Three Point Chiral Recognition and Resolution of Amino Alcohols Through Well‐Defined Interaction Inside a Metallocavity

Abstract

Recognition and separation of one enantiomer over its mirror image is important because of the different biochemical activity shown by chiral compounds.[1] For example, a-limonene and linalool have a different smell [2] depending on the chirality and one enantiomer of the antidepressant drug methylphenidate is 13 times more potent [3] than its isomer. Ideally, recognition of an enantiomer requires recognition of three out of four different groups around an sp 3 -hybridised carbon centre.[4] Recognition of the groups in biological receptors often uses non-covalent interactions as observed in the case of adrenaline receptors. [5,6] The involvement of hydrogen bonds and other weak interactions in the recognition process has the advantage of easy recovery of the guest, but the lability of the guest makes the isolation of the hostguest complex more difficult.Recognition and separation of enantiomers by using synthesised hosts has been approached from diverse angles, [7] including a few that use a rigid metal-organic framework [8] (MOF). Although separation by using a chiral adsorbent as the stationary phase has progressed substantially, [7b-d] the understanding of recognition at the molecular level is limited to molecular modelling due to the difficulty in structural characterisation of large organic or MOF hosts.[1, 9-10] For example, Kim and co-workers used structurally characterised porous channels of a chiral metal complex as a host to enhance the stereoselectivity of an organic reaction, but structural characterisation with the adduct was not possible. [9] A low molecular weight rigid host would, in principle, facilitate structural characterisation, but it is challenging to accommodate three different recognition sites within a small host. Chin and co-workers, by using a chiral Co III complex as the host, showed the chiral interaction between the host and chiral guest in a set of structurally characterised covalently bonded host-guest complexes, but chiral separation was not possible because the interactions were weak due to the open nature of the cavity. [11] In a continuation of our earlier attempts [12] at synthesising a rigid chiral host by using metal complexes, we now present the first report on the synthesis and structural characterisation of a medium-sized chiral metallocavity and its hostguest complexes in which two different chiral amino alcohols were recognised through well-defined three point recognition resulting in chiral separation.We chose amino alcohols [13] as the target guest because of their structural similarity to adrenaline and noradrenaline, a hormone and neurotransmitter, respectively, (Scheme 1) and amino alcohols have two different hydrogen-bonding capable groups. Thus, binding with the host can be enhanced by electrostatic attraction between the cationic ammonium form of the amino alcohol and the use of an anionic host.A schematic representation of the sequence of reactions has been shown in Scheme 2.

Encapsulation of a Water Octamer Chain in a Chiral 2D Sheetlike Supramolecular Coordination Network Composed of Dinickel–Dicarboxylate Subunits

“…On the basis of these two examples, it is inferred that the deprotonation of the phenolic −OH group depends on the intramolecular hydrogen bonding and not on the amount of the base used. Using other neutral or monoanionic ligands, like imidazole, SCN − , or benzoate, three other 1: 21,22 In the case of [Ni(Hhissal) 2 ]•H 2 O, the ligand acts as a monoanion due to strong intermolecular hydrogen bonding between the phenolic OH group and the carboxylate group of the next molecule. On the other hand, in [Ni(Hhissal)(benzoate)(H 2 O)]•H 2 O, the intramolecular hydrogen bonding between one of the oxygens of the benzoate group and the OH group of the ligand is responsible for it to be a neutral species even when 2 equiv of the base is used.…”

“…On the basis of these two examples, it is inferred that the deprotonation of the phenolic −OH group depends on the intramolecular hydrogen bonding and not on the amount of the base used. Using other neutral or monoanionic ligands, like imidazole, SCN – , or benzoate, three other 1:1 complexes [Ni­(hissal)­(imidazole) 2 ], [Ni­(Hhissal)­(SCN)­(H 2 O)]·H 2 O, and [Ni­(Hhissal)­(benzoate)­(H 2 O)]·H 2 O have been reported. , In the case of [Ni­(Hhissal) 2 ]·H 2 O, the ligand acts as a monoanion due to strong intermolecular hydrogen bonding between the phenolic OH group and the carboxylate group of the next molecule. On the other hand, in [Ni­(Hhissal)­(benzoate)­(H 2 O)]·H 2 O, the intramolecular hydrogen bonding between one of the oxygens of the benzoate group and the OH group of the ligand is responsible for it to be a neutral species even when 2 equiv of the base is used.…”

“…in amino acids, these serve as a good candidate for the formation of hydrogen-bonded networks. In recent years, transition metal complexes of reduced Schiff base ligands composed of amino acids and salicylaldehyde have been studied. − Numerous coordination polymers and supramolecular coordination networks (SCNs) of such ligands have also been reported in the literature. , Hydrogen bonding, along with other weak interactions, like π–π and cation−π interactions, is the significant feature of these supramolecular networks. − One such ligand, H 2 hissal ligand (H 2 hissal = histidinesalicylic acid), has been used in SCNs of several transition metal ions such as Ni­(II), Cu­(II), Zn­(II), and Fe­(III). − This nonplanar ligand is unique with the presence of an imidazole moiety along with a phenolic −OH group in addition to the amino and the carboxylate groups.…”

A review of recent advances in mass spectrometric methods for gas-phase chiral analysis of pharmaceutical and biological compounds

“…The three-point model has been successfully used in traditional wet chiral analysis methods such as chiral liquid chromatography [27] and also is the basis of the current mass spectrometric analysis methods [28]. Although, the three-point rule is commonly invoked, the fundamental understanding of the nature of chiral recognition has been pursued on a phenomenological basis [16,24].…”

Racemic drug resolution: a comprehensive guide

“…This resolution technique is based on the three-point interaction between an analyte and a chiral selector. 4,5 In a matched pair, one of the enantiomers forms three-point interactions with the chiral selector (transient diastereomer) and elutes slowly. These types of diastereomers are thermodynamically and kinetically stable and less soluble.…”