Epoxide Ring-Opening Reactions for Abundant Production of Mugineic Acids and Nicotianamine Probes.

A succinct synthetic approach to mugineic acids and 2'-hydroxynicotianamine was established. Unlike all other synthetic methods, this approach utilized epoxide ring-opening reactions to form two C-N bonds and is characterized by the absence of redox reactions. Mugineic acid was synthesized from three readily available fragments on a gram scale in 6 steps. The protected 2'-hydroxynicotianamine was also synthesized in 4 steps, and the dansyl group, serving as a fluorophore, was introduced through a click reaction after propargylation of the 2'-hydroxy group. The dansyl-labeled nicotianamine (NA) iron complexes were internalized by oocytes overexpressing ZmYS1 (from maize) or PAT1 (from human) transporters, indicating successful transport of the synthesized NA-probe through these transporters.

Synthesis and Behavior of DNA Oligomers Containing the Ambiguous Z-Nucleobase 5-Aminoimidazole-4-carboxamide.

5-Amino-1-ß-D-ribofuranosylimidazole-4-carboxamide 5'-monophosphate (ZMP) is a central intermediate in de novo purine nucleotide biosynthesis. Its nucleobase moiety, 5-aminoimidazole-4-carboxamide (Z-base), is considered an ambiguous base that can pair with any canonical base owing to the rotatable nature of its 5-carboxamide group. This idea of ambiguous base pairing due to free rotation of the carboxamide has been applied to designing mutagenic antiviral nucleosides, such as ribavirin and T-705. However, the ambiguous base-pairing ability of Z-base has not been elucidated, because the synthesis of Z-base-containing oligomers is problematic. Herein, we propose a practical method for the synthesis of Z-base-containing DNA oligomers based on the ring-opening reaction of an N1-dinitrophenylhypoxanthine (HxaDNP) base. Thermal denaturation studies of the resulting oligomers revealed that the Z-base behaves physiologically as an A-like nucleobase, preferentially forming pairs with T. We tested the behavior of Z-base-containing DNA oligomers in enzyme-catalyzed reactions: in single nucleotide insertion, Klenow fragment DNA polymerase recognized Z-base as an A-like analog and incorporated dTTP as a complementary nucleotide to Z-base in the DNA template; in PCR amplification, Taq DNA polymerase similarly incorporated dTTP as a complementary nucleotide to Z-base. Our findings will contribute to the development of new mutagenic antiviral nucleoside analogs.

1,3a,6a-Triazapentalene derivatives as photo-induced cytotoxic small fluorescent dyes.

1,3a,6a-Triazapentalene (TAP) is a compact fluorescent chromophore whose fluorescence properties vary greatly depending on the substituents on the TAP ring. This study investigated the photo-induced cytotoxicities of various TAP derivatives. Among the derivatives, 2-p-nitrophenyl-TAP showed significant cytotoxicity to HeLa cells under UV irradiation but no cytotoxicity without UV. In addition, the photo-induced cytotoxicity of 2-p-nitirophenyl-TAP was found to be cancer cell selective and effective against HeLa cells and HCT 116 cells. Under UV irradiation, 2-p-nitrophenyl-TAP generated reactive oxygen species (ROS) that induced an apoptosis and ferroptosis in cancer cells. Therefore, it was revealed that 2-p-nitrophenyl-TAP is the most compact dye that can generate ROS by photoirradiation.

Total Syntheses of Proposed Structures of 4,10-Dihydroxy-8,12-guaianolides.

The first total syntheses of two 4,10-dihydroxy-8,12-guaianolides that were reported to be natural products were achieved. Toward the syntheses of a collection of related guaianolides, the typical 5,7-fused system of 8,12-guaianolides was constructed by a ring expansion reaction of a hydroxylated coronafacic acid analogue that can be practically synthesized and optically resolved. The total syntheses of these compounds revealed that the previously reported structures of both natural products were incorrect.

Efficient construction of the hexacyclic ring core of palau'amine: the pK a concept for proceeding with unfavorable equilibrium reactions.

Palau'amine has received a great deal of attention as an attractive synthetic target due to its intriguing molecular architecture and significant immunosuppressive activity, and we achieved its total synthesis in 2015. However, the synthesized palau'amine has not been readily applicable to the mechanistic study of immunosuppressive activity, because it requires 45 longest linear steps from a commercially available compound. Here, we report the short-step construction of the ABCDEF hexacyclic ring core of palau'amine. The construction of the CDE tricyclic ring core in a single step is achieved by our pK a concept for proceeding with unfavorable equilibrium reactions, and a palau'amine analog without the aminomethyl and chloride groups is synthesized in 20 longest linear steps from the same starting material. The palau'amine analog is confirmed to retain the immunosuppressive activity. The present synthetic approach for a palau'amine analog has the potential for use in the development of palau'amine probes for mechanistic elucidation.

Concise Total Synthesis of Tronocarpine.

A concise total synthesis of tronocarpine, a chippiine-type indole alkaloid, was accomplished. The key feature of this total synthesis is a one-pot construction of the pentacyclic skeleton containing an azabicyclo[3.3.1]nonane core by tandem cyclization from an indole derivative with all carbon side chains and functional groups. This tandem cyclization consists of α,ß-unsaturated aldehyde formation, intramolecular aldol reaction, six-membered lactamization, azide reduction, and seven-membered lactamization. The stereochemical outcome in this tandem cyclization is controlled by the stereocenter at the C14 position. This strategy can be utilized to synthesize other chippiine-type alkaloids with azabicyclo[3.3.1]nonane skeletons.

Synthesis and Antimicrobial Evaluation of Side-Chain Derivatives based on Eurotiumide A.

Side-chain derivatives of eurotiumide A, a dihydroisochroman-type natural product, have been synthesized and their antimicrobial activities described. Sixteen derivatives were synthesized from a key intermediate of the total synthesis of eurotiumide A, and their antimicrobial activities against two Gram-positive bacteria, methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), and a Gram-negative bacterium, Porphyromonas gingivalis, were evaluated. The results showed that derivatives having an iodine atom on their aromatic ring instead of the prenyl moiety displayed better antimicrobial activity than eurotiumide A against MSSA and P. gingivalis. Moreover, we discovered that a derivative with an isopentyl side chain, which is a hydrogenated product of eurotiumide A, is the strongest antimicrobial agent against all three strains, including MRSA.

Asymmetric Total Syntheses and Structure Elucidations of (+)-Eurotiumide F and (+)-Eurotiumide G.

Asymmetric total syntheses of dihydropyran containing natural products, (+)-eurotiumide F and (+)-eurotiumide G have been described. These total syntheses revealed the absolute configuration of eurotiumide F and G, and confirmed the reported structure of eurotiumide F and revised the reported structure of eurotiumide G. Highlight of these syntheses is thermal rearrangement with 4-methoxyisochroman-1-one derivative having propargyl ether on phenolic ether under thermal condition to construct dihydropyran ring. X-Ray crystallographic analysis of (+)-eurotiumide G clarified the stereochemistry at the C1-position.

A Concise Asymmetric Total Synthesis of (+)-Epilupinine.

Asymmetric total synthesis of (+)-epilupinine was achieved in just three steps using only commercially available common reagents. The total synthesis involved alkylations of N-nosylamide, ozone oxidation, and sequential reactions of the removal of the nosyl group, intramolecular dehydrative condensation, intramolecular Mannich reaction catalyzed by l-proline, and a reduction.

Synthesis and Evaluation of a 1,3a,6a-Triazapentalene (TAP)-Bonded System.

A method of synthesizing a directly connected 1,3a,6a-triazapentalene (TAP) ring system as a linearly bonded aromatic system with a planar form was established. Various TAP-dimers and a 2-alkyl-TAP-trimer were synthesized and their fluorescence properties were evaluated. Although the direct connection of the TAP ring with other TAP rings did not affect the fluorescence properties in diluted solvent, TAP-dimers showed unique fluorescence properties derived from the aggregation state under highly concentrated conditions. In particular, TAP-dimer 5 f showed aggregation-induced emission in highly concentrated solution, and 5 b showed typical mechanochromic fluorescence in the solid state despite their compact molecular size.

Cu(I)-/Base-Mediated Domino [5 + 3 + 1] Annulation for Highly π-Extended Carbazole Frameworks and DFT Mechanistic Insights.

An efficient synthesis of highly π-extended carbazoles is described via an unexpected domino [5 + 3 + 1] annulation approach. The Cu(I)-/base-promoted reactions of 2-nitrocinnamaldehydes with benzyl cyanides provide diverse benzo[ b]carbazoles. The reaction is proposed to proceed via a sequential Michael addition/intramolecular addition of an enol into a nitro group, 6π- electrocyclization, and the final oxidative aromatization as supported by density functional theory calculations. Some of the synthesized carbazoles showed significant potential in fluorescence sensing of Cu2+ ions.

Direct Synthesis of Polycyclic Tropinones by a Condensation-[4+3]-Cycloaddition Cascade Reaction.

A concise method of constructing polycyclic tropinone frameworks was developed. The single-step synthesis of polycyclic tropinone consists of an intramolecular [4+3] cycloaddition reaction of N-nosyl-pyrrole with oxyallyl cation that was generated in situ by an intermolecular condensation reaction of the nucleophilic functional groups on a tethered pyrrole with the aldehyde of 2-(silyloxy)-acrolein. This cascade reaction afforded various polycyclic tropinones including tri-, tetra-, and pentacyclic systems in high yields as single diastereomers.

Significant stabilization of palladium by gold in the bimetallic nanocatalyst leading to an enhanced activity in the hydrodechlorination of aryl chlorides.

The stabilization effect of Au towards Pd changed the reactivity of Pd in Au/Pd bimetallic nanoclusters, altering the reaction mechanism from homogeneous to heterogeneous in dechlorination reaction of aryl chlorides. This phenomenon was illustrated by the observed enhancement of the rate of reaction by in situ generated Au-rich bimetallic Au/Pd nanoclusters.

Mechanism of the Aerobic Homocoupling of Phenylboronic Acid on Au20⁻: A DFT Study.

The mechanism of the gold nanocluster-catalyzed aerobic homocoupling of arylboronic acids has been elucidated by means of DFT calculations with Au20(-) as a model cluster for the Au:[poly(N-vinylpyrrolidin-2-one)] catalyst. We found that oxygen affects the adsorption of phenylboronic acid and, by lowering the energy barrier, a water molecule enhances dissociation of the C-B bond, which is probably the rate-determining step. The key role of oxygen is in activating the surface of the gold cluster by generating Lewis acidic sites for adsorption and activation of the phenylboronic acid, leading to the formation of biphenyl through a superoxo-like species. Moreover, the oxygen adsorbed on the Au nanocluster can act as an oxidant for phenylboronic acid, giving phenol as a byproduct. As shown by NBO analysis, the basic aqueous reaction medium facilitates the reductive elimination process by weakening the Au-C bond, thereby enhancing the formation of biphenyl. The coupling of phenyl and reductive elimination of biphenyl occur at the top or facet site with low-energy-barrier through spillover of phenyl group on Au NC. The present findings are useful for the interpretation or design of other coupling reactions with Au NC.

Low-temperature carbon-chlorine bond activation by bimetallic gold/palladium alloy nanoclusters: an application to Ullmann coupling.

This paper describes the unique catalytic activity of bimetallic Au/Pd alloy nanoclusters (NCs) for Ullmann coupling of chloroarenes in aqueous media at low temperature. The corresponding reaction cannot be achieved by monometallic Au and Pd NCs as well as their physical mixtures. On the basis of quantum chemical calculation, it was found that the crucial step to govern the unusual catalytic activity of Au/Pd is the dissociative chemisorption of ArCl, which is unlikely in the monometallic Au and Pd NCs.

Enantioselective synthesis of a chiral nitrogen-doped buckybowl.

Bowl-shaped aromatic compounds, namely buckybowls constitute a family of curved polycyclic aromatic carbons along with fullerenes and carbon nanotubes. Doping of heteroatoms to the carbon frameworks of such aromatic compounds drastically modulates their physical and chemical properties. In contrast to nitrogen-doped azafullerenes or carbon nanotubes, synthesis of azabuckybowls, nitrogen-doped buckybowls, remains an unsolved challenging task. Here we report the first enantioselective synthesis of a chiral azabuckybowl, triazasumanene. X-ray crystallographic analysis confirmed that the doping of nitrogen induces a more curved and deeper bowl structure than in all-carbon buckybowls. As a result of the deeper bowl structure, the activation energy for the bowl inversion (thermal flipping of the bowl structure) reaches an extraordinarily high value (42.2 kcal per mol). As the bowl inversion corresponds to the racemization process for chiral buckybowls, this high bowl inversion energy leads to very stable chirality of triazasumanene.

Aerobic oxidation of methanol to formic acid on Au20-: a theoretical study on the reaction mechanism.

The aerobic oxidation of methanol to formic acid catalyzed by Au(20)(-) has been investigated quantum chemically using density functional theory with the M06 functional. Possible reaction pathways are examined taking account of full structure relaxation of the Au(20)(-) cluster. The proposed reaction mechanism consists of three elementary steps: (1) formation of formaldehyde from methoxy species activated by a superoxo-like anion on the gold cluster; (2) nucleophilic addition by the hydroxyl group of a hydroperoxyl-like complex to formaldehyde resulting in a hemiacetal intermediate; and (3) formation of formic acid by hydrogen transfer from the hemiacetal intermediate to atomic oxygen attached to the gold cluster. A comparison of the computed energetics of various elementary steps indicates that C-H bond dissociation of the methoxy species leading to formation of formaldehyde is the rate-determining step. A possible reaction pathway involving single-step hydrogen abstraction, a concerted mechanism, is also discussed. The stabilities of reactants, intermediates and transition state structures are governed by the coordination number of the gold atoms, charge distribution, cooperative effect and structural distortion, which are the key parameters for understanding the relationship between the structure of the gold cluster and catalytic activity in the aerobic oxidation of alcohols.