Pushing the boundaries of VCD spectroscopy in natural product chemistry.

Vibrational circular dichroism (VCD) is one of the most powerful techniques to assess the stereochemistry of chiral molecules in solution state. The need for quantum chemical calculations to interpret experimental data, however, has precluded its widespread use by non-experts. Herein, we propose the search and validation of IR and VCD spectral markers to circumvent the requirement of DFT calculations allowing for absolute configuration assignments even in complex mixtures. To that end, a combination of visual inspection and machine learning based methods is used. Monoterpene mixtures are selected for this proof-of-concept study.

Anti-SARS-CoV-2 Activity and Cytotoxicity of Amaryllidaceae Alkaloids from Hymenocallis littoralis.

The Amaryllidaceae species are well-known as a rich source of bioactive compounds in nature. Although Hymenocallis littoralis has been studied for decades, its polar components were rarely explored. The current phytochemical investigation of Amaryllidaceae alkaloids from H. littoralis led to the identification of three previously undescribed compounds: O-demethyl-norlycoramine (1), (-)-2-epi-pseudolycorine (2) and (+)-2-epi-pseudolycorine (3), together with eight known compounds: 6α-hydroxyhippeastidine (4), 6ß-hydroxyhippeastidine (5), lycorine (6), 2-epi-lycorine (7), zephyranthine (8), ungeremine (9), pancratistatin (10) and 9-O-demethyl-7-O-methyllycorenine (11). Among the eight previously reported compounds, five were isolated from H. littoralis for the first time (compounds 4, 5, 7, 8, and 9). Compounds 1, 4, 5, 7, 8, and 11 exhibited weak anti-SARS-CoV-2 activity (EC50 = 40-77 µM) at non-cytotoxic concentrations. Assessment of cytotoxicity on the Vero-E6 cell line revealed lycorine and pancratistatin as cytotoxic substances with CC50 values of 1.2 µM and 0.13 µM, respectively. The preliminary structure-activity relationship for the lycorine-type alkaloids in this study was further investigated, and as a result ring C appears to play a crucial role in their anti-SARS-CoV-2 activity.

Epimeric Mixture Analysis and Absolute Configuration Determination Using an Integrated Spectroscopic and Computational Approach-A Case Study of Two Epimers of 6-Hydroxyhippeastidine.

Structural elucidation has always been challenging, and misassignment remains a stringent issue in the field of natural products. The growing interest in discovering unknown, complex natural structures accompanies the increasing awareness concerning misassignments in the community. The combination of various spectroscopic methods with molecular modeling has gained popularity in recent years. In this work, we demonstrated, for the first time, its power to fully elucidate the 2-dimensional and 3-dimensional structures of two epimers in an epimeric mixture of 6-hydroxyhippeastidine. DFT calculation of chemical shifts was first performed to assist the assignment of planar structures. Furthermore, relative and absolute configurations were established by three different ways of computer-assisted structure elucidation (CASE) coupled with ORD/ECD/VCD spectroscopies. In addition, the significant added value of OR/ORD computations to relative and absolute configuration determination was also revealed. Remarkably, the differentiation of two enantiomeric scaffolds (crinine and haemanthamine) was accomplished via OR/ORD calculations with cross-validation by ECD and VCD.

Exploring machine learning methods for absolute configuration determination with vibrational circular dichroism.

The added value of supervised Machine Learning (ML) methods to determine the Absolute Configuration (AC) of compounds from their Vibrational Circular Dichroism (VCD) spectra was explored. Among all ML methods considered, Random Forest (RF) and Feedforward Neural Network (FNN) yield the best performance for identification of the AC. At its best, FNN allows near-perfect AC determination, with accuracy of prediction up to 0.995, while RF combines good predictive accuracy (up to 0.940) with the ability to identify the spectral areas important for the identification of the AC. No loss in performance of either model is observed as long as the spectral sampling interval used does not exceed the spectral bandwidth. Increasing the sampling interval proves to be the best method to lower the dimensionality of the input data, thereby decreasing the computational cost associated with the training of the models.

Antiplasmodial Oleanane Triterpenoids from Terminalia albida Root Bark.

Phytochemical investigation of the n-BuOH extract of the roots of Terminalia albida Sc. Elliot (Combretaceae) led to the isolation and identification of 10 oleanane triterpenoids (1-10), among which six new compounds, i.e., albidanoside A (2), albidic acid A (4), albidinolic acid (5), albidienic acid (8), albidolic acid (9), and albidiolic acid (10), and two triterpenoid aglycones, i.e., albidic acid B (6) and albidic acid C (7), were isolated here for the first time from a natural source, along with two known compounds. The structures of these constituents were established by means of 1D and 2D NMR spectroscopy and ESI mass spectrometry. The isolated compounds were evaluated for their antiplasmodial and antimicrobial activity against the chloroquine-resistant strain Plasmodium falciparum K1, Candida albicans, and Staphylococcus aureus. Compounds 1-4, 6, 7, and 8 showed moderate antiplasmodial activity with IC50 values between 5 and 15 µM. None of the tested compounds were active against C. albicans or S. aureus. These findings emphasize the potential of T. albida as a source for discovery of new antiplasmodial compounds.

Solvation and the secondary structure of a proline-containing dipeptide: insights from VCD spectroscopy.

In this study we investigate the IR and VCD spectra of the diastereomeric dipeptide Boc-Pro-Phe-(n-propyl) 1 in chloroform-d1 (CDCl3) and the strongly hydrogen bonding solvent dimethylsulfoxide-d6 (DMSO-d6). From comparison of the experimental spectra, the amide II spectral region is identified as marker signature for the stereochemistry of the dipeptide: the homochiral LL-1 features a (+/-)-pattern in the amide II region of the VCD spectrum, while the amide II signature of the diastereomer LD-1 is inverted. Computational analysis of the IR and VCD spectra of LL-1 reveals that the experimentally observed amide II signature is characteristic for a ßI-turn structure of the peptide. Likewise, the inverted pattern found for LD-1 arises from a ßII-turn structure of the dipeptide. Following a micro-solvation approach, the experimental spectra recorded in DMSO-d6 are computationally well reproduced by considering only a single solvent molecule in a hydrogen bond with N-H groups. Considering a second solvent molecule, which would lead to a cleavage of intramolecular hydrogen bonds in 1, is found to give a significantly worse match with the experiment. Hence, the detailed computational analysis of the spectra of LL- and LD-1 recorded in DMSO-d6 confirms that the intramolecular hydrogen bonding pattern, that stabilizes the ß-turns and other conformations of LL- and LD-1 in apolar solvents, remains intact. Our findings also show that it is essential to consider solvation explicitly in the analysis of the IR and VCD spectra of dipeptides in strongly hydrogen bonding solvents. As the solute-solvent interactions affect both conformational preferences and spectral signatures, it is also demonstrated that this inclusion of solvent molecules cannot be circumvented by applying fitting procedures to non-solvated structures.

Impact of conformation and intramolecular interactions on vibrational circular dichroism spectra identified with machine learning.

Vibrational Circular Dichroism (VCD) spectra often differ strongly from one conformer to another, even within the same absolute configuration of a molecule. Simulated molecular VCD spectra typically require expensive quantum chemical calculations for all conformers to generate a Boltzmann averaged total spectrum. This paper reports whether machine learning (ML) can partly replace these quantum chemical calculations by capturing the intricate connection between a conformer geometry and its VCD spectrum. Three hypotheses concerning the added value of ML are tested. First, it is shown that for a single stereoisomer, ML can predict the VCD spectrum of a conformer from solely the conformer geometry. Second, it is found that the ML approach results in important time savings. Third, the ML model produced is unfortunately hardly transferable from one stereoisomer to another.

Tackling Stereochemistry in Drug Molecules with Vibrational Optical Activity.

Chirality plays a crucial role in drug discovery and development. As a result, a significant number of commercially available drugs are structurally dissymmetric and enantiomerically pure. The determination of the exact 3D structure of drug candidates is, consequently, of paramount importance for the pharmaceutical industry in different stages of the discovery pipeline. Traditionally the assignment of the absolute configuration of druggable molecules has been carried out by means of X-ray crystallography. Nevertheless, not all molecules are suitable for single-crystal growing. Additionally, valuable information about the conformational dynamics of drug candidates is lost in the solid state. As an alternative, vibrational optical activity (VOA) methods have emerged as powerful tools to assess the stereochemistry of drug molecules directly in solution. These methods include vibrational circular dichroism (VCD) and Raman optical activity (ROA). Despite their potential, VCD and ROA are still unheard of to many organic and medicinal chemists. Therefore, the present review aims at highlighting the recent use of VOA methods for the assignment of the absolute configuration of chiral small-molecule drugs, as well as for the structural analysis of biologics of pharmaceutical interest. A brief introduction on VCD and ROA theory and the best experimental practices for using these methods will be provided along with selected representative examples over the last five years. As VCD and ROA are commonly used in combination with quantum calculations, some guidelines will also be presented for the reliable simulation of chiroptical spectra. Special attention will be paid to the complementarity of VCD and ROA to unambiguously assess the stereochemical properties of pharmaceuticals.

CFA-18: a homochiral metal-organic framework (MOF) constructed from rigid enantiopure bistriazolate linker molecules.

In this work, we introduce the first enantiopure bistriazolate-based metal-organic framework, CFA-18 (Coordination Framework Augsburg-18), built from the R-enantiomer of 7,7,7',7'-tetramethyl-6,6',7,7'-tetrahydro-3H,3'H-5,5'-spirobi[indeno[5,6-d]-[1,2,3]triazole] (H2-spirta). The enantiopurity and absolute configuration of the new linker were confirmed by several chiroselective methods. Reacting H2-spirta in hot N,N-dimethylformamide (DMF) with manganese(ii) chloride gave CFA-18 as colorless crystals. The crystal structure with the composition [Mn2Cl2(spirta)(DMF)2] was solved using synchrotron single-crystal X-ray diffraction. CFA-18 shows a framework topology that is closely related to previously reported metal-azolate framework (MAF) structures in which the octahedrally coordinated manganese(ii) ions are triazolate moieties, and the chloride anions form crosslinked one-dimensional helical chains, giving rise to hexagonal channels. In contrast to MAFs crystallizing in the centrosymmetric space group R3[combining macron], the handedness of the helices found in CFA-18 is strictly uniform, leading to a homochiral framework that crystallizes in the trigonal crystal system within the chiral space group P3121 (no. 152).