Christopher Golz

Regio- and Stereoselective Synthesis of Spiropyrrolizidines and Piperazines through Azomethine Ylide Cycloaddition Reaction

A series of original spiropyrrolizidine derivatives has been prepared by a one-pot three-component [3 + 2] cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, l-proline, and the cyclic ketones 1H-indole-2,3-dione (isatin), indenoquinoxaline-11-one and acenaphthenequinone. We disclose an unprecedented isomerization of some spiroadducts leading to a new family of spirooxindolepyrrolizidines. Furthermore, these cycloadducts underwent retro-1,3-dipolar cycloaddition yielding unexpected regioisomers. Upon treatment of the dipolarophiles with in situ generated azomethine ylides from l-proline or acenaphthenequinone, formation of spiroadducts and unusual polycyclic fused piperazines through a stepwise [3 + 3] cycloaddition pathway is observed. The stereochemistry of these N-heterocycles has been confirmed by several X-ray diffraction studies. Some of these compounds exhibit extensive hydrogen bonding in the crystalline state. To enlighten the observed regio- and stereoselectivity of the [3 + 2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction is under kinetic control.

Antibacterial Azaphilones from an Endophytic Fungus, Colletotrichum sp. BS4

Three new compounds, colletotrichones A-C (1-3), and one known compound, chermesinone B (4a), were isolated from an endophytic fungus, Colletotrichum sp. BS4, harbored in the leaves of Buxus sinica, a well-known boxwood plant used in traditional Chinese medicine (TCM). Their structures were determined by extensive spectroscopic analyses including 1D and 2D NMR, HRMS, ECD spectra, UV, and IR, as well as single-crystal X-ray diffraction, and shown to be azaphilones sharing a 3,6a-dimethyl-9-(2-methylbutanoyl)-9H-furo[2,3-h]isochromene-6,8-dione scaffold. Owing to the remarkable antibacterial potency of known azaphilones coupled to the usage of the host plant in TCM, we evaluated the antibacterial efficacy of the isolated compounds against two commonly dispersed environmental strains of Escherichia coli and Bacillus subtilis, as well as against two human pathogenic clinical strains of Staphylococcus aureus and Pseudomonas aeruginosa. Compound 1 exhibited marked antibacterial potencies against the environmental strains that were comparable to the standard antibiotics. Compound 3 was also active against E. coli. Finally, compound 2a exhibited the same efficacy as streptomycin against the clinically relevant bacterium S. aureus. The in vitro cytotoxicity of these compounds on a human acute monocytic leukemia cell line (THP-1) was also assessed. Our results provide a scientific rationale for further investigations into endophyte-mediated host chemical defense against specialist and generalist pathogens.

A ligand-directed divergent catalytic approach to establish structural and functional scaffold diversity

The selective transformation of different starting materials by different metal catalysts under individually optimized reaction conditions to structurally different intermediates and products is a powerful approach to generate diverse molecular scaffolds. In a more unified albeit synthetically challenging strategy, common starting materials would be exposed to a common metal catalysis, leading to a common intermediate and giving rise to different scaffolds by tuning the reactivity of the metal catalyst through different ligands. Herein we present a ligand-directed synthesis approach for the gold(I)-catalysed cycloisomerization of oxindole-derived 1,6-enynes that affords distinct molecular scaffolds following different catalytic reaction pathways. Varying electronic properties and the steric demand of the gold(I) ligands steers the fate of a common intermediary gold carbene to selectively form spirooxindoles, quinolones or df-oxindoles. Investigation of a synthesized compound collection in cell-based assays delivers structurally novel, selective modulators of the Hedgehog and Wnt signalling pathways, autophagy and of cellular proliferation.

L-Isoleucine derived bifunctional phosphine catalyses asymmetric [3 + 2]-annulation of allenyl-esters and -ketones with ketimines

The zwitterionic 1,3-dipoles generated by the addition of a bifunctional L-isoleucine derived N-acylaminophosphine to allenic esters as well as ketones were successfully trapped with isatin derived ketimines in a [3 + 2]-annulation reaction to deliver 3,2′-dihydropyrrolyl spirooxindoles in high yields (up to 88%) and with excellent enantioselectivities (up to >99%). The asymmetric annulation reaction provides a facile access to biologically relevant small molecules embodying the natural product spirocyclic core.

Three cyclic pentapeptides and a cyclic lipopeptide produced by endophytic Fusarium decemcellulare LG53

Three new cyclic pentapeptides (1–3) and a known cyclic lipopeptide, fusaristatin A (4), were isolated from an endophytic fungus, Fusarium decemcellulare LG53, harbored in a Chinese medicinal plant Mahonia fortunei. The planar structures of the new compounds were elucidated by extensive spectroscopic analyses using HRMSn and NMR. Their absolute configurations were unambiguously determined by single crystal X-ray diffraction and Marfeys method. Interestingly, compounds 1–3 exhibited no antibacterial activity against a panel of Gram-positive and Gram-negative bacteria. In order to explore the plausible ecological relevance of the compounds within the context of microbial crosstalk and communication strategies, we designed antagonistic and dual-culture assays combined with matrix-assisted laser desorption ionization imaging high-resolution mass spectrometry (MALDI-imaging-HRMS) to investigate the interaction of F. decemcellulare LG53 with another fungal endophyte Glomerella acutata LG52 isolated from the same tissue of the plant. Compound 4 was found to display an allelopathic effect on endophytic G. acutata LG52. Our results provide a proof-of-concept of balanced antagonism that might be occurring between endophytes inhabiting the same plant tissues in distinct ecological niches.

Design of novel dispirooxindolopyrrolidine and dispirooxindolopyrrolothiazole derivatives as potential antitubercular agents

With the aim to develop new potent antitubercular agents, a series of novel dispirooxindolopyrrolidines and dispirooxindolopyrrolothiazoles have been synthesized via a three-component 1,3-dipolar cycloaddition of (Z)-3-arylidenebenzofuran-2-ones, substituted isatin derivatives and α-aminoacids. The stereochemistry of the spiroadducts has been confirmed by an X-ray diffraction analysis. All the target heterocycles were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and the most active compounds were subjected to cytotoxicity studies against (RAW 264.7) cell lines. Among them, twelve compounds showed potent anti-tubercular activity with MIC ranging from 1.56 to 6.25 μg/mL. In particular dispirooxindolopyrrolothiazole derivatives 5c and 5f were found to be the most active (MIC of 1.56 μg/mL) with a good safety profile (27.53% and 20.74% at 50 μM, respectively). This is the first report demonstrating the benzofuranone oxindole hybrids as potential antimycobacterial agents.

Asymmetric Roadmap to Diverse Polycyclic Benzopyrans via Phosphine-Catalyzed Enantioselective [4 + 2]-Annulation Reaction

The catalytic addition of the amino acid derived bifunctional N-acylaminophosphine to an α-substituted allene ester generated a zwitterionic dipole that engaged the vinylogous ester function of 3-cyano-chromones in a [4 + 2] annulation reaction to deliver tetrahydroxanthones embodying three consecutive chiral centers in high yields and with excellent enantioselectivities. The established asymmetric synthesis further paves the way to two different classes of complex, sp(3)-rich tetracyclic benzopyrans via efficient cascade reactions.

Epigenetic Modulation of Endophytic Eupenicillium sp. LG41 by a Histone Deacetylase Inhibitor for Production of Decalin-Containing Compounds

An endophytic fungus, Eupenicillium sp. LG41, isolated from the Chinese medicinal plant Xanthium sibiricum, was subjected to epigenetic modulation using an NAD+-dependent histone deacetylase (HDAC) inhibitor, nicotinamide. Epigenetic stimulation of the endophyte led to enhanced production of two new decalin-containing compounds, eupenicinicols C and D (3 and 4), along with two biosynthetically related known compounds, eujavanicol A (1) and eupenicinicol A (2). The structures and stereochemistry of the new compounds were elucidated by extensive spectroscopic analysis using LC-HRMS, NMR, optical rotation, and ECD calculations, as well as single-crystal X-ray diffraction. Compounds 3 and 4 exist in chemical equilibrium with two and three cis/trans isomers, respectively, as revealed by LC-MS analysis. Compound 4 was active against Staphylococcus aureus with an MIC of 0.1 μg/mL and demonstrated marked cytotoxicity against the human acute monocytic leukemia cell line (THP-1). We have shown that the HDAC inhibitor, nicotinamide, enhanced the production of compounds 3 and 4 by endophytic Eupenicillium sp. LG41, facilitating their isolation, structure elucidation, and evaluation of their biological activities.

Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines.

A natural product inspired synthesis of 6,6,5-tricyclic compounds via a silver(I)-catalyzed formal 1,3-dipolar cycloaddition of coumarins with α-iminoesters was developed. The reaction proceeds in a stepwise reaction course under formation of the trans-substituted diastereomer with respect to the 1,3-dipole and shows a broad substrate scope.

Highly Enantioselective Intramolecular 1,3‐Dipolar Cycloaddition: A Route to Piperidino‐Pyrrolizidines

Enantioselective catalytic intermolecular 1,3-dipolar cycloadditions are powerful methods for the synthesis of heterocycles. In contrast, intramolecular enantioselective 1,3-dipolar cycloadditions are virtually unexplored. A highly enantioselective synthesis of natural-product-inspired pyrrolidino-piperidines by means of an intramolecular 1,3-dipolar cycloaddition with azomethine ylides is now reported. The method has a wide scope and yields the desired cycloadducts with four tertiary stereogenic centers with up to 99% ee. Combining the enantioselective catalytic intramolecular 1,3-dipolar cycloaddition with a subsequent diastereoselective intermolecular 1,3-dipolar cycloaddition yielded complex piperidino-pyrrolizidines with very high stereoselectivity in a one-pot tandem reaction.