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1.
Chemistry ; 26(68): 15855-15858, 2020 Dec 04.
Article in English | MEDLINE | ID: mdl-32996646

ABSTRACT

The anaerobe Clostridium acetobutylicum belongs to the most important industrially used bacteria. Whereas genome mining points to a high potential for secondary metabolism in C. acetobutylicum, the functions of most biosynthetic gene clusters are cryptic. We report that the addition of supra-physiological concentrations of cysteine triggered the formation of a novel natural product, clostrisulfone (1). Its structure was fully elucidated by NMR, MS and the chemical synthesis of a reference compound. Clostrisulfone is the first reported natural product with a diphenylsulfone scaffold. A biomimetic synthesis suggests that pentamethylchromanol-derived radicals capture sulfur dioxide to form 1. In a cell-based assay using murine macrophages a biphasic and dose-dependent regulation of the LPS-induced release of nitric oxide was observed in the presence of 1.


Subject(s)
Clostridium acetobutylicum , Immunologic Factors , Sulfones , Animals , Clostridium acetobutylicum/chemistry , Clostridium acetobutylicum/drug effects , Clostridium acetobutylicum/genetics , Clostridium acetobutylicum/metabolism , Cysteine/pharmacology , Immunologic Factors/metabolism , Immunologic Factors/pharmacology , Macrophages/drug effects , Mice , Multigene Family , Sulfones/metabolism , Sulfones/pharmacology
2.
Chemistry ; 25(70): 16068-16073, 2019 Dec 13.
Article in English | MEDLINE | ID: mdl-31621964

ABSTRACT

The metal-free, highly selective synthesis of biaryls poses a major challenge in organic synthesis. The scope and mechanism of a promising new approach to (hetero)biaryls by the photochemical fusion of aryl substituents tethered to a traceless sulfonamide linker (photosplicing) are reported. Interrogating photosplicing with varying reaction conditions and comparison of diverse synthetic probes (40 examples, including a suite of heterocycles) showed that the reaction has a surprisingly broad scope and involves neither metals nor radicals. Quantum chemical calculations revealed that the C-C bond is formed by an intramolecular photochemical process that involves an excited singlet state and traversal of a five-membered transition state, and thus consistent ipso-ipso coupling results. These results demonstrate that photosplicing is a unique aryl cross-coupling method in the excited state that can be applied to synthesize a broad range of biaryls.

3.
Angew Chem Int Ed Engl ; 57(44): 14476-14481, 2018 10 26.
Article in English | MEDLINE | ID: mdl-30001481

ABSTRACT

Many pharmaceuticals feature biaryl motifs that are crucial for their binding to the target. Yet, benchmark methods for selective cross-couplings rely on highly toxic heavy metal catalysts, which are unfavorable in the synthesis of pharmaceuticals. Metal-free coupling reactions, on the other hand, may require harsh conditions and lack selectivity. We report a novel, metal-free cross-coupling reaction that involves the tethering of two phenyl groups by a temporary, traceless sulfonamide linker that directs a photochemical aryl fusion into a single coupling product. The perfect regio- and chemoselectivity of the reaction could be rationalized by a cyclic intermediate, which fragments into the biaryl and volatile side products. Using a flow reactor, we synthesized numerous substituted biaryl building blocks for important therapeutics in high yields, such as antibiotics, antitumor, neuroprotective and cholesterol-lowering agents as well as antiarthritic non-steroidal antiinflammatory drugs (NSAIDs). The new method was successfully employed in a total synthesis of cannabinol, an important analgesic and antiemetic therapeutic. We also report a metal-free synthesis of key building blocks used for the preparation of sartans, antihypertensive agents that rank among the top blockbuster drugs worldwide. This safe and convenient protocol is a valuable alternative for the widely used metal-dependent aryl cross-coupling methods.


Subject(s)
Pharmaceutical Preparations/chemistry , Catalysis , Metals/chemistry
4.
Mol Microbiol ; 96(1): 148-62, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25582336

ABSTRACT

Aspergillus fumigatus is an opportunistic human pathogenic fungus causing life-threatening infections in immunocompromised patients. Adaptation to different habitats and also virulence of the fungus depends on signal perception and transduction by modules such as the cyclic AMP-dependent protein kinase A (PKA) pathway. Here, by transcriptome analysis, 632 differentially regulated genes of this important signaling cascade were identified, including 23 putative transcriptional regulators. The highest upregulated transcription factor gene was located in a previously unknown secondary metabolite gene cluster, which we named fmp, encoding an incomplete non-ribosomal peptide synthetase, FmpE. Overexpression of the regulatory gene fmpR using the Tet(On) system led to the specific expression of the other six genes of the fmp cluster. Metabolic profiling of wild type and fmpR overexpressing strain by HPLC-DAD and HPLC-HRESI-MS and structure elucidation by NMR led to identification of 5-benzyl-1H-pyrrole-2-carboxylic acid, which we named fumipyrrole. Fumipyrrole was not described as natural product yet. Chemical synthesis of fumipyrrole confirmed its structure. Interestingly, deletion of fmpR or fmpE led to reduced growth and sporulation of the mutant strains. Although fmp cluster genes were transcribed in infected mouse lungs, deletion of fmpR resulted in wild-type virulence in a murine infection model.


Subject(s)
Aspergillus fumigatus/genetics , Cyclic AMP-Dependent Protein Kinases/genetics , Fungal Proteins/metabolism , Gene Expression Profiling , Gene Expression Regulation, Fungal , Proline/analogs & derivatives , Animals , Aspergillus fumigatus/metabolism , Aspergillus fumigatus/pathogenicity , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Fungal Proteins/chemistry , Fungal Proteins/isolation & purification , Lung/pathology , Mice , Multigene Family , Peptide Synthases/genetics , Proline/metabolism , Pulmonary Aspergillosis/microbiology , Pulmonary Aspergillosis/pathology , Signal Transduction/genetics
5.
Chem Sci ; 13(19): 5680-5686, 2022 May 18.
Article in English | MEDLINE | ID: mdl-35694362

ABSTRACT

The controlled synthesis of biphenyls, which play a prominent role in pharmaceuticals, agrochemicals, and liquid crystals, typically requires hazardous organometallic reagents, aryl halides, and heavy metal catalysts. We recently reported a metal-free, photochemical alternative ("photosplicing") for the selective preparation of a wide range of pharmaceutically important biphenyls. Whereas the traceless sulfonamide linker enables and controls the aryl coupling, unwanted toxic byproducts are released. Therefore, we designed over 25 different temporary linkers and tested them for their suitability for the photosplicing reaction in a flow reactor. We found that a surprisingly high number of functional groups enable light-induced aryl fusion and identified a number of linkers for environmentally friendly procedures. We also report that a thiol-ene (click) - photosplicing sequence enables a convenient route to biaryls such as liquid crystals. This work sheds light on thus far neglected photochemistry of temporary linkers, reduces toxic byproducts, and expands the available starting materials for metal-free biphenyl synthesis.

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