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.

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.

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.

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.

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 Synthesis of Gonytolide A: Strategic Use of an Aryl Halide Blocking Group for Oxidative Coupling.

The first synthesis of the chromanone lactone dimer gonytolide A has been achieved employing vanadium(V)-mediated oxidative coupling of the monomer gonytolide C. An o-bromine blocking group strategy was employed to favor para- para coupling and to enable kinetic resolution of (±)-gonytolide C. Asymmetric conjugate reduction enabled practical kinetic resolution of a chiral, racemic precursor and the asymmetric synthesis of (+)-gonytolide A and its atropisomer.

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.

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.

One-Pot Evolution of Ageladine†A through a Bio-Inspired Cascade towards Selective Modulators of Neuronal Differentiation.

A bio-inspired cascade reaction has been developed for the construction of the marine natural product ageladine A and a de novo array of its N1-substituted derivatives. This cascade features a 2-aminoimidazole formation that is modeled after an arginine post-translational modification and an aza-electrocyclization. It can be effectively carried out in a one-pot procedure from simple anilines or guanidines, leading to structural analogues of ageladine A that had been otherwise synthetically inaccessible. We found that some compounds out of this structurally novel library show a significant activity in modulating the neural differentiation. Namely, these compounds selectively activate or inhibit the differentiation of neural stem cells to neurons, while being negligible in the differentiation to astrocytes. This study represents a successful case in which the native biofunction of a natural product could be altered by structural modifications.

Syntheses of Dimeric Tetrahydroxanthones with Varied Linkages: Investigation of "Shapeshifting" Properties.

The 2,4'- and 4,4'-linked variants of the cytotoxic agent secalonic acid A and their analogues have been synthesized. Kinetic resolution of an unprotected tetrahydroxanthone scaffold followed by copper-mediated biaryl coupling allowed for efficient access to these compounds. Evaluation of the "shapeshifting" properties of 2,2'-, 2,4'-, and 4,4'-linked variants of the secalonic acids A in a polar solvent in conjunction with assays of the compounds against select cancer cell lines was conducted to study possible correlations between linkage variation and cytotoxicity.

Design and synthesis of strong root gravitropism inhibitors with no concomitant growth inhibition.

Herein, we describe a highly potent gravitropic bending inhibitor with no concomitant growth inhibition. Previously, we reported that (2Z,4E)-5-phenylpenta-2,4-dienoic acid (ku-76) selectively inhibits root gravitropic bending of lettuce radicles at 5 µM. Based on the structure-activity relationship study of ku-76 as a lead compound, we designed and synthesized various C4-substituted analogs of ku-76. Among the analogs, 4-phenylethynyl analog exhibited the highest potency for gravitropic bending inhibition, which was effective at only 0.01 µM. Remarkably, 4-phenylethynyl analog is much more potent than the known inhibitor, NPA. Substitution in the para position on the aromatic ring of 4-phenylethynyl group was tolerated without diminished activity. In addition, evaluation using Arabidopsis indicated that 4-phenylethynyl analog inhibits gravitropism by affecting auxin distribution in the root tips. Based on the effects on Arabidopsis phenotypes, 4-phenylethynyl analog may be a novel inhibitor that differs in action from the previously reported auxin transport inhibitors.

Cell surface biotinylation by azaelectrocyclization: easy-handling and versatile approach for living cell labeling.

Versatile method for living cell labeling has been established. Cell surfaces are initially biotinylated by azaelectrocyclization, and then treated with the fluorescence-labeled avidin or the anti-biotin antibody.

Taxonomic Reassessment of the Izumo Lineage of Hynobius utsunomiyaorum: Description of a New Species from Chugoku, Japan.

Here, we describe a new species of the genus Hynobius from Chugoku, Japan. In populations from central to eastern Shimane Prefecture, the Izumo Lineage of Hynobius utsunomiyaorum was clearly distinguished from the true Hynobius utsunomiyaorum based on morphological and molecular evidence. Thus, we describe the former lineage as a new species, Hynobius kunibiki sp. nov. Morphological comparisons revealed that H. utsunomiyaorum lacks a distinct yellow line on the ventral side of its tail, whereas the new species possesses this yellow line; most H. utsunomiyaorum individuals have distinct white spots on the lateral sides of their body and lack a fifth toe, whereas the new species largely lacks these spots, and all examined individuals had a fifth toe. The two species also differed significantly by several other morphological characteristics. The lentic species Hynobius setoi is morphologically similar to H. kunibiki sp. nov., but they differ significantly by various morphological characteristics. Despite their partial morphological similarity, these two species differed substantially in terms of their genetics. Finally, we show, in a phylogenetic tree including all Japanese Hynobius species, that the subgenus Hynobius can be divided into four genetic clades. Overall, this information will help develop conservation management strategies and policies for these species.

Design and chemical synthesis of root gravitropism inhibitors: Bridged analogues of ku-76 have more potent activity.

Previously, we found (2Z,4E)-5-phenylpenta-2,4-dienoic acid (ku-76) to be a selective inhibitor of root gravitropic bending of lettuce radicles at 5 µM, with no concomitant growth inhibition, and revealed the structure-activity relationship in this inhibitory activity. The conformation of ku-76 is flexible owing to the open-chain structure of pentan-2,4-dienoic acid with freely rotating single bonds, and the (2Z)-alkene moiety may be isomerized by external factors. To develop more potent inhibitors and obtain insight into the target biomolecules, various analogues of ku-76, fixed through conformation and/or configuration, were synthesized and evaluated. Stereochemical fixation was effective in improving the potency of gravitropic bending inhibition. Finally, we found highly potent conformational and/or configurational analogues (ku-257, ku-294 and ku-308), that did not inhibit root growth. The inhibition of root curvature by these analogues was comparable to that of naptalam.

Essential structural features of (2Z,4E)-5-phenylpenta-2,4-dienoic acid for inhibition of root gravitropism.

Previously, we found (2Z,4E)-5-phenylpenta-2,4-dienoic acid (ku-76) to be a selective inhibitor of root gravitropic bending of lettuce radicles at 5 µM, with no concomitant growth inhibition. Here, we describe a structure-activity relationship study of ku-76 to determine the essential structural features for the inhibitory activity. A series of ku-76 analogues was synthesized and the key features of ku-76 that are necessary for inhibition of lettuce root gravitropic bending were determined. The (2E,4E)-, (2Z,4Z)- (2E,4Z)- analogues were inactive, and 4,5-saturated and 4,5-alkynyl analogues also did not show inhibitory activity, demonstrating the importance of the (2Z,4E) diene unit. The aromatic ring was also crucial and could not be replaced with an alkyl chain. Derivatives in which the carboxylic acid was replaced with amides, alcohols, or esters were much less potent. These results suggest that the (2Z,4E)-diene, the carboxylic acid moiety, and the aromatic ring are essential for potent inhibitory activity against gravitropic bending.

Synthesis of Ynolates via Double Deprotonation of Nonbrominated Esters.

Herein, we report a double deprotonation method used for the preparation of ynolates starting from nonbrominated 2,6-di-tert-butylphenyl esters. The current method is superior to the previously described double lithium/halogen exchange approach because easily accessible starting materials are used. This method will be especially useful for preparation of ynolates bearing functional groups in organic synthesis.