秋山 隆彦

Described herein is the first example of an aliphatic, nonbenzylic hydride shift/cyclization sequence that contains two types of novel sp(3)-C-H functionalization: (1) construction of a tetraline skeleton via [1,5]-hydride shift/cyclization and (2) [1,6]-hydride shift/cyclization to form a five-membered ring (indane derivatives).

Amines to an end: Highly optically active α-CF3- functionalized amines can be obtained using metal-free reaction conditions. The method involves the transfer hydrogenation of CF3-substituted ketimines catalyzed by 1 and reductive amination of CF3-substituted ketones. The synthetic utility of this method was demonstrated by the synthesis of a CF3 analogue of NPS R-568. PMP=para-methoxyphenyl. © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A CF3 group attached to an alkene functionality was activated by a zero-valent niobium catalyst to generate niobium alkenylcarbenoid species. The niobium carbenoid species then underwent insertion to an internal aromatic C-H sigma bond to give indene derivatives in good yields. Isomerization in terms of the alkene geometry was also observed.

Benzothiazoline was employed as an efficient and versatile reducing agent for the chiral phosphoric acid-catalyzed transfer hydrogenation of α-imino esters. The corresponding α-amino esters were furnished with excellent enantioselectivities. Novel and readily removable benzothiazolines bearinga hydroxy group were also investigated. © 2010 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim.

An expeditious construction of a benzopyran skeleton via Lewis acid-catalyzed C-H functionalization was achieved. In this process, a [1,5] hydride shift and 6-endo cyclization successively occurred to give benzopyrans. The presence of substituents ortho to the alkoxy group significantly enhanced the reactivity, affording the desired compounds in excellent chemical yields with short reaction times.

Chiral phosphoric acid catalyzed Friedel-Crafts alkylation of indoles with 3, 3, 3-trifluoropyruvate gave the corresponding adducts in excellent yields with high enantioselectivities. Electron-deficient indoles, in particular, exhibited excellent enantioselectivities. (Chemical equation presented). © 2010 Wiley-VCH Verlag GmbH&Co. KGaA.

Phosphoroselenoyl chlorides were prepared by reacting four types of substituted 1,1'-bi-2-naphthols, PCl3, and elemental selenium in the presence of Et3N. The chlorides were converted to the corresponding acids via acid ammonium salts with high efficiency. The spectroscopic properties of these derivatives were used to elucidate the structures of the acids. Finally, the acids were applied to the hydrogenation reaction of imines using Hantzsch ester as a hydrogen donor.

A variety of indoles underwent enantioselective Friedel-Crafts alkylation with α,β-unsaturated acyl phosphonates in the presence of 10 mol% chiral BINOL-based phosphoric acid and subsequent treatment with methanol and DBU to give methyl 3-(indol-3-yl)propanoates in good yields and with high enantioselectivities. © 2010 The Royal Society of Chemistry.

The asymmetric Friedel-Crafts alkylation reaction of indoles with α,β-unsaturated ketones catalyzed by chiral phosphoric acid is reported. A wide range of indoles and 4,7-dihydroindoles were allowed to react with α,β-unsaturated ketones to give the corresponding 1,4-adducts in good to high chemical yields and with excellent enantioselectivities. © 2010 The Royal Society of Chemistry.

The Brønsted acid-catalyzed Nazarov cyclization of pyrrole derivatives was developed. Microwave irradiation accelerated the Nazarov cyclization significantly at 40 °C to give cyclopenta[b]pyrrole derivatives in excellent yields with high trans selectivity. © 2009 Elsevier Ltd. All rights reserved.

A novel chiral phosphoric acid bearing a biphenol backbone was synthesized and its catalytic activity was investigated in the enantioselective Mannich-type reaction of ketene silyl acetals with aldimines.

Aza-Darzens reaction of ethyl diazoacetate with aldimines, derived from phenyl glyoxal, furnished cis-aziridine carboxylates with excellent enantioselectivities by means of a chiral phosphoric acid.

The enantioselective hydrophosphonylation reaction of diisopropyl phosphite with aldimine furnished α-amino phosphonates with high enantioselectivities by means of a chiral phosphoric acid. DFT calculation of the effect of 3,3′-substituents of the phosphoric acid revealed the reason for the high enantioselectivities. © 2009 Elsevier Ltd. All rights reserved.

A facile construction of a heteropolycyclic framework is developed by exploiting the dual functionalization of allene. On treatment of phenethyl alcohol or amine bearing a terminal allene with the Brønsted acid, two consecutive reactions to allene, nucleophilic addition of heteroatom and the Friedel-Crafts reaction, occurred to give 2-oxa-or azabicyclo[2.2.2]octane skeleton. Copyright © 2009 The Chemical Society of Japan.

A simple method for the synthesis of quinazolines was developed by exploiting the "tert-amino effect." A catalytic amount of Br0nsted acid (TsOH·H 2O) worked as an effective activator for the concise construction of a quinazoline framework from o-formylaniline and amine. Copyright © 2009 The Chemical Society of Japan.

It was found that low-valent niobium species, which is generated from niobium(V) chloride and lithium aluminum hydride, in situ, is an efficient catalyst for activation of carbon-fluorine bonds. The low-valent niobium species catalyzed 1) hydrodefluorination of fluorobenzenes and alpha,alpha,alpha-trifluorotoluenes, and 2) intramolecular C-C coupling reactions of o-aryl-, o-alkenyl-, and o-alkyl-amino-alpha,alpha,alpha-trifluorotoluenes. In the latter reactions, fluorenes, indenes, and N-fused indoles were synthesized catalytically in good yields. Nb(0) is supposed to be an active species. Deuterium labeling experiments suggest that niobium fluorocarbenoid intermediates are generated from alpha,alpha,alpha-trifluorotoluenes in the latter C-C coupling reactions.

Let s resolve our differences: Implementation of an enantioselective Michael addition followed by an intramolecular aldol reaction catalyzed by two phosphoric acids has enabled the synthesis of cyclohexenone derivatives with excellent enantioselectivities. Prominent kinetic resolution was observed in the latter reaction. Ar=aromatic group, X=H, halogen, Y=H, Me, halogen. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Easy does it: A wide range of N-fused indole skeletons, which are core structures of many biologically potent molecules, are successfully furnished by a niobiumcatalyzed C(sp3)-H insertion reaction (see picture). The precursors are readily prepared by a palladium-catalyzed amination reaction of bromotrifluorotoluenes with cyclic amines. © 2009 Wiley-VCH Verlag.

Chiral effectiveness: The title transformation is applicable to a wide variety of substrates to give chiral cyclohexenones in high yields and with excellent enantioselecti vity (see scheme). To clarity the origin of the enantioselectivity ONIOM calculations were carried out © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

On treatment of allylphenylsilanes with t-BuOK and 18-crown-6 in DMSO, isomerization of the olefinic double bond and subsequent substitution of the phenyl group with a hydroxy group took place smoothly to afford alkenylsilanol derivatives in good yields. The reaction mechanism was investigated using O-18-labeled sulfoxide. We found that a (methylsulfinyl)methyl anion generated from DMSO participated in this reaction.

Mannich-type reactions of ketene silyl acetals with aldimines proceeded smoothly under the influence of 10 mol% of a cyclic chiral phosphate derivative derived from (R)-BINOL as a chiral Brønsted acid catalyst to furnish β-amino esters with excellent enantioselectivities. © Georg Thieme Verlag Stuttgart.

2-Trimethylsiloxyfuran underwent a vinylogous Mannich-type reaction with aldimines under the action of a new chiral phosphoric acid, bearing iodine on the 6,6'-positions of the binaphthyl group, as a chiral Bronsted acid to give gamma-butenolide derivatives bearing an amino functionality with high diastereo- and enantioselectivity.

It was found that zero-valent niobium is an efficient catalyst for the intramolecular C-C coupling reactions of o-aryl and o-alkenyl alpha,alpha,alpha-trifluorotoluene derivatives. The superstrong C-F bonds of CF3 groups and neighboring C(sp(2))-H bonds were doubly activated, and fluorenes and indenes were obtained in good yields. The niobium fluorocarbenoid species is proposed to be the key intermediate.

(Chemical Equation Presented) Crafty catalysts: Friedel-Crafts alkylation of indoles with nitroalkenes proceeded in the presence of phosphoric acid 1 and 3 Å molecular sieves to give Friedel-Crafts adducts with excellent enantioselectivities (see scheme). © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

We discussed Brønsted-acid-catalyzed reactions starting from achiral reactions and ending with catalyzed enantioselective reactions. Spectacular advancement has been made in the area of "stronger Brønsted-acid catalysis". The scope of the substrates is expanding at an unprecedented pace, and there is no doubt that more and more useful synthetic reactions will be developed in the near future. Mechanistic studies of chiral Brønsted-acid catalysis are required to expand the scope and develop even more efficient and novel types of chiral Brønsted-acid catalysis. Although chiral Brønsted-acid catalysis is, thus far, restricted to academic synthesis, industrial applications are expected from economic and environmental points of view. We believe that chiral Brønsted-acid catalysts and metal-oriented chiral catalysts will complement each other and make significant contributions to synthetic organic chemistry. © 2007 American Chemical Society.

Catalytic hydrodefluorinations of organofluorine compounds by low-valent niobium catalyst were developed. In the presence of niobium(V) chloride (typically, 5 mol%), fluorobenzenes, (alpha,alpha,alpha-trifluorotoluenes and (trifluoromethyl)pyridines were hydrodefluorinated with lithium aluminum hydride to give the corresponding benzenes, toluenes and methylpyridines in good yields, respectively. (C) 2007 Elsevier B.V. All rights reserved.

Mannich-type reaction of ketene silyl acetals with aldimines proceeded catalytically by means of a phosphoric acid diester, derived from (R)-BINOL, as a chiral Brønsted acid to afford β-amino esters with good diastereoselectivity in favor of the syn isomer and high enantioselectivity (up to 96% ee). The highest enantioselectivity was achieved by the phosphoric acid diester bearing 4-nitrophenyl groups on the 3,3′-positions of BINOL. The N-2-hydroxyphenyl group of aldimine was found to be essential for the present Mannich-type reaction. In combination with these experimental investigations, two possible monocoordination and dicoordination pathways were explored using density functional theory calculations (BHandHLYP/6-31G*). The present reaction proceeds via a dicoordination pathway through the zwitterionic and nine-membered cyclic transition state (TS) consisting of the aldimine and the phosphoric acid. The re-facial selectivity was also well-rationalized theoretically. The nine-membered cyclic structure and aromatic stacking interaction between the 4-nitrophenyl group and N-aryl group would fix the geometry of aldimine on the transition state, and the si-facial attacking TS is less favored by the steric hindrance of the 3,3′-aryl substituents. © 2007 American Chemical Society.

Mannich-type reaction of ketene silyl acetals with aldimines proceeded catalytically by means of a phosphoric acid diester, derived from (R)-BINOL, as a chiral Brønsted acid to afford β-amino esters with good diastereoselectivity in favor of the syn isomer and high enantioselectivity (up to 96% ee). The highest enantioselectivity was achieved by the phosphoric acid diester bearing 4-nitrophenyl groups on the 3,3′-positions of BINOL. The N-2-hydroxyphenyl group of aldimine was found to be essential for the present Mannich-type reaction. In combination with these experimental investigations, two possible monocoordination and dicoordination pathways were explored using density functional theory calculations (BHandHLYP/6-31G*). The present reaction proceeds via a dicoordination pathway through the zwitterionic and nine-membered cyclic transition state (TS) consisting of the aldimine and the phosphoric acid. The re-facial selectivity was also well-rationalized theoretically. The nine-membered cyclic structure and aromatic stacking interaction between the 4-nitrophenyl group and N-aryl group would fix the geometry of aldimine on the transition state, and the si-facial attacking TS is less favored by the steric hindrance of the 3,3′-aryl substituents. © 2007 American Chemical Society.

Allylsilane bearing malonate moiety underwent intramolecular carbocyclization reaction by means of AlCl3-nBu(3)N to give silyl-substituted cyclopentanes in good yields.

Equation presented In the presence of 5 mol % of niobium(V) chloride, α,α,α-trifluorotoluene derivatives were reduced with lithium aluminum hydride to give toluene derivatives in good yields. Stepwise, partial reduction of bis(trifluoromethyl)benzene derivative was also demonstrated. © 2007 American Chemical Society.

CF3 group of o-alkenyl-α,α,α-trifluorotoluenes underwent intramolecular coupling reaction with the alkene C-H bond under NbCl5/LiAlH4 system. Substituted indenes were obtained in good yields. Copyright © 2007 The Chemical Society of Japan.

Synthetic utility of the Fischer-type carbene complexes of chromium for the preparation of nitrogen-containing compounds is demonstrated. Alkoxy carbene complexes reacted with imines to give (optically active) 3-pyrrolines and beta-methoxy allylic amine derivatives in good yields. The amino carbene complexes reacted with alpha,beta-unsaturated aldehydes to give substituted pyrroles in good yields. (c) 2007 The Japan Chemical journal Forum and Wiley Periodicals, Inc.

The effect of sodium dodecyl sulfate (SDS) loading in fluoroboric acid catalyzed Mannich-type reactions of ketene silyl acetals with aldimines was studied. The reaction proceeded smoothly in the presence of 1 mol% of SDS. Formation of small particles was observed by transmission electron microscopy.

An enantioselective [3+2]-type cycloaddition of allenylstannane and α-imino ester was developed. Synthetic utility of the 4-stannyldehydroproline ester intermediate was demonstrated: iodine oxidation and Stille coupling reaction of the intermediate afforded optically active 4-iodo- and 4-aryldehydroproline esters in good yields and in high ees, respectively. © 2006 Elsevier Ltd. All rights reserved.

Chiral aromatic poly(ether ketone)s have been synthesized from 3,3′-diaryl-(R)-2,2′-dimethoxy-l,1′-binaphthyls and aromatic diols via nucleophilic aromatic substitution polymerization. Introduction of phosphoric ester units to the resulting poly(ether ketone)s has achieved through two-step polymer reactions. The novel polymeric chiral reagents were applied for asymmetric Mannich-type reaction.

Inverse electron-demand aza Diels-Alder reaction of aldimine with enol ethers proceeded under the influence of a phosphoric acid diester, derived from (R)-BINOL, to give tetrahydroquinoline derivatives with excellent enantioselectivity. Copyright © 2006 American Chemical Society.

Hydrogen bond catalysis and Bronsted acid catalysis are rapidly growing areas in organocatalysis. A number of chiral acid catalysts has been developed recently. Recent progress in the chiral Bronsted acid catalysis has been reviewed with a focus being placed on thiourea, TADDOL. and phosphoric acids.

By the treatment of 0.3 molar amount of NbCl5 and LiAlH4, o-arylated α,α,α-trifluorotoluenes afforded fluorene derivatives in good yields. C-F bonds of the CF3 group and the neighboring ortho C-H bond were doubly activated to give the coupling products. Copyright © 2006 American Chemical Society.

(Chemical Equation Presented) Brønsted, Brassard, Diels, and Alder: Aldimines 1 undergo aza-Diels-Alder reactions with Brassard's diene 2 in the presence of a chiral cyclic phosphate pyridinium salt 4 as a chiral Brønsted acid to give α,β-unsaturated δ-lactams 3 with excellent enantioselectivity. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Danishefsky's diene and aldimine underwent aza Diels-Alder reaction under the influence of chiral phosphoric;acid derived from (R)-BINOL as a chiral Bronsted acid to afford piperidinone derivatives in good to high enantioselectivity. Addition of CH,CO,H improved both reactivity and enantioselectivity.

Danishefsky's diene and aldimine underwent aza Diels-Alder reaction under the influence of chiral phosphoric;acid derived from (R)-BINOL as a chiral Bronsted acid to afford piperidinone derivatives in good to high enantioselectivity. Addition of CH,CO,H improved both reactivity and enantioselectivity.

Lewis acid mediated [3+2] cycloaddition reaction of chiral allylsilane, bearing a stereogenic center on the silyl substituents, with α-keto ester gave silyl-substituted tetrahydrofurans with good to high stereoselectivity. © 2006 The Japan Institute of Heterocyclic Chemistry All rights reserved.

Danishefsky's diene and aldimine underwent aza Diels-Alder reaction under the influence of chiral phosphoric acid derived from (A)-BINOL as a chiral Brønsted acid to afford piperidinone derivatives in good to high enantioselectivity. Addition of CH3CO2H improved both reactivity and enantioselectivity. © Georg Thieme Verlag Stuttgart.