Chromic properties of dibenzo[j,l]fluoranthenes exhibiting different resonance contributions.

Chromic molecules change colour in response to external stimuli and are utilized in applications such as food additive detection, light dimmers, and biological probes. One of the common design strategies for organic chromic molecules is based on changes in the π-conjugation. We have hypothesized that non-alternant polyaromatic hydrocarbon (PAH) skeletons can be used as backbones for chromic molecules. Herein, we synthesized hydroxy-substituted dibenzo[j,l]fluoranthenes, a class of non-alternant PAHs, as novel chromic compounds and evaluated their halochromic properties by UV-vis and fluorescence spectroscopy. Under basic conditions, the 1-hydroxy derivatives show a hyperchromic shift, whereas the 9-hydroxy derivatives show a bathochromic shift and fluorescence although the skeleton of the chromophore is the same. Density functional theory calculations indicated that the different chromic properties are attributed to the differences in their resonance structures.

Intramolecular Ynamide-Benzyne (3+2) Cycloadditions.

We report herein intramolecular (3+2) cycloaddition reactions between ynamides as three-atom components and benzyne. In these intramolecular reactions, the two-bond formation is realized by exploiting benzyne precursors that contain a chlorosilyl group as a linking functionality. This method thus highlights the ambivalent character of the intermediate indolium ylide, which exhibits both nucleophilic and electrophilic properties at its C2 atom.

Rotaxane Synthesis by an End-Capping Strategy via Swelling Axle-Phenols.

A method for rotaxane synthesis by enlargement of the size of the terminal phenol group of the axle component by aromatic bromination has been developed. This method may be regarded as an end-capping strategy involving the swelling of the phenol group at the axle terminal. The advantages of the present strategy include: ready availability of axle components with a variety of swelling precursors, wide product scope (19 examples given including a [3]rotaxane), mild conditions for the swelling process, rich potential for the derivatization of the brominated rotaxanes, and possible release of the axle component by degradative dethreading of the thermally stable brominated rotaxanes under the basic conditions.

AI-Driven Synthetic Route Design Incorporated with Retrosynthesis Knowledge.

Computer-aided synthesis planning (CASP) aims to assist chemists in performing retrosynthetic analysis for which they utilize their experiments, intuition, and knowledge. Recent breakthroughs in machine learning (ML) techniques, including deep neural networks, have significantly improved data-driven synthetic route designs without human intervention. However, learning chemical knowledge by ML for practical synthesis planning has not yet been adequately achieved and remains a challenging problem. In this study, we developed a data-driven CASP application integrated with various portions of retrosynthesis knowledge called "ReTReK" that introduces the knowledge as adjustable parameters into the evaluation of promising search directions. The experimental results showed that ReTReK successfully searched synthetic routes based on the specified retrosynthesis knowledge, indicating that the synthetic routes searched with the knowledge were preferred to those without the knowledge. The concept of integrating retrosynthesis knowledge as adjustable parameters into a data-driven CASP application is expected to enhance the performance of both existing data-driven CASP applications and those under development.

Catalytic Substrate-Selective Silylation of Primary Alcohols via Remote Functional-Group Discrimination.

Silylation of alcohols has generally been known to take place at the sterically most accessible less-hindered hydroxy group. Herein, the catalyst-controlled substrate-selective silylation of primary alcohols, in which the selectivity was controlled independently of the innate reactivity of the hydroxy group, based on the steric environment, is reported. The chain-length-selective silylation of 1,n-amino alcohol derivatives was achieved and 1,5-amino alcohol derivatives showed outstandingly high reactivity in the presence of analogues with a shorter or longer chain length under catalyst-controlled conditions. A highly substrate-selective catalytic silylation of pentanol analogues was also developed, in which the remote functionality at C(5) from the reacting hydroxy groups was effectively discriminated on silylation.

Oxidative ß-Cleavage of Fused Cyclobutanols Leading to Hydrofuran-Fused Polycyclic Aromatic Compounds.

Treatment of aryl-fused bicyclo[4.2.0]octanols with an oxidant such as phenyliodine diacetate (PIDA) or hypochlorous acid gave dihydrofuran-containing polycyclic aromatic compounds by selective ß-cleavage of the cyclobutanol moiety. Mechanistic studies suggest that the oxygen atom of the hydrofuran ring is incorporated from the hydroxy group of the substrate via intramolecular addition. The oxidative transformation should serve as a new method to prepare functionalized polycyclic aromatic compounds.

Helical Nanographenes Embedded with Contiguous Azulene Units.

The azulene moiety, composed of contiguous pentagonal and heptagonal rings, is a structural defect that alters the electronic, magnetic, and structural properties of graphenes and graphene nanoribbons. However, nanographenes embedded with an azulene cluster have not been widely investigated because these compounds are difficult to synthesize in their pure form. Herein, azulene-embedded nanographenes bearing a unique cove-type edge were synthesized by a novel synthetic protocol. Experimental and theoretical investigations revealed that this cove edge imparts stable helical chirality, unlike normal cove edges. The in-solution self-association behavior and the structural, electronic, and electrochemical properties were also described in detail.

Total Syntheses of Allelopathic 4-Oxyprotoilludanes, Melleolides, and Echinocidins.

Stereocontrolled total syntheses of allelopathic 4-oxyprotoilludane sesquiterpenes, melleolide, melleolide F, and echinocidins B and D were achieved. The curved 5/6/4 tricyclic system with an angular hydroxy group was built via three key transformations: (1) Me3Al-catalyzed [2 + 2] cycloaddition of a ketene silyl acetal with a propiolate, (2) reductive ring-opening of a cyclic hemiketal, and (3) the intramolecular Morita-Baylis-Hillman reaction. This synthetic route represents a new and reliable strategy to obtain protoilludanes with several oxy-functional groups.

Prediction and Interpretable Visualization of Retrosynthetic Reactions Using Graph Convolutional Networks.

Recently, many research groups have been addressing data-driven approaches for (retro)synthetic reaction prediction and retrosynthetic analysis. Although the performances of the data-driven approach have progressed because of recent advances of machine learning and deep learning techniques, problems such as improving capability of reaction prediction and the black-box problem of neural networks persist for practical use by chemists. To spread data-driven approaches to chemists, we focused on two challenges: improvement of retrosynthetic reaction prediction and interpretability of the prediction. In this paper, we propose an interpretable prediction framework using graph convolutional networks (GCN) for retrosynthetic reaction prediction and integrated gradients (IG) for visualization of contributions to the prediction to address these challenges. As a result, from the viewpoint of balanced accuracies, our model showed better performances than the approach using an extended-connectivity fingerprint. Furthermore, IG-based visualization of the GCN prediction successfully highlighted reaction-related atoms.

Synthesis of Functionalized Medium-Sized trans-Cycloalkenes by 4π Electrocyclic Ring Opening/Alkylation Sequence.

Development of a novel synthetic method for medium-sized trans-cycloalkenes (TCAs) is described. Functionalized TCAs are readily prepared from simple cycloalkanones in a few steps, namely, enol silyl ether formation, [2+2] cycloaddition, and domino 4π electrocyclic ring opening/alkylation (conjugate addition). The first example of central-to-planar chirality transfer from enantiomerically enriched cyclobutenes to TCAs is also described.

Synthesis and Properties of Tribenzocarbazoles via an Acid-Promoted Retro (2+2)-Cycloaddition of Azapropellanes.

We describe herein the development of a new method to synthesize tribenzocarbazoles via an acid-promoted retro (2+2)-cycloaddition of azapropellanes, which were prepared by potassium hexamethyldisilazide (KHMDS)-promoted (2+2)-cycloaddition. The tribenzocarbazoles showed strong fluorescence both in solution and the solid state. The structural, electronic, and optical properties of the synthetic tribenzocarbazoles are also described.

Synthesis and biological evaluation of steroidal derivatives bearing a small ring as vitamin D receptor agonists.

A novel series of 3-ketolithocholic acid derivatives as well as estrone derivatives bearing a small ring for the conformational fixation of the side chain were synthesized by using a catalytic [2+2] cycloaddition and a ring-contraction rearrangement. The steroidal derivatives were evaluated for transcriptional activation of vitamin D receptor by luciferase reporter assays. Among them, two estrone derivatives showed a higher efficacy of the transactivation of vitamin D receptor than 3-ketolithocholic acid, and the small ring moieties were found to be important for the efficacy.

Total Synthesis of (-)-Histrionicotoxin through a Stereoselective Radical Translocation-Cyclization Reaction.

Stereoselective total syntheses of (-)-histrionicotoxin and (-)-histrionicotoxin 235A are described. The 1-azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation-cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (-)-histrionicotoxin 235A through a one-pot partial-reduction-allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3-amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (-)-histrionicotoxin.

Striking Difference between Succinimidomethyl and Phthalimidomethyl Radicals in Conjugate Addition to Alkylidenemalonate Initiated by Dimethylzinc.

We used dimethylzinc to develop a conjugate addition reaction of imidomethyl radicals to alkylidenemalonates, in which we observed a significant difference between succinimidomethyl and phthalimidomethyl radicals. This reaction provides new access to γ-aminobutyric acid derivatives, which often function as neurotransmitters.

Oxa- and Azacycle Formation via Migrative Cyclization of Sulfonylalkynol and Sulfonylalkynamide with N-Heterocyclic Carbene.

An N-heterocyclic carbene promotes cyclization of sulfonylalkynols and sulfonylalkynamides that accompanies 1,2-migration of the sulfonyl groups. This reaction provides a novel access to oxa- and azacycles possessing a pendent vinyl sulfone functionality, which, in turn, is amenable for further transformations.

π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms.

The search for new drugs that could treat tropical protozoan diseases, such as malaria or neglected tropical diseases (NTDs), motivates many medicinal chemists. New classes of antiprotozoal drugs that act through a novel mechanism of action must be developed. This review presents our efforts toward finding new candidate treatments for malaria, American trypanosomiasis, human African trypanosomiasis and leishmaniasis based on π-delocalized lipophilic cations (DLCs). DLCs, such as rhodacyanines, azarhodacyanines, ß-carbolinium salts, and phenoxazinium salts, displayed strong antiprotozoal activities with highly selective indices. Several DLCs displayed moderate to excellent in vivo efficacies against Plasmodium berghei when administered intraperitoneally or orally. This review also discusses chemical biology approaches to understanding the mechanism of action underlying the antimalarial rhodacyanines.

Use of a Catalytic Chiral Leaving Group for Asymmetric Substitutions at sp3 -Hybridized Carbon Atoms: Kinetic Resolution of ß-Amino Alcohols by p-Methoxybenzylation.

A catalytic strategy was developed for asymmetric substitution reactions at sp3 -hybridized carbon atoms by using a chiral alkylating agent generated in situ from trichloroacetimidate and a chiral phosphoric acid. The resulting chiral p-methoxybenzyl phosphate selectively reacts with ß-amino alcohols rather than those without a ß-NH functionality. The use of an electronically and sterically tuned chiral phosphoric acid enables the kinetic resolution of amino alcohols through p-methoxybenzylation with good enantioselectivity.

An Arylative Ring Expansion Cascade of Fused Cyclobutenes via Short-Lived Intermediates with Planar Chirality.

An arylative ring expansion cascade has been developed for the synthesis of medium-sized carbocycles from fused cyclobutenes. This reaction proceeds through a short-lived cis,trans-cycloalkadiene intermediate that is formed by thermal 4π electrocyclic ring opening. Chirality transfer experiments provide direct evidence for the transient generation of the intermediate.

Development of a Brønsted acid-promoted arene-ynamide cyclization toward the total syntheses of marinoquinolines A and C and aplidiopsamine A.

A Brønsted acid-promoted arene-ynamide cyclization has been developed to construct the 3H-pyrrolo[2,3-c]quinolines. This reaction consists of the generation of a highly reactive keteniminium intermediate from arene-ynamide activated by a Brønsted acid and electrophilic aromatic substitution reaction to give arene-fused quinolines in high yields. This methodology enabled facile access to marinoquinolines A and C and aplidiopsamine A.

Organocatalytic Activation of the Leaving Group in the Intramolecular Asymmetric SN 2' Reaction.

A Brønsted-acid-catalyzed intramolecular enantioselective SN 2' reaction was developed utilizing trichloroacetimidate as a leaving group. The findings indicated that dual activation of the substrates is operative. This metal-free allylic alkylation allows highly enantioselective access to 2-vinylpyrrolidines bearing various substituents.