廣谷 功

Copyright © 2020 American Chemical Society. Herein we report a one-step, catalytic, Markovnikov-selective, and scalable method for the synthesis of saturated sulfur heterocycles, which are found in the structures of pharmaceuticals and natural products, from an alkenyl thioester. Unlike a potentially labile alkenyl thiol, an alkenyl thioester is stable and easy to prepare. Powerful catalysis via a cobalt hydride hydrogen atom transfer and radical-polar crossover mechanism enabled simultaneous cyclization and deprotection. The substrate scope was expanded by extensive optimization of the reaction conditions and tuning of the thioester unit. This is a rare instance of thioesters showing nucleophilic behavior. This method was also applicable to alkenyl selenoesters.

Two different kind of sequential cyclization-functionalization are developed. Namely, cyclization-chlorination of 2-ethynylaniline derivatives using CuCl2 gave 3-chloro- and 3,5-dichloroindole derivatives. The plausible mechanism for this reaction is also discussed. On the other hand, the reaction between 2-ethynylaniline derivatives and Cu(NO3)(2)center dot 3H(2)O in THF provided C4-nitro compound. After being changed the solvent from THF to DMF, followed by heating, 5-nitroindole derivatives was afforded.

A mild, general, scalable, and functional group tolerant intramolecular hydroarylation of unactivated olefins using a Co(salen) complex, a N-fluoropyridinium salt, and a disiloxane reagent was reported. This method, which was carried out at room temperature, afforded six-membered benzocyclic compounds from mono-, 1,1- or trans-1,2-di, and trisubstituted olefins.

A mild, general, and functional group tolerant intramolecular hydroalkoxylation and hydroacyloxylation of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent is described. This reaction was carried out at room temperature and afforded five- and six-membered oxygen heterocyclic compounds, such as cyclic ethers and lactones. The Co complex was optimized for previously rare medium ring formation by hydrofunctionalization of unactivated olefins. The powerful Co catalyst system also enables the deprotective hydroalkoxylation of O-protected alkenyl alcohol and hydroacyloxylation of alkenyl ester to afford cyclic ethers and lactones directly. The substrate scope and mechanistic proof of deprotection were investigated. The experimental evidence supports the concerted transition state of the bond-forming step involving a cationic Co complex.

We developed an addition reaction of fluorous solvents to olefins using salen cobalt (Co) complex, N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, and 1,1,3,3-tetramethyldisiloxane. This reaction condition was found to activate olefins, which enabled them to be attacked by 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), both of which are electronically weak nucleophiles.

A revised structure for trichodermatide A, which is a C10 epimer of the originally reported structure, is proposed. The revision is supported by the X-ray structure of a synthetic intermediate synthesized according to our previous route for trichodermatide A. The revised stereochemistry was also supported by NOESY experiment. Finally, we synthesized Trauner's compound corresponding to the originally reported structure from our synthetic intermediate of trichodermatide A through a Mitsunobu reaction at C10.

Functional group tolerance is one of the important requirements for chemical reactions, especially for the synthesis of complex molecules. Herein, we report a mild, general, and functional group tolerant intramolecular hydroamination of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent. This method, which was carried out at room temperature (or 0 degrees C), afforded three-, five-, six-, and seven-membered ring nitrogen-containing heterocyclic compounds and was compatible with diverse functional groups.

Catalytic hydrofluorination of olefins using a cobalt catalyst was developed. The exclusive Markovnikov selectivity, functional group tolerance, and scalability of this reaction make it an attractive protocol for the hydrofluorination of olefins. A preliminary mechanistic experiment showed the involvement of a radical intermediate. © 2013 American Chemical Society.

A unique Markovnikov hydroalkoxylation of unactivated olefins with a cobalt complex, silane, and N-fluoropyridinium salt is reported. Further optimization of reaction conditions yielded high functional group tolerance and versatility of alcoholic solvent employed, including methanol, i-propanol, and t-butanol. Use of trifluorotoluene as a solvent made the use of alcohol in stoichiometric amount possible. Mechanistic insight into this novel catalytic system is also discussed. Experimental results suggest that catalysis involves both carbon radical and carbocation intermediates.

A novel catalytic method for synthesizing 4-aryl-2-quinolinones is reported. The process involves two mechanistically independent, sequential Pd(II)-catalyzed reactions-the oxidative Heck reaction and the intramolecular C-H amidation-both of which smoothly proceed in the presence of a single catalytic system in a one-pot manner.

The coupling reaction of aryl iodides with arylboronic acids to give biaryl compounds can be efficiently performed without adding a transition metal catalyst. The key to success is the use of dimethyl carbonate as a solvent. This finding provides a new strategy for constructing a biaryl linkage.

We successfully synthesized two enantiomers of bicyclic enones, (7R,7aR)- and (7S,7aS)-9, from the hemiacetal 2a, which we first synthesized from the symmetrical diketone la via diastereoselective carbon oxygen bond formation between one of the carbonyl groups and the chiral alcohol on the C2 side chain in a 2,2-disubstituted 1,3-cycloalkanedione derivative. We also report the total synthesis of natural (+)-lycopladine A [(+)-6] from (7R,7aR)-9 and the formal synthesis of unnatural (-)-lycopladine A [(-)-6] from (7S,7aS)-9.

Molecular oxygen (O(2)) was successfully employed as a reoxidant in cyclizations of thiobenzanilides 1a-s through a palladium-catalyzed C-H functionalization/intramolecular C-S bond formation process, leading to an efficient, green method for the synthesis of 2-arylbenzothiazoles 2a-s. Addition of cesium fluoride (CsF) greatly enhanced the reactions, which produced variously substituted 2-arylbenzothiazoles with good functional group tolerance. Thioureas 4a-j were also found to be suitable substrates for the cyclization process using a palladium/O(2) catalyst system, thus generating 2-aminobenzothiazoles 5a-j. One-pot syntheses of 2-aminobenzothiazoles 5a-j from aryl isothiocyanates 6 and amines 7 were also successful.

Desulfurization of thioamides was accomplished using a semicatalytic amount of Bu(4)NBr. The corresponding amides were obtained in high yields, with good functional group compatibility.

The C2-side chain hydroxyl group of 1,3-cycloalkanedione discriminates between two ketones depending on its chirality. It chooses one ketone to form hydrogen bond with the oxygen atom of the TBDPS-oxymethyl group, but chooses the other ketone upon conversion to the isopropyl acetal. Two optically pure diastereomers, whose absolute configuration at the angular position is opposite for each other, were thus synthesized from this single chiral source through simple operations. This method may be applied for the synthesis of a variety of compounds with asymmetric quaternary centers. (C) 2010 Elsevier Ltd. All rights reserved.

A catalytic synthetic approach For the synthesis of nolinone compounds through a Pd-catalyzed C(sp(2))-H functionalization/intramolecular amidation sequence is described. The cyclization process efficiently proceeds in the presence of a catalytic amount of PdCl2 and Cu(OAc)(2) under an O-2 atmosphere, providing practical access to a range of variously substituted 4-aryl-2-quinolinones.

Diastercoselective Birch reduction-alkylation reactions of bicyclic beta-alkoxy-alpha,beta-unsaturated carbonyl compounds and tricyclic analogues were investigated. Although the relative configuration of the product was altered according to the Structure of the starting material, stercoselectivity of the reaction could be accounted for by similar reaction pathways. The product from the tricyclic beta-alkoxy-alpha,beta-unsaturated carbonyl compound corresponded to the trichothecene skeleton.

Catalytic activities of NHC-derived nickel-pincer complexes for the Suzuki-Miyaura coupling reactions of aryl/alkenyl to-sylates and mesylates are described. In the presence of a catalytic amount of nickelacycle 1a, a wide array of tosylates and mesylates reacted with several aryl- and alkenylboronic acids to afford the coupling products, generally in high yields. Fine tuning of the reaction conditions for each class of electrophiles was achieved only by choosing the appropriate reaction medium (DME for tosylates, dioxane for mesylates). ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Awajanomycin, which was isolated from marine-derived fungus, possesses unique structural features and cytotoxic activity against A549 cells. Due to its unique structure, no total synthesis has yet been reported, and neither the relative stereochemistry nor the absolute configuration has been determined. We report the synthesis of the core ring system of awajanomycin, which includes: (i) regioselective addition of the acetate unit onto C4-position of N-Boc-3-methoxycarbonyl-2-pyridinone; (ii) stereoselective installation of a hydroxyl group on C3-position; and (iii) stereo- and regioselective epoxide-opening reaction by Me(3)Al. (c) 2009 Elsevier Ltd. All rights reserved.

Air- and moisture-stable NHC (N-heterocyclic carbene)-derived CNC-type pincer complexes of nickel(II) 4a-d were successfully synthesized, and their structures were fully characterized using X-ray crystallography and analytical and spectroscopic methods. These complexes exhibit a high catalytic activity for the Suzuki-Miyaura coupling reaction of aryl bromides and chlorides with aryl- and alkenylboronic acids, providing an array of biphenyls and stilbenes generally in high yields. (C) 2008 Elsevier B. V. All rights reserved.

The stereoselective synthesis of 6Z-pandanamine by base-promoted 5-exo-dig-selective cyclization reaction of bis-2-en-4-ynoic acid derivative as a key step is described

Palladium-catalyzed C-H activation followed by intramolecular amination reaction of enamine compounds was achieved using a Pd(OAc)(2) (10 mol%)/Cu(OAc)(2) (100 mol%) catalyst system in DMSO. This work introduces an entirely new approach to 3-substituted indoles.

Catalytic synthesis of 2-substituted benzothiazoles from thiobenzanilides was achieved in the presence of a palladium catalyst through C-H functionalization/C-S bond formation. This method features the use of a novel catalytic system consisting of 10 mol % of Pd(II), 50 mol % of Cu(I), and 2 equiv of Bu(4)NBr that produced variously substituted benzothiazoles in high yields with good functional group tolerance.

Piperidine alkaloids are expected to be lead compounds for new medicines because of their various biological activities. In order to establish the efficient synthetic methods for a variety of functionalized piperidine alkaloids, we have developed Michael addition reaction between silyl ketene acetals and 2-pyridinone derivatives in the presence of Lewis acid. Recently we have examined the reactivity of substrates having a methoxycarbonyl group at the C3 or the C5-position on the 2-pyridinone ring for control of the regioselectivity. As a result, when the reaction was applied to the substrate having the C3-methoxycarbonyl group, C4-substituted product was selectively obtained in the presence of a catalytic amount of Lewis acid. On the other hand, the reaction of the substrate having the C5-methoxycarbonyl group provided C6-substituted product in the presence of a catalytic amount of Lewis acid and azabicyclic compound with 2 equivalents of Me_3Al. On the examination of the reaction mechanism, it was found that the active Lewis acid was not Me_3Al, but the complex produced from Me_3Al and silyl ketene acetal. These reactions were applied to the syntheses of natural products. The enantioselective synthesis of the DE ring system of camptothecin, anti-tumor natural product, was accomplished in six steps. Next, we have studied the synthesis of awajanomycin, which is a new anti-tumor natural product isolated from marine-derived fungus in 2006. Since its absolute configuration has not been determined yet, we planned the stereoselective synthesis of awajanomycin as an optically active form. To construct its azabicyclic part, we have examined introduction of functional groups to the Michael adduct.

The one-pot conversion of thioenols into benzo[b]thiophenes was achieved by using a simple palladium catalyst such as PdCl(2) or PdCl(2)(cod).

The catalytic activities of a pincer type bis(imidazolin-2-ylidene)nickel(II) complex were evaluated. The complex was found to be an effective catalyst in the Kumada-Tamao-Corriu and Suzuki-Miyaura coupling reactions of a broad range of aryl-X (X = Br, Cl and F) compounds, providing a variety of biaryl compounds, generally in good yield.

A method for the catalytic C-H activation of hydrazone compounds followed by intramolecular amination is described. It requires the use of a catalytic amount of Pd(OAc)(2) in the presence of Cu(OAc)(2) and AgOCOCF3, which efficiently effects the cyclization to afford variously substituted indazoles. The reactions proceed under relatively mild conditions and thus tolerate a variety of functional groups, including alkoxycarbonyl and cyano groups and halogen atoms.

Syntheses of 3-substituted indazoles and benzoisoxazoles were efficiently accomplished with the aid of Pd-catalyzed intramolecular carbon-nitrogen and carbon-oxygen bond formations. The catalyst system described herein allows the cyclization to proceed under very mild conditions and thus could be applied to a wide range of substrates with acid- or base-sensitive functional groups. A total synthesis for the indazole ring-containing natural product nigellicine is also described. (c) 2007 Elsevier Ltd. All rights reserved.

We systematically investigated, for the first time, the relationship between regioselectivity and acid/base effects in the cyclization reactions between carboxylic acids and carbon-carbon triple bonds. We found novel acid- and base-promoted cyclizations to selectively give isocoumarin or pyran-2(2H)-one and phthalide or furan-2(5H)-one skeletons, respectively, and established a catalytic version of regioselective heterocyclic ring synthesis. Density functional theory calculations and application to a short route to thunberginol A were also described.

The DE ring system of (20S)-camptothecin had been prepared from commercially available nicotinic acid in six steps utilizing the nucleophilic addition reaction of the silyl ketene acetal to the pyridinone ring as a key step.

An air- and moisture-stable nickel(II) complex of bis-carbene pincer complex 2 has been synthesized, and its catalytic activity for the Heck reaction and the Suzuki coupling reaction was investigated.

The reaction conditions for the Pd-catalyzed cyclization reaction of 2-(2-carbomethoxyethynyl)aniline derivatives were investigated. The amounts of Pd(PPh3)(4), methyl propiolate, and ZnBr2 could be significantly reduced compared with those reported in our preliminary publication by careful tuning of the solvent and the reaction temperature. In addition to the above results, formal syntheses of pyrroloquinoline quinone (PQQ) and its analogue from 2-amino-5-nitrophenol using a Pd-complex-catalyzed sequential coupling-cyclization reaction between methyl propiolate and 2-iodoaniline derivatives are described. (c) 2005 Elsevier Ltd. All rights reserved.

We have developed a highly regioselective synthesis of heterocycles via palladium-catalyzed annulation reaction of heteroatom-substituted allenes. Various aryl halides were reacted and one regioisomer was observed exclusively in all reactions. In addition, subsequent functionalizations of annulated products were carried out using alkyl metal reagents, and the introduction of alkyl moieties was accomplished.

Results of the optimized cyclization reaction of 2-ethynyl aniline derivatives to indoles catalyzed by copper(II) salts are described. The reactions can be carried out in a mixture of H2O and MeOH in the presence of 1-ethylpiperidine at room temperature. These conditions can be applied to a bulky substrate, which is difficult to be cyclized efficiently by existing reaction conditions. Furthermore, this reaction condition was applied to a catalyst recycling reaction system. (c) 2005 Elsevier Ltd. All rights reserved.

The stereoselective introduction of an allyl group into the angular position of 2-(TBS-oxymethyl)-2,3,4,6,7,8hexahydro-l-benzopyran-5-one was accomplished using Birch reduction and an enolate trapping reaction. It was determined that the allyl group was introduced via an unexpected conformation-flipped from the initially formed one. Two diastereomeric Wieland-Miescher type compounds, having the allyl group at the angular position, were synthesized as optically pure forms.

The sequential coupling and cyclization reactions between aryl halides and methyl propiolate were investigated. The electron-withdrawing groups on the aromatic ring are essential for producing the methyl indole-2-carboxylate derivatives. On the other hand, the presence of an extra methyl propiolate and Pd(PPh(3))(4) were required to provide an efficient catalytic system for the cyclization reactions. This reaction was used for the total synthesis of duocarmycin SA.

The efficient method for the preparation of 3-substituted indazoles was developed using the palladium catalyzed intra-molecular amination reaction of 2-bromophenyl hydrazone derivatives. Good functional group compatibility was observed under mild reaction conditions and various 3-substituted indazoles were obtained in moderate to excellent yield.

2-エチニルアニリン誘導体を基質とするインドール閉環反応とその合成化学的応用に関してまとめた総論．

The development of efficient methods for the indole synthesis catalyzed by Cu(II) salts and its applications were investigated. Cu(OAc)(2) has been proved to be the best catalyst for the synthesis of various 1-p-tolylsulfonyl or 1-methylsulfonylindoles, which have both electron-withdrawing and electron-donating groups on the aromatic ring and C2 position of indoles. For the primary aniline derivatives, Cu(OCOCF3)(2) showed good activities, while Cu(OAc)(2) was a good catalyst for the cyclization of secondary anilines. This methodology could be applied to the sequential cyclization reaction for the compounds which have the electrophilic part in the same molecule. By prior treatment with KH, the sequential cyclization was realized to provide the tricyclic ring systems, but it was limited to five- and six-membered rings for the second cyclization. Finally, formal and total synthesis of hippadine with the Cu(II)-promoted indole synthesis as the key step was accomplished.

The reaction of N-tosyl-2-pyridinone with tert-butyldimethylsilyl ketene acetal, catalyzed by a Lewis acid, has been investigated. While both the C-4 Michael adduct 3 and the bicyclic compound 5 were isolated from aluminum chloride- or trimethylaluminum-catalyzed reactions, the former was afforded as the sole product from diethylaluminum chloride- or trimethylsilyl trifluoromethanesulfonate- catalyzed reactions. During investigation of a synthesis of corynantheidol, a method for construction of the key intermediate 30 was accomplished via, (1), the efficient conversion of the enamine moiety to an alkenyl bromide (20-->22), followed by the Sonogashira coupling reduction (22-->23); ( 2), selective reduction of the acetylene and intramolecular cyclization (25-->26); (3), the coupling reaction with the indole unit (27-->30).

The efficient cyclization reactions of the N-methanesulfonyl or N-ethoxycarbonyl derivatives of 2-ethynylanilines, functionalized on the benzene ring and/or the acetylene terminal into indoles catalyzed by either Cu(OTf)2 or Cu(OAc)2 are accomplished. The application of this reaction to the tandem cyclization reaction is also described. © 2002 Elsevier Science Ltd. All rights reserved.

The protecting effect of betulin against cadmium toxicity was investigated using 11 inds of analogues. It was elucidated by analyzing the analogue activities that both hydroxyl groups on C-3 and C-28 and the isopropenyl group on C-19 played important roles for expressing efficient activities. In addition, the cytotoxicity of betulin was also reduced by being functionalized using the above functional group. Copyright © 2002 Elsevier Science Ltd.

The regioselectivity of the cyclization reaction of 2-ethynylbenzyl alcohol and 2-ethynylbenzylamine derivatives promoted by TBAF was investigated. Six-membered ring derivatives were obtained from the compounds, which have a butyl group on the triple bond. Whereas five-membered ring products were afforded from the substrates having hydrogen or aromatic substituents on the acetylene moiety. It was also concluded that both the tetrabutylammonium cation and fluoride anion were essential for the cyclization. Thus, the actual mechanism and catalytic cycle were also suggested. © 2001 Elsevier Science Ltd. All rights reserved.

Vignafuran 2, 2-(4-hydroxy-2-methoxyphenyl)-6-methoxybenzofuran-3-carboxylic acid methyl ester 3, and coumestrol 4 were efficiently synthesized from the same starting material, 4-bromoresorcinol 14a, through the common intermediate, diarylacetylene 7. The key steps of these syntheses were the tetrabutylammonium fluoride (TBAF)-catalyzed benzo[b]furan ring formation for 2 and the carbonylative ring closure methodology catalyzed by a Pd complex for 3 and 4. © The Royal Society of Chemistry 2000.

The first enanticontrolled synthesis of five naturally occurring polyoxygenated cyclohexenylmethanol dibenzoates has been achieved to confirm three [(-)-zeylenol, (-)-uvarigranol G, (+)-pipoxide], revise one [(-)-tonkinenin A] and disprove one [(-)-epizeylenol] of the proposed structures.