Multicomponent Synthesis of 3(2H)-Furanones Initiated by Copper(II)-Catalyzed Alkyne-Carbonyl Cross Metathesis.

The cooperative Lewis- and Brønsted acid catalysis makes convergent synthesis of 3(2H)-furanones through a three-component coupling of 1,3-diynes, alkyl glyoxylates and water. Control experiments support that Lewis acid-catalyzed highly chemo-, regio- and stereoselective alkyne-carbonyl metathesis of 1,3-diynes and alkyl glyoxylates might be the initial step of this multicomponent annulation. Further chemo- and regioselective hydration of the alkyne-carbonyl metathesis product and subsequent oxa-Michael addition promoted by Brønsted acid results in the formation of two C-O bonds of the five-membered oxygen heterocycle.

Antibacterial insights into alternariol and its derivative alternariol monomethyl ether produced by a marine fungus.

Alternaria alternata FB1 is a marine fungus identified as a candidate for plastic degradation in our previous study. This fungus has been recently shown to produce secondary metabolites with significant antimicrobial activity against various pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and the notorious aquaculture pathogen Vibrio anguillarum. The antibacterial compounds were purified and identified as alternariol (AOH) and its derivative, alternariol monomethyl ether (AME). We found that AOH and AME primarily inhibited pathogenic bacteria (MRSA or V. anguillarum) by disordering cell division and some other key physiological and biochemical processes. We further demonstrated that AOH could effectively inhibit the unwinding activity of MRSA topoisomerases, which are closely related to cell division and are the potential action target of AOH. The antibacterial activities of AOH and AME were verified by using zebrafish as the in vivo model. Notably, AOH and AME did not significantly affect the viability of normal human liver cells at concentrations that effectively inhibited MRSA or V. anguillarum. Finally, we developed the genetic operation system of A. alternata FB1 and blocked the biosynthesis of AME by knocking out omtI (encoding an O-methyl transferase), which facilitated A. alternata FB1 to only produce AOH. The development of this system in the marine fungus will accelerate the discovery of novel natural products and further bioactivity study.IMPORTANCEMore and more scientific reports indicate that alternariol (AOH) and its derivative alternariol monomethyl ether (AME) exhibit antibacterial activities. However, limited exploration of their detailed antibacterial mechanisms has been performed. In the present study, the antibacterial mechanisms of AOH and AME produced by the marine fungus Alternaria alternata FB1 were disclosed in vitro and in vivo. Given their low toxicity on the normal human liver cell line under the concentrations exhibiting significant antibacterial activity against different pathogens, AOH and AME are proposed to be good candidates for developing promising antibiotics against methicillin-resistant Staphylococcus aureus and Vibrio anguillarum. We also succeeded in blocking the biosynthesis of AME, which facilitated us to easily obtain pure AOH. Moreover, based on our previous results, A. alternata FB1 was shown to enable polyethylene degradation.

Gold(I)-Catalyzed Ring-Closing Alkyne-Carbonyl Metathesis for the Synthesis of Butenolides.

Alkyne-carbonyl metathesis is a type of carbon-carbon forming reaction involving the construction a carbon-carbon double bond and a carbonyl group in one transformation. Herein, a Au(I)-catalyzed ring-closing alkyne-carbonyl metathesis protocol has been developed to make densely substituted γ-butenolides from propargyl α-ketoesters. It features 100 % atom economy, excellent substrate flexibility and benign functional group tolerance. Mechanistic studies demonstrate that the coordinative interaction between the gold catalyst and the alkyne might initiate the transfer of an oxygen atom and the formation of the carbon-carbon double bond. By using this gold-catalyzed ring-closing alkyne-carbonyl metathesis as a key step reaction, four naturally occurring butenolide-type compounds including decumbic acid (45 % yield for 3 steps), deoxyisosporothric acid (32 % yield for 5 steps), lichesterinic acid (34 % yield for 5 steps) and isomuronic acid (6 % yield for 8 steps) have been synthesized starting from commercially available starting materials.

Construction of 4-Acyl-2-quinolones through Sc(OTf)3-Catalyzed Ring-Closing Alkyne-Carbonyl Metathesis.

An atom-economical protocol to construct densely substituted 4-acyl-2-quinolones from N-(2-alkynylphenyl)-α-ketoamides has been developed through Sc(OTf)3-catalyzed ring-closing alkyne-carbonyl metathesis. Mechanistic experimental studies support that coordinative interaction between Sc(OTf))3 and the substrate, the formation of an oxetene intermediate, and an electrocyclic ring-opening of the oxetene might be involved.

Gold-Catalyzed Cycloisomerization of Propargyl Pyruvates Enabling Unified Access to Tricladolides C and D, Chaetomellic Anhydride A, and Tyromycin A.

Gold-catalyzed cycloisomerization of propargyl pyruvates has been developed as a key reaction to prepare maleic anhydride-type natural products. By combining with chemoselective epoxidation of the formed γ-alkylidenebutenolides and oxidative cleavage of epoxides, the first synthesis of tricladolide D and racemic tricladolide C has been achieved in 52 and 16% overall yields with five to seven steps starting from commercially available compounds. Further catalytic hydrogenation of alkenylated maleic anhydrides derived from γ-alkylidenebutenolides produced chaetomellic anhydride A (19% yield for six steps) and tyromycin A (15% yield for six steps), which provides flexible synthetic approaches to these naturally occurring dialkylated maleic anhydrides distinct from the documented ones.

Direct synthesis of highly functionalized furans from donor-acceptor cyclopropanes via DBU-mediated ring expansion reactions.

A DBU-mediated, unprecedented formal ring expansion reaction of 2-acyl-3-arylcyclopropane-1,1-dicarbonitriles for the synthesis of multisubstituted furan derivatives is reported. This transformation represents the regioselective ring-opening reaction of cyclopropane-1,1-dicarbonitriles and annulation using an intramolecular addition cascade reaction protocol for the synthesis of fully substituted furans includes use of readily available starting materials, mild reaction conditions, and it is transition-metal catalyst free, has good functional tolerance, and broad substrate scope.

Regioselective construction of 1,3-diaryl tetrahydroindazolones via the three-component reaction of 1,3-cyclohexanediones, ß-nitrostyrenes and arylhydrazines.

1,5,6,7-Tetrahydro-4H-indazol-4-one derivatives were successfully synthesized using a one-pot three-component system that combines substituted ß-nitrostyrenes, 1,3-cyclohexanediones and phenylhydrazines. This reaction involves a highly efficient domino sequence consisting of the aza-Michael reaction, intramolecular O-nucleophilic addition, nucleophilic addition, and ring opening of furan as the key unit steps. Notably, the highly regioselective construction of the tetrahydro-4H-indazolone moiety and the introduction of functionalized aromatic rings were achieved.

DBU-mediated [4 + 1] annulations of donor-acceptor cyclopropanes with carbon disulfide or thiourea for synthesis of 2-aminothiophene-3-carboxylates.

DBU-mediated [4 + 1] annulations of donor-acceptor cyclopropanes with carbon disulfide or thiourea to form 2-aminothiophene-3-carboxylate derivatives have been discovered. This reaction proceeds via the ring opening of donor-acceptor cyclopropanes to produce a 2-(iminomethylene)but-3-enoate intermediate, followed by the attack of an S-nucleophile for regioselective intermolecular nucleophilic addition, intramolecular S-nucleophilic addition, and final aromatization. A variety of functional groups could be tolerated under the reaction conditions.