担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Herein, we summarize our recent efforts toward developing catalytic methods for the synthesis of N-unsubstituted ketimines and their applications to one-pot reactions for producing various nitrogen-containing compounds. This account provides detailed background, optimization, scope, and mechanistic information. We hope this work will stimulate future studies on the implementation of N-unsubstituted ketimines.

DOI： 10.1055/a-2131-3448

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

<p>Digitalization of information on organic reactions is essential for developing next-generation organic syntheses with artificial intelligence and machine-learning (ML) methods. In this regard, reliable information on functional group compatibility and chemoselectivity is critical for understanding the applicability of the reactions. Herein, we report the digitalization of organic reactions using a functional group evaluation (FGE) kit that allows for accurate and rapid assessment of information on the functional group compatibility and chemoselectivity of given organic reactions. Our 26 FGE compounds were used to evaluate 4 types of organic reactions (i.e., cross-coupling, proline-catalyzed aldol, condensation, and ketimine synthesis reactions). As a result, we obtained valuable information for developing a new model of retrosynthetic analysis tools and a deeper understanding of these reactions.</p>

DOI： 10.1246/bcsj.20230047

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CiNii Research

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

We report an organocatalyzed direct enantioselective hydrophosphonylation of N-unsubstituted ketimines that affords N-unprotected α-tetrasubstituted α-aminophosphonates without protection/deprotection steps. The reaction is suitable for N-unsubstituted isatin-derived and trifluoromethyl ketimines, affording products in high yields with excellent enantioselectivity. Applications of the reaction and a proposed transition state model are also described.

DOI： 10.1021/acscatal.2c05953

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Catalytic control of chemoselectivity is crucial in the synthesis of highly functionalized compounds. Although there are reports of efficient chemoselective reactions of alcohols and amines as nucleophiles, there are no reports of the chemoselective activation of alcohols and amines as electrophiles. In this study, highly O- and N-selective electrophilic activation of allylic alcohols and amines was achieved in Pd-catalyzed direct allylic alkylation. Allylamines were inherently more reactive than allylic alcohols (N-selectivity). On the other hand, the addition of catalytic amounts of 9-phenanthreneboronic acid preferentially activated allylic alcohols over allylamines (O-selectivity). Density functional theory (DFT) calculations suggested that the N-selectivity is due to the selective activation of allylic amines with ammonium cations, and boronate formation accelerates the activation of allylic alcohols.

DOI： 10.1248/cpb.c22-00745

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CiNii Research

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

A one-pot catalytic synthesis of α-tetrasubstituted amino acid derivatives via in situ generation of N-unsubstituted ketimines is reported. Because of the irreversible formation of N-unsubstituted ketimines, the yields were higher than those generated under the conventional one-pot reaction conditions. This process prevents the need to isolate unstable N-unsubstituted ketimines with alkyl substituents and streamlines the synthesis of highly congested α-amino acid derivatives.

DOI： 10.1021/acs.orglett.2c02587

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Retarded revascularization after progressive occlusion of large conductance arteries is a major cause of bad prognosis for peripheral artery disease (PAD). However, pharmacological treatment for PAD is still limited. We previously reported that suppression of transient receptor potential canonical (TRPC) 6 channel activity in vascular smooth muscle cells (VSMCs) facilitates VSMC differentiation without affecting proliferation and migration. In this study, we found that 1−benzilpiperadine derivative (1−BP), a selective inhibitor for TRPC3 and TRPC6 channel activities, induced VSMC differentiation. 1‐ BP‐treated mice showed increased capillary arterialization and improvement of peripheral circulation and skeletal muscle mass after hind‐limb ischemia (HLI) in mice. 1−BP had no additive effect on the facilitation of blood flow recovery after HLI in TRPC6−deficient mice, suggesting that suppression of TRPC6 underlies facilitation of the blood flow recovery by 1−BP. 1−BP also improved vascular nitric oxide bioavailability and blood flow recovery after HLI in hypercholesterolemic mice with endothelial dysfunction, suggesting the retrograde interaction from VSMCs to endothelium. These results suggest that 1−BP becomes a potential seed for PAD treatments that target vascular TRPC6 channels.

DOI： 10.3390/cells11132041

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）

<p>Herein we report our recent efforts on the greener catalytic synthetic methods of nitrogen-containing compounds using <i>N</i>-unprotected ketimines. We found that alkynylation of <i>N</i>-unprotected trifluoromethyl ketimines proceeded in the presence of zinc catalysts, providing the products in good yield with broad functional group tolerance and unique chemoselectivity. Next, we extended the methodology to catalytic stereoselective addition reactions and found that a direct Mannich-type reaction, a Friedel-Crafts-type alkylation reaction, a decarboxylative Mannich-type reaction, and an arylation reaction proceeded in the presence of appropriate metal or organocatalysts to give α-tetrasubstituted amines in high yield and stereoselectivity. The detailed scope and some mechanistic insights of these reactions are also presented.</p>

DOI： 10.5059/yukigoseikyokaishi.80.2

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CiNii Research

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

A catalytic enantioselective Strecker reaction of isatin-derived N-unsubstituted ketimines directly afforded the N-unprotected α-aminonitriles with a tetrasubstituted carbon stereocenter in up to 99% ee without requiring protection/deprotection steps. One-pot Strecker reactions from the parent carbonyl compounds were also realized with comparable yields and enantioselectivities. Direct transformations of the N-unprotected α-aminonitrile products streamlined the synthesis of unnatural amino acid derivatives and achieved the shortest one-pot stereoselective routes to a biologically active compound reported to date.

DOI： 10.1021/acs.orglett.1c01194

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記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）

CiNii Research

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

2-Acylimidazoles are widely used as post-Transformable carboxylic acid equivalents in chemoselective and enantioselective reactions. Their transformations, however, require pretreatment with highly reactive, toxic methylating reagents to facilitate C-C bond cleavage. Here, we demonstrate that such pretreatment can be avoided and the C-C bond cleaved under neutral conditions without the use of additional reagents or catalysts. The scope of the reaction, including the use of products reported in the literature as substrates, and some mechanistic insights are described.

DOI： 10.1021/acs.joc.0c01458

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Catalytic addition reactions to N-unsubstituted (N-unprotected) imines can provide a more straightforward synthesis of amines. This direct process eliminates the unnecessary protecting-group manipulations that are required with N-substituted (N-protected) imines and can contribute to the development of green chemistry. Although their use has been limited due to difficulties associated with the nature of N-unsubstituted imines, recently developed catalytic methods enable the use of N-unsubstituted imines as electrophiles in various catalytic addition reactions. To facilitate an understanding of the state of the art development of synthetic methodologies, herein we review recent progress on catalytic addition reactions to N-unsubstituted imines. We begin with an overview of the chemistry of N-unsubstituted imines, followed by a summary of recent progress categorized according to the reaction type. We hope this review will help to stimulate further development of greener syntheses of nitrogen-containing compounds.

DOI： 10.1021/acscatal.0c01212

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担当区分：責任著者   記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）

Benzophenone imine and its derivatives are useful ammonia equivalents for synthesizing primary amines, readily achieving the selective formation of primary amines and obtaining easily deprotectable imines as the product. These advantages have led to the development of various CN bond-forming reactions in recent years. In this Highlight Review, we summarize the progress related to their reaction patterns.

DOI： 10.1246/cl.200099

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CiNii Research

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Enantioselective addition of boronic acids to N-unsubstituted isatin-derived ketimines was realized using rhodium(I)/chiral diene catalysts. The reactions can be performed in the presence of catalytic amounts of a base to give adducts in high yield with high enantioselectivity. Preliminary mechanistic information including a computational model to explain the observed enantioselectivity is also provided.

DOI： 10.1002/asia.201901745

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

N-Unprotected ketimines are useful substrates and intermediates for synthesizing valuable nitrogen-containing compounds, but their potential applicability is limited by the available synthetic methods. To address this issue, we report a scandium(III) triflate catalyzed direct synthesis of N-unprotected ketimines. Using commercially available reagents and Lewis acid catalysts, ketones were directly transformed into the corresponding N-unprotected ketimines in high yields with broad functional group tolerance, even in multigram scales. The reactions were readily applicable for one-pot synthesis of important compounds such as a glycine Schiff base without isolation of N-unprotected ketimine intermediates. Preliminary mechanistic studies to clarify the reaction mechanism are also described.

DOI： 10.1021/acs.orglett.9b04038

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

This paper describes the mechanistic aspects of nickel(II)-catalyzed direct alcoholysis of 8-aminoquinoline amides. Kinetic experiments suggested that the nickel(II) catalyst existed in an oligomeric form in the resting state, and the 8-aminoquinoline generated after cleavage coordinated to the nickel(II) catalyst to decelerate the reaction. In addition, density functional theory calculations revealed that the reactions proceeded via the intermediate with N,N,O-tridentate coordination of 8-aminoquinoline amides to the nickel(II) metal center, and that the alcoholysis reaction did not involve deprotonation of the N-H bond of 8-aminoquinoline amides, in contrast to the proposed mechanism for C-H bond functionalization reactions of 8-aminoquinoline amides.

DOI： 10.3987/COM-19-S(F)30

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記述言語：英語   掲載種別：研究論文（学術雑誌）

We previously reported the identification of a novel antimitotic agent with carbazole and benzohydrazide structures: N′-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-iodobenzohydrazide (code number NP-10). However, the mechanism(s) underlying the cancer cell-selective inhibition of mitotic progression by NP-10 remains unclear. Here, we identified NP-10-interacting proteins by affinity purification from HeLa cell lysates using NP-10-immobilized beads followed by mass spectrometry. The results showed that several mitosis-associated factors specifically bind to active NP-10, but not to an inactive NP-10 derivative. Among them, NUP155 and importin β may be involved in NP-10-mediated mitotic arrest. Because NP-10 did not show antitumor activity in vivo in a previous study, we synthesized 19 NP-10 derivatives to identify more effective NP-10-related compounds. HMI83-2, an NP-10-related compound with a Cl moiety, inhibited HCT116 cell tumor formation in nude mice without significant loss of body weight, suggesting that HMI83-2 is a promising lead compound for the development of novel antimitotic agents.

DOI： 10.1038/s41598-019-53259-2

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Benzophenone imine is a useful ammonia equivalent in the Buchwald-Hartwig amination and an important intermediate for the synthesis of N-protected primary amines. However, the conventional synthesis of benzophenone imine requires stoichiometric amounts of metal reagents or high-pressure conditions. Herein we report a facile method for preparing benzophenone imine to enhance its potential utility. The reaction is performed by mixing commercially available benzophenone and bis(trimethylsilyl)amine in the presence of a catalytic amount of tetrabutylammonium fluoride at ambient temperature and pressure and can be readily applied to a multigram-scale synthesis even in a standard academic laboratory setup. Preliminary mechanistic studies and the application of the reaction to one-pot benzophenone imine synthesis/Buchwald-Hartwig amination are also reported.

DOI： 10.1021/acs.oprd.9b00226

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

A study of ammonium salt-accelerated hydrazinolysis of unactivated amides is described. We first studied the reaction mechanism by kinetic experiments and DFT calculations and found that cooperation of the hydrazinium salt and hydrazine is important for promoting the cleavage of unactivated amides. Next, we applied the reaction to a microwave flow process, and the amine products were isolated on a multigram scale.

DOI： 10.1021/acs.oprd.8b00424

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）

CiNii Research

担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）

CiNii Research

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Although BINOL-derived phosphoric acids are among the most widely used chiral Brønsted acid organocatalysts, their structures are mostly limited to 3,3′-disubstituted ones and simple 3-mono-substituted ones without any polar functionalities on the 3-substituent have not been used in highly enantioselective reactions. This work reports such 3-mono-substituted analogues as effective organocatalysts in direct highly enantioselective Friedel–Crafts-type alkylation of N-unprotected α-ketiminoester. The origin of the observed high enantioselectivity with the 3-mono-substituted catalyst is also discussed.

DOI： 10.1002/chem.201804078

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

The first catalytic enantioselective decarboxylative Mannich-type reaction of N-unprotected ketimines is reported, directly providing N-unprotected 3-tetrasubstituted 3-aminooxindoles in high yield and ee without protection/deprotection steps. The utility of this reaction is demonstrated in the short step synthesis of (+)-AG-041R.

DOI： 10.1021/acs.orglett.8b02306

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Direct catalytic enantioselective alkynylation of carbonyl compounds and imines is one of the most efficient approaches for the synthesis of propargylic alcohols and propargylamines, which are potent building blocks for synthesizing functionalized molecules. While a variety of methods for the reactions with aldehydes and aldimines have been established, the reactions with ketones and ketimines remain underdeveloped due to their reduced reactivity and difficulty in stereocontrol. In this account, we summarized our studies on direct enantioselective alkynylation reaction of α-ketoester and α-ketiminoesters catalyzed by phenylbis(oxazolinephebox)-rhodium(III) complexes, affording enantioenriched propargyl alcohols and propargylamines with a tetrasubsti-tuted carbon stereocenter under proton-transfer conditions. The catalytic system was compatible to a wide range of functional groups, including electrophilic formyl groups, and allowed for the development of an efficient method to access enantioenriched α-CF3-substituted thalidomide analogs. Mechanistic studies revealed that generation of the (alkynyl(phebox)Rh(III) complex from the (diacetatophebox)Rh(III) complex determined the overall reaction rate in the initial stages of the reaction. These results, along with the observed facile exchange of the alkynyl ligand on the (alkynylphebox)Rh(III) complexes, led us to use (trimethylsilylethynylphebox)Rh(III) complexes as a new pre-catalyst. The new catalytic system with (trimethylsilylethynylphebox)Rh (III) precatalysts exhibited enhanced catalytic performance, reduced catalyst loading to as low as 0.5 mol%, and expanded the substrate scope of the reaction with less reactive α-ketiminophos-phonate and cyclic N-sulfonyl α-ketiminoesters.

DOI： 10.5059/yukigoseikyokaishi.76.226

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CiNii Research

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Direct catalytic C−C bond-forming addition to N-unprotected ketimines is an efficient and straightforward method of synthesizing N-unprotected tetrasubstituted amines that eliminates prior protection/deprotection steps and allows facile transformation of the products. Despite its advantages, however, N-unprotected ketimines have difficulties in C−C bond-forming reactions, and only a limited number of reactions and substrates are reported compared with their N-protected counterparts. Herein we report that N-unprotected trifluoromethyl ketimines are effective for C−C bond-forming reactions using Mannich-type reactions as a model case. We demonstrate that Lewis acid catalysis was effective for promoting reactions with various N-unprotected trifluoromethyl ketimines, and thiourea organocatalysis was effective for promoting highly enantioselective reactions with various carbonyl nucleophiles, providing direct access to various N-unprotected α- and/or β-tetrasubstituted amino acid esters. Furthermore, direct construction of vicinal tetrasubstituted chiral carbon stereocenters was achieved for the first time in a highly enantio- and diastereoselective manner. These results demonstrate the potential of N-unprotected ketimines as substrates applicable to many other addition reactions.

DOI： 10.1002/chem.201703516

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Boronic acid was used to accelerate a three-component reaction of indoles, thiols, and glyoxylic acids for the synthesis of α-sulfanyl-substituted indole-3-acetic acids. Boronic acid catalysis to activate the α-hydroxy group in α-hydroxycarboxylic acid intermediates and intramolecular assistance by free carboxylic acid were the keys to accelerating the product formation.

DOI： 10.1021/acs.orglett.7b02727

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Direct catalytic alcoholysis of unactivated amides is one of the most difficult challenges in organic chemistry, and an applicable method for cleaving amides used as directing groups in regioselective functionalization reactions has not been reported. Herein, we report direct catalytic alcoholysis of 8-aminoquinoline amides, which are highly effective directing groups in regioselective functionalization reactions. The reactions proceeded with a simple combination of substrates, air-stable catalysts, and alcohols, affording the corresponding esters in good yields with broad functional group tolerance. Highly chemoselective cleavage of the 8-aminoquinoline amides in the presence of related carbonyl functionalities and preliminary mechanistic studies are also described.

DOI： 10.1021/acscatal.7b00442

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記述言語：英語   掲載種別：研究論文（学術雑誌）

This review summarizes our studies of the direct enantioselective alkynylation of α-ketoesters and α-ketiminoesters catalyzed by [bis(oxazoline)phenyl]rhodium(III) ((phebox)Rh(III)) complexes. The reactions provide chiral α-tetrasubstituted propargyl alcohols and propargylamines under proton-transfer conditions in high yield and with high enantioselectivity. The unique nature of (phebox)Rh(III) complexes allows the reactions to occur in the presence of various functional groups, including an electrophilic aldehyde functionality. Mechanistic studies revealed that the generation of (alkynyl)Rh(III) complexes limited the overall reactivity, which led us to use (trimethylsilylethynyl)(phebox)Rh(III) complexes as efficient pre-catalysts. The use of (trimethylsilylethynyl)(phebox)Rh(III) complexes reduced catalyst loading to as low as 0.5 mol%, and expanded the substrate scope to unprecedented α-ketiminophosphonate and cyclic N-sulfonyl α-ketiminoesters.

DOI： 10.3987/REV-16-SR(S)4

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

This note describes the construction of tetrasubstituted carbon stereocenters via palladium-catalyzed allylation of sp3 C–H bonds of 2,2,2-trifluoroethylamine derivatives. The presence of 2-pyridyl group of the imines derived from 1-substituted-2,2,2-trifluoroethylamine was key to promoting the reaction efficiently, allowing an access to a variety of 1-allylated 2,2,2-trifluoroethylamine derivatives with tetrasubstituted carbon stereocenters.

DOI： 10.1248/cpb.c17-00580

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PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Direct catalytic alkynylation of N-unprotected trifluoromethyl ketimines is reported for the first time. A combination of catalytic amounts of diethylzinc and carboxylic acids promoted the reactions under proton-transfer conditions, allowing an unprecedented direct access to N-unprotected α-tetrasubstituted primary amines without additional deprotection steps.

DOI： 10.1039/c7cc02194a

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Diethylenetriamine is effective for the direct cleavage of unactivated carbamates and ureas without additional reagents and catalysts. Various carbamates and ureas were cleaved to afford products in good yield, and the reactions were not affected by air or moisture. Unique chemoselective cleavage of carbamate and urea in the presence of amides was also achieved.

DOI： 10.1021/acs.orglett.6b03016

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Mechanistic studies and expansion of the substrate scope of direct enantioselective alkynylation of α-ketiminoesters catalyzed by adaptable (phebox)rhodium(III) complexes are described. The mechanistic studies revealed that less acidic alkyne rather than more acidic acetic acid acted as a proton source in the catalytic cycle, and the generation of more active (acetato-κ2O,O′)(alkynyl)(phebox)rhodium(III) complexes from the starting (diacetato)rhodium(III) complexes limited the overall reactivity of the reaction. These findings, as well as facile exchange of the alkynyl ligand on the (alkynyl)rhodium(III) complexes led us to use (acetato-κ2O,O′)(trimethylsilylethynyl)(phebox)rhodium(III) complexes as a general precatalyst for various (alkynyl)rhodium(III) complexes. Use of the (trimethylsilylethynyl)rhodium(III) complexes as precatalysts enhanced the catalytic performance of the reactions with an α-ketiminoester derived from ethyl trifluoropyruvate at a catalyst loading as low as 0.5 mol % and expanded the substrate scope to unprecedented α-ketiminophosphonate and cyclic N-sulfonyl α-ketiminoesters.

DOI： 10.1021/jacs.6b01590

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Background The mitotic spindles are among the most successful targets of anti-cancer chemotherapy, and they still hold promise as targets for novel drugs. The anti-mitotic drugs in current clinical use, including taxanes, epothilones, vinca alkaloids, and halichondrins, are all microtubule-targeting agents. Although these drugs are effective for cancer chemotherapy, they have some critical problems; e.g., neurotoxicity caused by damage to neuronal microtubules, as well as innate or acquired drug resistance. To overcome these problems, a great deal of effort has been expended on development of novel anti-mitotics. Methods We identified novel microtubule-targeting agents with carbazole and benzohydrazide structures: N′-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-methylbenzohydrazide (code number HND-007) and its related compounds. We investigated their activities against cancer cells using various methods including cell growth assay, immunofluorescence analysis, cell cycle analysis, tubulin polymerization assay, and tumor inhibition assay in nude mice. Results HND-007 inhibits tubulin polymerization in vitro and blocks microtubule formation and centrosome separation in cancer cells. Consequently, it suppresses the growth of various cancer cell lines, with IC<inf>50</inf> values in the range 1.3-4.6 μM. In addition, HND-007 can inhibit the growth of taxane-resistant cancer cells that overexpress P-glycoprotein. Finally, HND-007 can inhibit HeLa cell tumor growth in nude mice. Conclusions and general significance Taken together, these findings suggest that HND-007 is a promising lead compound for development of novel anti-mitotic, anti-microtubule chemotherapeutic agents.

DOI： 10.1016/j.bbagen.2015.04.013

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）

Development of direct catalytic anti-Markovnikov addition reactions of oxygen nucleophiles to simple alkenes is a difficult challenge due to the propensity to form Markovnikov adducts under ordinary reaction conditions. Herein selected recent examples that realize these reactions with high anti-Markovnikov selectivity are summarized.

DOI： 10.5059/yukigoseikyokaishi.72.1402

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記述言語：英語   掲載種別：研究論文（学術雑誌）

An increased supply of scarce or inaccessible natural products is essential for the development of more sophisticated pharmaceutical agents and biological tools, and thus the development of atom-economical, step-economical and scalable processes to access these natural products is in high demand. Herein we report the development of a short, scalable total synthesis of (-)-α-kainic acid, a useful compound in neuropharmacology that is, however, limited in supply from natural resources. The synthesis features sequential platinum-catalyzed direct allylic aminations and thermal ene-cyclization, enabling the gram-scale synthesis of (-)-α-kainic acid in six steps and 34% overall yield.

DOI： 10.1002/chem.201406557

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Hydrazinolysis of unactivated amide bonds is significantly accelerated by the addition of ammonium salts. The reactions proceed at 50–70 °C to give amines with broad substrate scope that outperforms existing amide bond cleavage reactions. Application to peptide and amino sugar derivatives is also demonstrated. © Partner Organisations 2014.

DOI： 10.1039/c4cc02014f

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Lanthanum trifluoromethanesulfonate is an effective single-component catalyst for synthesizing a variety of amides directly from esters and amines under mild conditions. Highly selective amidation of esters and amines, as well as catalyst-controlled amidation of esters, demonstrated the effectiveness of the catalyst system. © 2014 American Chemical Society.

DOI： 10.1021/ol500593v

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記述言語：英語   掲載種別：研究論文（学術雑誌）

A green way to amino acids: α-Tetrasubstituted α-amino acid derivatives are formed in high yield and enantioselectivity by using a Rh-catalyzed enantioselective alkynylation of α-ketiminoesters. This reaction, which involves a proton transfer and can be conducted at room temperature, has high substrate scope (see scheme; Cbz=benzyloxycarbonyl, Fmoc=9-fluorenylmethyloxycarbonyl). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI： 10.1002/chem.201301237

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Easy does it! The chemoselective oxidative ?-C(sp3)H alkylation/cyclization reaction of N-benzyl carbamates using simple mono-, di-, and trisubstituted olefins provides functionalized N-heterocycles such as oxazinones (see picture). A TEMPO oxoammonium salt serves as the oxidant, making it possible to carry out the reaction at low temperatures. Neither a metal catalyst nor preactivation in the ?-position to the nitrogen group are needed.

DOI： 10.1002/anie.201202354

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Now accessible: Sterically hindered vicinal tetrasubstituted carbon stereocenters, which are not accessible by asymmetric hydrogenation, were constructed by a catalytic asymmetric C-C bond formation (see scheme; Dpp=diphenylphosphinoyl). By changing the Group 2 metal center, stereodivergent access to α,β-tetrasubstituted α,β-diamino esters was realized. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI： 10.1002/anie.201101034

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

(Chemical Presented) Well compatible: The trifluoromethylations and perfluoroalkylations of aryl iodides and some aryl bromides with trifluoromethyl and perfluoroalkylcopper(I) phenanthroline complexes occur with broad scope at 25-50 8C (see scheme). The trifluoromethyl complex is prepared from inexpensive reagents and can be used in situ or isolated. The reactions tolerate a range of substituents and also occur with heteroaromatic systems. © 2011 Wiley-VCH Verlag GmbH & Co. KGaA.

DOI： 10.1002/anie.201100633

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記述言語：英語   掲載種別：研究論文（学術雑誌）

The catalytic asymmetric aza-Morita-Baylis-Hillman reaction using unactivated methyl acrylate is described. A simple Lewis acidic metal catalyst, such as La(OTf)3, was not suitable for the reaction, but rare earth metal alkoxide/linked-BINOL complexes possessing bifunctional Lewis acid and Brønsted base properties efficiently promoted the reaction in combination with an achiral nucleophilic organocatalyst. The combined use of a La(O-iPr)3/(S,S)-TMS-linked-BINOL complex with a catalytic amount of DABCO promoted the aza-Morita-Baylis-Hillman reaction of a broad range of N-diphenylphosphinoyl imines. Products from aryl, heteroaryl, and alkenyl imines were obtained in 67-99% yield and 81-95% ee. It is noteworthy that isomerizable alkyl imines could be employed as well, giving products in 78-89% yield and 94-98% ee. Initial rate kinetic studies as well as kinetic isotope effect experiments using α-deuterio-methyl acrylate support the importance of both the nucleophilicity of La-enolate and the Brønsted basicity of a La-catalyst for promoting the reaction. © 2010 American Chemical Society.

DOI： 10.1021/ja103294a

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記述言語：英語   掲載種別：研究論文（学術雑誌）

(Chemical Equation Presented) Construction of contiguous tetrasubstituted chiral carbon stereocenters via direct catalytic asymmetric aldol reaction of α-substituted α-isothiocyanato esters with unactivated simple ketones is described. A Bu2Mg/Schiff base catalyst promoted the aldol addition/cyclization sequence at room temperature, giving protected α-amino-β-hydroxy esters with contiguous tetrasubstituted chiral carbon stereocenters in 99 to 68% yield, 98:2 to 74:26 dr, and 98 to 82% ee. © 2009 American Chemical Society.

DOI： 10.1021/ja908571w

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Full details of the kinetic resolution of tertiary nitroaldols derived from simple ketones are described. Mixed BINOL/biphenol La-Li heterobimetallic complexes gave the best selectivity in retro-nitroaldol reactions of racemic tertiary nitroaldols. Using a 2:1 mixture of La-Li3-(binaphthoxide 1a)3 complex (LLB) and La-Li3-(biphenoxide 1e)3 complex, chiral tertiary nitroaldols were obtained in 80-97% ee and 30-47% recovery yield. Transformations of products were also investigated. © 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2009.02.031

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

(Chemical Equation Presented) Dynamic Duo: A Lewis basic bidentate phosphine oxide was effective for activating and modulating the properties of Brønsted basic lanthanum aryl oxides. The Lewis base 1/lanthanum aryl oxide system was suitable for anti-selective Mannich-type reactions of trichloromethyl ketones (see scheme), affording unique building blocks for azetidine-2-carboxylic acids as well as β-amino acids. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

DOI： 10.1002/anie.200803682

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記述言語：英語   掲載種別：研究論文（学術雑誌）

(Chemical Equation Presented) Not so Mannich now: A heterobimetallic La/Li/pybox complex was key in direct catalytic asymmetric Mannich-type reactions, using α-keto anilides as synthetic homoenolate equivalents to afford γ-amino amide products in up to > 99% yield, 95% ee, and >97:3 syn-selectivity. Stereoselective reduction of the α-keto moiety afforded the β-alkyl-γ-amino-α-hydroxy amide with three contiguous stereocenters (PG=protecting group). © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

DOI： 10.1002/anie.200801564

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Catalytic asymmetric direct Mannich-type reactions of α-substituted nitroacetates using a new bench-stable homodinuclear Ni2-Schiff base 1b complex are described. The Ni2-1b complex gave Mannich products, precursors for anti-α,β-diamino acids with an α-tetrasubstituted carbon stereocenter, in >99-91% ee. The Ni2-1b complex was also applicable to direct Mannich-type reactions of malonates and β-keto ester, giving products in high stereoselectivity (up to 99% ee, dr >97:3). Preliminary mechanistic studies suggested that the dinuclear Ni metal centers had key roles to achieve good reactivity and high stereoselectivity. Copyright © 2008 American Chemical Society.

DOI： 10.1021/ja710398q

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記述言語：英語   掲載種別：研究論文（学術雑誌）

DOI： 10.15227/orgsyn.085.0001

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Direct catalytic asymmetric Mannich-type reaction of a trichloromethyl ketone as a propionate equivalent donor is described. A new lanthanum aryloxide-iPr-pybox + lithium aryloxide combined catalyst was the most effective, promoting the reaction of N-2-thiophenesulfonyl imines with the trichloromethyl ketone. syn-Mannich adducts were obtained from various aryl, heteroaryl, alkenyl, and alkyl imines in > 99-72% yield, syn/anti of > 30:1-8:1, and 98-92% ee (from a propionate equivalent donor) using 2.5-10 mol % catalyst. The Mannich adduct was converted not only into ester but also into useful building blocks. Copyright © 2007 American Chemical Society.

DOI： 10.1021/ja073285p

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記述言語：英語   掲載種別：研究論文（学術雑誌）

The full details of the asymmetric epoxidation of α,β- unsaturated esters catalyzed by yttrium complexes with biaryldiol ligands are described. An yttrium-biphenyldiol catalyst, generated from Y(OiPr) 3-biphenyldiol ligand-triphenylarsine oxide (1:1:1), is suitable for the epoxidation of various α,β-unsaturated esters. With this catalyst, β-aryl α,β-unsaturated esters gave high enantioselectivities and good yields (≤99% ee). The reactivity of this catalyst is good, and the catalyst loading could be decreased to as little as 0.5-2 mol % (the turnover number was up to 116), while high enantiomeric excesses were maintained. For β-alkyl α,β-unsaturated esters, an yttrium-binol catalyst, generated from Y-(OiPr)3-binol ligand-triphenylphosphine oxide (1:1:2), gave the best enantioselectivities (≤97% ee). The utility of the epoxidation reaction was demonstrated in an efficient synthesis of (-)-ragaglitazar, a potential antidiabetes agent. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

DOI： 10.1002/asia.200600309

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Catalytic asymmetric Michael reactions of a malonate to acyclic α,β-unsaturated N-acylpyrroles as ester equivalent acceptors are described. A La(O-iPr)3/(S,S)-linked-BINOL complex, which is suitable for Michael addition to cyclic enones, is not suitable for acyclic α,β-unsaturated N-acylpyrroles. A new (S,S)-Ph-linked-BINOL chiral ligand was developed to improve enantioselectivity, and a La(O-iPr)3/(S,S)-Ph-linked-BINOL complex with the addition of HFIP afforded Michael adducts in good yield and enantioselectivity (up to 96% ee). © 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2007.02.112

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Catalytic asymmetric epoxidation of α-methyl α,β- unsaturated carboxylic acid derivatives was achieved using anilide as a template. The Pr(Oi-Pr)3-6,6́-Ph-BINOL complex (10 mol%) with a Ph3P(O) (30 mol%) additive promoted the epoxidation of anilides in up to 99% yield and 88% ee. For α-methyl-β-Ph α,β- unsaturated anilide, the Gd(Oi-Pr)3-6,6′-I-BINOL complex (10 mol%) with Ar3P(O) (30 mol%, Ar = 4-methoxyphenyl) was suitable, giving epoxide in 87% yield and 78% ee. © Georg Thieme Verlag Stuttgart.

DOI： 10.1055/s-2006-956491

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記述言語：英語   掲載種別：研究論文（学術雑誌）

A kinetic resolution of tertiary nitroaldols derived from simple ketones is described. Mixed BINOL/biphenol La-Li heterobimetallic complexes gave the best selectivity in retro-nitroaldol reactions of racemic tertiary nitroaldols. By using a mixture of La-Li3-(1a)3 complex (LLB 2a) and La-Li3-(1b)3 (LLB* 2b) complex in a ratio of 2/1, chiral tertiary nitroaldols were obtained in 80-97% ee and 30-47% recovery yield. Copyright © 2006 American Chemical Society.

DOI： 10.1021/ja064858l

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Chemical transformers! Catalytic nucleophilic activation of trichloromethyl ketones allows applications in intermolecular carbon-carbon bond-forming reactions. Mannich adducts such as azetidines can be obtained from the primary products in high yield and syn selectivity. PG = protecting group. (Chemical Equation Presented) © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

DOI： 10.1002/anie.200600227

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記述言語：英語   掲載種別：研究論文（学術雑誌）

(Chemical Equation Presented) An achiral unit is shown to be better than a chiral unit in promoting an asymmetric reaction. Non-C2-symmetric linked-binols 1 with one chiral 1,1′-bi-2-naphthol unit and one flexible achiral unit are employed as ligands in direct catalytic asymmetric Mannich-type reactions (see scheme; TON = turnover number). With as little as 0.01 mol% of ligand 1 a and 0.04 mol% of Et2Zn, the reaction proceeded smoothly to give the product in 98% ee. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA.

DOI： 10.1002/anie.200500425

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Full details of a direct catalytic asymmetric Mannich-type reaction of a hydroxyketone using a Et2Zn/(S,S)-linked-BINOL complex are described. By choosing the proper protective groups on imine nitrogen, either anti- or syn-β-amino alcohol was obtained in good diastereomeric ratio, yield, and excellent enantiomeric excess using the same zinc catalysis. N-Diphenylphosphinoyl (Dpp) imine 3 gave anti-β-amino alcohols in anti/syn = up to >98/2, up to >99% yield, and up to >99.5% ee, while Boc-imine 4 gave syn-β-amino alcohols in anti/syn = up to 5/95, up to >99% yield, and up to >99.5% ee. The high catalyst turnover number (TON) is also noteworthy. Catalyst loading was successfully reduced to 0.02 mol % (TON = up to 4920) for the anti-selective reaction and 0.05 mol % (TON = up to 1760) for the syn-selective reaction. The Et2Zn/(S,S)-linked-BINOL complex exhibited far better TON than in previous reports of catalytic asymmetric Mannich-type reactions. Mechanistic studies to clarify the reason for the high catalyst efficiency as well as transformations of Mannich adducts are also described.

DOI： 10.1021/ja0482435

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本年度の研究目的は、前年度までに達成された直接的触媒的不斉反応を基盤として、タキソールよりも強力な抗ガン活性を有する天然物(+)-Discodermolideの触媒的不斉全合成に取り組むことであった。しかしながら、本合成に必要なアルドール型の反応の開発には困難を極めた。そこで、本研究当初の研究目的であったトリクロロメチルケトンをエステル等価求核剤とする直接的触媒的不斉反応の更なる展開について検討を行ったところ、ルイス塩基の構造をビスフォスフィンオキシドへと変化させることにより、これまでとは逆の高アンチ選択的な直接的触媒的マンニッヒ型反応が進行することが明らかとなった。また、本反応系はアリールオキシド部位の構造を変化させることにより、エナンチオ選択的反応へと展開可能であった。さらに、本研究の過程において、Pyboxやビスフォスフィンオキシドといったルイス塩基が存在しないと反応が進行しないことが明らかとなり、この知見をもとにルイス塩基によるブレンステッド塩基の活性化というこれまでにない新たな概念を確立することができた。また、得られたマンニッヒ体は他の方法では合成困難な多置換アゼチジンカルボン酸誘導体へと変換可能であることも見いだした。一方、本反応の開発過程でフェノール類のイミンへのオルト位選択的直接的触媒的不斉付加反応が進行することを新たに見いだした。本反応は従来等量の金属試薬が必要であったものが触媒量の希土類触媒により進行している点で興味深い。現在本反応の条件最適化、基質一般性などについて検討をおこなっており。結果がまとまり次第速やかに一流雑誌に発表予定である。