根本 哲宏

© 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.

The enantioselective formal synthesis of (−)-aurantioclavine is described. The core tricyclic skeleton was synthesized using a Pd-catalyzed Heck insertion–allylic amination cascade. The stereocenter was constructed by a highly enantioselective organocatalytic asymmetric aziridination reaction.

We developed a novel synthetic method of the core structure of dragmacidin E bearing a 7-membered ring fused bis(indolyl)pyrazinone skeleton. Formation of the 7-membered ring-fused tricyclic indole skeleton was accomplished using a palladium-catalyzed Heck insertion-allylic arnination cascade. Vicinal difunctionalization of the 7-membered ring was realized via a rhodium-catalyzed amino-acetoxylation.

We report asymmetric dearomatization of phenols using Ag carbenoids from alpha-diazoacetamides. The Ag catalyst promoted intramolecular dearomatization of phenols, whereas a Rh or Cu catalyst caused C-H insertion and a Buchner reaction. Studies indicated Ag carbenoids have a carbocation-like character, making their behavior and properties unique. Highly enantioselective transformations using Ag carbenoids have not been reported. We achieved a Ag carbenoid-mediated chemo- and highly enantios elective phenol dearomatization with substrate generality for the first time.

Metal nitrenoids and metal carbenoids exhibit similar reactivity for insertion into a C-H bond and a C=C double bond. These reactions have attracted the attention of organic chemists due to their unusual bond-forming ability, but the reactivity difference between these chemical species has not been studied. In this paper, we examined the reactivity difference using the corresponding Rh nitrenoid and Rh carbenoid precursors. The Rh nitrenoid inserted into an intramolecular C(sp(3))-H bond adjacent to an amide nitrogen, affording functionalized spiroaminals that are ubiquitous in natural products, while the Rh carbenoid inserted into an amide C-N bond. The totally different reactivity was rationalized by the relatively low energy barrier for the C-H insertion reaction of the Rh nitrenoid. Computational analysis suggests that the origin of the discrepancy is the electrophilicity of the coordinating atoms to the Rh complex.

A synthetic study of pactamycin is described. Enantioselective construction of the aminocyclopentitol core of pactamycin bearing five contiguous stereocenters was achieved based on an organocatalytic asymmetric aziridination of 2-cyclopentene-1-one, a regio- and diastereoselective 1,3-dipolar cycloaddition, and a rhodium-catalyzed C-H amination reaction.

We developed a highly effective organocatalytic system for asymmetric aziridination of cyclic enones. Catalytic asymmetric aziridination of 2-cyclopenten-1-one with t-butyl p-toluenesulfonyloxy carbamate proceeded using 20 mol % of (1R,2R)-1,2-diphenylethylenediamine derivative with an N-4,4-dimethylcyclohexyl group 1h, producing chiral aziridine ketone (1R,5R)-4 in 82% yield with 99% ee. Organocatalyst 1h was also an effective catalyst for the asymmetric aziridination of other cyclic enones. The obtained chiral aziridine ketone (1R,5R)-4 could be successfully transformed into the key intermediate for the synthesis of (-)-allosamizoline, demonstrating the utility of this asymmetric aziridination for the synthesis of aminocyclopentitol derivatives. (C) 2016 Elsevier Ltd. All rights reserved.

This account describes the development of novel dearomatization reactions of phenols using transition-metal-catalyzed ipso-Friedel-Crafts-type processes. In general, phenols function as O-nucleophiles in transition-metal-catalyzed allylic substitution reactions, providing the corresponding aryl ethers. We found that, however, an intramolecular ipso-Friedel-Crafts allylic alkylation of phenols proceeded smoothly in the presence of a palladium catalyst, producing various spiro[4.5]cyclohexadienone derivatives. This finding led us to launch detailed investigations into this type of reaction. Pd-catalyzed intramolecular Friedel-Crafts allylic alkylation of phenols was next examined to synthesize 10-vinyl 9,10-dihydrophenanthrene derivatives. This reaction was successfully extended to a catalytic asymmetric process. We also developed a novel synthetic method for spiro[5.5]cyclohexadienones based on a Pd-catalyzed intramolecular ipso-Friedel-Crafts-type addition of phenols to (3)-propargylpalladium(II) intermediates. Mechanistic studies revealed that the present reaction proceeds through a rearomatization-assisted oxidative addition. Moreover, a Au-catalyzed intramolecular ipso-Friedel-Crafts alkenylation of phenols with a terminal alkyne is discussed. 1 Introduction 2 Pd-Catalyzed Intramolecular Friedel-Crafts Allylic Alkylation of Phenols 2.1 Synthesis of Spirocyclohexadienone Derivatives by Pd-Catalyzed Intramolecular ipso-Friedel-Crafts Allylic Alkylation of Phenols 2.2 Mechanistic Considerations 2.3 Application to Cascade Reaction Processes 2.4 Asymmetric Synthesis of Dihydrophenanthrene Derivatives by Pd-Catalyzed Asymmetric Intramolecular Friedel-Crafts Allylic Alkylation of Phenols 3 Dearomatization of Phenols by Activation of Propargyl Carbonates with a Pd Catalyst 4 Au-Catalyzed Intramolecular ipso-Friedel-Crafts Alkenylation of Phenols 5 Summary and Outlook

A formal amide insertion reaction for the synthesis of nitrogen-bridged polycyclic frameworks with diverse functionalities was developed using a sustainable copper catalyst as an advantageous alternative to precious rhodium catalysts. The remarkable feature of this methodology is the amount of catalyst loading (0.05 mol%). The optimized reaction conditions enable access to aromatic ring-fused 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, and 6-azabicyclo[3.2.2]nonane derivatives in moderate to excellent yields.

A formal synthesis of anatoxin-a was accomplished by using rhodium-catalyzed formal amide insertion reaction. The key reaction was performed on a gram scale using 0.4 mol % of Rh-2((NHCOBu)-Bu-t)(4) catalyst, affording a 9-azabicyclo[4.2.1]nonane derivative in good yield. The nitrogen-bridged molecule was converted to Wiseman's intermediate through diastereoselective reduction, site-selective deoxygenation and functional group interconversions. (C) 2016 Elsevier Ltd. All rights reserved.

This review describes the development of novel dearomatization reactions of phenols using transition metal catalysis. We found that an intramolecular ipso-Friedel-Crafts allylic alkylation of phenols proceeded smoothly in the presence of Pd catalyst, producing various spiro[4.5]cyclohexadienone derivatives. The present methods could be applied to a catalytic asymmetric reaction. An asymmetric intramolecular Friedel-Crafts allylic alkylation of phenols to produce chiral 10-vinyl 9,10-dihydrophenanthrenes was also investigated. The developed process was successfully applied to the enantioselective synthesis of bioactive natural products. We also developed a novel method for synthesizing spirocycles based on a Pd-catalyzed intramolecular ipso-Friedel-Crafts alkylation of phenols to η³-propargylpalladium(II) complexes. Mechanistic studies revealed that the present reaction proceeds through a rearomatization-assisited oxidative addition. An Au-catalyzed carbocyclization of phenols with a terminal alkyne via an intramolecular ipso-Friedel-Crafts alkenylation is also discussed.

Various nitrogen-bridged bicyclic skeletons are found in bioactive natural products and pharmaceuticals. The development of a new reaction to construct these molecular frameworks has attracted considerable attention in synthetic organic chemistry. We developed a novel synthetic method for obtaining a wide variety of nitrogen-bridged bicyclic compounds with a catalytic process, Rh-catalyzed formal carbenoid insertion into an amide C-N bond. Using 0.1-0.4 mol % Rh-2((NHCOBu)-Bu-t)(4) catalyst, various azabicydo[X.Y.Z]alkane derivatives were obtained in good to excellent yield, successfully demonstrating the broad substrate scope of the developed process. Experimental and computational studies to elucidate the reaction mechanism revealed that the formal insertion reaction of a carbenoid into an amide C-N bond proceeded via the formation of Rh-associated N-ylides, followed by an acyl group-selective Stevens [1,2]-shift through a concerted addition/elimination process on the sp(2)-hybridized carbon.

A novel Pd-catalyzed cascade cyclization by intramolecular Heck insertion of an alleneallylic amination sequence was developed. Allenes tethered to ortho-iodoaniline derivatives at the meta-position were reacted with 5-10 mol % of Pd catalyst and 4 equiv of K2CO3 in DMSO at 90 degrees C, producing 3,4-fused tricyclic 3-alkylidene indoline derivatives in moderate to excellent yield. The reaction products were divergently transformed into three types of 3,4-fused tricyclic indole derivatives, successfully demonstrating the versatile properties of the reaction products.

We have developed a novel method for synthesizing trisubstituted cyclopropane derivatives by a palladium-catalyzed intramolecular allylic alkylation of -aryl esters. By using -aryl -(methoxycarbonyl) -vinyl -lactones as substrates, decarboxylative formation of -allylpalladium(II) intermediates followed by an intramolecular allylic alkylation of the ester enolates proceeded in the presence of 5 mol% of a palladium catalyst, producing 1-aryl-1-(methoxycarbonyl)-2-vinylcyclopropanes in good to excellent yields and high diastereoselectivities. The relative configuration of the major isomer was determined by transforming the product into a known intermediate of milnacipran synthesis. When we extended our method to asymmetric catalysis, we obtained methyl (1S,2S)-1-phenyl-2-vinylcyclopropanecarboxylate in up to 55% ee by using (S)-[2-(diphenylmethoxy)-1,1-binaphthalen-2-yl](diphenyl)phosphine as a chiral monodentate phosphorus ligand.

Gephyrotoxin 287C, a bioactive alkaloid bearing a perhydropyrrolo[1,2-a]quinoline skeleton with five stereocenters, is an attractive target for synthetic organic chemistry. We achieved an enantioselective total synthesis of (+)-gephyrotoxin 287C, for which the key steps were palladium-catalyzed asymmetric allylic amination using a chiral diaminophosphine oxide (DIAPHOX) preligand, diastereoselective intramolecular Mannich reaction, and tin tetrachloride-catalyzed diastereoselective conjugate addition/protonation.

Functionalized quinolizidin-4-ones and indolizidin-3-ones were synthesized from mixed N,O-acetals with a terminal alkyne unit and nucleophiles with two reactive sites by a gold(I)/Bronsted acid relay catalysis with 40-90% yield. The reactions are proposed to proceed through gold-catalyzed carboalkoxylation of the alkynes with the internal mixed N,O-acetals, giving the corresponding cyclic enols, which are transformed to spirocyclic compounds by a Bronsted acid catalyst. The latter spirocyclization process occurs under thermodynamic control, providing polycyclic quinolizidin-4-one and indolizidin-3-one derivatives diastereoselectively. (C) 2015 Elsevier Ltd. All rights reserved.

We developed a novel method of synthesizing nitrogen-containing fused-polycyclic compounds using tyramine derivatives as substrates. The method is based on the dearomatization of phenols via an intramolecular ipso-Friedel-Crafts allenylation and sequential bond-forming-cleavage reactions initiated by the construction of an indole skeleton. Structurally diverse fused-heterocycles were produced in reaction sequences requiring only a few steps.

Herein we report an enantioselective synthesis of (R)-Sumanirole wherein an organocatalytic asymmetric aziridination of 2-nitrocinnamaldehyde was the key step. (C) 2014 Elsevier Ltd. All rights reserved.

We have developed a novel synthetic method to furnish spiro[4.5]cyclohexadienones using an gold-catalyzed carbocyclization of phenols with a terminal alkyne via an intramolecular ipso-Friedel-Crafts alkenylation. Using 2-5 mol% of gold catalyst, 1 equiv. of methanesulfonic acid, and 1 equiv. of 2,6-di-tert-butylpyridine, a variety of spiro[4.5]cyclohexadienone derivatives with an exocyclic olefin unit was obtained in good to excellent yields. The divergent synthesis of dihydronaphthalene derivatives was also examined based on the newly developed gold catalysis.

A novel method for synthesizing 4,5-fused tricyclic quinoline derivatives based on an acid-promoted intramolecular Friedel-Crafts allenylation of anilines. Using aryl group-substituted propargyl alcohol derivatives with a meta-substituted N-Boc aniline unit as substrates, a four-step reaction sequence involving an acid-promoted intramolecular Friedel-Crafts allenylation of anilines, an acid-promoted intramolecular C-N bond formation, deprotection of the Boc group, and air oxidation proceeded in a single pot, producing the corresponding 4,5-fused tricyclic quinoline derivatives in 31-84% yield. (C) 2014 Elsevier Ltd. All rights reserved.

We have succeeded in the highly diastereoselective synthesis of cyclobutane-fused multicyclic compounds using a scandium-catalyzed cascade cyclization. Using 3-10 mol% of scandium(III) triflate [Sc(OTf)(3)], various cyclobutane-fused tetrahydroquinoline derivatives as well as its chromane, thiochromane, and tetrahydronaphthalene analogues were obtained in good to excellent yields. Derivatizations of the reaction products, as well as the plausible reaction mechanism, are also discussed.

Two different cascade cyclization processes were developed using aryl group-substituted propargyl alcohol derivatives with a p-hydroxybenzylamine unit as common substrates. Using TFA as an acid promoter, an intramolecular ipso-Friedel-Crafts alkylation of phenol derivatives, formation of an iminium cation via a rearomatization-promoted C-C bond cleavage, an aza-Prins reaction, and a 6-membered ring formation proceeded sequentially, producing a variety of fused-tricyclic dihydroquinoline derivatives in 45-99% yield. In addition, a one-pot sequential silver acetate-catalyzed hydroamination/etherification-acid-promoted skeletal rearrangement was examined using the same series of substrates, affording fused-tricyclic indole/benzofuran derivatives in 66-89% yield.

We developed a novel method for synthesizing fused-tricyclic indole derivatives with a 3-aminomethyl indole motif through a reaction cascade involving ipso-Friedel-Crafts alkylation of phenols, rearomatization of the spirocyclohexadienone unit, and iso-Pictet-Spengler reaction. Using TFA as an acid promoter, six-, seven-, and eight-membered ring-fused indoles were obtained in 31-99% yield. (C) 2014 Elsevier Ltd. All rights reserved.

An acid-promoted novel cascade cyclization is described. Using 8 equiv of trifluoroacetic acid or a catalytic amount of Lewis acid as the promoter, structurally diverse polycyclic cyclopenta[b]indoles were obtained in moderate to excellent yield. This cascade process was extremely effective for the synthesis of 8-membered ring-fused cyclopenta[b]indole derivatives.

A novel method for synthesizing 3-arylpyrrolidine and 4-arylpiperidine derivatives through an acid-promoted skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramolecular ipso-Friedel-Crafts-type addition of phenols to allyl cations, formation of iminium cations through rearomatization of the spirocyclohexadienone units, and an intramolecular aza-Prins reaction, proceeded sequentially to afford 3-arylpyrrolidine and 4-arylpiperidine derivatives in good yield with high diastereoselectivity. (c) 2013 Elsevier Ltd. All rights reserved.

We developed a novel synthetic method for allenyl spiro[4.5]cyclohexadienone derivatives based on a base-promoted intramolecular ipso-Friedel-Crafts addition of phenols to propargyl bromides. The present spirocyclization proceeded in a CH2Cl2-tert-BuOH mixed solvent system using potassium tert-butoxide as the base, and produced the corresponding spiro[4.5]cyclohexadienone derivatives with an allene motif in up to 99% yield. This-type allenyl spirocycle was also accessible through Pd-catalyzed intramolecular ipso-Friedel-Crafts alkylation when a propargyl carbonate derivative with a naphthol unit was used as a substrate. Acid-promoted skeletal rearrangement of the reaction adducts was also examined. (C) 2013 Elsevier Ltd. All rights reserved.

For the total synthesis of novel cyclodepsipeptide homophymine A, (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid was successfully synthesized by Evans' asymmetric alkylation and the anti-selective asymmetric hydrogenation of a chiral alpha-amino-beta-keto ester as the key steps.

A novel and efficient synthetic method for functionalized spiro[4.5]cyclohexadienones was developed based on the palladium-catalyzed sequential process: Heck insertion to an allene-intramolecular ipso-Friedel-Crafts allylic alkylation cascade. Using 5mol% of palladium catalyst, a wide variety of spirocycles was obtained in good to excellent yields. The developed cascade process was also applicable to the synthesis of tetrahydronaphthalene derivatives.