IMPLICATIONS OF CHIRAL INVERSION ON ENVIRONMENTAL BEHAVIOR

Enantiomers of chiral compounds often undergo enantioselective interactions in a chiral system. Chiral systems are common in the environment. They can be provided by various biotic and abiotic substances such as organic solvents, energy sources such as plane-polarized light, solid organic matter, solid surfaces, and biological building blocks such as proteins, oligosaccharides, phospholipids, and nucleic acids. Interactions in a chiral environment can be visualized using the three-point model (Figure 2.8). The moieties around a chiral element have high binding energy in the eutomer compared to the distomer. Hence, when a eutomer undergoes chiral inversion, it loses its affinity for the biological receptor. The stereoconfiguration of chiral compounds often elicit enantiomer-specific molecular binding, catalysis, and stabilization. Such enantiomer-specific interactions cause the enantioselectivity observed in the therapeutic and toxicological properties, environmental behavior, and human and environmental health effects. Hence, in the past three decades, research interest on the configurational stability of chiral pharmaceuticals and pesticides increased steadily.

Chiral inversion influences the biological properties and fate of configurationally labile pollutants. If the receptor was responsible for the biodegradation of the chiral pollutant in the environment, then the more persistent distomer will be enriched. However, if the distomer is the one that undergoes chiral inversion, then the chiral pollutant will be less persistent. In addition, if the more potent enantiomer undergoes chiral inversion, then the overall toxicity of the chiral pollutant decreases. Hence, chiral inversion has implications on the fate and toxicity of chiral pollutants in the environment and in food.

FACTORS INFLUENCING CHIRAL INVERSION IN THE ENVIRONMENT

Enantiomers undergo diverse types of chiral inversion depending on their form of chirality (helical, axial, or center) or the functional groups present around the chiral element. Table 2.1 shows the distinct types of chiral inversion that have been observed in pharmaceutical compounds. Chiral inversion can occur in humans and the environment due to solvent, heat, enzymatic, photo, and pH induction. Enzyme-mediated chiral inversion is the most observed pathway in humans and the

Chiral inversion of enantiomers and its implications on the environmental behavior of the contaminant. (From Sanganyado et al. (2020). Used with permission from Elsevier Ltd.)

FIGURE 2.8 Chiral inversion of enantiomers and its implications on the environmental behavior of the contaminant. (From Sanganyado et al. (2020). Used with permission from Elsevier Ltd.)

environment. Solvent-, heat-, and photo-induced chiral inversion occurs in compounds with lower energy barriers.

Solvent-Induced Chiral Inversion

Understanding the stability of chiral pollutants in solvents is important for accurate quantitative human and environmental risk assessment. Solvents play a key role in the transport of chiral pollutants in the environment as w'ell as in enantioselective analysis. For example, chiral pollutants are often found in aquatic environments where they can persist for short or lengthy periods depending on the stability of the compound. Previous studies have shown that some enantiomers that have low' energy barriers such as helical compounds can undergo chiral inversion in water. A helical nanostructure formed by a L-glutamide amphiphile underwent helical inversion following exposure to water (Liu et al., 2019). It w'as proposed that the left-handed helices had hydrogen bonding predominantly while right-handed helices had rt-rt stacking (Liu et al., 2019). The addition of water affected the hydrogen bonding between L-glutamide amphiphile. In another study, water was showrn to slow down the cyclization chiral a-diimines and promoted the rotation of the C-N bond (Aresu et al., 2013). These studies demonstrate that water-induced chiral inversion is important in synthesis of chiral compounds. Water-induced chiral inversion in compounds with a chiral center mainly occurs in enantiomers with low energy inversion barrier. Such compounds are normally less sterically hindered and often have a nitrogen rather than a carbon chiral center. Hence, the chiral inversion has been observed in amines (R,N, R is an alkyl group) but not in aminium salts (R,NH+), w'hich have a higher energy inversion

TABLE 2.1

Nature and Mechanisms of Chiral Inversion in Chiral Compounds of Pharmaceutical Concern

Compound

Nature of Chiral Inversion

Comment

Biphenyl and chlorobiphenyls

Exocyclic bond rotation

The enantiomers span a wide range of inversion barriers.

Gossypol

Exocyclic bond rotation

High inversion barrier warrants chiral stability to the enantiomers.

Peptides

Peptide bond rotation

The three-dimensional structure is stabilized by amino groups.

Lidocaine

N—CO bond rotation

Various conformational groups impact the pharmacological properties.

Cyclobutane, cyclopentane and cyclohexane

Rotation of the single endocyclic bonds

Partial rotation on the endocyclic single bond resulting in ring reversal.

Amfepramone and cathinone

Reversible chiral inversion at a configurationally labile asymmetric a-carbon

Metabolic racemization not catalyzed by an enzyme.

Hyoscyamine

Reversible chiral inversion at a configurationally labile asymmetric a-carbon

Racemization occurs slowly during storage.

Oxazepam

Reversible chiral inversion at a configurationally labile asymmetric a-carbon

Racemization occurs fast.

Piperidine and A'-methylpiperidine

Ring reversal combined with nitrogen inversion

Conformational behavior about the nitrogen stereogenic center influenced by the presence of methyl group.

Source: From Testa et al. (2016). Used with permission from Elsevier Ltd.

barrier (Kaur and Vikas, 2017). Liu et al. (2005) found that synthetic pyrethroid insecticides underwent chiral inversion in water at the asymmetric a-carbon position. Further studies confirmed that water induced chiral inversion of synthetic pyrethroids such as cypermethrin and permethrin (Qin et al., 2006; Qin and Gan, 2007). However, the extent of chiral inversion caused by water is influenced by temperature and pH. A previous study found fenpropathrin, malathion, and phenthoate racemized more rapidly at pH 7.0 than at pH 5.8 (Li et al., 2010). This was probably because the chiral inversion in these chiral organophosphorus pesticides was via proton exchange at the asymmetric carbon. It was proposed that chiral inversion occurred following an exchange between an active proton at the asymmetric a-carbon and a protic solvent such as an alcohol or water. Briefly, the proton at the asymmetric a-carbon is comparatively acidic and can be donated resulting in an intermediate carbanion (Figure 2.9). The parent compound can be regenerated in protic solvents at different sides of the carbanion face. Chiral inversion will result depending on the face the proton is regenerated. Such a process can occur in the environment. Hence, these results suggest that abiotic processes such as dissolution in water may contribute to changes in enantiomeric composition of chiral pollutants in aquatic environments (Sanganyado et al., 2020). However, there are few studies that have investigated water-induced chiral inversion in the environment.

Chiral inversion has profound consequences on pharmacology and the accuracy of enantioselec- tive analysis techniques. A previous study found that phosphate, hydroxyl ions, albumin, and amino acids catalyzed the chiral inversion of thalidomide in mammals (Reist et al., 1998). The yield of basic amino acids was higher than neutral and acidic amino acids, and this suggested that chiral inversion of thalidomide was base catalyzed. Hence, the catalysis activity observed in albumin was

Proposed chiral inversion mechanism of fenpropathrin in protic solvents such as alcohols and water

FIGURE 2.9 Proposed chiral inversion mechanism of fenpropathrin in protic solvents such as alcohols and water. (Used with permission from Li et al.. 2010.) ascribed to the presence of basic amino acid functional groups. It was proposed that chiral inversion in thalidomide occurred via electrophilic substitution. In analytical chemistry, chiral analytes are often stored in solvents prior to analysis and they can undergo chiral inversion during storage. Axially chiral 1,1 '-binaphthyls were shown to undergo solvent-dependent chiral inversion in the presence of polar and nonpolar solvents (Takaishi et al., 2020). Chiral inversion occurred following the inversion of an excimer chirality due to intermolecular hydrogen bond interactions in the excited state. An excimer is a highly unstable dimeric or heterodimeric molecule that is formed by two smaller molecules. Cypermethrin was shown to undergo rapid enantiomerization at the asymmetric a-carbon position in isopropanol and methanol (Qin and Gan, 2007). However, no chiral inversion was observed when the cypermethrin was stored in methylene chloride, acetone, or hexane. Interestingly, the degree of enantiomerization was influenced by the temperature and presence of water as a co-solvent. These results show that the mobile phase conditions during enantioselective analysis can affect the accuracy of the analytical technique. Furthermore, chiral inversion in enan- tiopure commercial pesticides due to storage conditions can result in a decrease in the pesticide’s efficacy.

 
Source
< Prev   CONTENTS   Source   Next >