Yuanqing Ding

Determination of Absolute Configuration of Natural Products: Theoretical Calculation of Electronic Circular Dichroism as a Tool

Determination of absolute configuration (AC) is one of the most challenging features in the structure elucidation of chiral natural products, especially those with complex structures. With revolutionary advancements in the area of quantum chemical calculations of chiroptical spectroscopy over the past decade, the time dependent density functional theory (TDDFT) calculation of electronic circular dichroism (ECD) spectra has emerged as a very promising tool. The principle is simply based on the comparison of the calculated and experimental ECD spectra: the more closely they match, the more reliable conclusion for the AC assignment can be drawn. This review attempts to use several examples representing monomeric flavonoids, rotationally restricted biflavonoids, complex hexahydroxydiphenoyl-containing flavonoids, conformationally flexible and restrained sesquiterpenoids, cembrane-africanene terpenoids, dihydropyranocoumarins, alkaloids, and dihydroxanthones to illustrate the applicability of this approach in determining the AC of structurally diverse natural products. The findings clearly indicate that the TDDFT calculation of ECD spectra can quantify the contribution of individual conformers and the interaction of multiple chromophores, making it possible to determine the AC of complex chiral molecules. The calculated electronic transitions and molecular orbitals provide new insight into the interpretation of ECD spectra at the molecular level.

Antioxidant activity of the dihydrochalcones Aspalathin and Nothofagin and their corresponding flavones in relation to other Rooibos ( Aspalathus linearis ) Flavonoids, Epigallocatechin Gallate, and Trolox.

The antioxidant activity of rooibos flavonoids, including the dihydrochalcones aspalathin and nothofagin and their corresponding flavone glycosides, was evaluated using the ABTS radical cation, metal chelating, and Fe(II)-induced microsomal lipid peroxidation assays. Epigallocatechin gallate (EGCG) and Trolox were used as reference standards. Optimized geometric conformers of aspalathin and nothofagin, in addition to calculated physicochemical properties, were considered to explain interaction with the microsomal membrane structure and thus relative potency of the dihydrochalcones. The most potent radical scavengers were aspalathin (IC50 = 3.33 microM) and EGCG (IC50 = 3.46 microM), followed by quercetin (IC50 = 3.60 microM) and nothofagin (IC50 = 4.04 microM). The least effective radical scavengers were isovitexin (IC50 = 1224 microM) and vitexin (IC50 > 2131 microM). Quercetin (IC50 = 17.5 microM) and EGCG (IC50 = 22.3 microM) were the most effective inhibitors of lipid peroxidation. Aspalathin (IC50 = 50.2 microM) and catechin (IC50 = 53.3 microM) displayed similar potencies. Nothofagin (IC50 = 1388 microM) was almost as ineffective as its flavone glycoside analogues.

Anti-infective Discorhabdins from a Deep-Water Alaskan Sponge of the Genus Latrunculia

Bioassay- and LC-MS-guided fractionation of a methanol extract from a new deep-water Alaskan sponge species of the genus Latrunculia resulted in the isolation of two new brominated pyrroloiminoquinones, dihydrodiscorhabdin B and discorhabdin Y (2), along with six known pyrroloiminoquinone alkaloids, discorhabdins A (3), C (4), E (5), and L (6), dihydrodiscorhabdin C (7), and the benzene derivative 8. Compounds 3, 4, and 7 exhibited anti-HCV activity, antimalarial activity, and selective antimicrobial activity. Although compounds 3 and 7 displayed potent and selective in vitro antiprotozoal activity, Plasmodium berghei-infected mice did not respond to these metabolites due to their toxicity in vivo.

New acylphloroglucinol derivatives with diverse architectures from Hypericum henryi.

Hyphenrones A-F (1-6), six polycyclic polyprenylated acylphloroglucinol derivatives with four architectures including three unprecedented cores as exemplified by 1, 3, and 4, were isolated from Hypericum henryi. Compounds 3 and 4 possess two unique 5/8/5 and 6/6/5/8/5 fused ring systems, respectively. Their absolute configurations were defined by experimental and calculated ECD of 4 and X-ray diffractions of 5 and 6, coupled with their putative biosynthetic origins. Three compounds exhibited interesting AChE inhibitory activities.

4-Arylflavan-3-ols as Proanthocyanidin Models: Absolute Configuration via Density Functional Calculation of Electronic Circular Dichroism

Density functional theory/B3LYP has been employed to optimize the conformations of selected 4-arylflavan-3-ols and their phenolic methyl ether 3-O-acetates. The electronic circular dichroism spectra of the major conformers have been calculated using time-dependent density functional theory to validate the empirical aromatic quadrant rule applied to the assignment of the absolute configuration of this class of compounds. The modest 6-31G* basis set was sufficient to produce reasonable spectra. The calculated Cotton effects at 220-240 nm, crucial for the assignment of the C-4 absolute configuration, result from electronic transitions of the molecular orbitals involving the pi-electrons of the spatially close aromatic A-ring and 4-aryl moieties. The sign of this Cotton effect is determined by the orientation of the 4-aryl substituent: the negative and positive Cotton effects are associated with 4alpha- and 4beta-aryl substituents, respectively.

Polycyclic Polyprenylated Acylphloroglucinol Congeners Possessing Diverse Structures from Hypericum henryi.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of hybrid natural products sharing the mevalonate/methylerythritol phosphate and polyketide biosynthetic pathways and showing considerable structural and bioactive diversity. In a systematic phytochemical investigation of Hypericum henryi, 40 PPAP-type derivatives, including the new compounds hyphenrones G-Q, were obtained. These compounds represent 12 different structural types, including four unusual skeletons exemplified by 5, 8, 10, and 17. The 12 different core structures found are explicable in terms of their biosynthetic origin. The structure of a known PPAP, perforatumone, was revised to hyphenrone A (5) by NMR spectroscopic and biomimetic synthesis methods. Several compounds exhibited inhibitory activities against acetylcholinesterase and human tumor cell lines. This study deals with the structural diversity, function, and biogenesis of natural PPAPs.

Beyond polymaxenolide: Cembrane-africanane terpenoids from the hybrid soft coral Sinularia maxima x S. polydactyla.

The effects of natural hybridization on secondary metabolite production and diversification have only recently been studied in plants and have essentially been overlooked in marine organisms. Chemical investigation of the hybrid soft coral Sinularia maxima x S. polydactyla resulted in the isolation of five new terpenoids, 7E-polymaxenolide (1), 7E-5-epipolymaxenolide (2), and polymaxenolides A-C (3-5), possessing a cembrane-africanane skeleton. Their structures were established by detailed analysis of NMR and MS data. The contentious issue of defining the absolute configuration at the stereogenic centers of the conformationally mobile cembrane macrocyclic ring was addressed by joint application of electronic circular dichroism and X-ray diffraction analyses.

Enantiomeric Discorhabdin Alkaloids and Establishment of Their Absolute Configurations Using Theoretical Calculations of Electronic Circular Dichroism Spectra

Enantiomeric pairs of the cytotoxic pyrroloiminoquinone marine alkaloids discorhabdins B (2), G*/I (3), L (4), and W (5) have been isolated from Latrunculia species sponges collected at different locations around the coast of New Zealand. The absolute configuration of all compounds was secured by comparison of observed data with the results of time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) spectra. Enantiomeric discorhabdins exhibit equipotent antiproliferative biological activity.

A New Metabolite with a Unique 4-Pyranone−γ-Lactam–1,4-Thiazine Moiety from a Hawaiian-Plant Associated Fungus

An endophytic fungus Paraphaeosphaeria neglecta FT462 isolated from the Hawaiian-plant Lycopodiella cernua (L.) Pic. Serm produced one unusual compound (1, paraphaeosphaeride A) with the 4-pyranone-γ-lactam-1,4-thiazine moiety, along with two new compounds (2 and 3, paraphaeosphaerides B and C, respectively) and the known compound (4). Compounds 1-3 were characterized by NMR and MS spectroscopic analysis. The absolute configuration of the 3-position of compound 1 was determined as S by electronic circular dichroism (ECD) calculations. Compound 3 also showed STAT3 inhibition at 10 μM.

Puupehanol, a sesquiterpene-dihydroquinone derivative from the marine sponge Hyrtios sp.

Puupehanol (1), a new sesquiterpene-dihydroquinone derivative, was isolated from the marine sponge Hyrtios sp., along with the known compounds puupehenone (2) and chloropuupehenone (3) that are responsible for the antifungal activity observed in the extract. The structure of 1 was established as (20R,21R)-21-hydroxy-20,21-dihydropuupehenone by extensive spectroscopic and computational methods. Compound 2 exhibited potent activity against Cryptococcus neoformans and Candida krusei with MFCs of 1.25 and 2.50 microg/mL, respectively.