Enantiomerically pure oxiranes are valuable electrophilic, chiral synthons [1] and have been introduced into pharmaceutical applications for the synthesis of biologically active polyethers. Stereochemical characterization plays an important role in medicinal chemistry, since chirality is fundamental in the definition of the activity of several biologically active compounds. Consequently, analytical techniques allowing for the stereochemistry to be fully characterized are receiving increasing attention. The absolute configuration of methyl trans-3-(3,4- dimethoxyphenyl)glycidate (trans-1), a recently synthesized building block for the synthesis of methylated analogues of biologically active polymers from different species of comfrey and bugloss [2], was investigated by means of enantioselective high-performance liquid chromatography hyphenated with a circular dichroism detection system (eHPLC-CD) [3]. A Lux Cellulose-4 and a Lux Cellulose-2 columns were successfully employed for the preparative and analytical enantioresolution of racemic trans-1 [4]. The CD spectra of the enantiomeric fractions of trans-1 were then measured both by off-line analysis after preparative chromatographic separation and by stopped-flow measurements during the eHPLC-CD analysis [3]. This last strategy resulted more reliable, because the risk of degradation of the analyte was drastically reduced. The absolute configuration of each enantiomeric fraction was finally determined by comparison of the experimental CD spectra with quantum mechanical (QM) calculations based on time-dependent density functional theory (TD-DFT). The conformationally-averaged theoretical CD spectrum of (2S,3R)-1 reproduced with a reasonable degree of accuracy the CD spectrum of the first-eluted fraction of trans-1 on the Lux Cellulose-2 column: consequently, a full stereochemical characterization of the enantiomers of trans-1 was achieved and the elution order on Lux Cellulose-2 was determined. [1] H.C. Kolb, M.S. VanNieuwenhze, K.B. Sharpless, Catalytic asymmetric dihydroxylation, Chem. Rev. 94 (1994) 2483–2547. [2] V. Barbakadze, L. Gogilashvili, L. Amiranashvili, M. Merlani, K. Mulkijanyan, Novel biologically active phenolic polymers from different species of genera Symphytum and Anchusa (Boraginaceae), J. Chem. Eng. Chem. Res. 1 (2014) 47–53. [3] C. Bertucci, D. Tedesco, Advantages of electronic circular dichroism detection for the stereochemical analysis and characterization of drugs and natural products by liquid chromatography, J. Chromatogr. A 1269 (2012) 69–81. [4] K. Lomsadze, M. Merlani, V. Barbakadze, T. Farkas, B. Chankvetadze, Enantioseparation of chiral epoxides with polysaccharide-based chiral columns in HPLC, Chromatographia 75 (2012) 839–845.
Stereochemical characterization of methyl trans-3-(3,4-dimethoxyphenyl)glycidate by enantioselective HPLC-CD analysis and TD-DFT calculations
Daniele Tedesco
;Edoardo Fabini;Carlo Bertucci
2015
Abstract
Enantiomerically pure oxiranes are valuable electrophilic, chiral synthons [1] and have been introduced into pharmaceutical applications for the synthesis of biologically active polyethers. Stereochemical characterization plays an important role in medicinal chemistry, since chirality is fundamental in the definition of the activity of several biologically active compounds. Consequently, analytical techniques allowing for the stereochemistry to be fully characterized are receiving increasing attention. The absolute configuration of methyl trans-3-(3,4- dimethoxyphenyl)glycidate (trans-1), a recently synthesized building block for the synthesis of methylated analogues of biologically active polymers from different species of comfrey and bugloss [2], was investigated by means of enantioselective high-performance liquid chromatography hyphenated with a circular dichroism detection system (eHPLC-CD) [3]. A Lux Cellulose-4 and a Lux Cellulose-2 columns were successfully employed for the preparative and analytical enantioresolution of racemic trans-1 [4]. The CD spectra of the enantiomeric fractions of trans-1 were then measured both by off-line analysis after preparative chromatographic separation and by stopped-flow measurements during the eHPLC-CD analysis [3]. This last strategy resulted more reliable, because the risk of degradation of the analyte was drastically reduced. The absolute configuration of each enantiomeric fraction was finally determined by comparison of the experimental CD spectra with quantum mechanical (QM) calculations based on time-dependent density functional theory (TD-DFT). The conformationally-averaged theoretical CD spectrum of (2S,3R)-1 reproduced with a reasonable degree of accuracy the CD spectrum of the first-eluted fraction of trans-1 on the Lux Cellulose-2 column: consequently, a full stereochemical characterization of the enantiomers of trans-1 was achieved and the elution order on Lux Cellulose-2 was determined. [1] H.C. Kolb, M.S. VanNieuwenhze, K.B. Sharpless, Catalytic asymmetric dihydroxylation, Chem. Rev. 94 (1994) 2483–2547. [2] V. Barbakadze, L. Gogilashvili, L. Amiranashvili, M. Merlani, K. Mulkijanyan, Novel biologically active phenolic polymers from different species of genera Symphytum and Anchusa (Boraginaceae), J. Chem. Eng. Chem. Res. 1 (2014) 47–53. [3] C. Bertucci, D. Tedesco, Advantages of electronic circular dichroism detection for the stereochemical analysis and characterization of drugs and natural products by liquid chromatography, J. Chromatogr. A 1269 (2012) 69–81. [4] K. Lomsadze, M. Merlani, V. Barbakadze, T. Farkas, B. Chankvetadze, Enantioseparation of chiral epoxides with polysaccharide-based chiral columns in HPLC, Chromatographia 75 (2012) 839–845.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
