of BPA, the resolution of 4-chloro-mandelic acid with BPA has been investigated, and the single crystal structure of the resulting less soluble diastereomeric title salt, is reported on herein.…”

Efficient Preparation of (R)‐2‐chloromandelic Acid Via a Recycle Process of Resolution

“…1,2 The preparation of (R)-1 has been investigated by the following general methods: 1) asymmetric synthesis via metal catalyst [3][4][5] or biocatalyst; 6,7 2) racemic resolution by chromatography; 8 3) enzymatic resolution; [9][10][11][12][13][14][15] and 4) diastereomeric salt resolution. [16][17][18][19][20] In methods (1-3), (R)-1 can be obtained in high optical purity. However, these methods are used mainly in the laboratory because of the high price of efficient chiral catalysts and the limitation of equipment.…”

“…Four kinds of resolving agents were used to resolve rac-1: N-benzyl-α-phenylethanamine, 16,17 alanine, 18 1-aryl-2-amino-1,3-propane-diol, 19 and aryloxypropylamine. 20 These resolutions can be achieved via diastereomeric salts, which are always composed of the acid 1 and amine resolving agents.…”