Gennaro Pescitelli

Probing molecular chirality by CD-sensitive dimeric metalloporphyrin hosts.

This feature article reviews dimeric metalloporphyrin hosts employed as chirality probes in chiral recognition processes involving synthetic compounds and natural products. Upon formation of a chiral host-guest supramolecular complex between an achiral bis-metalloporphyrin derivative and a chiral non-racemic guest, a CD response occurs in the porphyrin spectral region, which is diagnostic of the guests absolute configuration. Several bis-porphyrin hosts used in the stereochemical investigation of organic compounds are described and the scope of their application as chirality probes critically assessed. The review encompasses the description of structural features of the host-guest complexes, the nature of the chirality transfer mechanism and the practical application in solving stereochemical problems. In particular, with reference to the method based on bis-porphyrin tweezers, we describe recent advances based on the use of molecular modeling, which have broadened the applicability of the tweezer methodology and allowed extraction of deeper structural information contained in the experimental CD data.

New Mono‐ and Dimeric Members of the Secalonic Acid Family: Blennolides A–G Isolated from the Fungus Blennoria sp.

Blennolides A-G (2-8), seven unusual chromanones, were isolated together with secalonic acid B (1) from Blennoria sp., an endophytic fungus from Carpobrotus edulis. This is the first reported isolation of the blennolides 2 and 3 (hemisecalonic acids B and E), the existence of which as the monomeric units of the dimeric secalonic acids had long been postulated. A compound of the proposed structure 4 (beta-diversonolic ester) will need to be revised, as its reported data do not fit those of the established structure of blennolide C (4). Other monomers, the blennolides D-F (5-7) seem to be derived from blennolides A (2) and B (3) by rearrangement of the hydroaromatic ring. The heterodimer 8, composed of the monomeric blennolide A (2) and the rearranged 11-dehydroxy derivative of blennolide E (6), extends the ergochrome family with an ergoxanthin type of skeleton. The structures of the new compounds were elucidated by detailed spectroscopic analysis and further confirmed by an X-ray diffraction study of a single crystal of 2. The absolute configurations were determined by TDDFT calculations of CD spectra, including the solid-state CD/TDDFT approach. Preliminary studies showed strong antifungal and antibacterial activities of these compounds against Microbotryum violaceum and Bacillus megaterium, respectively. They were also active against the alga Chlorella fusca and the bacterium Escherichia coli.

Absolute structural elucidation of natural products—A focus on quantum‐mechanical calculations of solid‐state CD spectra

In this review article we examine state-of-the-art techniques for the structural elucidation of organic compounds isolated from natural sources. In particular, we focus on the determination of absolute configuration (AC), perhaps the most challenging but inevitable step in the whole process, especially when newly isolated compounds are screened for biological activity. Among the many methods employed for AC assignment that we review, special attention is paid to electronic circular dichroism (CD) and to the modern tools available for quantum-mechanics CD predictions, including TDDFT. In this context, we stress that conformational flexibility often poses a limit to practical CD calculations of solution CD spectra. Many crystalline natural products suitable for X-ray analysis do not contain heavy atoms for a confidential AC assignment by resonant scattering. However, their CD spectra can be recorded in the solid state, for example with the KCl pellet technique, and analyzed possibly by nonempirical means to provide stereochemical information. In particular, solid-state CD spectra can be compared with those calculated with TDDFT or other high-level methods, using the X-ray geometry as input. The solid-state CD/TDDFT approach, described in detail, represents a quick and reliable tool for AC assignment of natural products.

An exciton-coupled circular dichroism protocol for the determination of identity, chirality, and enantiomeric excess of chiral secondary alcohols.

Chiral mono-ols are among the most sought after targets in asymmetric synthesis, and therefore, their chemical characterization and associated enantiomeric excess (ee) values are commonly reported. A simple optical method for determining alcohol identity and ee could be widely used. Toward this end, an in situ-generated multicomponent assembly that creates diastereomeric tris(pyridine) metal complexes incorporating chiral secondary alcohols was explored using exciton-coupled circular dichroism (ECCD). Qualitative models were proposed to predict the preferential diastereomer and its twist, and computational studies provided a rationalization of the CD spectra. Different ECCD spectra found for diastereomers formed in the self-assembled tris(pyridine) complexes were used to determine the absolute configurations of chiral mono-ols. Linear discriminant analysis was successfully employed to classify the alcohol analytes, thereby allowing identification of the alcohols. Conformational effects imparted by heteroatoms were also explored, further expanding the substrate scope. Finally, ee calibration curves allowed the determination of the ee of unknown samples of three chiral secondary alcohols with an average error of 3%. The assay described here is unique because no preparation of structurally elaborated chiral hosts is needed.

In situ assembly of octahedral Fe(II) complexes for the enantiomeric excess determination of chiral amines using circular dichroism spectroscopy.

A method for discriminating between α-chiral primary amine enantiomers is reported. The method utilizes circular dichroism (CD) spectroscopy and a sensing ensemble composed of 2-formyl-3-hydroxypyridine (4) and Fe(II)(TfO)(2). Aldehyde 4 reacts rapidly with chiral amines to form chiral imines, which complex Fe(II) to form a series of diastereomeric octahedral complexes that are CD-active in both the UV and visible regions of the spectrum. NMR studies showed that for enantiomerically pure imine complexes, the Δ-fac isomer is preferred. A statistical analysis of the distribution of stereoisomers accurately modeled the calibration curves for enantiomeric excess (ee). CD signals appearing in the UV region were bisignate, and the nulls of the CD signals were coincident with maxima in the UV spectrum, consistent with exciton coupling. Time-dependent density functional theory and semiempirical calculations confirmed that the CD signals in the UV region arise from coupling of the π-π* transitions in the imine chromophores and that they can be used to describe the signs and magnitudes of the curves accurately. The CD signals in the visible region arise from metal-to-ligand charge-transfer bands, and these signals can be used to determine the ee values of chiral amines with an average absolute error of ±5%. Overall, the strategy presented herein represents a facile in situ assembly process that uses commercially available simple reagents to create large optical signals indicative of ee values.

Good Computational Practice in the Assignment of Absolute Configurations by TDDFT Calculations of ECD Spectra

Quantum-mechanical calculations of chiroptical properties have rapidly become the most popular method for assigning absolute configurations (AC) of organic compounds, including natural products. Black-box time-dependent Density Functional Theory (TDDFT) calculations of electronic circular dichroism (ECD) spectra are nowadays readily accessible to nonexperts. However, an uncritical attitude may easily deliver a wrong answer. We present to the Chirality Forum a discussion on what can be called good computational practice in running TDDFT ECD calculations, highlighting the most crucial points with several examples from the recent literature. Chirality 28:466-474, 2016.

Structural and Stereochemical Studies of alpha-Methylene-gamma-lactone-Bearing Cembrane Diterpenoids from a South China Sea Soft Coral Lobophytum crassum

Four new alpha-methylene-gamma-lactone-bearing cembranoids, 20-acetylsinularolide B (6), presinularolide B (7), 3-dehydroxylpresinularolide B (8), and 3-dehydroxyl-20-acetylpresinularolide B (9), together with five known analogues, sinularolides B-E (1- 4) and 20-acetylsinularolide C (5), were isolated from a South China Sea soft coral Lobophytum crassum. Their structures and relative stereochemistry were established by a combination of detailed spectroscopic data analysis and chemical correlations. The structures of 1- 9 were further confirmed by an X-ray diffraction study on a single crystal of sinularolide B (1). The absolute configurations of sinularolide B (1) and presinularolide B (7) were determined by a novel solid-state CD/TDDFT approach and by a modified Moshers method, respectively. This study also revealed that the coupling constant between the lactonic methine protons ((3) J 1,2) varies considerably with different functional groups on the cembrane ring and that the determination of the stereochemistry of lactone ring fusion based on this coupling constant is risky. In a bioassay, sinularolides B and C (1 and 2) and new cembranoids 7 and 8 showed in vitro cytotoxicity against the tumor cell lines A-549 and P-388.

Xanthones and oxepino[2, 3-b]chromones from three endophytic fungi.

Three new metabolites, microsphaeropsones A-C (1-3) with a unique oxepino[2,3-b]chromen-6-one (ring-enlarged xanthone) skeleton, were isolated from the endophytic fungus Microsphaeropsis species, co-occurring with their putative biogenetic anthraquinoide precursors citreorosein (4) and emodin (5). From another Microsphaeropsis species, large amounts of fusidienol A (8 a), smaller amounts of emodin (5), the known aromatic xanthones 9 a and 9 b, the new 3,4-dihydrofusidienol A (8 b), and the new aromatic xanthone 9 c were isolated. The endophyte Seimatosporium species produced a new aromatic xanthone, seimatoxanthone A (10), and 3,4-dihydroglobosuxanthone A (12), closely related to alpha-diversolonic ester (13) from Microdiplodia sp.. The structures were determined mainly by extensive 1D and 2D NMR experiments and supported by X-ray single-crystal analysis of 1 and the oxidation product 7. The absolute configurations of the microsphaeropsones A-C (1-3) were established by comparison of the electronic and vibrational circular dichroism (ECD and VCD) spectra of 1 with time-dependent DFT (TDDFT) and DFT calculations by using either the solid-state structures or DFT-optimized geometries as inputs. Preliminary studies indicated that 1, 2, and enone 7 showed antibacterial, fungicidal, and algicidal properties.

Inherent chirality dominates the visible/near-ultraviolet CD spectrum of rhodopsin.

The visible (alpha) and near-UV (beta) CD bands of rhodopsin have been studied extensively, but their source(s) have never been definitively established. Do they result from the intrinsic chirality of the polyene chromophore of the protonated Schiff base of retinal (retPSB) or from the coupling of the transitions of this chromophore with those of protein groups? We have calculated the contributions of these two mechanisms to the CD of rhodopsin. The intrinsic CD of the retPSB chromophore was calculated using time-dependent density functional theory (TDDFT) and, for comparison, the semiempirical ZINDO method. First-order perturbation theory was used to calculate the effects of coupling of the retPSB transitions with the pi pi* transitions of the aromatic chromophores and the pi pi* and n pi* transitions of the peptide groups in rhodopsin. Calculations were performed for eight structures based upon the two molecules in the asymmetric unit of four crystal structures. The most reliable results were obtained from TDDFT calculations on the structure of Okada et al. (J. Mol. Biol. 2004, 342, 571), PDB 1U19. Averaging over the two molecules in the asymmetric unit, the intrinsic rotational strengths are 0.62 +/- 0.00 DBM (Debye-Bohr magneton) and 0.90 +/- 0.03 DBM for the alpha- and beta-bands, respectively. The contributions from coupling with protein groups are, respectively, -0.32 +/- 0.05 and -0.01 +/- 0.03 DBM. Our results show that the visible/near-UV CD bands of rhodopsin are determined by the intrinsic chirality of the retPSB chromophore and that the contributions of coupling with the protein are significantly smaller for the alpha-band and negligible for the beta-band.

Systematic investigation of CD spectra of aryl benzyl sulfoxides interpreted by means of TDDFT calculations.

The CD spectra of 13 crystalline aryl benzyl sulfoxides 1a-m with various substituents on the two aromatic rings were recorded in solution and in the solid state. Solution CD spectra were very homogeneous along the series, consisting in most cases of a couplet-like feature in the 200-300 nm region. The red-shifted component of the couplet, corresponding to the sulfoxide-centered n-pi* transition, is always positive for (R) absolute configuration in accordance with Mislows rule. The presence of a strong electron-withdrawing substituent on the phenyl ring (nitro or ester group) alters the shape of the CD spectrum. CD calculations using the TDDFT method were run for eight representative compounds using DFT-optimized geometries. In all cases, calculated spectra were in very good agreement with experimental ones and allowed for rationalization of the diverse spectral behaviors. It is demonstrated that TDDFT//DFT calculations represent a reliable option for assigning the absolute configuration of this class of compounds whenever crystals suitable for X-ray are not available. Solid-state CD spectra recorded with the KCl pellet technique were in some cases in agreement with those in solution. However, in other cases new and strong CD signals appeared which were interpreted as being due to intermolecular couplings in the crystals.