Reliable HPLC separation, vibrational circular dichroism spectra, and absolute configurations of isoborneol enantiomers

Abstract

Resolution of chiral compounds has played an important role in the pharmaceutical field, involving detailed studies of pharmacokinetics, physiological, toxicological, and metabolic activities of enantiomers. Herein, a reliable method by high-performance liquid chromatography (HPLC) coupled with an optical rotation detector was developed to separate isoborneol enantiomers. A cellulose tris(3, 5-dimethylphenylcarbamate)-coated chiral stationary phase showed the best separation performance for isoborneol enantiomers in the normal phase among four polysaccharide chiral packings. The effects of alcoholic modifiers and column temperature were studied in detail. Resolution of the isoborneol racemate displayed a downward trend along with an increase in the content of ethanol and column temperature, indicating that less ethanol in the mobile phase and lower temperature were favorable to this process. Moreover, two isoborneol enantiomers were obtained via a semipreparative chiral HPLC technique under optimum conditions, and further characterized by analytical HPLC, and experimental and calculated vibrational circular dichroism (VCD) spectroscopy, respectively. The solution VCD spectrum of the first-eluted component was consistent with the Density Functional Theory (DFT) calculated pattern based on the SSS configuration, indicating that this enantiomer should be (1S, 2S, 4S)-(+)-isoborneol. Briefly, these results have provided reliable information to establish a method for analysis, preparative separation, and absolute configuration of chiral compounds without typical chromophoric groups.

Vibrational Circular Dichroism Absolute Configuration of Natural Products From 2015 to 2019

“…The VCD spectrum provided its AC as (+)-(2R,6R)−29 after solvation model density (in CCl 4 ) B3LYP/6-31G(d,p) DFT calculations. 32 The isolation of (+)-(7R)-podocephalol (30) from Lasianthaea aurea and the preparation of its derived (−)-(7R)podocephalyl acetate (31) (Figure 7) permitted the first conformational, VCD configurational and supramolecular studies of an arhimachalene. 35 A study of the endophytic fungus Nemania bipapillata (AT-05), isolated from the marine red alga Asparagopsis taxiformis, provided new botryane sesquiterpenoid (+)-(2R,4S,5R,8S)− 4-deacetyl-5-hydroxybotryenalol (32) and the bisnorsesqiterpene (+)-(2R,4S,8S)-nemenonediol B (33) ( Figure 8) whose AC followed from VCD studies.…”

“…The VCD spectra compared well with the calculated spectra of the 2 enantiomers. 31 VCD studies of 2 isolates 32 from Bubonium graveolens provided their AC as (−)-(1S,5R,6S)-2,7,7-trimethylbicyclo[3.1.1] hept-2-en-6-yl acetate (19) and its acetyl derivative 20 (Figure 4). The compounds were already known in the species, although this is the first report on the AC of (−)-20.…”

Chiral Separations in Preparative Scale: A Medicinal Chemistry Point of View

“…Recent examples of applications at preparative scale on polysaccharide-based CSPs include: the enantioseparation of tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetic acid (TPA), a key intermediate for the synthesis of HIV protease inhibitors (enantiomeric purity of 99%) [54]; racemic coumarin derivatives [55]; isoborneol enantiomers [56]; high-affinity 5-HT7 receptor ligand (enantiomeric purity of 100%) [57]; synthetic E2F inhibitor HLM006474 (enantiomeric ratio higher than 99.5/0.5) [58]; novel pan-sigma receptor (SR) modulators, potentially useful in cancer treatment (enantiomeric excess higher than 95%) [59]; among others. Recently, we reported the enantioseparation of cathinone derivatives (amphetamine-like stimulant effects) at multi-milligram scale using the same type of CSPs (Figure 3) [60,61].…”

Enantiomeric Mixtures in Natural Product Chemistry: Separation and Absolute Configuration Assignment

“…The ultraviolet (UV) detector is still the most used, but chiral detectors based on polarimetry or ECD has become a tendency for e.r. determinations [ 25 , 26 , 62 , 63 ]. The use of tandem mass spectrometry for complex sample matrices is also well established [ 64 ].…”

“…The separation of the enantiomers of isoborneol, a monoterpenoid, is a fine example of the use of polysaccharide-based CSPs in LC. The enantiomers were separated on semipreparative scale under normal elution mode using an optical rotatory detector, and their ACs were determined by VCD [ 63 ]. It is important to mention that chiral monoterpenoids, due to their volatility and few or no functional groups for interaction with the chiral selector, is usually enantionseparated by gas chromatography with cyclodextrin derivatives as chiral selectors [ 72 ].…”