Absolute Configuration in 4-Alkyl- and 4-Aryl-3,4-dihydro-2(1H)-pyrimidones:  A Combined Theoretical and Experimental Investigation

Abstract

Structural features (orientation of the carboxyl group, ring puckering), electronic absorption, and circular dichroism spectra of 4-alkyl- and 4-aryl-dihydropyrimidones 1-5 are calculated by semiempirical (AM1, INDO/S), ab initio (HF/6-31G, CIS/6-31G, RPA/6-31G), and density functional theory (B3LYP/6-31G) methods. These calculations allow an assignment of the absolute configuration by comparison of simulated and experimental CD spectra. Although the ab initio methods greatly overestimate electronic transition energies, the general appearance of the experimental CD spectra is quite nicely reproduced by these calculations. Thus, comparison of experimental with calculated CD spectra is a reliable tool for the assignment of the absolute configuration. For 4-methyl derivatives 1, the first enantiopure DHPM examples with no additional aromatic substituent, the stereochemistry at C4 provided by the theoretical results is confirmed by X-ray structure determination of the diastereomeric salt 6. Additional support is the consistent HPLC elution order found for all investigated DHPMs on a cellulose-derived chiral stationary phase.

Absolute configuration of eremophilane sesquiterpenes from Petasites hybridus: Comparison of experimental and calculated circular dichroism spectra

“…For instance, despite the same absolute configuration at C 4 , 4-alkyl dihydropyrimidones display completely different CD spectra from those of 4-aryl derivatives. 58 Complete stereochemical characterization may become necessary as part of further pharmacological characterization of these compounds from the medicinal plant Petasites hybridus. [68][69][70] This work may become the basis for further molecular mechanics and DFT calculations in the field of eremophilane research comparable to those, which have been extensively applied in phytochemistry of other sesquiterpene classes in the context of conformational analysis; for example, theoretical studies on potentially active centers and molecular interactions; simulation of the enzymebinding by inhibitors; elucidation of structure-activity relationships; and determination of the absolute configuration and calculation of CD spectra.…”

An Efficacious Protocol for 4‐Substituted 3,4‐Dihydropyrimidinones: Synthesis and Calcium Channel Binding Studies

“…♣ The C-4 ( S ) configuration of the major enantiomer was also corroborated with the CD spectra (Figure 3) of 16 with that of a 4-methyl DHPM of known absolute configuration. [34] …”

The Generation of Dihydropyrimidine Libraries Utilizing Biginelli Multicomponent Chemistry

“…Alternatively, chiral separation can also be performed by capillary electrophoresis (CE) with chiral modifiers and buffers [64]. The absolute configuration of enantiomerically pure DHPMs is easily derived from circular dichroism (CD) spectra [65]. Despite the advances made in resolution strategies over the past years rapid access to enantiomerically pure DHPM derivatives for high-throughput screening, i.e.…”