Computational methods and points for attention in absolute configuration determination

Abstract

With the rapid development of high performance computers and computational methods, including software, an increasing number of experimental chemists have tried to use computational methods such as optical rotation (OR, including the matrix model), optical rotatory dispersion (ORD), electronic circular dichroism (ECD or CD), vibrational circular dichroism (VCD), and magnetic shielding constants—nuclear magnetic resonance (NMR)—to explain and/or assign absolute configuration (AC) for various compounds. Such reports in the field of natural products have increased dramatically. However, every method has its range of application. This leads, in some cases, to incorrect conclusions by researchers who are not familiar with these methods. In this review, we provide experimental chemists and researchers with more computational details and suitable suggestions, and especially hope that this experience may help readers avoid computational pitfalls. Finally, we discuss the use of simplified models to replace original complex structures with a long side chain. The fundamental basis for using models to represent complex chiral compounds, such as in OR calculations, is the existence of conformation pairs with near canceling conformer contributions that justify the use of models rather than the original compounds. Using examples, we here introduce the transition state (TS) calculation, which may benefit readers in this area for use and mastery for their AC study. This review will summarize the general concepts involved in the study of AC determinations.

Vibrational Circular Dichroism Spectroscopy of Chiral Molecular Crystals: Insights from Theory

“…Interestingly, any of the overabundant absorption peaks in the mid‐IR can potentially show VCD and thereby indicate how the transition is connected to the chiral structure. This property has made VCD spectroscopy the method of choice when it comes to the determination of absolute configurations [5–9] …”

“…This property has made VCD spectroscopy the method of choice when it comes to the determination of absolute configurations. [5][6][7][8][9] Vibrational spectroscopy in the mid-IR addresses the intramolecular degrees of freedom, but it is also susceptible to intermolecular effects. This is due to the fact that the strength and polarity of chemical bonds themselves are affected by noncovalent interactions, which manifests in frequency shifts in the IR spectrum.…”

Pitfalls in the Optimization of Conformer Populations to Maximize the Similarity between Predicted and Experimental Chiroptical Spectra

“…Chiroptical spectroscopy is often used for the determination of the absolute configurations (ACs) of chiral molecules, by comparing the observed chiroptical properties with those obtained by quantum chemical calculations. , To calculate a theoretical chiroptical property, one must first generate a valid set of structures, which may be obtained using manual structure building, conformational search algorithms (such as Conflex, Spartan, or PC model), molecular dynamics simulations, or the more sophisticated conformer-rotamer ensemble sampling tool (CREST) . The populations of conformers are then derived from geometry optimization for identifying minimum energy structures and subsequent energy-based Boltzmann population weighting, using Gibbs, electronic, or zero-point energies.…”

7.1′,8.3′- and 7.3′,8.5′-Connected Bicyclo[3.2.1]octanoids and Oxabicyclo[3.2.2]nonane-Type Neolignans from Ocotea aciphylla: Structures and Absolute Configurations

“…After a combination of column chromatography on silica gel, gel filtration on Sephadex LH-20, and semipreparative reversedphase HPLC separations of the aforementioned hexane and CH 2 Cl 2 phases, 14 new neolignans, comprising 11 bicyclo[3.2.1]octanoids of the macrophyllin type formed through a 7.3′,8.5′ coupling between C 6 −C 3 units, one of which with an unusual side chain at C-1′ (2−12), two belonging to a rare group of bicyclo[3.2.1]octanoids exhibiting a 7.1′,8.3′ linkage (14,15), and one oxabicyclo[3.2.2]nonanetype neolignan (13), were obtained. Additionally, known compounds including a guianin-type neolignan originating from a 7.3′,8.1′ coupling (16), nectamazin A (1), the sesquiterpenes cubenol, epicubenol, torreyol, eudesm-4(15)ene-1β,6α-diol, germacrene D, and spathulenol, the phenylpropanoids dillapiol (17) and isoelemicin (18), and the phytosterols sitosterol, stigmasterol, and campesterol were also isolated. Neolignans 1, 2, 4, and 5 and the phytosterols were obtained from both the leaves and trunk bark.…”

“…Among these neolignans, 13 are new compounds, including 11 representatives of the macrophyllin type, with one bearing an uncommon side chain at C-1′, and two formed through a rare 7.1′,8.3′ oxidative coupling between C 6 −C 3 units. Furthermore, a novel oxabicyclo[3.2.2]nonane type (13) was also obtained, along with a known neolignan with a guianin-type neolignan skeleton (16) and nectamazin A (1). Additionally, six known cadinane-, eudesmane-, aromadendrane-, and germacrane-type sesquiterpenoids, two known phenylpropanoid derivatives (17,18), and the phytosterols sitosterol, stigmasterol, and campesterol were also isolated.…”