Dopamine-Derived Guanidine Alkaloids from a Didemnidae Tunicate: Isolation, Synthesis, and Biological Activities.

Mellpaladines A-C (1-3) and dopargimine (4) are dopamine-derived guanidine alkaloids isolated from a specimen of Palauan Didemnidae tunicate as possible modulators of neuronal receptors. In this study, we isolated the dopargimine derivative 1-carboxydopargimine (5), three additional mellpaladines D-F (6-8), and serotodopalgimine (9), along with a dimer of serotonin, 5,5'-dihydroxy-4,4'-bistryptamine (10). The structures of these compounds were determined based on spectrometric and spectroscopic analyses. Compound 4 and its congeners dopargine (11), nordopargimine (15), and 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)ethan-1-amine (16) were synthetically prepared for biological evaluations. The biological activities of all isolated compounds were evaluated in comparison with those of 1-4 using a mouse behavioral assay upon intracerebroventricular injection, revealing key functional groups in the dopargimines and mellpaladines for in vivo behavioral toxicity. Interestingly, these alkaloids also emerged during a screen of our marine natural product library aimed at identifying antiviral activities against dengue virus, SARS-CoV-2, and vesicular stomatitis Indiana virus (VSV) pseudotyped with Ebola virus glycoprotein (VSV-ZGP).

Isolation and Structure Determination of cis-OPDA-α-Monoglyceride from Arabidopsis thaliana.

cis-12-oxo-Phytodieneoic acid-α-monoglyceride (1) was isolated from Arabidopsis thaliana. The chemical structure of 1 was elucidated based on exhaustive 1D and 2D NMR spectroscopic measurements and supported by FDMS and HRFDMS data. The absolute configuration of the cis-OPDA moiety in 1 was determined by comparison of 1H NMR spectra and ECD measurements. With respect to the absolute configuration of the ß-position of the glycerol backbone, the 2:3 ratio of (S) to (R) was determined by making ester-bonded derivatives with (R)-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride and comparing 1H NMR spectra. Wounding stress did not increase endogenous levels of 1, and it was revealed 1 had an inhibitory effect of A. thaliana post germination growth. Notably, the endogenous amount of 1 was higher than the amounts of (+)-7-iso-jasmonic acid and (+)-cis-OPDA in intact plants. 1 also showed antimicrobial activity against Gram-positive bacteria, but jasmonic acid did not. It was also found that α-linolenic acid-α-monoglyceride was converted into 1 in the A. thaliana plant, which implied α-linolenic acid-α-monoglyceride was a biosynthetic intermediate of 1.

Determination of N-centered stereochemistry in N22-methylated chlorophyll-a derivatives and their epimer-dependent optical spectra.

An N-centered epimeric mixture of chlorophyll-a derivatives methylated at the inner nitrogen atom was separated by reverse-phase high-performance liquid chromatography. Circular dichroism (CD) spectroscopic analyses of the epimerically pure N22-methyl-chlorins revealed that the minor first-eluted and major second-eluted stereoisomers were (22S)- and (22R)-configurations, respectively. Their visible absorption and CD spectra in solution were dependent on the N22-stereochemistry. The epimer-dependent spectral changes were independent of the substituents at the peripheral 3-position of the core chlorin chromophore.

Total Synthesis, Absolute Configuration, and Phytotoxic Activity of Foeniculoxin.

Foeniculoxin is a major phytotoxin produced by Italian strains of Phomopsis foeniculi. The first total synthesis is described utilizing the ene reaction and Sonogashira cross-coupling reaction as key steps. The absolute configuration of the C6' was determined using chiral separation and an advanced Mosher's method. The phytotoxicity of the synthesized compound was demonstrated via syringe-based infiltration into Chenopodium album and Arabidopsis thaliana leaves. Synthetic foeniculoxin induced various defects in A. thaliana leaf cells before lesion formation, including protein leakage into the cytoplasm from both chloroplasts and mitochondria and mitochondrial rounding and swelling. Furthermore, foeniculoxin and the antibiotic hygromycin B caused similar agglomeration of mitochondria around chloroplasts, highlighting this event as a common component in the early stages of plant cell death.

Scope and limitations of absolute configuration determination of allenic natural products using the CCC stretching VCD signal.

The allene functional group in natural products isolated so far exists in a non-racemic form, but its axial chirality is difficult to elucidate. Allenes exhibit a characteristic antisymmetric CCC stretching mode at around 1950 cm-1, and their VCD properties have not been studied in detail. This work, for the first time, applied VCD spectroscopy to allenic natural products and allenic molecules with other asymmetric centers focusing on the antisymmetric CCC stretching mode. This vibrational mode yielded a negligibly weak VCD signal for several molecules, but in the presence of electron-withdrawing and/or conjugating substituents, it generated a stronger one. Its sign was found to be influenced by the nature of substituents. These findings should deepen the understanding of the VCD properties of the allene functional group and should be useful for future studies of chiral allenes.

Vibrational circular dichroism spectroscopy in the C-D, XY, and XYZ stretching region.

Vibrational circular dichroism (VCD) spectroscopy is a powerful technique for structural analysis of chiral molecules, but information available from VCD spectra of large molecular systems can be limited by severe overlap of vibrational bands. While common chiral molecules do not absorb in the 1900-2400 cm-1 region, observation of VCD signals in this spectrally-isolated region is possible for molecules containing C-D, XY, and XYZ chromophores. Thus, a strategic introduction of these chromophores to a target molecule may produce VCD signals informative for molecular structures. VCD spectroscopy in the 1900-2400 cm-1 region is a rather unexplored research field and its basic properties remain to be investigated. This perspective article discusses insight obtained so far on the usefulness and physicochemical aspects of VCD spectroscopy in this region with briefly summarizing previous experimental VCD studies including classic examples as well as our recent results. We show that anharmonic effects such as overtones and combination bands often complicate VCD patterns. On the other hand, some molecules exhibit characteristic VCD signals that can be well interpreted by harmonic DFT spectral calculations for structural analysis. This article also discusses several examples of the use of this region for studying solute-solvent interactions and for VCD signal augmentation.

Deuterium labelling to extract local stereochemical information by VCD spectroscopy in the C-D stretching region: a case study of sugars.

Stereochemical elucidation of molecules with multiple chiral centers is difficult. Even with VCD spectroscopy, excluding all but one diastereomeric structural candidate is challenging because the stereochemical inversion of one chiral center among many centers does not always result in noticeable differences in their VCD spectra. This work demonstrates that the introduction of a suitable VCD chromophore with absorption in the 2300-1900 cm-1 region can be used for extracting local stereochemical information and for the stereochemical assignment of the C-1 position of various sugars as a case study. Through studies on a series of epimeric pairs of monosaccharides and their derivatives, we found that the introduction of one -OCD3 group to each C-1 position produced almost mirror-image VCD patterns in the 2300-1900 cm-1 region depending on the C-1 stereochemistry irrespective of the other molecular moieties. This work also shows that comparison of the observed VCD signals and the calculated ones enables the stereochemical assignment of a chiral center in the vicinity of the chromophore. This study provides a proof of concept that the use of a VCD chromophore in the 2300-1900 cm-1 region enables the analysis of selected stereochemistry of suitable molecular systems. Further studies on this concept should lead to the development of a method useful for the structural elucidation of other types of complex molecules.

Enantiodivergent One-Pot Synthesis of Axially Chiral Biaryls Using Organocatalyst-Mediated Enantioselective Domino Reaction and Central-to-Axial Chirality Conversion.

Enantiodivergent one-pot synthesis of biaryls was developed using a catalytic amount of a single chiral source. A domino organocatalyst-mediated enantioselective Michael reaction and aldol condensation provided centrally chiral dihydronaphthalenes with excellent enantioselectivity, from which an enantiodivergent chirality conversion from central-to-axial chirality was achieved. Both enantiomers of biaryls were obtained with excellent enantioselectivity. All transformations can be conducted in a single reaction vessel. A plausible reaction mechanism for the enantiodivergence is proposed.

Exploration of chromophores for a VCD couplet in a spectrally transparent infrared region for biomolecules.

Interactions of two chromophores such as carbonyl groups yield a strong VCD couplet that reflects the molecular structures. The use of VCD couplets for biomacromolecular structural studies has been hampered by severe signal overlap caused by numerous functional groups that originally exist in biomacromolecules. Nitrile, isonitrile, alkyne, and azido groups show characteristic IR absorption in the 2300-2000 cm-1 region, where biomolecules do not strongly absorb. We herein examined the usefulness of these functional groups as chromophores to observe a strong VCD couplet that can be readily interpreted using theoretical calculations. Studies on a chiral binaphthyl scaffold possessing two identical chromophores showed that nitrile and isonitrile groups generate moderately-strong but complex VCD signals due to anharmonic contributions. The nature of their anharmonic VCD patterns is discussed by comparison with the VCD spectrum of a mono-chromophoric molecule and by anharmonic DFT calculations. On the other hand, through studies on diazido binaphthyl and diazido monosaccharide, we demonstrated that the azido group is more promising for structural analysis of larger molecules due to its simple, strong VCD couplet whose spectral patterns are readily predicted by harmonic DFT calculations.

Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step.

Invited for the cover of this issue is the group of Yujiro Hayashi at the University of Tohoku University. The image depicts the spinning motion of a figure skater, which illustrates the transformation of the chiral information investigated in this work. Read the full text of the article at 10.1002/chem.201905814.

Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step.

The pot-economical, highly enantioselective synthesis of axially chiral biaryls was developed by using one-pot organocatalyst-mediated domino and aromatization reactions as key steps. The axial information of the precursor, which also has central chirality, was completely inverted in the final biaryls. The inversion of the axial information occurred in the conversion of the central chirality to the axial chirality of an oxidative aromatization step.

Correction: Synthetic-biology-based discovery of a fungal macrolide from Macrophomina phaseolina.

Correction for 'Synthetic-biology-based discovery of a fungal macrolide from Macrophomina phaseolina' by Yohei Morishita et al., Org. Biomol. Chem., 2020, DOI: 10.1039/d0ob00519c.

Synthetic-biology-based discovery of a fungal macrolide from Macrophomina phaseolina.

A synthetic biology approach based on genome mining and heterologous biosynthesis is a powerful tool for discovering novel natural products from a tremendous gene resource. We carried out fungal genome mining guided by a polyketide synthase gene using a public database and found a putative macrolide biosynthetic gene cluster with a highly reducing polyketide synthase gene and a thioesterase gene in Macrophomina phaseolina. Reconstitution of the cluster in Aspergillus oryzae, a model heterologous host for fungal natural product biosynthesis, produced a new 12-membered macrolide, phaseolide A. The absolute stereochemistry was elucidated by vibrational circular dichroism spectroscopy and the crystalline sponge method.

Post-genomic approach based discovery of alkylresorcinols from a cricket-associated fungus, Penicillium soppi.

Polyketide synthase (PKS) gene-guided genome mining in a cricket-associated fungus, Penicillium soppi, revealed a cryptic biosynthetic gene cluster that contained a highly reducing PKS (HR-PKS), a type III PKS, and a P450 gene. Heterologous expression of the cluster in Aspergillus oryzae led to the isolation of novel alkylresorcinols with a unique Z,E,Z-triene motif. This study displays an unusual biosynthetic mechanism of an HR-PKS and a new releasing mechanism via a type III PKS in fungi.

Use of plant hormones to activate silent polyketide biosynthetic pathways in Arthrinium sacchari, a fungus isolated from a spider.

Plant hormones were evaluated for their ability to activate fungal secondary metabolite production. Three synthetic cytokinins, kinetin, 6-benzylaminopurine, and forchlorfenuron, showed remarkable enhancement of the production of aromatic polyketides derived from emodin in a fungus, Arthrinium sacchari, and allowed us to isolate a new polyketide. Furthermore, we firstly demonstrated the potential of plant hormones to activate a wide range of fungal secondary metabolite production processes.

Preparation of Carbodiimides with One-Handed Axial Chirality.

The axial chirality of carbodiimide was proposed in 1932, but the synthesis of carbodiimide with one-handed axial chirality has not been achieved because of the low barrier of racemization. This work presents a strategy to use a conformationally restrained cyclic structure for creating carbodiimides whose biases of the axial chirality (labeled as SNCN/ RNCN) are higher than 100:1, as determined by vibrational circular dichroism spectroscopy and density functional theory calculations.

Enantio- and Diastereoselective Synthesis of Latanoprost using an Organocatalyst.

An enantioselective total synthesis of latanoprost was achieved. Its chiral cyclopentane core structure was constructed through an organocatalyst-mediated [3+2]-cycloaddition reaction, and chirality in the ω-side chain was generated by prolinate-anion-mediated α-aminoxylation of an aldehyde. Highly diastereoselective domino acetalization and an oxy-Michael reaction were key steps for the generation of C9 chirality.

Synthesis and Photochemical Properties of Axially Chiral Bis(dinaphthofuran).

Both enantiomers of axially chiral bis(dinaphthofuran) were prepared in only two steps from 1'-hydroxy-4'-methoxy-2,2'-binaphthalenyl-1,4-dione, followed by optical resolution via high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP). The absolute configurations were determined by comparison of experimental and calculated vibrational circular dichroism (VCD) spectra. Synthetic bis(dinaphthofuran) exhibited a broad and unstructured emission derived from an intramolecular excimer in both solution and solid state. The methylene bridge brings both chromophores close to each other and induces significant changes in the photophysical behavior. Chiral bis(dinaphthofuran) displayed a bathochromic shift in emission, as compared to the racemic mixture in the solid state. Furthermore, the compounds showed high circularly polarized luminescence (CPL) with a dissymmetry factor ( glum) of 10-3 at 405 nm upon excitation at 265 nm in a methanol solution. This compound serves as a model for the design and synthesis of organic materials having CPL activity.

Modifying oligoalanine conformation by replacement of amide to ester linkage.

Oligo(lactic acid) is an ester-analogue of short oligoalanine sequence and adopts a rigid left-handed helical structure. In this study, oligo(lactic acid) was incorporated into oligoalanine sequences and their conformations were studied by vibrational circular dichroism and electronic circular dichroism spectroscopy. The results suggested that oligo(lactic acid) moiety in these sequences maintains a left-handed helix and increases the conformational propensity of the oligoalanine moiety to form a left-handed polyproline type II-like helix. The importance of the chirality of oligo(lactic acid) moiety for the oligoalanine conformation was also studied. The results obtained in this study should be useful in developing ester-containing oligopeptides that function better than normal peptides.