Takahiko Akiyama

Described herein is a chiral magnesium bisphosphate-catalyzed asymmetric double C(sp3)-H bond functionalization triggered by a sequential hydride shift/cyclization process. This reaction consists of stereoselective domino C(sp3)-H bond functionalization: (1) a highly enantio- and diastereoselective C(sp3)-H bond functionalization by chiral magnesium bisphosphate (first [1,5]-hydride shift), and (2) a highly diastereoselective C(sp3)-H bond functionalization by an achiral catalyst (Yb(OTf)3, second [1,5]-hydride shift).

Copyright © 2018, Georg Thieme Verlag. All rights reserved. An enantioselective transfer hydrogenation reaction of alkynyl ketimine bearing a trifluoromethyl group was accomplished. Chemoselective reduction of ketimine was achieved by the combined use of chiral phosphoric acid and benzothiazoline to give α-trifluoromethyl propargylamine in good to high yields and with excellent enantioselectivity.

The Tishchenko reaction is one of the useful methods for ester synthesis. Intra- and intermolecular Tishchenko reactions using metallic zinc are described. A practical Tishchenko reaction using metallic zinc was applied to various benzaldehydes to give products in good to excellent yields (up to 95%). A sequential reaction with Ullmann coupling afforded lactones in high yields from 2-bromobenzaldehyde derivatives.

We report herein a highly efficient kinetic resolution of PHANOL by chiral phosphoric acid catalyzed asymmetric acylation. PHANOL enantiomers were well differentiated by the chiral environment of chiral phosphoric acid, and both the corresponding monoester and PHANOL were obtained with excellent enantioselectivities (98% ee and 92% ee, respectively). Detailed examination of the substrates suggests that the presence of two hydroxy groups in PHANOL was critical for both reactivity and enantioselectivity.

Asymmetric synthesis of tetrahydrobenzodiazepines was achieved by transfer hydrogenation of dihydrobenzodiazepines with benzothiazoline having a hydrogenbonding donor substituent by means of a newly synthesized chiral phosphoric acid. This method was applicable to various racemic dihydrobenzodiazepines to give the corresponding products in good yields with excellent diastereoselectivities and enantioselectivities taking advantage of the dynamic kinetic resolution. Furthermore, the effect of bulky substituent at 3,3'-position on the catalyst and hydrogen-bonding donor substituent on benzothiazoline was fully elucidated by the theoretical study.

Takahiko Akiyama was born in Kurashiki (Japan) in 1958 and did his undergraduate and graduate studies at The University of Tokyo. After working at Shionogi Research Laboratories, Shionogi & Co., Ltd., as a research chemist, he was appointed as an assistant professor at Ehime University in 1988. He was a visiting scholar at Stanford University from 1992 to 1993. He joined Gakushuin University as an associate professor in 1994 and was promoted to full professor in 1997. He is a recipient of the Chemical Society of Japan Award for Creative Work (2009), Daiichi-Sankyo Award for Medicinal Organic Chemistry (2009), Nagoya Silver Medal (2012), Arthur C. Cope Scholar Award (2016), and Humboldt Research Award (2016). His current research interests include the development of new and useful synthetic methodologies based on the design of novel chiral BrOnsted acid catalysts as well as the utilization of transition-metal catalysts. Abstract In 2004, BINOL-derived chiral phosphoric acids have been recognized as versatile BrOnsted acid catalysts and a range of different catalytic reactions have since been developed. As illustrated in the following cluster, the field is still growing strongly and new catalyst motifs and reactions are currently being developed by groups all over the world. In this preface, a closer look at the synthetic utility of chiral phosphoric acids and their derivatives before 2004 is taken.

A strategy for oxidative kinetic resolution of racemic indolines was developed, employing salicylaldehyde derivative as the pre-resolving reagent and chiral phosphoric acid as the catalyst. The iminium intermediate, formed by the condensation reaction of an enantiomer of indoline with salicylaldehyde derivative, was hydrogenated by the same enantiomer of indoline to afford another enantiomer of indoline by a self-redox mechanism. The oxidative kinetic resolution of 2-aryl-substituted indolines proceeded to give enantiomers in good yields with excellent enantioselectivities.

The titanium tetrachloride-catalyzed hydrodefluorination reaction of trifluorotoluene derivatives was developed using triethylsilane as the reducing agent. The reaction produced various toluene derivatives with high chemoselectivities by means of readily accessible reagents. This hydrodefluorination process was extended to the intramolecular Friedel-Crafts benzylation reaction, furnishing polycyclic aromatics of various ring sizes in good yields.

Described herein are differences in behavior between a Hantzsch ester and a benzothiazoline as hydrogen donors in the chiral phosphoric acid catalyzed asymmetric reductive amination of ketones with p-anisidine. The asymmetric reductive amination of ketones with a Hantzsch ester as a hydrogen donor provided the corresponding chiral amines exclusively, regardless of the structures of the ketones, whereas a similar transformation with a benzothiazoline provided chiral amines and p-methoxyphenyl-protected primary amines in variable yields, depending on the structures of both the ketones and benzothiazolines. Because a benzothiazoline has an N,S-acetal moiety that is vulnerable to p-anisidine, the primary amine can be formed through transimination of the benzothiazoline with p-anisidine followed by reduction of the resulting aldimine with remaining benzothiazoline.

Described herein are differences in behavior between a Hantzsch ester and a benzothiazoline as hydrogen donors in the chiral phosphoric acid catalyzed asymmetric reductive amination of ketones with p-anisidine. The asymmetric reductive amination of ketones with a Hantzsch ester as a hydrogen donor provided the corresponding chiral amines exclusively, regardless of the structures of the ketones, whereas a similar transformation with a benzothiazoline provided chiral amines and p-methoxyphenyl-protected primary amines in variable yields, depending on the structures of both the ketones and benzothiazolines. Because a benzothiazoline has an N,S-acetal moiety that is vulnerable to p-anisidine, the primary amine can be formed through transimination of the benzothiazoline with p-anisidine followed by reduction of the resulting aldimine with remaining benzothiazoline.

BrØnsted acids have been employed primarily as catalysts for the formation and cleavage of C-O bonds, such as hydrolysis and formation of esters and acetals. BrØnsted acids have emerged as efficient catalysts for a range of carbon-carbon bond formation reactions. In addition to common BrØnsted acids such as HCl, H<inf>2</inf>SO<inf>4</inf>, and acetic acid, trifluoromethanesulfonic acid (TfOH) was developed as a super strong BrØnsted acid, which is 100 times stronger than sulfuric acid. In addition to the chiral phosphoric acids, chiral dicarboxylic acids, chiral disulfonic acids, and chiral sulfonimides have emerged as stronger BrØnsted acids, and their synthetic utility has gained wide acceptance.

B(C6F5)(3)-catalyzed hydrodesulfurization of carbonsulfur bonds was achieved using triethylsilane as the reducing agent. The corresponding products were obtained in good yields under mild reaction conditions. This protocol could be applied to the reduction of sulfides, including benzyl and alkyl sulfides and dithianes, with high chemoselectivities.

Chiral 2-substituted 2,3-dihydro-4-quinolones were synthesized based on the chiral phosphoric acid catalyzed intramolecular aza-Michael addition reaction using N-unprotected 2-aminophenyl vinyl ketones as substrates in good yields with high enantioselectivities.

A concise route to 3-aryl-1-trifluoromethyltetrahydroisoquinolines by a benzylic [1,5]-hydride shift-mediated C-H bond functionalization was developed. The [1,5]-hydride shift of the benzylic C(sp(3))-H bond to the trifluoromethylketimine derived from para-anisidine occurred smoothly to produce cis-1-trifluoromethyl-3-aryltetrahydroisoquinolines in good to excellent chemical yields with good diastereoselectivities. In contrast, use of the N-H ketimine furnished N-unprotected tetrahydroisoquinolines in good yields in favor of the trans-isomer.

The asymmetric reduction of ketimines is an important method for the preparation of amines in optically pure form. Inspired by the biological system using NAD(P)H, Hantzsch ester has been extensively employed as a hydrogen donor in combination with chiral phosphoric acid for the transfer hydrogenation of ketimines to furnish amines with high to excellent enantioselectivities. We focused on 2-substituted benzothiazoline as a hydrogen donor in the phosphoric acid catalyzed transfer hydrogenation reaction of ketimines for the following reasons: (1) benzothiazoline is readily prepared just by mixing 2-aminobenzenethiol and aldehyde, (2) both reactivity (hydrogen donating ability) and enantioselectivity would be controlled by tuning the 2-substituent of benzothiazoline, and (3) benzothiazoline can be stored in a refrigerator under inert atmosphere without conceivable decomposition. Both the 2-position of benzothiazoline and the 3,3'-position of phosphoric acid are tunable in order to achieve excellent enantioselectivity. Benzothiazoline proved to be useful hydrogen donor in combination with chiral phosphoric acid for the transfer hydrogenation reaction of ketimine derivatives to afford the corresponding amines with high to excellent enantioselectivities by tuning the 2-substituent of benzothiazoline. Ketimines derived from acetophenone, propiophenone, a-keto ester, trifluoromethyl ketone, and difluoromethyl ketone derivatives proved to be suitable substrates. Benzothiazoline could be generated in situ starting from 2-aminobenzenethiol and aromatic aldehyde in the presence of ketimine and chiral phosphoric acid and successfully worked in the sequential transfer hydrogenation reaction. The reductive amination of dialkyl ketones also proceeded with high enantioselectivities. Use of 2-deuterated benzothiazoline led to the formation of a-deuterated amines with excellent enantioselectivities. The kinetic isotope effect (k(H)/k(C) = 3.8) was observed in the competitive reaction between H- and D-benzothiazoline, which explicitly implies that the cleavage of the CH (CD) bond is the rate-determining step in the transfer hydrogenation reaction. Benzothiazoline yielded products with higher enantioselectivity in the transfer hydrogenation reaction of ketimines, particularly ketimines derived from propiophenone derivatives, than Hantzsch ester. DFT study elucidated the mechanism, as well as the difference in selectivity, between benzothiazoline and Hantzsch ester. The chiral phosphoric acid activates ketimines and benzothiazoline by means of the Bronsted acidic site (proton) and the Bronsted basic site (phosphoryl oxygen), respectively, to accelerate the hydride transfer reaction.

A chiral Bronsted acid catalyzed dehydrogenative kinetic resolution of tetrahydroquinoline derivatives, which are representative of cyclic secondary amines, based on their hydrogen transfer to aromatic imines was efficiently achieved with high enantioselectivities. This hydrogen transfer of tetrahydroquinolines to imines was not driven by their aromatization to quinolines. This dehydrogenative kinetic resolution could be also applied to the asymmetric synthesis of various benzofused heterocycles containing secondary amine cores.

Described herein is a highly enantioselective synthesis of fused piperidine and pyrrolidine derivatives with all-carbon stereogenic centers. The enantioselective reductive amination from Cs-symmetric 1,3-dione derivatives proceeded in a highly stereoselective manner by taking advantage of the desymmetrization approach to afford fused heterocycles with contiguous stereogenic centers in good to excellent enantioselectivities (up to 98% ee).

The use of functionalised allylboronic esters in the catalytic enantio-selective allylboration of aldehydes is described for the first time. gamma-Silylallyl pinacolate derivatives give rise to alpha-silyl homoallylic alcohols in high yields, with complete diastereoselectivities and high enantio-selectivities, in most of the cases. The usefulness of such intermediates is showcased by their transformation into fluorinated allylic alcohols.

We report herein a highly enantioselective synthesis of multisubstituted biaryl chlorides/iodides by sequential halogenation reactions (desymmetrization/kinetic resolution sequence). The selectivity of biaryl chlorides/iodides obtained in the first asymmetric reaction (desymmetrization) could be enhanced by the kinetic resolution-type asymmetric bromination to afford the corresponding chiral biaryl chlorides/iodides in excellent selectivities (up to 99% ee).

The chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of various ketimines was achieved by the use of 2-aryl indoline as the hydrogen donor. Corresponding chiral amines were obtained in good chemical yields with excellent enantioselectivities.

Chiral phosphoric acid catalyzed transfer hydrogenation of ketimines derived from propiophenone derivatives and reductive amination of alkyl ethyl ketone derivatives were extensively examined in the presence of two representative hydrogen donors. The excellent enantioselective transfer hydrogenation was achieved by use of benzothiazoline as a hydrogen donor. The theoretical studies elucidated that the unsymmetrical structure of benzothiazoline plays an important role in high enantioselective hydrogenation.

The high-yield reduction of aromatic ketimines into amines by using a novel catalyst based on a metallacarborane structure, 8,8'-mu-phosphate[(1,2-dicarba-closo-undecaborane)-3,3'-cobalt(-1)(1',2'-dicarba-closo-undecaborane)] acid, is described.

Described herein are two novel types of double C(sp(3))-H bond functionalizations triggered by a sequential hydride shift/cyclization process: (1) construction of a bicyclo[3.2.2]nonane skeleton by a [1,6]- and [1,5]-hydride shift sequence and (2) sequential [1,4]- and [1,5]-hydride shift mediated construction of a linear tricyclic skeleton.

The Mannich reaction is a useful method for the preparation of β-amino carbonyl compounds of biological interest starting from aldehyde, amine, and carbonyl compounds. The classical Mannich reaction was limited to highly reactive aldehydes such as formaldehyde and acetaldehyde, a secondary amine. Development of the direct Mannich-type reaction expanded the scope of the Mannich reaction, and efficient method for the highly stereoselective Mannich-type reactions were extensively studied and reported. This chapter focuses on the enantioselective catalyzed version of the Mannich-type reactions, starting from the metal-catalyzed indirect and direct Mannich-type reactions. Vinylogous Mannich reactions are also included. Organocatalyzed Mannich-type reactions are compiled according to the catalysts employed: proline and derivatives, thiourea, cinchona alkaloid, Brønsted acid, and so on. © 2014 Elsevier Ltd. All rights reserved.

A highly enantioselective fluorination of beta-ketoesters catalyzed by chiral sodium phosphate is achieved. In this process, the simultaneous formation of sodium enolate and sodium phosphate under basic conditions is the key to achieving excellent selectivity. Indanone derivatives as well as benzofuranone derivatives could be employed in this reaction to afford the fluorinated adducts in good yields with good to excellent enantioselectivities.

Described herein is a [1,4]-hydride shift mediated expeditious synthesis of 1-aminoindane derivatives. A wide variety of substrates could be employed in this reaction to afford various indane derivatives in good to excellent chemical yields. Examination of the amine moiety revealed that the sterically hindered amine is the key to achieving both low catalyst loading and excellent chemical yields.

We describe herein a chiral phosphoric acid catalyzed Friedel-Crafts reaction of indoles with beta-alkoxycarbonyl-beta-disubstituted nitroalkenes. A wide variety of substrates participated in this reaction to afford indoles having all-carbon quaternary centers with excellent selectivities ( up to 97% ee). Further investigation suggested that the olefin geometry and the employment of NH-indole derivatives are responsible for both reactivity and selectivity.

A good mix: The title reaction of o-alkynylacetophenones with the Hantzsch ester in the presence of a chiral copper/phosphate catalyst proceeds in good yields with excellent enantioselectivities. The key intermediate for enantiocontrol is the ion pair of the carbonyl ylide with a chiral phosphate anion, and this process provides straight forward access to highly enantioriched chiral isochromenes. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hold the benzothiazoline: Highly enantioselective transfer hydrogenation of difluoromethyl ketimines with benzothiazolines catalyzed by a chiral phosphoric acid furnishes α-difluoromethylated amines in good yields and with excellent enantioselectivity, irrespective of the stereochemistry of the starting materials. PMP=p-methoxyphenyl. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

We describe herein the “1H NMR-assisted catalyst screening method,” which enables us to find the suitable catalyst easily and predict enantioselectivity with the same accuracy as the computational method. Based on this method, we constructed multisubstituted biaryls that occur frequently in many biologically active compounds, chiral ligands, and organocatalysts, with excellent enantioselectivities via chiral phosphoric acid-catalyzed asymmetric bromination. © 2013 The Royal Society of Chemistry.

The oxidative kinetic resolution of 2-substituted indoline derivatives was achieved by hydrogen transfer to imines by means of a chiral phosphoric acid catalyst. The oxidative kinetic resolution was applicable to racemic alkyl- or aryl-substituted indolines, and the remaining indolines were obtained in good yields with excellent enantioselectivities.

An efficient and practical protocol for the reduction of aldimines, ketimines, and alpha-imino esters in the presence of catalytic amount of molecular iodine with Hantzsch ester at ambient temperature afforded the corresponding amines in excellent yields. (C) 2013 Elsevier Ltd. All rights reserved.

Described herein is the enantioselective synthesis of multisubstituted biaryl derivatives by chiral phosphoric acid catalyzed asymmetric bromination. Two asymmetric reactions (desymmetrization and kinetic resolution) proceeded successively to afford chiral biaryls in excellent enantioselectivities (up to 99% ee). Both experimental and computational studies suggested that this excellent selectivity could be achieved via a highly organized hydrogen bond network among a substrate, a catalyst (chiral phosphoric acid), and a brominating reagent (N-bromophthalimide).

Chiral phosphoric acid derived from (R)-BINOL function efficiently as chiral Brønsted acid for a number of transformations which include Mannich-type reactions, cycloaddition reactions, transfer hydrogenation reactions, Friedel-Crafts alkylation reactions, and desymmetrization reactions. © 2012 Wiley-VCH Verlag GmbH &amp Co. KGaA.

In the presence of 2 mol% of TiCl4, α,α,α- trifluorotoluene derivatives were reduced with LiAlH4 to furnish toluene derivatives in high yields. Selective reduction of bis(trifluoromethyl) benzene derivative is effected. The difference of the reactivity between TiCl4 and NbCl5 is also discussed. © 2013 Elsevier B.V. All rights reserved.

A number of metal salt catalyzed enantioselective versions of Mannich and Mannich-type reactions were developed in the late 1990s. After emergence of organocatalysis in 2000, organocatalyzed versions of Mannich reactions have been extensively studied. In this review chapter, organocatalyzed enantioselective Mannich reactions and related reactions published from 2000 to mid-2010 are reviewed. The Mannich reactions are classified into three activation modes, namely, (1) activation of nucleophile by chiral amines by formation of enamine, (2) activation of nucleophile by chiral base thereby forming chiral enolate, (3) activation of imine by chiral Brønsted acid. © 2012 Elsevier Ltd. All rights reserved.

A remarkable kinetic resolution was achieved in a chiral phosphoric acid catalyzed intramolecular aldol reaction. Its combination with an enantioselective Michael reaction resulted in the formation of cyclohexenone derivatives with excellent enantioselectivities. DFT calculations on the intramolecular aldol reaction revealed the importance of the 3,3'-substituents of the phosphoric acid for the high enantioselectivity in the kinetic resolution process.

By use of 2-deuterated benzothiazoline as a deuterium donor in combination with a chiral phosphoric acid, the transfer deuteration of ketimine and alpha-iminoester took place smoothly to give alpha-deuterated amines in high yields with excellent enantioselectivities. The remarkable kinetic isotope effect suggests that carbon-deuterium bond cleavage is the rate-determining step.

An expeditious route to furnish an isoquinoline skeleton via hydride shift mediated C-H bond functionalization was developed. In this process, an unusual [1,5]-H shift without the assistance of the adjacent heteroatom took place to produce tetrahydroisoquinoline derivatives in good to excellent chemical yields. The formal synthesis of (+/-)-tetrahydropalmatine was achieved by exploiting this new transformation.

A benzothiazoline bearing 4-carboxyphenyl group at 2-position was developed as an efficient hydrogen donor for the transfer hydrogenation reaction. Introduction of the carboxyl group significantly facilitated the removal of the residual benzothiazoline and benzothiazole by washing with aqueous basic solution. The present approach provides a convenient and straightforward access to various amines with broad substrate scope and in good yields. (C) 2011 Elsevier Ltd. All rights reserved.

The chiral phosphoric acid-catalyzed enantioselective reductive amination of aliphatic ketones with aromatic amines was successfully achieved by the use of benzothiazoline as the hydrogen donor. Corresponding chiral aliphatic amines were obtained with excellent enantioselectivities.

The concise construction of 3-aryltetralin skeleton via hydride shift mediated C-H bond functionalization was achieved. In this process, the benzylic [1,5]-H shift occurred smoothly to furnish tetralin derivatives in good to excellent chemical yields. The electronic and steric properties of the aromatic ring adjacent to the C-H bond influenced significantly the reactivity of this transformation.

We synthesized chiral phosphoric acids bearing 3,3'-substituents starting from (R)-BINOL and demonstrated their catalytic activity as chiral Bronsted acid. Proper choice of the 3,3'-substituents of the phosphoric acid is critical to attain excellent enantioselectivity. We wish to describe in this article the background of development of the catalyst, design of the catalyst, and application of them to a range of asymmetric reactions: (1) nucleophilic addition to aldimines, (2) cycloaddition toward aldimines, (3) Friedel-Crafts alkylation of indoles with nitroalkene, alpha,beta-unsaturated ketone, and trifluoropyruvate, (4) kinetic resolution in the intramolecular aldol reaction, and (5) desymmetrization in the intramolecular aldol reaction. We also studied the role of the phosphoric acid and elucidated that phosphoryl oxygen played a critical role as a Lewis basic site.

Reductive amination of aldehyde and amine proceeded smoothly in the presence of benzothiazoline as efficient hydrogen source by means of 20 mol% trifluoroacetic acid to give the corresponding amines in excellent yields. Hydrogen-donor abilities of benzothiazoline, benzimidazoline, and benzoxazoline were compared.

Reductive amination of aldehyde and amine proceeded smoothly in the presence of benzothiazoline as efficient hydrogen source by means of 20 mol% trifluoroacetic acid to give the corresponding amines in excellent yields. Hydrogen-donor abilities of benzothiazoline, benzimidazoline, and benzoxazoline were compared.

A biphenol-based chiral phosphoric acid bearing a 9-anthryl group at each of the 3,3'-positions catalyzed the asymmetric Mannich-type reaction of N-Boc Imine with difluoroenol silyl ethers In the presence of MS3A In THF to afford beta-amino-alpha,alpha-difluoroketones In good yields and with excellent enantioselectivities. Optically pure 3,3-difluoroazetidin-2-one was readily synthesized from the Mannich-adduct.

Chiral phosphoric acid-catalyzed asymmetric C-H functionalization has been achieved. In this process, enantiotopic C(sp(3))-hydrogen is selectively activated by chiral phosphoric acid to afford tetrahydroquinoline derivatives with excellent enantioselectivities (up to 97% ee).