根本 哲宏

The total synthesis of dragmacidins G and H was achieved for the first time by employing nucleophilic aromatic substitution and site-selective cross-coupling reactions using appropriately functionalized pyrazines as substrates. The evaluation of antibacterial activities of dragmacidin G, dragmacidin H, and synthetic analogues against Staphylococcus aureus and the efflux pump-deficient Salmonella Typhimurium revealed that the presence of a Br group on the indole ring adjacent to the sulfide unit was important for increasing antibacterial activities.

Herein, we report the unusual skeletal rearrangement of spiro[4.5]decadienone to benzoxepane. In particular, Lewis acid-promoted epoxide-opening ipso-cyclization of aryl epoxides afforded spiro[4.5]decadienone intermediates. Subsequent thermal activation assembled a benzoxepane core via rearomative molecular reorganization. The sequence was high-yielding and highly diastereoselective but sensitive to the aromatic substitution pattern and the epoxide side chain. Mechanistic studies suggested that the rearrangement proceeded via an uncommon intramolecular enolate attack onto the electrophilic O of p-quinone oxonium zwitterion. DFT calculations helped rationalize the product distribution and the origin of diastereoselectivity. Initial investigation into the application of this chemical transformation is also presented.

Herein we report a scandium-catalyzed regioselective synthesis of 5-carbonyl-4-hydroxybenzofurans via a phenol-directed intramolecular Friedel-Crafts reaction. This synthetic method was applied for the total synthesis of furanoflavones. Experimental studies and density functional theory calculations suggest that hydrogen bond interactions between the phenolic hydroxy group and the scandium complex realize regioselective intramolecular cyclization.

We developed an enantioselective synthetic method of constructing a seven-membered ring-fused indole skeleton with contiguous stereocenters for the synthesis of dragmacidin E. Introduction of chirality at the benzylic position was achieved by Ir-catalyzed asymmetric hydrogenation. After construction of the tricyclic molecular framework using Pd-catalyzed cascade cyclization, the tetrasubstituted carbon center was created using the Ag nitrene-mediated C-H amination reaction. The developed method provided access to the functionalized seven-membered ring-fused indole skeleton with a hydroxymethyl branch in the tetrasubstituted carbon.

Iboga-type indole alkaloids are a promising compound group of potentially effective drugs. The common indole-fused pentacyclic skeleton is composed of an isoquinuclidine, and both enantiomers of this architecture are naturally present. In this study, we used enzymatic desymmetrization to obtain an optically active isoquinuclidine possessing four chiral carbon centers from a prochiral diester in one step. In addition, we synthesized a pentacyclic intermediate for catharanthine in an enantioenriched form through the late-stage construction of the common Iboga scaffold.

C-H insertion and amide insertion reactions using metal-carbene species provide a powerful synthetic method for direct functionalization of kinetically inert or thermodynamically stable chemical bonds. Our group previously developed an amide insertion reaction using a rhodium-dimer complex, constructing an array of nitrogen-bridged heterocycles. Another research group reported C-H insertion reactions using structurally related substrates and rhodium catalysts. Detailed mechanistic studies were not provided, however, and therefore, the origin of the chemoselectivity was ambiguous. Here we describe our theoretical investigation of the chemoselectivity between the amide insertion reaction and C-H functionalization. An energy gap of the identified transition states in the reaction coordinates could support the reported experimental results and the observed chemoselectivity. Moreover, frontier molecular orbital analysis revealed that functionalities adjacent to the metal-carbene species could affect orbital populations and their energy levels, resulting in the construction of a completely distinctive ring system.

Although transition metal-catalyzed reactions have evolved with ligand development, ligand design for palladium-catalyzed photoreactions remains less explored. Here, we report a secondary phosphine oxide ligand bearing a visible-light sensitization moiety and apply it to Pd-catalyzed radical cross-coupling reactions. The tautomeric phosphinous acid coordinates to palladium in situ, allowing for pseudo-intramolecular single-electron transfer between the ligand and palladium. Molecular design of the metal complexes aided by time-dependent density functional theory calculations enables the involvement of allyl radicals from π-allyl palladium(II) complexes, and alkyl and aryl radicals from the corresponding halides and palladium(0) complex. This complex enables radical cross-couplings by ligand-to-Pd(II) and Pd(0)-to-ligand single-electron transfer under visible-light irradiation.

<title>Abstract</title>Although computational simulation-based natural product syntheses are in their initial stages of development, this concept can potentially become an indispensable resource in the field of organic synthesis. Herein we report the asymmetric total syntheses of several resveratrol dimers based on a comprehensive computational simulation of their biosynthetic pathways. Density functional theory (DFT) calculations suggested inconsistencies in the biosynthesis of vaticahainol A and B that predicted the requirement of structural corrections of these natural products. According to the computational predictions, total syntheses were examined and the correct structures of vaticahainol A and B were confirmed. The established synthetic route was applied to the asymmetric total synthesis of (−)-malibatol A, (−)-vaticahainol B, (+)-vaticahainol A, (+)-vaticahainol C, and (−)-albiraminol B, which provided new insight into the biosynthetic pathway of resveratrol dimers. This study demonstrated that computation-guided organic synthesis can be a powerful strategy to advance the chemical research of natural products.

Heavy atom-containing molecules cause a photoreaction by a direct S0→Tn transition. Therefore, even in a hypervalent iodine compound with a benzene ring as the main skeleton, the photoreaction proceeds under 365–400nm wavelength light, where UV-visible spectra are not observed by usual measurement method. Some studies, however, report hypervalent iodine compounds that strongly absorb visible light. Herein, we report the synthesis of two visible light-absorbing hypervalent iodines and their photooxidation properties under visible light irradiation. We also demonstrated that the S0→Tn transition causes the photoreaction to proceed under wavelengths in the blue and green light region.

Reaction of 3-formylindole, aniline, and TMSCN under conditions of the Strecker reaction yielded a Friedel-Crafts reaction product rather than the usual aminonitrile. This abnormal Strecker reaction can be applied to various aniline and 3-formylindole derivatives. DFT calculations revealed that the most thermodynamically stable product is generated in the reaction.

Machine learning to create models on the basis of big data enables predictions from new input data. Many tasks formerly performed by humans can now be achieved by machine learning algorithms in various fields, including scientific areas. Hypervalent iodine compounds (HVIs) have long been applied as useful reactive molecules. The bond dissociation enthalpy (BDE) value is an important indicator of reactivity and stability. Experimentally measuring the BDE value of HVIs is difficult, however, and the value has been estimated by quantum calculations, especially density functional theory (DFT) calculations. Although DFT calculations can access the BDE value with high accuracy, the process is highly time-consuming. Thus, we aimed to reduce the time for predicting the BDE by applying machine learning. We calculated the BDE of more than 1000 HVIs using DFT calculations, and performed machine learning. Converting SMILES strings to Avalon fingerprints and learning using a traditional Elastic Net made it possible to predict the BDE value with high accuracy. Furthermore, an applicability domain search revealed that the learning model could accurately predict the BDE even for uncovered inputs that were not completely included in the training data.

Hydrocarbazolones are a key structural unit in many natural bioactive compounds and are thus a valuable synthetic target. A rhodium-catalyzed C−H functionalization reaction with acceptor/acceptor diazo compounds was developed for synthesizing 2,3-fused indole variants. An α,β-unsaturated enone was utilized as a directing group for site-selective C−H activation and as an electrophile for the subsequent cyclization. Overall, the developed annulation enabled the rapid assembly of synthetically valuable hydrocarbazolones from readily available indoles. Additionally, computational investigations were conducted to elucidate the reaction pathway and rationalize the experimentally observed site-selectivity. (Figure presented.).

Herein, we report the development of an asymmetric intramolecular cyclopropanation reaction under silver catalysis. The strategy is based on diazo-free silver–carbene generation, providing γ-lactam fused cyclopropane in an enantioenriched form. The ring system of the product is frequently encountered in bioactive molecules and pharmaceuticals. To highlight the utility of this method, the fused cyclopropane was converted into drug candidate molecules in short steps. In addition, computational investigations were performed to elucidate the reaction pathway. The computation based on density functional theory rationalized the experimentally observed chemoselectivity between the desired cyclopropanation and overoxidation process.

Polypyrrole-based polyamides are used as sequence-specific DNA probes. However, their cellular uptake and distribution are affected by several factors and have not been extensively studied in vivo. Here, we generated a series of fluorescence-conjugated polypyrrole compounds and examined their cellular distribution using live zebrafish and cultured human cells. Among the evaluated compounds, Py3-FITC was able to visualize collagen-rich tissues, such as the jaw cartilage, opercle and bulbus arteriosus, in early-stage living zebrafish embryos. Then, we stained cultured human cells with Py3-FITC and found that the staining became more intense as the amount of collagen was increased. In addition, Py3-FITC-stained HR cells, which represent a type of ionocyte on the body surface of living zebrafish embryos. Py3-FITC has low toxicity, and collagen-rich tissues and ionocytes can be visualized when soaked in Py3-FITC solution. Therefore, Py3-FITC may be a useful live imaging tool for detecting changes in collagen-rich tissue and ionocytes, including their mammalian analogues, during both normal development and disease progression.

© 2020 American Chemical Society. Arene dearomatization is a straightforward method for converting an aromatic feedstock into functionalized carbocycles. Enantioselective dearomatizations of chemically inert arenes, however, are quite limited and underexplored relative to those of phenols and indoles. We developed a method for diazo-free generation of silver-carbene species from an ynamide and applied it to the dearomatization of nonactivated arenes. Transiently generated norcaradiene could be trapped by intermolecular [4 + 2] cycloaddition, synthesizing polycycles with five consecutive stereogenic centers. This protocol constitutes the first highly enantioselective reaction based on the diazo-free generation of silver-carbene species. Mechanistic investigations revealed a dearomatization followed by two different classes of pericyclic reactions, as well as the origin of the chemo- and enantioselectivity.

Didymeline is an alkaloid with an azaspiro tricyclic skeleton with various functionalities. Despite the fact that its unique architecture is synthetically attractive, its total synthesis has never been achieved before. Herein, we present synthetic studies on the core structure of didymeline. Accordingly, a spiro ring system was constructed through dearomatization of a phenol derivative with α-diazoamide unit. Based on the resulting 2-azaspiro[4,5]decane variant, a tricyclic molecule was synthesized via base-promoted intramolecular ring closure. For an asymmetric synthesis, an enantioselective dearomatization was also examined under silver catalysis, which led to the formation of an all-carbon substituted quaternary stereogenic center.

© 2020 American Chemical Society. All rights reserved. Although intense research over the last 2 decades revealed a diverse proficiency of nitrene species in chemistry disciplines, control of the selectivity in the reaction manifold has remained a challenge. We report herein the development of site-selective and chemoselective C-H functionalization involving nitrene species to synthesize densely functionalized spiroaminals. A rhodium catalyst generally used in nitrene chemistry gave amide C-N insertion products and/or the corresponding ketones, whereas a silver catalyst with an achiral bisoxazoline (BOX) ligand provided C-H insertion products. Mechanistic analysis based on integrated experimental and computational studies indicated that the nitrene transfer occurred through an asynchronous concerted process involving triplet spin-correlated radical pairs, affording the corresponding stereodefined spiromolecules.

© 2020 The Pharmaceutical Society of Japan Catalytic dearomative transformations of phenol variants via an ipso-Friedel-Crafts reaction could provide a straightforward method for the rapid assembly of functionalized spiromolecules as versatile synthetic scaffolds. We previously reported a dearomative spirocyclization reaction by merging Brønsted acid and hydrogen-bonding catalysis. However, it was unclear how the reaction proceeded and how the synergic effect was triggered. Described herein are the computational studies used to elucidate the reaction mechanism. Such calculations indicated that the applied catalysts, maleic acid and Schreiner's thiourea, work cooperatively. The synergic effect enabled the chemoselectivity to interconvert between phenol dearomatization and O-H insertion, which is a major side reaction. This investigation also revealed that not only does the Schreiner's thiourea catalyst serve as a hydrogen bonding donor, but the sulfur atom in thiourea possesses a general base function. The dual functional support of the thiourea along with maleic acid would thus realize the chemoselective prioritization of dearomatization over the O-H insertion reaction under mild conditions.

© 2020 American Chemical Society. A chemoselective dearomatization of the less reactive benzenoid unit in β-naphthol was developed. Spirocyclization with a reductant constructs a pivotal structure for drug candidates. One-pot oxidative conversion enabled the tandem dearomatization of β-naphthol, producing conjugated tetraenone variants. The potential utility of the product as an F-selective anion sensor was also demonstrated. Theoretical studies revealed the intermediacy of silver-carbenoid species leading to chemoselective spirocyclization over arene cyclopropanation.

Copyright © 2020 American Chemical Society. Despite a growing body of studies on directing-group (DG)-assisted C-H activation strategies, efficient exploitation of the used DG remains underexplored. We developed a rhodium-catalyzed C-H functionalization of indoles at the C4 position using α,β-unsaturated enones as versatile DGs. Combined experimental and theoretical analyses revealed that the C-H activation process was reversible and the course of Rh-carbene generation controlled the overall site-selectivity of the C-H functionalization. The introduced malonate unit and the used enone DG were cyclized in a further C-C bond forming process to assemble 3,4-fused tricyclic indoles in an asymmetric manner. Telescoping the two reaction sequences provided rapid entry into this densely functionalized indole architecture from readily available chemical feedstock.

Copyright © 2020 American Chemical Society. Benzophenone has an S0 → S1 absorption band at 365 nm. However, the rarely reported S0 → Tn transition occurs upon irradiation at longer wavelengths. Herein, we employed benzophenone as a catalyst and exploited its S0 → Tn transition in C(sp3)-H alkynylations with hypervalent iodine reagents. The selective benzophenone excitation prevented alkynylating reagent decomposition, enabling the reaction to proceed under mild conditions. The reaction mechanism was investigated by spectroscopic and computational studies.

Copyright © 2020 American Chemical Society. An asymmetric dearomatization of indoles bearing α-diazoacetamide functionalities was developed for synthesizing high-value spiro scaffolds. A silver phosphate chemoselectively catalyzed the sterically challenging dearomatization, whereas more typically used metal catalysts for carbene transfer reactions, such as a rhodium complex, were not effective and instead resulted in a Büchner ring expansion or cyclopropanation. Mechanistic studies indicated that the spirocyclization occurred through a silver-assisted asynchronous concerted process and not via a silver-carbene intermediate. Analyses based on natural bond orbital population and a distortion/interaction model indicated that the degree of C-Ag mutual interaction is crucial for achieving a high level of enantiocontrol. In addition, an oxidative disconnection of a C(sp3)-C(sp2) bond in the product provided unconventional access to the corresponding chiral spirooxindole.

© 2020 Elsevier Ltd We previously reported a synthetic method of spirocyclohexadienones using an Pd-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of para-substituted phenol derivatives. However, the mechanism for the step leading to spirocyclization and driving force behind the remarkably easier formation of the five-membered spirocyclohexadienone as compared with the six-membered spirocyclohexadienone were unclear. Herein, detailed density functional theory (DFT) calculations for the spirocyclization were performed to obtain a plausible reason for the observed behavior. In addition, the mechanistic basis of the characteristic ortho-selectivity in the related Pd-catalyzed intramolecular Friedel–Crafts allylic alkylation of meta-substituted phenol derivatives was elucidated. DFT calculations and experimental studies revealed that the ortho-selective allylation proceeded via an unexpected eleven-membered oxapalladacycle-mediated intramolecular Friedel–Crafts type process.

© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim According to the Grotthuss–Draper law, light must be absorbed by a substrate to initiate a photoreaction. There have been several reports, however, on the promotion of photoreactions using hypervalent iodine during irradiation with light from a non-absorbing region. This contradiction gave rise to a mystery regarding photoreactions involving hypervalent iodine. We demonstrated that the photoactivation of hypervalent iodine with light from the apparently non-absorbing region proceeds via a direct S0→Tn transition, which has been considered a forbidden process. Spectroscopic, computational, and synthetic experimental results support this conclusion. Moreover, the photoactivation mode could be extended to monovalent iodine and bromine, as well as bismuth(III)-containing molecules, providing new possibilities for studying photoreactions that involve heavy-atom-containing molecules.

© 2020 Elsevier Ltd A new method for synthesizing 3,4-fused tricyclic 3-alkylidene dihydrobenzofuran derivatives was developed. Treatment of propargyl iodophenol derivatives with a tethered alkene at the three contiguous positions under the radical cascade reaction conditions induced the reaction of the generated vinyl radical intermediates with the internal alkene, producing tricyclic 3-alkylidene dihydrobenzofurans in 25%–93% yield. The reaction products could be utilized as the precursors for 3,4-fused tricyclic benzofurans.

© 2020 American Chemical Society. In this study, a visible-light-induced intermolecular C-H bond imidation of arenes was achieved at ambient condition. By using simple phthalimide with (diacetoxyiodo)benzene and molecular iodine, direct metal-/photocatalyst-free C-N bond formation was achieved. The imidation protocol was designed by using time-dependent density functional theory calculations and experimentally demonstrated for 28 substrates with as high as 96% yield. Mechanistic studies indicated that radical-mediated aromatic substitution occurred via photolysis of N-iodophthalimide under visible-light irradiation.

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim An enantioselective insertion reaction of silver carbenes generated from donor–acceptor-substituted diazo compounds into the O−H bond of phenols was developed. A homobinuclear silver complex with a chiral phosphorous ligand was created in situ from AgNTf2 and (S)-XylylBINAP (in a 2:1 mole ratio). Detailed mechanistic studies using combined experimental and computational techniques revealed that one silver atom center of the catalyst forms a silver carbene and another one works as a Lewis acid for the nucleophilic addition of a phenol. Two counter-anions, two water molecules, and two silver atoms cooperatively mediate the subsequent protonation event to lower the activation energy and control enantioselectivity, affording an array of valuable α-aryl-α-aryloxy esters.

© 2019 John Wiley & Sons, Ltd. Hypervalent iodines are widely used in organic chemistry, and their most important feature is the three-center four-electron bond. However, there have been few reports on the measurement of their bond dissociation enthalpy (BDE). Therefore, in many cases, BDE is estimated by computational calculations. However, the value of a calculated BDE usually varies depending on the choice of functional and basis set, and the best method for making an accurate evaluation of the three-center four-electron bond has not been determined. We succeeded in determining the best functional and basis set to calculate the three-center four-electron bond to within 0.79% error and 0.53 standard deviation. Using the optimal functional and basis set, the first and second BDEs of several hypervalent iodines are calculated, and as the effect of benzene substituents was investigated, negative correlation was observed in the Hammett plot. In addition, the effect of ortho-substituent in cyclic hypervalent iodine was found to be significant. Furthermore, the decomposition route of hypervalent iodine is calculated. The value of a calculated BDE usually varies depending on the choice of functional and basis set. We succeeded in determining the best functional and basis sets to calculate the three-center four-electron bond of hypervalent iodine to within 0.79% error and 0.53 standard deviation. Using the optimal functional and basis sets, the first and second BDEs of several hypervalent iodines are calculated, and additionally, the decomposition route of hypervalent iodine is calculated.

© 2019 Elsevier Ltd A chemoselective domino annulation reaction of β-naphthols with methyl aryldiazoacetate is described. The gold catalyst promoted C–H functionalization of β-naphthols, whereas a rhodium or copper complex led to O–H insertion reactions. Consecutive intramolecular lactonization occurred after site-selective alkylation at the 1-position of β-naphthol, providing functionalized naphthofuranone derivatives. The product was transformed into a chiral molecule bearing an all-carbon quaternary stereogenic center with high enantioselectivity.

© 2019 American Chemical Society. Although (+)-catharanthine is an attractive alkaloid for both clinical research and organic synthetic chemistry, only a limited number of approaches for its catalytic asymmetric synthesis exist. Herein, we describe a novel strategy for synthesizing a chiral intermediate of (+)-catharanthine via phosphoric acid-catalyzed asymmetric desymmetrization of a meso-isoquinuclidine possessing a 1,3-diol unit that was synthesized by a formal amide insertion reaction.

© 2019 American Chemical Society. This article describes the development of a robust and scalable synthetic process for K-8986 (1). To solve the problems in terms of the physicochemical properties of 6 (a free base unit of 1), we have screened the suitable salt forms of the target. The monomaleate salt was the most suitable form for the API. To overcome challenges regarding the unremovable impurity Imp B caused by the carryover of piperazine in the medicinal chemistry route, we designed and developed a novel synthetic route. This route furnished more opportunities to purify the synthetic intermediates after introduction of the piperazine unit. Both impurities and co-products in each step of the revised synthesis could be easily removed via filtration, leveraging the low solubility of benzothiazine derivatives. The newly established process was applied to the synthesis of 1 (the monomaleate salt of 6) on a practical scale, achieving high purity and reproducibility.

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim The past few decades have witnessed extensive efforts to disclose the unique reactivity of metal–nitrenes, because they could be a powerful synthetic tool for introducing the amine functionality into unactivated chemical bonds. The reactivity of metal–nitrenes, however, is currently mainly confined to aziridination (an insertion into a C=C bond) and C−H amination (an insertion into a C−H bond). Nitrene insertion into an amide C−N bond, however, has not been reported so far. In this work we have developed a rhodium-catalyzed one-nitrogen insertion into amide C−N and sulfonamide S−N bonds. Experimental and theoretical analyses based on density functional theory indicate that the formal amide insertion proceeds via a rhodium-coordinated ammonium ylide formed between the nitrene and the amide nitrogen, followed by acyl group transfer concomitant with C−N bond cleavage. Mechanistic studies have allowed rationalization of the origin of the chemoselectivity observed between the C−H and amide insertion reactions. The methodology presented herein is the first example of an insertion of nitrene into amide bonds and provides facile access to unique diazacyclic systems with an N−N bond linkage.

© 2019 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim In this personal account, our recent studies of novel synthetic methods of 3,4-fused tricyclic indole derivatives using 3-alkylidene indoline derivatives as versatile precursors are discussed. Two types of cascade reactions producing 3,4-fused tricyclic 3-alkylidene indolines were developed based on a palladium-catalyzed intramolecular Heck insertion to an allene-allylic amination cascade and a platinum-catalyzed intramolecular Friedel-Crafts type C−H coupling-allylic amination cascade. Furthermore, three types of 3,4-fused tricyclic indoles were accessible from a single 3-alkylidene indoline precursor via acid-promoted olefin isomerization or oxidative treatments. The application of the developed methods to the synthesis of natural products bearing a 3,4-fused tricyclic indole skeleton, (−)-aurantioclavine, fargesine, and synthetic studies of dragmacidin E are also highlighted.

© Society of Synthetic Organic Chemistry. All rights reserved. Metal carbenoids exhibit unique reactivities towards stable chemical bonds. Such reactive species are recognized as powerful tools for direct functionalization of unactivated compounds. Meanwhile, the high and versatile reactivity of metal carbenoids sometimes become problematic in the development of chemoselective reactions, because organic molecules often include some reactive sites to metal carbenoids such as C-H bonds, multiple bonds, and heteroatoms. Therefore, considerable efforts have focused on the control of chemoselectivity of metal carbenoid-mediated reactions in recent years. We have been interested in the potential of metal carbenoids to develop an unusual reaction and succeeded in developing catalyst-controlled highly chemoselective reactions for the synthesis of complex molecules. Herein we summarized our achievements; an insertion reaction of Rh-carbenoid into an amide C-N bond and a dearomative ipso-Friedel-Crafts (DIFC) reaction mediated by chiral Ag-carbenoid species. An application of the amide insertion reaction to the natural product synthesis is also described.

© 2019 The Japan Institute of Heterocyclic Chemistry Received Synthetic method of LSD1 inhibitor-pyrrole-imidazole polyamide conjugates for region-specific alterations of histone modification is described. A (1S,2R)-tranylcypromine (PCPA) unit was coupled with an L-lysine part using a nosyl strategy. Conjugation of the inhibitor part with PIP tetramer units was achieved by amide bond formation using PyBOP as a condensation reagent.