Determination of absolute structure using Bayesian statistics on Bijvoet differences

Area of Science:

• Crystallography and Structural Chemistry
• Computational Chemistry and Molecular Modeling
• Pharmaceutical Sciences and Drug Discovery

Background:

• Determining the absolute structure of enantiopure compounds is crucial in pharmaceutical development.
• Existing methods, like the Flack x parameter, have limitations in precision and applicability.
• Bijvoet-pair intensity differences are key to distinguishing enantiomers but require robust analytical frameworks.

Purpose of the Study:

• To develop a novel probabilistic approach for absolute structure determination of enantiopure compounds.
• To provide a more precise measure of chiral composition uncertainty compared to existing methods.
• To validate the method's efficacy for biologically relevant molecules, particularly those with oxygen as the primary scatterer.

Main Methods:

• A new probabilistic formalism based on Bijvoet-pair intensity differences was developed.
• The method calculates relative probabilities for different chiral structure models.
• The approach generates an absolute structure parameter analogous to the Flack x parameter, with associated standard uncertainty.

Main Results:

• The new method provides relative probabilities for chiral composition models.
• The derived uncertainty is approximately half that of the standard Flack x parameter.
• Reliable absolute configuration assignments were achieved using Cu Kalpha and, in some cases, Mo Kalpha diffraction data.

Conclusions:

• The proposed probabilistic method offers a more accurate and reliable determination of absolute structure.
• This approach is particularly advantageous for analyzing diffraction data from pharmaceutical compounds.
• The method demonstrates the feasibility of accurate absolute configuration determination even with standard X-ray sources.