Circular dichroism spectroscopy and DFT calculations in determining absolute configuration and E/Z isomers of conjugated oximes

Abstract

The primary purpose of this work was to demonstrate the suitability of circular dichroism (CD) spectroscopy in stereochemical studies of α,β-unsaturated oximes, with particular emphasis on determination of E and Z geometry of the oxime double bond. As models for this study, O-phenyl and O-triphenylmethyl (trityl) oximes of 4-hydroxy-2-methylcyclopent-2-en-1-one were selected. These model compounds differ in both absolute configuration at C4 carbon atom and E-Z configuration of the oxime double bond. The basic dichroic technique applied was electronic circular dichroism (ECD) assisted by quantum-chemical calculations and vibrational circular dichroism (VCD) for selected cases. Such an approach enabled effective implementation of both goals. Thus, we were able to associate the signs of Cotton effects in the range of 190-240 nm with the absolute configuration at C4 and within 240-300 nm with the E- or Z-geometry of the oxime double bond. Within this work, optical activity of the protecting trityl group was also studied towards formation of the propeller-shaped conformations by using the same combined CD/DFT methodology. As shown, the helical structure of the trityl group has a considerable influence on the ECD spectra. However, the MPM and PMP conformers of the trityl group are in fact almost equally populated in the conformational equilibrium, making it impossible to distinguish them. On the other hand, rotamers of the hydroxyl group at C4 show a decisive impact on the VCD spectra in both phenoxy and trityl oximes.

A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases

“…In recent times CD, in its electronic and vibrational ranges (ECD and VCD, respectively), is becoming an increasingly important and productive research tool because it effectively determines the absolute configuration, conformation, and optical purity of chiral molecules. This is evidenced by, for example, the constantly growing number of literature reports on its practical and successful use, such as these few newest links indicated here [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Computational methods and points for attention in absolute configuration determination

“…Thus, it was assigned as (Z)-10a. As another method, ECD, which will be referred to later, it is also a good way to assign the E/Z structures (Rode and Frelek, 2017).…”

E/Z configurational determination of oximes and related derivatives through quantum mechanics NMR calculations: scope and limitations of the leading probabilistic methods

“…16,17 Despite these important advances, the methods described have their own scopes and limitations, which prompted the development of alternative approaches. 18 In this regard, NMR calculations with quantum-based methods represent a simple, useful and convenient strategy to facilitate the assignment of complex molecules. [19][20][21][22][23] These tools have been consolidated over time to the extent that nowadays they are routinely used in structural elucidation, complementing synergistically experimental NMR spectroscopy.…”