Analytical chemistry on many-center chiral compounds based on vibrational circular dichroism: Absolute configuration assignments and determination of contaminant levels

Mark A.J. Koenis, Eveline H. Tiekink, Davita M.E. van Raamsdonk, Nadav U. Joosten, Susanne A. Gooijer, Valentin P. Nicu, Lucas Visscher, Wybren J. Buma*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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Abstract

The absolute configuration of a chiral molecule is key to its biological activity. Being able to find out what this configuration is, is thus crucial for a wide range of applications. The difficulties associated with such a determination steeply rise as the number of chiral centers in a given compound becomes larger. Concurrently, it becomes increasingly more challenging to determine the levels and identity of potential stereochemical contaminants in a given sample with one and the same technique, leading in practice to extensive and laborious efforts employing multiple analytical techniques. Here, experimental and theoretical studies based on Vibrational Circular Dichroism (VCD) are presented for dydrogesterone, a synthetic drug employed in reproductive medicine that is a prototypical example of such a multi-center chiral compound. We show that our approach allows us to distinguish and assign its absolute configuration without prior knowledge to one of the 64 possible stereoisomers associated with the six chiral centers. Studies on mixtures of dydrogesterone and 6-dehydroprogesterone, one of the diastereomers of dydrogesterone and generally the dominant impurity of dehydrogesterone, show that we can identify the presence of both compounds from one single VCD spectrum. Moreover, we find that we can determine diastereomeric contamination levels as low as 5% from the experimental VCD spectra.

Original languageEnglish
Pages (from-to)100-105
Number of pages6
JournalAnalytica Chimica Acta
Volume1090
Early online date14 Sep 2019
DOIs
Publication statusPublished - 20 Dec 2019

Keywords

  • Absolute configuration
  • Density functional calculation
  • Diastereomeric impurity levels
  • Pharmaceutics
  • Stereochemistry
  • Vibrational optical activity

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