A Strategy Based on "Ambident Anthracene" for the Synthesis of Higher-Order Iptycenes.

An efficient method for the synthesis of higher-order iptycenes using an "ambident anthracene" building block is presented. For that purpose, an iterative elongation strategy involving the ring-opening of an endoxide to give a highly reactive anthranoxide, followed by a Diels-Alder reaction with an aryne was used. The method systematically provides higher-order iptycenes, including trideciptycene, which is currently the iptycene with the longest chain to have been synthesized. X-ray crystallography revealed interesting structures in which solvent molecules fill the cavities of these iptycenes, thus creating a "honeycomb" structure with the solvent molecules arranged in tubular spaces.

A Strategy Based on "Ambident Anthracene" for the Synthesis of Higher-Order Iptycenes.

Invited for the cover of this issue is the group of Takayuki Iwata and Mitsuru Shindo at Kyushu University. The image depicts the longest-chain iptycene synthesized in this study, showing the connections between iptycene synthetic units by using transparent cases. Read the full text of the article at 10.1002/chem.202303687.

Practical Synthesis of α,α-Dibromo Esters from Aldehydes.

Herein, we report an efficient and practical method for synthesizing α,α-dibromo esters, which are the precursors of ynolates, through the dibromination of aldehydes followed by oxidative esterification using iodine. Our method was successfully employed in a large-scale synthesis to yield more than 30 g of dibromo esters. These two steps can be performed in a one-pot manner, which makes the method adaptable even for aldehydes having low boiling points.

Intramolecular Hiyama Coupling: Synthesis of 1,8,13-Trisubstituted Chiral Triptycenes with Three Different Substituents by Intramolecular Substituent Transfer.

Herein, we describe Hiyama coupling via intramolecular substituent transfer from silicon on one blade of triptycenes to another to yield 1,8,13-trisubstituted chiral triptycenes. This reaction is attributed to the proximity effect of substituents on triptycene, which plays an important role in not only the formation of the oxy-palladacycle but also the activation of the silyl group to facilitate σ-bond metathesis. After bromination and nucleophilic ring opening, the second intramolecular Hiyama coupling provided various 1,8,13-trisubstituted chiral triptycenes. The optical resolution of 1,8,13-triptycene afforded an optically active form for the first time.

Lotus japonicus karrikin receptors display divergent ligand-binding specificities and organ-dependent redundancy.

Karrikins (KARs), smoke-derived butenolides, are perceived by the α/ß-fold hydrolase KARRIKIN INSENSITIVE2 (KAI2) and thought to mimic endogenous, yet elusive plant hormones tentatively called KAI2-ligands (KLs). The sensitivity to different karrikin types as well as the number of KAI2 paralogs varies among plant species, suggesting diversification and co-evolution of ligand-receptor relationships. We found that the genomes of legumes, comprising a number of important crops with protein-rich, nutritious seed, contain two or more KAI2 copies. We uncover sub-functionalization of the two KAI2 versions in the model legume Lotus japonicus and demonstrate differences in their ability to bind the synthetic ligand GR24ent-5DS in vitro and in genetic assays with Lotus japonicus and the heterologous Arabidopsis thaliana background. These differences can be explained by the exchange of a widely conserved phenylalanine in the binding pocket of KAI2a with a tryptophan in KAI2b, which arose independently in KAI2 proteins of several unrelated angiosperms. Furthermore, two polymorphic residues in the binding pocket are conserved across a number of legumes and may contribute to ligand binding preferences. The diversification of KAI2 binding pockets suggests the occurrence of several different KLs acting in non-fire following plants, or an escape from possible antagonistic exogenous molecules. Unexpectedly, L. japonicus responds to diverse synthetic KAI2-ligands in an organ-specific manner. Hypocotyl growth responds to KAR1, KAR2 and rac-GR24, while root system development responds only to KAR1. This differential responsiveness cannot be explained by receptor-ligand preferences alone, because LjKAI2a is sufficient for karrikin responses in the hypocotyl, while LjKAI2a and LjKAI2b operate redundantly in roots. Instead, it likely reflects differences between plant organs in their ability to transport or metabolise the synthetic KLs. Our findings provide new insights into the evolution and diversity of butenolide ligand-receptor relationships, and open novel research avenues into their ecological significance and the mechanisms controlling developmental responses to divergent KLs.

(-)-Xanthatin as a Killer of Human Breast Cancer MCF-7 Mammosphere Cells: A Comparative Study with Salinomycin.

Experimental evidence accumulated by our research group and others strongly suggests that (-)-xanthatin, a xanthanolide sesquiterpene lactone, exhibits anti-proliferative effects on human breast cancer cells (in vitro) as well as anti-tumor effects in experimental animals (in vivo). In cancer biology, it is now critically important for anti-cancer agents to selectively target cancer stem cells (CSCs) in order to overcome cancer therapeutic resistance and recurrence. However, it has not yet been established whether (-)-xanthatin abrogates the formation of breast CSCs. In the present study, we utilized chemically synthesized pure (-)-xanthatin and a culture system to obtain mammospheres from human breast cancer MCF-7 cells, which are a CSC-enriched population. We herein demonstrated for the first time that (-)-xanthatin exhibited the ability to kill mammospheres, similar to salinomycin, an established selective killer of CSCs. A possible anti-proliferative mechanism toward mammospheres by (-)-xanthatin is discussed.

Retro-Friedel-Crafts-Type Acidic Ring-Opening of Triptycenes: A New Synthetic Approach to Acenes.

The triptycene scaffold has been ring-opened by using a retro-Friedel-Crafts-type reaction under acidic conditions to give its corresponding anthrone product. 9-Hydroxytriptycenes and unsubstituted triptycene undergo ring-opening reaction under strongly acidic conditions, such as with TfOH. An investigation of the substitution effect has revealed that the electron-donating group on the arene moiety allows the reaction to proceed in the presence of a weaker acid, such as TFA. In addition, the reaction has been successfully applied toward the synthesis of tetracene.

Retro-Friedel-Crafts-Type Acidic Ring-Opening of Triptycenes: A New Synthetic Approach to Acenes.

Invited for the cover of this issue is the group of Takayuki Iwata, Mitsuru Shindo, and co-workers at Kyushu University. The image depicts ring-opening of triptycenes to afford corresponding anthrones by acid treatment. Read the full text of the article at 10.1002/chem.202104160.

Quadruple Role of Pd Catalyst in Domino Reaction Involving Aryl to Alkyl 1,5-Pd Migration to Access 1,9-Bridged Triptycenes.

A Pd-catalyzed domino reaction of 1,8,13-tribromo-9-methoxytriptycenes is reported. Under conventional Suzuki coupling conditions, the triptycenes underwent multiple transformations to give 1,9-bridged triptycenes. Based on mechanistic investigations, a single Pd catalyst functions as Pd0 , PdII and PdIV species to catalyze four distinct processes: (1) aryl to alkyl 1,5-Pd migration, (2) intramolecular arylation, (3) homocoupling of phenylboronic acid and (4) Suzuki coupling. DFT calculations revealed that 1,5-Pd migration likely proceeds via both concerted PdII and stepwise PdIV routes. Asymmetric synthesis of the chiral triptycenes, as well as optical resolution, and further transformation are also reported.

Anthranoxides as Highly Reactive Arynophiles for the Synthesis of Triptycenes.

We report herein an efficient method to synthesize triptycenes by the reaction of benzynes and anthranoxides, which are electron-rich and readily prepared from the corresponding anthrones. Using this method, 1,9-syn-substituted triptycenes were regioselectively obtained employing 3-methoxybenzynes. This method was also applied to synthesize pentiptycenes. A DFT study revealed that the cycloaddition of lithium anthranoxide and benzyne proceeds stepwise.

Catalytic and Aerobic Oxidative Biaryl Coupling of Anilines Using a Recyclable Heterogeneous Catalyst for Synthesis of Benzidines and Bicarbazoles.

In this study, a heterogeneous rhodium-catalyzed oxidative homocoupling reaction of anilines utilizing molecular oxygen as the sole oxidant is reported. Employing a commercially available and recyclable Rh/C catalyst enabled the oxidative dimerization of various anilines, including N,N-disubstituted and N-monosubstituted anilines, as well as diarylamines, triarylamines, and carbazoles. Additionally, the catalytic protocol was extended to the ortho-ortho coupling of anilines, affording 2,2'-diaminobiphenyls with high regioselectivity. Notably, the developed approach provides rapid access to diversely functionalized benzidines and diaminobiphenyls in an operationally simple, practical, and environmentally friendly manner.

Synthesis of Distorted 1,8,13-Trisilyl-9-hydroxytriptycenes by Triple Cycloaddition of Ynolates to 3-Silylbenzynes.

1,8,13-Trialkyl(aryl)silyl-9-hydroxytriptycenes (trisilyltriptycenes) were synthesized by the triple addition of ynolates and 3-silylbenzynes with high regioselectivity. Benzene rings in the resulting triptycenes were highly distorted where the dihedral angles between the substituents were as high as 35°. The distortion energy induced step-by-step halogenation reactions to yield halogenated triptycenes, including chiral triptycenes. The 1,8,13-trihalogenated triptycenes were then converted to 1,8,13-functionalized triptycenes.

Asymmetric Total Synthesis of (-)-Stemonamine and Its Stereochemical Stability.

The first asymmetric total synthesis of (-)-stemonamine is described. The key reactions included intramolecular acylation to construct the seven-membered ring and a tandem [2+2] cycloaddition-Dieckmann condensation reaction using an ynolate to form the fully substituted cyclopentenone moiety. Racemization and epimerization of the natural product were first experimentally demonstrated.

Aerobic C-H Oxidation of Arenes Using a Recyclable, Heterogeneous Rhodium Catalyst.

A novel, practical protocol for the aerobic direct C-H acetoxylation of arenes, employing a recyclable heterogeneous rhodium catalyst, is reported herein. The trifluoroacetoxylation of 2-amido-substituted anthracenes proceeded at the 9-position with exclusive regioselectivity. The oxidation of variously substituted anthracenes and other polycyclic aromatics with molecular oxygen as a terminal oxidant proceeded under mild conditions, providing products in good to excellent yields.

A Novel Bongkrekic Acid Analog-Mediated Modulation of the Size of Lipid Droplets: Evidence for the Appearance of Smaller Adipocytes.

Thiazolidinediones (TZDs) are known as peroxisome proliferator-activated receptor γ (PPARγ) activators, and are used in the treatment of diabetes. Although the usefulness of TZDs has been demonstrated, some of their side effects are becoming an obstacle to their clinical applicability; edema is known to be evoked by the "structural characteristics" of TZD, but not by the PPARγ activation. Thus, novel therapeutic modalities (i.e., non-TZD-type PPARγ activators) having different structures to those of TZDs are desired. We previously identified bongkrekic acid (BKA) as a PPARγ activator using the human breast cancer MCF-7 cell line as a model system. In the present study, we newly synthesized BKA analogs and examined the usefulness of BKA and its analogs as PPARγ activators in differentiated adipocyte cells. Among the chemicals investigated, one of the BKA analogs (BKA-#2) strongly stimulated PPARγ and the differentiation of 3T3-L1 cells similar to pioglitazone, a positive control. Furthermore, BKA-#2 reduced the size of lipid droplets in the mature adipocyte cells. The possible modulation mechanism by BKA-#2 is discussed.

Regioselective One-Pot Synthesis of Triptycenes via Triple-Cycloadditions of Arynes to Ynolates.

We developed the novel one-pot synthetic method of substituted triptycenes by the reaction of ynolates and arynes. This four-step process involves three cycloadditions and electrocyclic ring opening of the strained Dewar anthracene. Each of the three related but structurally distinct classes of nucleophiles (ynolate, enolate, and anthracenolate) reacts with o-benzyne in the same predictable manner controlled by chelation and negative hyperconjugation. The resulting functionalized C3 -symmetrical triptycenes hold promise in the design of functional materials.

Heterogeneous Rhodium-Catalyzed Aerobic Oxidative Dehydrogenative Cross-Coupling: Nonsymmetrical Biaryl Amines.

The first heterogeneously catalyzed oxidative dehydrogenative cross-coupling of aryl amines is reported herein. 2-Naphthylamine analogues were reacted with various electron-rich arenes using a heterogeneous Rh/C catalyst under mild aerobic conditions, thus affording nonsymmetrical biaryl amines in excellent yields with high selectivities. This reaction provides a mild, operationally simple, and efficient approach for the synthesis of biaryls which are important to pharmaceutical and materials chemistry.

Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues.

Bongkrekic acid (BKA), isolated from the bacterium Burkholderia cocovenenans, is an inhibitor of adenine nucleotide translocator, which inhibits apoptosis, and is thus an important tool for the mechanistic investigation of apoptosis. An efficient total synthesis of BKA has been achieved by employing a three-component convergent strategy based on Kocienski-Julia olefination and Suzuki-Miyaura coupling. It is noteworthy that segment B has been prepared as a new doubly functionalized coupling partner, which contributes to shortening of the number of steps. Torquoselective olefination with an ynolate has also been applied for the efficient construction of an unsaturated ester. Furthermore, it is revealed that 1-methyl-2-azaadamantane N-oxyl is an excellent reagent for final oxidation to afford BKA in high yield. Based on the total synthesis, several BKA analogues were prepared for structure-activity relationship studies, which indicated that the carboxylic acid moieties were essential for the apoptosis inhibitory activity of BKA. More easily available BKA analogues with potent apoptosis inhibitory activity were also developed.

Xanthocidin derivatives as topoisomerase IIα enzymatic inhibitors.

Few studies have examined xanthocidin, a biotic isolated from Streptomyces xanthocidicus in 1966, because its supply is limited. Based on its chemical structure, xanthocidin has the potential to become a lead compound in the production of agrochemicals and anti-cancer drugs; however, it is unstable under both basic and acidic conditions. We recently established the total synthesis of xanthocidin using the FeCl3-mediated Nazarov reaction, and obtained two stable derivatives (#1 and #2). The results of the present study demonstrated that these derivatives exhibited the inhibitory activity of topoisomerase IIα, known as a molecular target for cancer chemotherapy, and this was attributed to the respective exo-methylene ketone group without DNA intercalation. The results obtained also suggest that these derivatives may have value as lead compounds in the synthesis of topoisomerase IIα inhibitors.

cis-Cinnamic acid selective suppressors distinct from auxin inhibitors.

The activity of cis-cinnamic acid (cis-CA), one of the allelochemicals, in plants is very similar to that of indole-3-acetic acid (IAA), a natural auxin, and thus cis-CA has long been believed to be an analog of auxin. We have reported some structure-activity relationships studies by synthesizing over 250 cis-CA derivatives and estimating their inhibitory activities on root growth inhibition in lettuce. In this study, the compounds that showed low- or no-activity on root growth inhibition were recruited as candidates suppressors against cis-CA and/or auxin and tested for their activity. In the presence of cis-CA, lettuce root growth was inhibited; however, the addition of some cis-CA derivatives restored control-level root growth. Four compounds, (Z)-3-(4-isopropylphenyl)acrylic acid, (Z)-3-(3-butoxyphenyl)acrylic acid, (Z)-3-[3-(pentyloxy)phenyl]acrylic acid, and (Z)-3-(naphthalen-1-yl)acrylic acid were selected as candidates for a cis-CA selective suppressor they allowed the recovery of root growth from inhibition by cis-CA treatment without any effects on the IAA-induced effect or elongating activity by themselves. Three candidates significantly ameliorated the root shortening by the potent inhibitor derived from cis-CA. In brief, we have found some cis-CA selective suppressors which have never been reported from inactive cis-CA derivatives for root growth inhibition. cis-CA selective suppressors will play an important role in elucidating the mechanism of plant growth regulation.