Determination of the Absolute Configurations of Natural Products via Density Functional Theory Calculations of Optical Rotation, Electronic Circular Dichroism, and Vibrational Circular Dichroism:  The Cytotoxic Sesquiterpene Natural Products Quadrone, Suberosenone, Suberosanone, and Suberosenol A Acetate

Abstract

The determination of the absolute configurations (ACs) of chiral molecules using the chiroptical techniques of optical rotation (OR), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) has been revolutionized by the development of density functional theory (DFT) methods for the prediction of these properties. Here, we demonstrate the significance of these advances for the stereochemical characterization of natural products. Time-dependent DFT (TDDFT) calculations of the specific rotations, [alpha](D), of four cytotoxic natural products, quadrone (1), suberosenone (2), suberosanone (3), and suberosenol A acetate (4), are used to assign their ACs. TDDFT calculations of the ECD of 1 are used to assign its AC. The VCD spectrum of 1 is reported and also used, together with DFT calculations, to assign its AC. The ACs of 1 derived from its [alpha](D), ECD, and VCD are identical and in agreement with the AC previously determined via total synthesis. The previously undetermined ACs of 2-4, derived from their [alpha](D) values, have absolute configurations of their tricyclic cores identical to that of 1. Further studies of the ACs of these molecules using ECD and, especially, VCD are recommended to establish more definitively this finding. Our studies of the OR, ECD, and VCD of quadrone are the first to utilize DFT calculations of all three properties for the determination of the AC of a chiral natural product molecule.

Determination of the absolute configurations of natural products via density functional theory calculations of vibrational circular dichroism, electronic circular dichroism, and optical rotation: The iso‐schizozygane alkaloids isoschizogaline and isoschizogamine

“…It follows that the use of ECD for determining ACs is most effective when the low-energy electronic transitions are limited in number and density, and hence well-resolved experimentally. Such a situation was observed in our study of the ECD of the natural product quadrone, 43 where the carbonyl group n ? p* transition was well-resolved.…”

The online assignment of the absolute configuration of natural products: HPLC‐CD in combination with quantum chemical CD calculations

“…[23][24][25][26][27] This procedure has become a most valuable tool for assigning absolute configurations to a broad variety of chiral compounds of synthetic and natural origin, involving all kinds of chirality, not only stereogenic centers, but also axial and/or planar chirality. The chiral structures 1-10 in Figure 1 represent a small selection of compounds whose absolute configuration had as yet been unknown, but were clearly assigned by theoretical CD investigations in our group.…”

Determination of absolute configuration of conformationally flexible cis‐dihydrodiol metabolites: Effect of diene substitution pattern on the circular dichroism spectra and optical rotations

“…If the use of OR and CD confrontation yields opposite ACs, the AC determination using either phenomenon is ambiguous. 23 Such methodology has been used quite recently for the stereochemical characterization of cytotoxic natural products 24 and chiral rigid and flexible alkenes with satisfactory results.…”