荒井 秀

We report the synthesis of seven‐membered carbocycles through the dearomative intermolecular reaction of benzofurans with vinylcyclopropanes. The significant feature of this method involves activating benzofurans through energy transfer from an activated photocatalyst. Substituent effects were investigated for each substrate, and hydrocyclohepta[b]benzofurans with a tetrasubstituted carbon were obtained as a single diastereomer. This synthetic approach compliments the reported methodologies for synthesizing this type of skeleton and introduces a new feedstock for this skeleton with a different substitution pattern. Computational studies of the reaction mechanism suggested that the reaction proceeds stepwise through addition, small ring opening, and re‐cyclization. This novel synthetic approach opens up new possibilities for efficiently constructing seven‐membered carbocycles. Moreover, it provides a valuable platform for discovering unique molecules with diverse substitution patterns.

A trichloromethylative olefin lactonization reaction using an iridium photoredox catalyst was developed. The reactions proceeded at room temperature for olefins with various substituents and substitution patterns, and a variety of lactones with a tetrasubstituted carbon and trichloromethyl group were obtained regio‐ and stereoselectively. The reaction mechanism was elucidated through isotope labeling experiments. The chemical properties of the lactones containing the trichloromethyl groups were investigated, and synthetic transformations of the product were realized.

Highly regio- and stereoselective homodimerizative [2 + 2] cycloaddition of allenamides under nickel catalysis was developed. Xantphos is an essential ligand to give “tail to tail” products and DFT studies revealed that oxidative addition between a nickel(0) complex and two distal C[dbnd]C bonds of the allenamides would be a key process. Sequential formation of the metallacycle intermediate would proceed in both a regio- and stereoselective manner to give the corresponding cyclobutane as a single isomer.

<jats:p>Vinylallenes have been recognized as versatile C2 and C4 components for nickel-catalyzed intramolecular [4+2] and [2+2] cycloadditions. The former reaction was promoted by a Ni(0) complex (up to quantitative yield),...</jats:p>

Synthesis of cyano-functionalized nitrogen heterocycles under palladium, nickel, and cobalt catalysis is described. These transformations include the activation of C-C multiple bonds to give the functionalized pyrrolidines and their related compounds. The palladium-catalyzed reactions promote nucleophilic cyanation to non-activated terminal alkynes. Nickel catalysis enables to install H and CN functionalities into allenes with regio- and stereoselective manner. In the case of cobalt-catalyzed hydrocyanation, hydroacylation and hydroarylation, simple olefins as well as enamines are suitable substrates to construct highly functionalized hetero- and carbocycles. The applications of the above methodologies for the synthesis of alkaloids and related compounds are also described.

A mild, general and efficient hydrocyanation and hydroarylation of enamines catalyzed by Co(salen) complexes are described. Both reactions include regioselective C[sbnd]H bond formation of enamines, and the corresponding products are obtained in high yield. Hydroarylation critically discriminates the benzyl and benzoyl aromatic rings on nitrogen in cyclization step, and the corresponding isoindolinones including quaternary carbons are exclusively given.

A Ni-catalyzed [2+2+2] cycloaddition reaction between allene-ynes and various mono-, di- and tri-substituted allenes is described. This protocol effectively differentiates allenyl π components and shows broad substrate generality to give highly functionalized carbocycles. A DFT study played a key role in revealing a detailed reaction mechanism that controls site-, regio- and stereoselectivity, which are thought to originate in the substituent effect on π-bonds in the early transition state. (Figure presented.).

A nickel-catalyzed [2 + 2] cycloaddition of bisallenes has been described. Simple bisallenes are employed for the formation of “head to head” cycloadducts in the presence of Ni(0) with xantphos. The dienyl moiety in a product were applicable for various [4 + 2] cycloaddition reactions. Allene-allenamides under Ni-xantphos system gave the tricyclic compounds through sequential [2 + 2]–[4 + 2] cycloaddition reaction in highly stereoselective manner.

Nickel-catalyzed regioselective hydrocyanation of terminal alkynes is described. A tosylamide functionality at the propargyl position was the most suitable group for controlling the regiochemistry for C–CN bond formation as well as rate enhancement. A gram-scale synthesis was achieved by minimizing the catalyst loading to 2 mol%. The major HCN adduct could be transformed to the corresponding indoline through construction of a benzylic quaternary carbon under iron catalysis.

Regio- and stereoselective sulfonylation of allenes under Cu catalysis is described. Allenyl sp carbons exclusively react with TsCN to give the corresponding alkenyl sulfones. The reaction is initiated by addition of tosyl radical to form benzyl radical intermediates, which determines the reaction pathway. The structure of the products is highly dependent on the substituents on allenes.

Since a cyano group can be transformed to carboxylic acids, amino- and hydroxymethyl groups as well as aldehydes, its installation, particularly catalytic protocol, has been one of the challenging issues in synthetic chemistry. Hydrocyanation of non-activated C-C multiple bonds has been one of the most powerful methods to install a CN group although selectivity control in products has been major challenge because simple olefin such as styrene derivatives is the only substrate to give higher regioselectivity in HCN addition process. In this review, the authors summarize.

An efficient synthesis of carbo-and heterocycles using CC, CO and CN bonds under cobalt catalysis is described. The substituents on olefins are key for controlling the regio-and chemoselectivity in the initial hydrogen atom transfer step and quaternary carbons are efficiently constructed under mild conditions. Cyclopropane cleavage and tandem cyclization give highly functionalized bicyclic skeletons in a single operation.

This article describes the formal synthesis of quebrachamine based on regio- and stereoselective hydrocyanation of 1,3-disubstituted allenes. Allenyl C–C double bonds are effectively discriminated through Ni-catalyzed hydrocyanation and a CN group is utilized as a synthon of piperidine ring. Several steps from HCN adduct afforded known intermediates to quebrachamine.

A nickel-catalyzed hydrocyanation triggered by hydronickelation of the carbon-carbon double bonds of allenes followed by cyclopropane cleavage is described. The observed regio- and stereochemistries in the products are strongly influenced by the initial hydronickelation step, and allenyl- and methylenecyclopropanes reacted smoothly to promote the cleavage of cyclopropane. In contrast, this cleavage was not observed with vinylidenecyclopropanes, because the initial hydronickelation does not give a suitable intermediate for cleavage of the cyclopropanes. (Figure presented.).

The transfer of axial chirality of allenes is beginning to be exploited as a powerful method for creating central chirality, particularly through the use of transition metal catalysis. In this communication, the transfer of axial chirality of chiral allenes via nickel-catalysed hydrocyanation is achieved through both regio- and face-selective hydronickelation as well as regioselective reductive elimination. This protocol was applied to 12 substrates and gave chiral carbonitriles with up to 97% ee. Further application to hydrocyanative cyclization using a chiral allene-yne is also presented, along with a discussion of the corresponding mechanism of racemization.

This review focuses on the total synthesis of lundurines A–C. Their main structural feature is a unique cyclopropa[b]indole core that has been found only in these alkaloids. In addition to this characteristic structure, the biological activity makes them as attractive synthetic targets. However, almost two decades passed from their isolation and structural determination in 1995 to their first total synthesis. The first part of this review summarizes the synthetic approaches to the tri- and tetracyclic ring systems of lundurine as well as an inter- and intramolecular cyclopropanation strategy that gives the cyclopropa[b]indole core. The second part presents a detailed description of four total syntheses that were reported from 2014 to 2016. In addition, the asymmetric total synthesis of the related alkaloids grandilodine C and lapidilectine B is described.

Enantioselective total syntheses of the Kopsia alkaloids (+)-grandilodine C and (+)-lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)-grandilodine C was achieved by palladium-catalyzed intramolecular allylic amination and ring-closing metathesis to give 8- and 5-membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)-lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies. Enantioselective total syntheses and determination of the absolute stereochemistry of the Kopsia alkaloids (+)-grandilodine C and (+)-lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and following enantioselective deprotonation, lactone formation, vinylation, allylic amination, and ring-closing metathesis, gave the above alkaloids in optically active form.

Regio- and stereoselective hydrocyanation under nickel catalysis is described. This report shows that allenyl C-C double bonds are discriminated and converted to the corresponding carbonitriles as a single product. The key functionalities for achieving high regio- and stereocontrol are aryl and cyclopropyl groups in the substrates. This journal is

A total synthesis of the Kopsia tenuis alkaloid (-)-lundurine B has been achieved. A quaternary chiral carbon has been created by an asymmetric deprotonation using a symmetric spiro cyclohexanone intermediate with a chiral lithium amide. The hexacyclic skeleton was sequentially constructed through metal-mediated reactions. The absolute stereochemistry of intermediate 5 has been unambiguously established by X-ray crystallographic analysis. This is the first description of the absolute stereochemistry of Kopsia tenuis alkaloids based on chemical synthesis.

A total synthesis of (±)-lundurines A and B is described. These natural products have a unique hexacyclic skeleton which includes a cyclopropane-fused indoline. A stereospecific construction of the pentasubstituted cyclopropane core was achieved, by radical cyclization using SmI2, with perfect stereoselectivity. Cyclizations to give seven- and five-membered heterocycles, under palladium and ruthenium catalysis, respectively, accomplished the total syntheses. The late-stage construction of the F ring by ring-closing metathesis enabled access to the title compounds from a spiroindoline intermediate which is a common structure of other kopsia alkaloids. To the core: The total synthesis of (±)-lundurines A and B is described. One of the key reactions is a SmI2-mediated cyclopropanation, which delivered the core structure with perfect stereocontrol of the quaternary carbon centers. Palladium- and ruthenium-catalyzed cyclizations were also effective for constructing seven- and five-membered heterocycles, respectively, to complete the total syntheses. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A total synthesis of (±)-lundurine B was accomplished. A combination of stereoselective intramolecular cyclopropane formation and aryl amination furnished cyclopropane-fused indoline stereoselectively. Ring-closing metathesis (RCM) of siloxy diene and intramolecular aminoacetal formation followed by bridgehead vinylation of an anti-Bredt iminium cation led to the construction of six- and seven-membered rings with a quaternary carbon center. After the formation of dihydropyrrole by RCM, the Boc-protecting group of indoline was converted into the corresponding methyl carbamate via silyl carbamate to complete the total synthesis of (±)-lundurine B. The characteristic rearrangement of the cyclopropane-fused indoline skeleton is also described. © 2014 American Chemical Society.

A [2+2] cycloaddition reaction of allene-ynes under thermal conditions with/without a metal complex is described. A key feature of this reaction is that a 2-benzothiazolylphenyl group bearing a C-C triple bonds remarkably promotes the reaction to give the corresponding cyclobutenes with or without metal catalysts. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A proposed structure for schizocommunin (Z)-1hydroxy and its geometric isomer (E)-1hydroxy, which exist in a keto form, has been synthesized. However, the spectroscopic data of (Z)-1keto and (E)-1keto were not consistent with those reported for natural schizocommunin. After reinvestigating the spectral data for natural schizocommunin, we synthesized the quinazolinone derivative (Z)-2 as a revised structure for schizocommunin. All of the spectral data of (Z)-2 were completely identical to those reported for natural schizocommunin. (Z)-2 showed moderate antiproliferative activity. © 2013 The American Chemical Society and American Society of Pharmacognosy.

The carbocyanative cyclization of allene-ynes and bis-allenes under nickel catalysis is described. The key steps are the regioselective hydronickelation of allenes and subsequent cyclization via carbometalation. The former step determines the reaction pathway, and the latter controls the stereochemistry of substituted olefins. The products are useful carbo- and heterocycles that include a cyano group, functionalized double bonds, and quaternary carbons. © 2013 American Chemical Society.

A nickel-catalyzed three-component coupling reaction through cyanation of a carbon-carbon triple bond is described. A nickel(0) complex effectively catalyzes a sequential coupling reaction between allenes, alkynes and hydrogen cyanide from acetone cyanohydrin in a highly regio-and stereoselective fashion. The trigger for this reaction is hydronickelation to allenes. The initial hydride attack predominantly occurs at the central carbon of the allene to give a p-allylnickel(II) species. Subsequent syncarbometalation connects a β-carbon of alkynoates and a less-hindered carbon of the allylnickel(II) species, and the corresponding cyanoalkenes are obtained as a single stereoisomer without any another organometallic reagents as a coupling partner. © 2013 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim.

Packed with functionality: The key step in the title reactions with acetone cyanohydrin is a regioselective hydronickelation of allenes. Subsequent carbometalation of the alkyne followed by reductive elimination gave cyano-functionalized tetrasubstituted alkenes in a regio- and stereoselective manner (see scheme; EWG=electron-withdrawing group, Ts=p-toluenesulfonyl). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anti carbocyanative cyclization using 1,6-enynes under nickel catalysis is described. This reaction is triggered by hydronickelation to alkenes followed by carbometalation. Steric repulsion caused by the bulky substituents on alkynes promotes isomerization of the carbon-carbon double bond geometry in an organonickel intermediate to introduce both alkyl and cyano groups in an anti fashion. © 2013 American Chemical Society.

Lundurine A, B, C, and D (1-4) were isolated from a Malaysian plant Kopsia tenuis by Kam and co-workers in 1995. They might be new seeds for anticancer drugs because selective anti-melanoma activities of Lundurine B and D have been reported. In addition, its unique hexacyclic skeleton including cyclopropane-fused indoline is attractive for synthetic organic chemists. Therefore, we have been studying total synthesis of Lundurines. According to Toke's protocol, iodine-mediated intramolecular cyclopropanation using 11 was studied (Table 1). Proper selection of solvent and temperature was important to prepare 10 with high yield and diastereoselectivity (entry 2, 6). 10 was converted into a cyclopropane-fused indoline 9 in 4 steps in good yield (Scheme 1). It is notable that 9 was unstable under acidic conditions, and removal of Boc group induced a cleavage of cyclopropane to give a quinoline 14 (Scheme 2). This tetracyclic lactone 9 was readily converted into a silyl enol ether 20 as a precursor of ring closing metathesis (Scheme 4, 5). Grubbs catalyst 2^<nd> generation was powerful enough for this cyclization to afford a tetracyclic cyclohexanone 6 after desilylation. To construct D and F heterocycles, introduction of nitrogen group on E ring was required (Scheme 6). Overman rearrangement seemed suitable for this purpose, because its intramolecular fashion might overcome some potential steric hindrance around E ring. Indeed, the rearrangement proceeded under heating condition to afford mixture of two diastereomers 26. Further investigations about construction of D and F rings are in progress. We recently started the second generation study on a synthesis of the tetracyclic structure of Lundurines using a new synthetic strategy: SmI_2-mediated reductive cyclopropanation (Figure 2). The key cyclization was proceeded well with addition of LiBr and afforded tetracyclic compound 27 (Scheme 7). This methodology enabled us to prepare 27 in shorter steps and higher yield.

This account describes the cyanopalladation of simple and nonactivated alkynes and their application to various cyclization and cycloaddition protocols. A unique feature of cyanopalladation is the direct nucleophilic cyanation with an external CN source such as TMSCN of simple alkynes, which can be effectively activated by Pd(II) under molecular oxygen. There are two possible pathways: syn- and anti-cyanopalladation, which are strongly influenced by the structure of the substrates. The former is usually the major pathway because nucleophilic cyanation is favored to occur at the less hindered alkynyl carbon. The latter could be controlled by the Markovnikov rule, with cyanide directly attacking the π-complex of alkynyl carbons from the site opposite Pd(II). Once the cyanoalkenyl Pd(II) species are formed by cyanopalladation, these intermediates act as useful precursors for sequential carbon-carbon bond-forming reactions, such as 5-exo and 6-endo cyclizations and [4+2] cycloaddition. Cyclization is triggered by regio- and stereoselective cyanopalladation, and [4+2] cycloaddition gives up to five stereogenic centers through the formation of four C-C bonds in a single operation. The reaction pathways and the origin of stereochemistry are also described. 1 Introduction 2 Catalytic 1,2-Dicyanation 2.1 Terminal Alkynes 2.2 Internal Alkynes 2.3 Synthetic Applications 3 Dicyanative Cyclization 3.1 5-exo Cyclization 3.2 Diyne Cyclization 3.2.1 Terminal Diynes 3.2.2 Internal Diynes 3.3 6-endo Cyclization 4 Dicyanative [4+2] Cycloaddition 5 Conclusion. © Georg Thieme Verlag KG · Stuttgart · New York.

Palladium-catalyzed dicyanative [4 + 2] cycloaddition using various ene-enynes was investigated. The key species in this process is a cyanoallene intermediate that is obtained by the cyanopalladation of conjugated enynes followed by 5-exo-cyclization. To achieve an efficient [4 + 2] cycloaddition reaction, both the smooth generation of this species and critical control of regioselectivity in the 6-endo-cyclization step are quite important. A study of the substrate scope revealed that the reaction is strongly affected by the steric bulk of the substituents on the enyne and alkene units and prefers to give trans-fused cycloadducts. The stereochemistry of olefins was reasonably transferred to the corresponding products. Further study proved that this transformation includes not a thermal [4 + 2] cycloaddition process via 1,2-dicyanoalkenes generated in situ but rather a palladium-mediated stepwise cyclization sequence to control a maximum of five contiguous stereogenic centers in a single operation. An intermolecular version using methyl acrylate with conjugated cyclic enynes and TMSCN also gave the corresponding [4 + 2] cycloadducts in a regioselective manner. © 2010 American Chemical Society.

A palladium-catalyzed dicyanative [4+2] cycloaddition reaction using dienynes with TMSCN under aerobic conditions is described. This new reaction triggered by the cyanopalladation of terminal alkynes includes regioselective direct cyanation to C-C triple bonds by TMSCN to give --allyl Pd intermediates, which promotes 5- exo followed by 6- endo cyclization. This protocol enables (1) the formation of four C-C bonds through one operation, (2) the construction of highly functionalized cyclohexene rings, and (3) the generation of five contiguous stereogenic centers in one operation. The intermolecular cycloaddition reaction between a conjugated enyne and methyl acrylate also proceeded in a regioselective fashion to give multifunctionalized carbocycles. © 2010 American Chemical Society.

A stereoselective dicyanative 5-exo- and 6endo-cyclization using various enynes has been investigated. The mode of cyclization is critically controlled by the structure of the substrates. For example, N-allyl derivatives prefer 5-exo-cyclization, while methacryloyl amides are transformed to the corresponding lactams with tetra substituted carbons at the alpha-position via 6-endo-cyclization. Both reactions include syn-cyanopalladation to carbon≡carbon triple bonds in the initial step, and sequential cyclization followed by reductive elimination in one operation enables the construction of the highly functionalized nitrogen heterocycles. The scope of suitable substrates and a proposed mechanism are also described. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

A stereoselective 1,2-dicyanation of various alkynes in the presence of trimethylsilyl cyanide (TMSCN) by palladium(II) catalysis under aerobic conditions is investigated. This reaction includes two cyanation pathways, syn- and anti-cyanopalladation to alkynes that are activated by Pd(II). High syn-selectivity was observed in the reaction using terminal alkynes that have bulky substituents at a propargyl position and aliphatic internal alkynes. Furthermore, a dramatic acceleration was observed with substrates having an N-arenesulfonyl functionality at a propargyl position, this indicates that both sulfoxide and carbon-carbon triple bond act as Lewis bases to Pd(II). © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Essential oxygen: The title transformation involves two different modes of cyanation, syn and anti cyanopalladation, as the key steps in this catalytic reaction. These processes enable successful dicyanative cyclization of diyne and enyne derivatives (see scheme). © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by formal 5-endo-trig cyclization was developed. A variety of fused and 2-substituted indoles were synthesized from enaminoesters prepared by condensation of β-ketoesters and o-iodoaniline. © 2008 Elsevier Ltd. All rights reserved.

A novel method for the synthesisof chiral hydroisoquinolines by asymmetricDiels-Alder reaction of nitrogen-containing dienophiles and suitably protected aminosiloxybutadienes has been developed. © 2009 The Chemical Society of Japan.

(Chemical Equation Presented) A new and facile access to cinnolines, dihydrocinnolines, and 1-aminoindolines was established by use of diazo functionalities. The hydrazines and hydrazones as cyclization precursors derived from 3-haloaryl-3-hydroxy-2-diazopropanoates, which are prepared by one-pot procedure utilizing phase-transfer catalysis, are successfully converted to the corresponding nitrogen heterocycle by Cu-catalyzed N-arylation. Furthermore, analysis of UV spectra proved that 4-oxo-3-carboxylates predominantly exist not as 4-hydroxycinnoline (enol form) but as cinnolone (keto form). © 2008 American Chemical Society.

Tricyclic core of manzamine B was successfully synthesized through asymmetric Diels-Alder reaction and RCM strategy. Cr-salen-F complex was found to be the most effective catalyst in DA reaction of aminodienes with heterocyclic dienophiles to give up to 97% ee. In the construction of 11-membered ring by RCM, first-Grubbs cat. gave better stereoselectivity. © 2006 Elsevier Ltd. All rights reserved.

A new type of furan-iminium cation cyclization was developed and successfully applied to the synthesis of 25, a central core of ircinal A. Compound 25 was efficiently converted to racemic ircinal A, a biogenetic and synthetic precursor of manzamine A. An asymmetric synthesis of ircinal A will also be discussed.

The one-pot synthesis of α-diazo-β-hydroxyesters from sodium azide under phase-transfer-catalyzed conditions has been achieved. This protocol includes three different chemical transformations promoted by a single catalyst in each step to give products in good to excellent yields. The reaction was applied to a catalytic asymmetric aldol-type reaction using α-diazoesters with aldehydes in the presence of a chiral quaternary ammonium salt and gave products with up to 81% ee. The diastereoselective transformation of the products to chiral α-amino-β-hydroxyester derivatives is also described. © 2005 Elsevier Ltd. All rights reserved.

A catalytic asymmetric Michael reaction using Schiff bases promoted by D2-symmetrical ammonium salts as phase-transfer catalysts is described. The reaction of glycine Schiff base (1a) gave the Michael adduct with up to 91% ee and tetrasubstituted carbons was also constructed using alanine Schiff base (3a) with up to 63% ee. © 2006 The Japan Institute of Heterocyclic Chemistry.