synthesis and applications of high-performance p-chiral

Review

Synthesis and applications of high-performanceP-chiral phosphine ligands

By Tsuneo IMAMOTO*1,†

(Edited by Ryoji NOYORI, M.J.A.)

Abstract: Metal-catalyzed asymmetric synthesis is one of the most important methods forthe economical and environmentally benign production of useful optically active compounds. Thesuccess of the asymmetric transformations is significantly dependent on the structure andelectronic properties of the chiral ligands coordinating to the center metals, and hence thedevelopment of highly efficient ligands, especially chiral phosphine ligands, has long been animportant research subject in this field. This review article describes the synthesis and applicationsof P-chiral phosphine ligands possessing chiral centers at the phosphorus atoms. Rationallydesigned P-chiral phosphine ligands are synthesized by the use of phosphine–boranes as theintermediates. Conformationally rigid and electron-rich P-chiral phosphine ligands exhibitexcellent enantioselectivity and high catalytic activity in various transition-metal-catalyzedasymmetric reactions. Recent mechanistic studies of rhodium-catalyzed asymmetric hydrogenationare also described.

Keywords: P-chiral phosphine ligand, phosphine–borane, catalytic asymmetric synthesis,asymmetric hydrogenation, enantioselection mechanism

1. Introduction

Catalytic asymmetric synthesis is one of themost efficient methods for the production of opticallyactive compounds used in pharmaceuticals, agro-chemicals, fragrances, and so on.1)–5) Among avail-able methodologies for asymmetric catalysis, tran-sition-metal-catalyzed reactions have been studiedfor more than six decades, and a variety of reactionsof this class have been developed. The enantioselec-tivities and catalytic activities of the reactions aregenerally largely affected by the chiral ligands aswell as the center metals.

Among various types of chiral ligands, phos-phine ligands play an outstanding role in asymmetriccatalysis owing to their intrinsic property of coordi-nating strongly to the transition metals and topromoting the catalytic reactions. A great number

of chiral phosphine ligands have been synthesizedand used in this class of asymmetric reactions.6)–20)

Chiral phosphine ligands are divided into twoclasses. One class includes backbone chirality ligandsthat possess their stereogenic centers on the linkingcarbon chain. Representative examples of this classare shown in Fig. 1. Most of the hitherto reportedchiral phosphine ligands belong to this class, andsome of them are used as benchmark ligands notonly for the synthesis of various chiral compoundsbut also for the development of new catalyticasymmetric reactions.

Another class is composed of P-chiral (P-chirogenic or P-stereogenic) phosphine ligands pos-sessing their stereogenic centers at the phosphorusatoms. Figure 2 shows the representative examplesof this class. Although P-chiral phosphine ligands aresmall in number compared with backbone chiralityligands, some of the ligands play a critical role in theearly stage of the study on Rh-catalyzed homoge-neous asymmetric hydrogenation.21)–23) In particular,the use of DIPAMP ligand, which was developedby Knowles and coworkers at Monsanto Company,provided high enantioselectivities of up to 96% in

*1 Graduate School of Science, Chiba University, Chiba,Japan.

† Correspondence should be addressed: T. Imamoto, De-partment of Chemistry, Graduate School of Science, Chiba Uni-versity, 1-33, Yayoicho, Inage-ku, Chiba 263-8522, Japan (e-mail:[email protected]).

Proc. Jpn. Acad., Ser. B 97 (2021) [Vol. 97,520

doi: 10.2183/pjab.97.026©2021 The Japan Academy

http://dx.doi.org/10.2183/pjab.97.026

1975, the highest at that time.24)–26) The same ligandwas successfully employed in the manufacture of (S)-3,4-dihydroxyphenylalanine (L-DOPA) that is usedto treat Parkinson’s disease.27),28) However, despitethose landmark achievements, P-chiral phosphineligands including DIPAMP have not been widelyused for more than 20 years. This is mainlyattributed to the synthetic difficulties in generatingoptically pure P-chiral phosphines. In addition, thefact that some phosphines bearing electron-with-

drawing groups are stereochemically unstable andgradually racemize via pyramidal inversion even atroom temperature may have discouraged researchers.Another reason is that many backbone chiralityphosphine ligands such as BINAP have beensynthesized and their superior catalytic performancehas been proven in various asymmetric syntheses.

On the other hand, in our studies of thesynthesis and reactions of phosphine–boranes, wefound that P-chiral phosphine ligands could besynthesized via the stereospecific removal of theBH3 group of chiral phosphine–boranes. This findinginspired us to study the design and synthesis of newP-chiral phosphine ligands and their applicationsin catalytic asymmetric synthesis. This review articlecontains our studies on phosphine–boranes and P-chiral phosphine ligands. It also mentions how wediscovered new research themes and developed them,taking on the many challenges that came with thework and overcoming the difficulties along the way.

2. Prologue to the study of P-chiralphosphine ligands

2.1. Use of cerium element in organic synthe-sis. After receiving my Ph.D. degree in physicalorganic chemistry in 1972, I went on to work at fouruniversities to pursue further studies in organicsynthesis. For 8 years, I worked as a postdoctoralfellow or an assistant professor, seeking tenure.Fortunately, in 1980, I was appointed assistantprofessor at Chiba University. I was 37, and thatappointment gave me an excellent opportunity tobegin my own research work. However, at thattime, my research group was quite small, and it wasalmost impossible to undertake a big project. Idecided to seek out new research subjects in thelargely unexplored areas. Perusing the periodic tableof elements in an effort to find elements that hadnot yet been utilized in organic synthesis, I arrived atthe conclusion that lanthanide elements were theperfect choice. Although Professors Kagan and Luchehad already reported their pioneering and outstand-ing investigations at that time,29)–32) I believed thatthis area offered the exciting possibility of discoveringnew and useful synthetic methods. Among 15lanthanides, I focused on cerium element becausecerium exists in high natural abundance, and itsmajor salts are commercially available at affordableprices.

After many attempts using metallic cerium orcerium(III) salts, we succeeded in preparing newreagents called “organocerium reagents” or

PAr2PAr2

BINAP (1980)

PPh2

PPh2O

O

H

HDIOP (1971)

Fe PPh2PPh2

NMe2

MeH

BPPFA (1974)

PPh2

PPh2

CHIRAPHOS(1977)

Fe PR'2PR2

Me

JosiPhos (1994)

HP P

R

RR

R

DuPhos (1991)

SEGPHOS (2001)

O

O

PAr2PAr2

SDP (2003)

PAr2PAr2

PPh2

PPh2

PHANEPHOS(1997)

O

O

Fig. 1. Representative examples of bisphosphine ligands withbackbone chirality. Figures in parentheses are the years whenthe ligands were published in journals.

PPPh

Ph

OMe

MeODIPAMP (1975)

BisP* (1998)

N

N P

P

Met-Bu

Me t-BuQuinoxP* (2005)

PP

H

Ht-Bu t-Bu

TangPhos (2002)

PPhMe

PPt-Bu Me

Me t-Bu

(1968)

PMeCy

CAMP (1972)

OMe

Fig. 2. Representative examples of P-chiral phosphine ligands.

Synthesis and applications of P-chiral phosphine ligandsNo. 9] 521

“cerium(III)-modified organometallic reagents”.These reagents are readily prepared by the reactionof organolithiums or Grignard reagents with anhy-drous cerium(III) chloride in tetrahydrofuran. Thecerium reagents undergo nucleophilic addition reac-tions with carbonyl groups more efficiently than theparent organometallic reagents. Thus, the reagentsreact with various carbonyl compounds to afford thecorresponding normal addition products in highyields, even though the substrates are susceptibleto so-called abnormal reactions, such as enolization,reduction, conjugate addition, condensation, andmetal–halogen exchange reaction (Scheme 1).33)–35)

Several reaction examples are shown in Scheme 2.This method, together with Knochel’s improvedmethod,36),37) is widely used in organic synthesis.

2.2. Working with phosphine–boranes. Theabove-mentioned cerium chloride methodology wasextended to a LiAlH4/CeCl3 system to examine

the enhanced or modified reducing ability of LiAlH4.Our initial experiments on the reduction of phosphineoxides and organic halides including fluorides dem-onstrated the powerful reducing ability of LiAlH4

under mild conditions.38) Notable is that variousphosphine oxides including sterically congested oneswere readily converted into the corresponding phos-phines in high yields. In contrast, the use of NaBH4

instead of LiAlH4 afforded only trace amounts of theproducts. Taking one step further, we conducted thereaction with a three-component reagent, LiAlH4–

NaBH4–CeCl3, to find that phosphine–boranes wereproduced in good to high yields (Scheme 3).39)

We were surprised to find that phosphine–borane compounds, including secondary ones havinga P–H bond, were virtually inert to air and hardlydecomposed even on contact with an acid or a base.Phosphine–boranes possess formal charges of D1 and!1 on the phosphorus and boron atoms, respectively,and are a kind of phosphorus ylide and boron atecomplex. I was fascinated by these structural featuresand decided to study phosphine–boranes from theperspective of organic synthesis. I emphasized thesignificance of this research to my collaboratorstudents by mentioning that two Nobel PrizeLaureates, G. Wittig and H.C. Brown, were involvedin our phosphine–borane research. The followingstudies were conducted in parallel with the synthesisand application of P-chiral phosphine ligands. Themain purpose of these studies was to create interest-

RLi + CeCl3 “RLi/CeCl3” R

OH

R2R1

R1COR2

RMgX + CeCl3 “RMgX/CeCl3” R

OH

R2R1

R1COR2

Scheme 1. Preparation of organocerium reagents and theirreactions with carbonyl compounds.

OMeMgBr/CeCl3

HO

95% (0%)

O

PhPhPhMgBr/CeCl3

PhPh

OHPh O

PhPh

Ph+

99% (90:10) (86% (6:94))

Ph CO2Me2 i-PrMgBr/CeCl3

Phi-Pr

HO i-Pr

97% (0%)88% (6%)

Li/CeCl3

O

Br

BrLi/CeCl3Ph

Br

BrOH

Ph

95% (trace)

OOH

n-Bu

I93% (trace)

n-BuLi/CeCl3

O

I

OH

THF, 0 °C

THF, 0 °C

THF, 0 °C

THF, –78 °C

THF, –78 °C

THF, –78 °C

Phi-Pr

0% (71%)

Ph

0% (19%)

O+ +

O

Ph

CO2Me

Scheme 2. Representative examples of the reactions of organocerium reagents with carbonyl compounds. Values in parentheses indicatethe yields obtained in the reactions without the use of cerium chloride.

T. IMAMOTO [Vol. 97,522

ing and fundamentally important chemical speciesand to find unprecedented reactions by utilizing thecharacteristic properties of phosphine–boranes.

2.2.1. Generation and reactions of tricoordinateboron dianions. Tricoordinate boron dianions havean isoelectronic relationship with tricoordinate car-banions, which are one of the most importantchemical species in organic chemistry. We wereinterested in whether or not the boron dianionsexhibit reactivities similar to the carbanions andintended to generate such chemical species by usingphosphine–boranes. After various trials, we suc-ceeded in the generation of the desired chemicalspecies possessing a formal !2 charge on the boronatom, and demonstrated their high nucleophilicityand strong basicity, which are similar to those ofcarbanions. Thus, tricyclohexylphosphine–monoio-doborane (1) was reacted with lithium 4,4B-di-tert-

butylbiphenylide (LDBB) to generate boron dianion2, which was allowed to react with various electro-philes to give the boron-functionalized phosphine–boranes (3) (Scheme 4).40) Similarly, the reduction oftri-tert-butylphosphine–monoiodoborane (4) withLDBB, followed by the reaction with electrophiles,furnished compounds 7. It is reasonable to considerthat the generated boron dianion 5 underwent apericyclic reaction at !78 °C and the resultingphosphide anion 6 was trapped by the electrophiles.This reaction was compared with the correspondingcarbanion species, tri-tert-butylphosphonium meth-ylide, which was reported to undergo the same typeof pericyclic reaction at a much higher temperature(20 °C).41) These results clearly indicate that thebasicity of the boron dianion is greater than that ofthe corresponding carbanion.

2.2.2. Synthesis of enantiopure tetracoordinateboron compound and stereochemistry of substitutionreactions at boron atom. Reports of nucleophilicsubstitution reactions at the tetracoordinate boronatom abound, but little attention has been given tothe stereochemistry of the reactions. We initiallysucceeded in synthesizing enantiopure B-stereogenictetracoordinate boron compound 8 containing abromo substituent as the leaving group and exam-ined the stereochemistry of both the nucleophilic andthe electrophilic substitution reactions (Scheme 5).42)

The reactions of 8 with nucleophiles afforded thesubstitution products 9 with excellent enantiomericexcesses. These results apparently demonstrate thatthe SN2 reaction at the sp3 boron atom proceededwith inversion of configuration. On the other hand,

CyPBH2I

CyCy

LDBB

t-Bu t-Bu2 Li+

CyP+B

CyCy

H H2–

2

Li+electrophile

CyPBH2E

CyCy

39–98%E = D, CH(OH)Me, COPh, CO2Et, CO2H,

(CH2)2OH, CONHPh, Me, Et, SPh,SePh, SiMe3

t-BuPBH2I

t-But-Bu

2 LDBB

–78 °C t-BuP

H2B

t-Bu

H

5

t-BuPBH3

t-But-Bu

PBH3

Et-Bu

E = H, D, CH2Ph

88–99%

electrophile

–78 °C

1 3

4 76

THF, –78 °C

Scheme 4. Generation and reactions of tricoordinate boron dianions.

R1 POR3

R2

LiAlH4/CeCl3THF, 20–60 °C

R1 P R3

R287–98%

R1 POR3

R2

NaBH4/CeCl3THF, 20–60 °C

R1 P R3

R2trace

R1 POR3

R2

LiAlH4/NaBH4/CeCl3THF, 20–60 °C

R1 P R3

R262–96%

BH3

Scheme 3. Transformation of phosphine oxides into phosphinesor phosphine–boranes.


the reduction of 8 with LDBB, followed by thereactions with electrophiles, provided completelyracemized products 10. These experimental factscan be explained by assuming that the intermediateboranyl radical or the boron dianion species would bestereochemically unstable and undergo rapid stereo-mutation under the reaction conditions.

2.2.3. Preparation and reactions of boranophos-phorylation reagents. Boranophosphates, which havean isoelectronic relationship with phosphates, areuseful in biochemical investigations. They also havepotential utility as carriers of 10B in boron neutroncapture therapy for cancer treatment. We tried todevelop new reagents for the synthesis of similarcompounds. As shown in Scheme 6, dimethyl bor-anophosphate monopotassium salt 11 and tetra-methyl boranopyrophosphate 12 were preparedfrom the borane adduct of trimethylphosphite. Theformer compound underwent substitution reactionswith various electrophilic reagents to generate com-pounds 13, whereas the latter reacted with metalalkoxides to give the corresponding boranophosphatederivatives such as compound 14.43) These are simplesynthetic routes to various boranophosphate deriva-tives, including the borano analogs of naturallyoccurring phosphates.

2.2.4. Synthesis and reactions of various phos-phine–borane derivatives. We examined the function-alization of the phosphine moiety of phosphine–boranes. As shown in Scheme 7, tertiary phosphine–boranes 15 bearing a methyl group at the phosphorusatom were subjected to deprotonation, followed bythe reaction with alkyl halides or carbonyl com-

pounds to give various phosphine–borane derivatives16. Oxidative dimerization proceeded smoothly toafford compounds 17 with the boranato group intact.Secondary phosphine–boranes 18 reacted with avariety of electrophiles in the presence of a base toyield corresponding phosphine–borane derivatives19, similarly to the reactions of secondary phosphineoxides.39),44)

B Br

CO2Me

Cy3PH

B H

CO2Me

Cy3PNu

BE

CO2Me

Cy3PH

electrophile

inversion

racemization

>99.5% ee Nu = CN: 96% eePhS: 99% ee

nucleophile

2 LDBB

E = Me, i-Bu, PhS

B

CO2Me

HCy3P+ :2– Li+

Cy3PBH2I

5 steps

8

–78 °C

–78 °C ~ rt

9

10: 0% ee

Scheme 5. Synthesis of enantiopure tetracoordinate boron com-pound and substitution reactions at boron atom. E = CH2OMe, SiPh2(t-Bu),

COMe, COPh

MeO PBH3OMe

OMe

KOH MeOH, 60 °C87%

MeO PBH3OK

OMe

0.5 MeSO2Cl

MeCN, 0 °C, 3.5 h98%

MeO PBH3O

OMePBH3

OMeOMe

MeO PBH3OE

OMe

ROLi

O

O

HO

PMeO BH3OMe

N

NH

O

O

Me

70%

11 12

electrophileMeCN, rt69–87%

13

14

Scheme 6. Preparation and reactions of boranophosphorylationreagents 11 and 12.

R1 PBH3

R2CH3

R1 PBH3

R2CH2E

R1 PBH3

R2CH2CH2 P

BH3

R2R1

E = SiMe3, Bu, CH2CH=CH2,CH(OH)Ph, CH(OH)Pr,COPh, CO2Me, etc.

1. s-BuLi2. electrophile

1. s-BuLi2. CuCl2

R1 PBH3

R2H

1. base

2. electrophileR1 P

BH3

R2E

E = alkyl, aryl, CH2CN, CO2Me,COR, CH2OH, CH(OH)Pr,(CH2)2OH, etc.

15

16

17

18 19

Scheme 7. Synthesis of phosphine–borane derivatives fromtertiary or secondary phosphine–boranes.


Our subsequent interest was the synthesis andreactions of optically active phosphine–boranes.Several phosphine–boranes bearing l-menthoxy orbornylthio group were prepared in diastereomericallypure form, and their reactions with nucleophiles orone-electron reducing agents were examined. Theresults shown in Schemes 8–10 indicate that chiralphosphine–boranes can be obtained in excellentenantiopurity, most of which are limited to com-

pounds bearing aryl groups at the phosphorusatom.45)–51)

Our study of the reactivities of phosphine–boranes was extended to the transformation of theboranato group moiety. After many trials, we foundthat phosphine–boranes reacted with amines suchas diethylamine and 1,4-diazabicyclo[2.2.2]octane toproduce parent tertiary phosphines and amine–boranes. Further trials using optically active phos-phine–boranes indicated that this deboranationproceeded with complete retention of configuration(Scheme 11).39),44) We were delighted with thefinding of this simple and unprecedented reactionand were convinced that various phosphines includ-ing optically active ones can be synthesized via thisdeboranation process. It is noteworthy that the BH3

group plays the role of protecting group of the labilephosphine moieties.

The conversion of the boranato group ofphosphine–boranes into oxygen or sulfur atom wasexamined. The reaction with hydrogen peroxide orm-chloroperbenzoic acid proceeded at 0 °C withcomplete retention of configuration to provide thecorresponding phosphine oxides. On the contrary, thereaction with iodine in the presence of water occurredat room temperature with inversion of configuration,while it was accompanied by partial racemization.The reaction with sulfur in the presence of N-methylmorpholine proceeded at 110 °C while retain-ing stereochemical integrity to give the correspondingphosphine sulfides in almost quantitative yields(Scheme 12).52)

The functionalization of phosphine–boranes atthe boron atom was then examined. It was foundthat one of the hydrogen atoms of the boranatogroup was readily replaced with a trifluoromethane-sulfonyloxy or methanesulfonyloxy group by thereaction with trifluoromethanesulfonic acid or meth-anesulfonic acid. The resulting triflate and mesylatewere subjected to a nucleophilic substitution reac-tion to afford the functionalized phosphine–boranes(Schemes 13 and 14).53),54)

Direct boron–carbon bond formation was alsoexamined through the reactions with metal carbe-

P OMenPhR1

BH3P R1PhR2

BH3R2Liinversion

R1 = Me, t-Bu, o-MeOC6H4 up to 99% eeR2 = Me, p-MeOC6H4

OMen = O

i-Pr

Scheme 8. Nucleophilic substitution reactions of enantiopurephosphine–boranes bearing l-menthoxy group.45),46)

P HPhMenO

BH3+

IOMe

Pd(PPh3)4(5 mol%)

K2CO3retention orinversion

OMe P OMenPh

BH3

OMe+

MeCN 100 : 0THF 4 : 96

PBH3

PhMenO

Scheme 10. Palladium-catalyzed arylation of enantiopure secon-dary phosphine–borane.50),51)

P XR1

R2

BH3P ER1

R2

BH31. Li+ [C10H8]• –

2. electrophile

R1, R2 = Ph, o-MeOC6H4,Me, Cy, t-Bu, 1-Ad

X = OMen, SBor

up to 99% eeE = H, Me, CH2Ph, etc.

H

SSBor =

Scheme 9. Stereospecific reduction of menthoxyphosphine–bor-anes or bornylthiophosphine–boranes with lithium naththale-nide.47)–49)

PR3R1

R2

BH3

retention

PR3R1

R2

R3N: Et2NH, morpholine, DABCO, etc.

R3N R3N•BH3

Scheme 11. Stereospecific deboranation of phosphine–boranes toform optically active phosphines.


noids. Scheme 15 shows our observation that sama-rium carbenoids undergo methylene insertion intothe B–H bond to afford B-alkylated compounds.55)

3. Synthesis of P-chiral phosphine ligands

3.1. Synthesis of P-chiral bisphosphine li-gands with aryl groups at phosphorus atoms.Motivated by the results mentioned above, we tried

to synthesize bidentate P-chiral phosphine ligandsusing phosphine–boranes as the intermediates. Ourinitial attempt commenced with the preparation ofDIPAMP, as shown in Scheme 16. Compound 20with 89% ee was successively reacted with s-BuLiand CuCl2 to give compound 21 with 99% ee afterremoval of the concomitantly formed meso-isomer.The subsequent reaction of 21 with diethylaminefurnished enantiopure (S,S)-DIPAMP, demonstrat-ing the potential utility of this phosphine–boranemethodology.39)

In a similar manner, new P-chiral phosphineligands 22a–d and their rhodium complexes 23a–dwere prepared from dichlorophenylphosphine(Scheme 17), and their enantioinduction abilitieswere evaluated in the hydrogenation of a typicalprobing substrate, methyl (Z)-,-acetamidocinna-mate (MAC). The hydrogenation results are shownin Scheme 18 together with that obtained by the useof a Rh-DIPAMP complex.

It is noted that complex 23b bearing an o-ethylphenyl group provided remarkably high enan-tioselectivity (97%) comparable to that (96%) of[Rh((S,S)-DIPAMP)(cod)]BF4. Complexes 23c and23d with larger ortho-alkyl substituents affordedalmost perfect enantioselectivities (>99%), exceedingthat of DIPAMP after 20 years.56),57) Anothersignificant fact is that the sense of the enantioselec-tivity of the newly synthesized ligands with (S,S)-configuration is the same as that of (S,S)-DIPAMPin the Rh-catalyzed asymmetric hydrogenation.These results clearly indicate that the coordinativeinteraction between methoxy oxygen atom andrhodium atom in the Rh-DIPAMP complex is notsignificant in the stereoregulation and the enantio-selection is determined by the steric effects of theligands.

P R3R1

R2

BH3P R3R1

R2

O

P R2R1

R3

O

retention

inversion

H2O2 or m-CPBA

75–85% ee

>99% ee

I2 , H2O

S8, N-methylmorpholine

retentionP R3R1

R2

BH3P R3R1

R2

S

>95% ee

Scheme 12. Stereospecific conversion of phosphine–boranes intophosphine oxides or phosphine sulfides.

CyPBH3

CyCy

TfOHCy

PBH2OTf

CyCy

nucleophileCy

PBH2Nu

CyCy

25–89%Nu = D, Cl, Br, CN, SPh,

Me, Bu, s-Bu

Scheme 13. Synthesis and substitution reactions of the trifluoro-methanesulfonyloxy derivative of tricyclohexylphosphine–bor-ane.

Me PMe

BH3Me

MeSO3H

89%Me P

MeBH2OMs

Me

Ph2P(H)BH3NaH96%

Me PMe

MeBH

HPPh

PhBH

HPPh

PhBH

HPPh

PhBH3Me P

Me

MeBH

HPPh

PhBH3

Scheme 14. Synthesis of organophosphorus compounds with alinear P–B bond chain.

R1PBH3

R3R2

RCHI2/SmR1

PBH2CH2R

R3R2

R = H, Me56–82%

THP–40 °C ~ rt

Scheme 15. Methylene insertion reactions of samarium carbe-noids into the B–H bond of phosphine–boranes.

PPPh

Ph

MeO

OMe

PMe

BH3Ph

OMe

1. s-BuLi2. CuCl2

Et2NH

84%

(S,S)-DIPAMP

PBH3BH3

PPhPh

OMe

OMe65%

20: 89% ee 21: 99% ee

Scheme 16. Synthesis of (S,S)-DIPAMP via phosphine–boranes.


3.2. Synthesis of electron-rich P-chiral phos-phine ligands and their enantioinduction ability.Although the above-mentioned ligands 22c and 22dexhibited higher enantioselectivity than DIPAMP,their molecular structures closely resembledDIPAMP, and hence we next tasked ourselveswith the development of structurally new P-chiralphosphine ligands. In 1990–1991, Burk and co-workers reported that enantiopure 1,2-bis(trans-2,5-dialkylphospholano)ethanes (BPE) and 1,2-(trans-2,5-dialkylphospholano)benzenes (DuPhos), both ofwhich are electron-rich bisphosphine ligands, exhib-ited exceedingly high enantioinduction abilities andcatalytic efficiencies in Rh- and Ru-catalyzed asym-metric hydrogenations.58)–61) Inspired by their out-standing achievements, we concentrated on thedesign and synthesis of new P-chiral phosphineligands.

Our ligand design concept was based on thequadrant diagram proposed by Knowles.26) Thenewly designed ligands are C2-symmetric bisphos-

phines, in which a large alkyl group and a small alkylgroup are bonded to each phosphorus atom, and theasymmetric environment around the center metalis quite clear (Fig. 3). This idea was immediatelyimplemented in experiments of the synthesis ofethylene-bridged ligands, (S,S)-1,2-bis(alkylmethyl-phosphino)ethanes named BisP* (24a–g), possessinga tertiary or secondary alkyl group as the large groupand a methyl group as the small group. The ligandswere air-sensitive semi-solids or oils, and hence theywere converted into air-stable rhodium complexes25a–g (Scheme 19).62)

The structure of complex 25a having a t-butylgroup as the large group was determined by single-crystal X-ray analysis. The ORTEP drawing shownin Fig. 4 clearly indicates the expected C2-symmetricenvironment, where the bulky t-butyl groups occupythe quasi-equatorial positions and the methyl groupsare located at the quasi-axial positions to form a 6-chelate structure. This evidently defined asymmetric

PPPh

Ph

R1

1. s-BuLi2. CuCl2

DABCOPBH3BH3

PPhPh

R1

R1

R2R1

PPPh

Ph

R2R1

R1R2

Rh+ BF4–

R2

R21. [RhCl(cod)]22. NaBF4

R2

PhPCl2

MgBrR1

R2

1.

2. LiOMen3. BH3•THF

resolution

POMen

BH3Ph

R1

R2

PMe

BH3Ph

R1

R2

1. LDBBTHF, –98 °C

2. MeI

22a, 23a: R1 = Me, R2 = H22b, 23b: R1 = Et, R2 = H22c, 23c: R1 = i-Pr, R2 = H22d, 23d: R1, R2 = –(CH2)4–

d–a32d–a22

POMen

BH3Ph

R1

R2 OMen = l-menthoxy

Scheme 17. Synthesis of enantiopure (S,S)-1,2-bis[(o-alkylphenyl)phenylphosphino]ethanes and their rhodium complexes.

23a: 92% ee23b: 97% ee23c: >99% ee23d: >99% ee[Rh((S,S)-DIPAMP)(cod)]BF4: 96% ee

PhNHAc

CO2Me+ H23 atm

PhNHAc

CO2Me

MAC

Scheme 18. Asymmetric hydrogenation of methyl (Z)-,-acet-amidocinnamate (MAC) catalyzed by 23a–d and [Rh((S,S)-DIPAMP)(cod)]BF4.

Fig. 3. (Color online) Quadrant diagram of metal complexes ofC2-symmetric P-chiral phosphine ligands.


environment led us to anticipate the high utility oft-Bu-BisP* ligand in asymmetric catalysis.

Subsequent to the above-mentioned work, wesynthesized structurally simpler methylene-bridgedbisphosphine ligands, (R,R)-bis(alkylmethylphosphi-no)methanes (MiniPHOS) (26a–d) (Scheme 20).63)

The complexation of t-Bu-MiniPHOS (26a) with Rh-diene complexes afforded two different four-mem-

bered Rh complexes depending on the diene ligand.Thus, the reaction of 26a with norbornadiene com-plexes [Rh(nbd)2]X (X F BF4, PF6) provided bische-lated complexes [Rh((R,R)-t-Bu-MiniPHOS)2]X,63)

whereas the reaction with a cyclooctadiene complex[Rh(cod)2]SbF6 afforded monochelated complex[Rh((R,R)-t-Bu-MiniPHOS)(cod)]SbF6.64) Figure 5shows an ORTEP drawing of the monochelated

PPR

MeRMe

PBH3BH3

PMeR Me

R

PPR

MeRMe

Rh+ BF4–[Rh(nbd)2]BF4

PMe

BH3RMe

PCH2Li

BH3RMe

s-BuLi/(–)-sparteineEt2O,–78 ~ –50 °C

24a, 25a: R = t-Bu24b, 25b: R = 1-adamantyl24c, 25c: R = 1-methylcyclohexyl24d, 25d: R = Et3C24e, 25e: R = c-C6H1124f, 25f: R = c-C5H924g, 25g: R = i-Pr

CuCl2

1. CF3SO3Hor HBF4

2. aq. KOHor K2CO3 24a–g: BisP*

25a–g

Scheme 19. Synthesis of (S,S)-1,2-bis(alkylmethylphosphino)ethanes (BisP*) and their rhodium complexes.

Fig. 4. X-ray structure of [Rh((S,S)-t-Bu-BisP*)(nbd)]BF4

(25a). Coordinated norbornadiene, counterion, and hydrogenatoms are not shown for clarity.

PPR

MeRMe

PBH3BH3

PMeR Me

RPMe

BH3RMe

1. s-BuLi/(–)-sparteine

2. RPCl23. MeMgBr4. BH3•THF

26a: R = t-Bu26b: R = c-C6H1126c: R = i-Pr26d: R = Ph

1. CF3SO3H2. aq. KOH

26a–d: MiniPHOS

Scheme 20. Synthesis of (R,R)-bis(alkylmethylphosphino)meth-anes (MiniPHOS).

Fig. 5. ORTEP drawing of [Rh((R,R)-t-Bu-MiniPHOS)(cod)]SbF6. The counter anion (SbF6!) and the hydrogen atoms are omitted for

clarity. Left: perspective view; right: front view.


complex. It is noted that the four-membered chelatering is almost entirely flat, the bulky t-butyl groupseffectively shield the diagonal quadrants, and thetwo methyl groups locate on the other diagonalquadrants, constructing the expected asymmetricenvironment just as we designed. This C2-symmetricRh-t-Bu-MiniPHOS complex is one of my favoritecompounds because of its very simple structure.

The prepared Rh complexes of BisP* andMiniPHOS ligands were used in the asymmetrichydrogenation of ,- and O-dehydroamino acidderivatives and enamides to evaluate their enantioin-duction abilities. In most cases, the ligands possessinga t-butyl group exhibited very high enantioselectiv-ities of up to 99.9%.62),63),65)–67) We were pleased tofind that the two ligands, t-Bu-BisP* and t-Bu-MiniPHOS, were applicable to other representativecatalytic asymmetric reactions, such as the Ir-catalyzed hydrogenation of imines and the Rh-catalyzed hydrosilylation of ketones.68),69)

Our next work was to develop more efficientchiral bisphosphine ligands. Day in and day out,we designed new P-chiral phosphine ligands usingmolecular models, finally designing ligand 27 con-sisting of two phospholane rings as our most promis-ing candidate. The ligand was expected to form metalcomplex 28 having three fused five-membered rings,and the complex would be quite rigid to effectivelyblock the two diagonal quadrants, eventually creat-ing an ideal asymmetric environment around themetal center (Fig. 6).

Initially, we presumed that ligand 27 could bereadily synthesized from 1-tert-butylphospholane–borane 29 via C2-symmetric precursor 30. How-ever, the oxidative coupling proceeded sluggishly toform undesired meso-isomer 31 in 10% yield(Scheme 21).70) To obtain the desired compound

30, we further examined the coupling reaction undervarious conditions and at the same time soughtother different synthetic routes; however, we wereunable to isolate 30. Meanwhile, I was astonished tofind the paper by Tang and Zhang describing thesynthesis and exceedingly high enantioinductionability of ligand 27 (Scheme 22).71) They usedphosphine sulfide 32 as the starting material toobtain oxidative coupling product 33 as the majorproduct. Actually, we had also carried out theexperiments using the same phosphine sulfide 32,but were unsuccessful in isolating the desired 33.To this day, I very much regret not being morepersistent in performing the experiments to achievethe first synthesis of ligand 27.

The superior performance of TangPhos in notonly Rh-catalyzed asymmetric hydrogenation reac-tions but also many other catalytic asymmetricreactions was demonstrated through extensive inves-tigations by Zhang and Tang.71)–73) Following toTangPhos, analogous P-chiral bisphosphacycle li-gands (34–39) bearing t-butyl groups at thephosphorus atom were reported (Fig. 7).74)–81) Wealso prepared ligands 35 and 36 consisting of morerigid four-membered phosphacycles, expecting thatthey would exhibit high enantioselectivity.75),76)

t-Bu-BisP*

P Pt-Bu t-Bu

HH

27

PPt-BuMe t-Bu

Me

P Pt-Bu t-Bu

HH

MP M P

28 front view

Fig. 6. Newly designed P-chiral phosphine ligand 27 and itsmetal complex 28.

Pt-Bu BH3

P P

HH

t-BuH3B BH3t-Bu1. s-BuLi/(–)-sparteine

2. CuCl2

27

P P

HH

t-BuH3B BH3t-Bu

29

30

31

10%

Scheme 21. An attempt to synthesize ligand 27 from phosphine–borane 29.

Pt-Bu S

P P

HH

t-BuS St-Bu

1. s-BuLi/(–)-sparteine

2. CuCl2

32 33

Cl3SiSiCl3P P

t-Bu t-Bu

HH

27 (TangPhos)

Scheme 22. Synthesis of ligand 27 (TangPhos) by Zhang andTang.


Among these ligands, Binapine (34),74) DuanPhos(37),77),78) BIBOP (38),79),80) and WingPhos(38)79),80) are widely used in both academia andindustry for the production of many useful opticallyactive compounds.82) I am amazed at the powerfulresearch activities of Professors Zhang and Tang andtheir coworkers. At the same time, I am delightedthat these remarkable developments originated fromthe discovery of the t-Bu-BisP* ligand.

3.3. Synthesis of air-stable P-chiral phos-phine ligands.

3.3.1. 2,3-Bis(tert-butylmethylphosphino)quinoxa-line (QuinoxP*). Enantiopure 1,2-bis(tert-butyl-methylphosphino)ethane (t-Bu-BisP*), a representa-tive P-chiral phosphine ligand developed in ourlaboratory, exhibits very high enantioselectivities inseveral catalytic asymmetric reactions. However, thisligand is an extremely air-sensitive semi-solid, andthis property has hampered its widespread applica-tion in catalytic asymmetric synthesis. In thiscontext, I pursued a new ligand that is not an oilymaterial but an air-stable crystalline solid to exhibitexcellent enantioinduction ability similar to t-Bu-BisP*. Newly designed ligand 2,3-bis(tert-butylmeth-ylphosphino)quinoxaline (40) (QuinoxP*) possessingthe quinoxaline backbone was prepared from enan-tiopure (R)-tert-butyl(hydroxymethyl)methylphos-

phine–borane (41) (Scheme 23).83) Compound 41was transformed by a ruthenium-catalyzed stereo-specific oxidative one-carbon degradation into (S)-tert-butylmethylphosphine–borane (42),84) whichwas deprotonated with n-BuLi and allowed to reactwith 2,3-dichloroquinoxaline, followed by treatmentwith TMEDA to furnish the desired ligand 40 in anenantiopure form. We were overjoyed to obtain theligand as an air-stable crystalline solid and to confirmits high performance in representative transition-metal-catalyzed asymmetric reactions.83),85)

In a similar manner, we prepared analogous C2-symmetric ligands, (R,R)-2,3-bis((1B-adamantyl)-methylphosphino)quinoxaline ((R,R)-Ad-QuinoxP*)(43) and (R,R)-2,3-bis((1B,1B,3B,3B-tetramethyl-butyl)methylphosphino)quinoxaline ((R,R)-TMB-QuinoxP*) (44) (Fig. 8). The former ligand, un-fortunately, did not crystallize, whereas the latterone was obtained as orange plates. Both ligandsshowed excellent performance as chiral ligands in afew representative catalytic asymmetric reac-tions.64),86)

3.3.2. 1,2-Bis(tert-butylmethylphosphino)benzene(BenzP*) and related ligands. For years, we wereextremely interested in the synthesis of 1,2-bis(tert-

P P

t-Bu t-Bu

HH

27 (TangPhos)71)

35 (DiSquareP*)75)

Pt-Bu

Pt-Bu

H

H

34 (Binapine)74)

P P

t-Bu t-Bu

HH

37 (DuanPhos)77),78)3676)

P P

t-Bu t-Bu

H

39 (ZhangPhos)81)

P

O O

P

HH

t-Bu t-BuR R3879),80)

R = H, MeO, Ph, etc.: BIBOPR = anthryl: WingPhos

H

PP

t-But-Bu

HH

PP

t-But-Bu

HH

Fig. 7. P-Chiral bisphosphacycle ligands with t-butyl groups.

PBH3

t-BuMe

OH

41

RuCl3 (5 mol%)K2S2O8, KOH

80%PH

BH3t-BuMe42

N

N P

P

Met-Bu

Me t-Bu40 (QuinoxP*)

1. n-BuLi

TMEDA

80%N

N P

P

Met-Bu

Me t-Bu

BH3BH3

2. 2,3-dichloro-quinoxaline

Scheme 23. Synthesis of QuinoxP*.

N

N P

PMe

Me

(R,R)-Ad-QuinoxP*

N

N P

PMe

Me

(R,R)-TMB-QuinoxP*43 44

Fig. 8. (R,R)-Ad-QuinoxP* and (R,R)-TMB-QuinoxP*.


butylmethylphosphino)benzene (BenzP*), an ortho-phenylene-bridged P-chiral bisphosphine ligand.Although the ligand has a simple molecular struc-ture, our attempts to synthesize it took approx-imately 10 years. Finally, in 2010, we found a methodthat enabled gram-scale synthesis.87)–89) We owe oursuccess to our private communication with ProfessorSylvain Jugé of the University of Bourgogne. When Ivisited Professor Jugé’s laboratory, he kindly taughtme the reaction of lithiated secondary phosphine–boranes with o-dibromobenzene to produce (2-bromophenyl)(dialkyl)phosphine–boranes.90) By ap-plying his protocol to the reaction of optically pure42 with 1,2-dibromobenzene, we were able to obtainenantiopure 45 in good yield (Scheme 24). Theconversion of 45 into BenzP* (46) in four stepswas accomplished in one pot.89) During the reactionsequence, the introduction of another t-butylmethyl-phosphino group at the ortho-position failed toproceed stereoselectively, resulting in the formationof a considerably large amount of the undesired meso-isomer as the co-product. Fortunately, however, onlythe desired (R,R)-BenzP* (46) was isolated as acolorless crystalline solid from the reaction mixture.It was also fortunate that the enantiopure BenzP*was considerably air-stable, in contrast to themixture of its stereoisomers, which was reported tobe an air-sensitive oil.91) This air-stable property ofthe ligand in conjunction with its high enantioinduc-tion ability makes it potentially useful in variouscatalytic asymmetric syntheses.

3.4. Synthesis of P-chiral bisphosphines viaenantiopure tert-butylmethylphosphine–borane.As has been described above, enantiopure tert-butylmethylphosphine–borane (42) plays a key rolein the synthesis of QuinoxP* and BenzP*. I findthis structurally simple secondary phosphine–boranevery attractive, because it consists of a stereogenicphosphorus atom, a boranato group, a hydrogen

atom, a methyl group, and a t-butyl group, all ofwhich play respective roles in ligand synthesis or inthe construction of an effective asymmetric environ-ment. Whereas this compound was initially preparedon a laboratory scale as described in Schemes 9 and23, its enantiomers are currently manufactured on alarge scale through the optical resolution of theracemate at Nippon Chemical Industrial Co., Ltd.

With both enantiomers in hand, we preparedvarious P-chiral phosphine ligands by the reactionswith electrophiles, followed by the removal of theboranato groups. The ligands prepared by thismethod are illustrated in Fig. 9. It should be notedthat both enantiomers of t-Bu-BisP* could beconveniently prepared from 1,2-dichloroethane.64)

Among these ligands, AlkynylP*,92) BulkyP*,93) 5,8-TMS-QuinoxP*,94) and 3H-QuinoxP*95)–97) haveshown unique and remarkably high enantioselectiv-ities in some transition-metal-catalyzed asymmetrictransformations.

4. Use of QuinoxP* and related air-stablephosphine ligands in transition-metal-

catalyzed asymmetric reactions

Since the commercialization of QuinoxP* andBenzP* by reagent dealers, these ligands have beenwidely used in both academia and industry for thedevelopment of new transition-metal-catalyzedasymmetric reactions as well as for the synthesis ofthe desired optically active compounds. The success-ful results obtained by the use of these ligands aremany, and hence, only representative examples aredescribed herein.

4.1. Asymmetric hydrogenation. The rho-dium-catalyzed asymmetric hydrogenation of func-tionalized alkenes is one of the most importantcatalytic asymmetric syntheses.98),99) Even thoughplentiful examples have been reported, the furtherdevelopment of the method by using new ligands isstill a popular research subject. We have examinedthe asymmetric hydrogenation of a variety offunctionalized alkenes by the use of QuinoxP* andanalogous ligands and found that the reactionresulted in excellent enantioselectivities and had abroad substrate scope. The hydrogenation reactionsof ,- or O-dehydroamino acid derivatives are shownin Schemes 25 and 26 as typical examples.85),93) It isworth noting that the ligands could be employedin the hydrogenation of not only (E)- but also (Z)-O-dehydroamino acid derivatives (Scheme 26). Theseresults indicate that the ligands, particularlyQuinoxP*, are useful for the production of chiral

PH

BH3t-BuMe42

P

P

Met-Bu

Me t-Bu46 (BenzP*)

1. n-BuLi2. 1,2-Br2C6H4

Br

PMe t-Bu

BH3

45

1. DABCO2. s-BuLi3. t-BuPCl24. MeMgBr

65%

38%

Scheme 24. Synthesis of BenzP*.


ingredients containing an amino acid or aminemoiety.85)

High enantioselectivities have also been ob-served in the asymmetric hydrogenation of ketonesusing QuinoxP* or BenzP*. For example, theasymmetric hydrogenation of O-secondary-aminoketones by a Rh-BenzP* catalyst was significantlypromoted by ZnCl2 to afford the correspondinghydrogenation products with excellent enantiomericexcesses in high yields (Scheme 27).100) This proce-dure is potentially useful for the production ofsynthetic intermediates of (S)-duloxetine, (R)-fluox-etine, and (R)-atomoxetine, which are used asantidepressant drugs.

Recently, the use of non-precious metals, such ascobalt, nickel, and iron, in asymmetric hydrogenationhas attracted increasing attention as an economicaland environmentally friendly methodology. Onereaction example using a cobalt-QuinoxP* catalystis shown in Scheme 28.101) In this reaction, the alkenemoiety was hydrogenated with very high enantiose-lectivity while keeping the alkyne intact.

Another example is the nickel-catalyzed asym-metric hydrogenation (Scheme 29).102) The use of amuch lower catalyst loading (0.0095mol%, S/C F

NHAcR1

R2

CO2Me

NHAcR1

R2

CO2Me**+ H2Rh(I)–L*

L* : QuinoxP*, BenzP*,BulkyP* up to 99.9% ee

Scheme 25. Rh(I)-catalyzed asymmetric hydrogenation of ,-dehydroamino acid derivatives.

NHAc

R1

NHAc

CO2R2

R1*+ H2Rh(I)–L*

L* : QuinoxP*, BenzP*,BulkyP* up to 99.9% ee

CO2R2

Scheme 26. Rh(I)-catalyzed asymmetric hydrogenation of O-dehydroamino acid derivatives.

Ar

O

NHMe + H2

25 atm

[Rh((R,R)-BenzP*)-(cod)]SbF6, ZnCl2,Cs2CO3

Ar

OH

NHMe

MeOH, rt, 48 h

Ar = 2-thienyl: 89% yield, 99% eeAr = Ph: 93% yield, 96% ee

S/C = up to 2000

Scheme 27. Rh(I)-catalyzed asymmetric hydrogenation of O-secondary-amino ketones.

NHAc

Ar

+ H2

NHAc

Ar

(R,R)-QuinoxP*CoCl2, Zn

MeCN

up to 99.9% eeS/C = up to 2000

Scheme 28. Cobalt-catalyzed asymmetric hydrogenation of con-jugated enynes.

PPt-Bu

Met-BuMe

t-Bu-BisP* t-Bu-MiniPHOS

N

N P

P

Met-Bu

Me t-Bu

QuinoxP*

P

P

Met-Bu

Me t-Bu

BenzP*

N

N P

P

t-But-Bu

Me t-Bu

3H-QuinoxP*

P

P

Met-Bu

Me t-BuDioxyP*

O

O

P

P

Me

t-Bu

t-Bu

Me

NP PMe

tt-Bu P PMe

t-Bu Me -Bu Met-Bu

PP

AlkynylP*

PPt-Bu

Met-BuMe

N P

P Met-Bu

Me t-Bu

BulkyP*

PPt-BuMe 1-Ad

1-Ad

PBH3

Ht-BuMe

PP t-BuMet-Bu Me

P

P

BipheP*

t-Bu

Me

Me

t-Bu

N

N P

P

Met-Bu

Me t-Bu

5,8-TMS-QuinoxP*

TMS

TMS

t-But-Bu

R

R

R = H, Me, Ph, t-Bu, i-Pr3Si

Fig. 9. (Color online) P-Chiral phosphine ligands prepared from enantiopure tert-butylmethylphosphine–borane.


10500) has resulted in the highest catalytic activityfor the Ni-catalyzed asymmetric hydrogenationreactions reported to date.

4.2. Carbon–carbon and carbon–heteroatombond-forming reactions. QuinoxP* and BenzP*have also been used in metal-catalyzed asymmetriccarbon–carbon and carbon–heteroatom bond-form-ing reactions. Scheme 30 shows an example of acarbon–carbon bond-forming reaction reported byBuchwald and coworkers.103) This allylation reactionof ketones with allene, an underutilized hydrocarbonfeedstock, proceeds without specialized equipmentor pressurization to give allylation products withhigh enantiomeric excesses.

Some air-stable P-chiral phosphine ligandshave found use in the enantioselective synthesisof optically active pharmaceutical ingredients.Scheme 31 shows an example reaction that wasestablished by the research group of Merck & Co.,

Inc. for the production of the HCV drug candidateelbasvir.104) It should be noted that the C–N couplingreaction with the formation of the optically activehemiaminal ether is catalyzed by the Pd(0)–Qui-noxP* mono-oxide complex produced by the reactionof Pd(OAc)2 with QuinoxP*.

In 2010, Ito et al. disclosed a direct enantio-convergent transformation of racemic substrateswithout racemization or symmetrization by the useof Cu(I)–QuinoxP* complex as the chiral catalyst.105)

By employing the modified ligand (R,R)-5,8-bis(tri-methylsilyl)quinoxaline ((R,R)-5,8-TMS-QuinoxP*),the substrate scope was significantly expanded fromfive-membered compounds to six- and seven-mem-bered ones (Scheme 32).94)

5. Mechanistic study of rhodium-catalyzedasymmetric hydrogenation offunctionalized alkenes: A newapproach for predicting thesense of enantioselectivity

As has been described in Section 3.2, we foundthat the asymmetric hydrogenation of ,-dehydro-amino acid derivatives with rhodium complex[Rh((S,S)-t-Bu-BisP*)(nbd)]BF4 (25a) provided(R)-configuration products with up to 99.9% ee.62)

With the results in hand, we at first tried to explainthe stereochemical outcome with respect to thehitherto reported empirical rule regarding the corre-lation between the catalyst ‘ or 6 conformer and theabsolute configuration of the products.26),106)–108) Therule predicts that the catalyst with ‘-conformationprovides (R)-enantiomer products and the catalystwith 6-conformation furnishes (S)-enantiomers.Therefore, according to the rule, our catalyst 25awith 6-conformation should provide (S)-configura-tion products. However, it turned out that the useof 25a afforded (R)-configuration products, whichare the opposite enantiomers of those predicted bythe empirical rule. On the other hand, in the caseof the (R,R)-t-Bu-MiniPHOS (26a)–Rh complex, the

aryl

aryl

N

alkyl

SO2-t-Bu+ H21–50 atm

(R,R)-QuinoxP*Ni(OAc)2

CF3CH2OH

HN

alkyl

SO2-t-Bu

up to 99.7% eeS/C = up to 10500

Scheme 29. Ni-catalyzed asymmetric hydrogenation of N-sulfon-yl imines.

(MeO)2MeSiH R2R1HO

up to 96% ee

R2

O

R1+ •

L*CuH

1 atmL*: (S,S)-QuinoxP*

Scheme 30. Enantioselective allylation of ketones with allene.

Cl

BrN O

Ph

Cl

Cl

94% ee

(R,R)-QuinoxP*Pd(OAc)2

NCl

OPh

elbasvir

K3PO4, toluene96%

Scheme 31. Synthesis of optically active hemiaminal ether viaPd-catalyzed C–N coupling.

YX

RLG

racemateX, Y = C, N or On = 0, 1, 2

+ B2(pin)2 YX

R B(pin)

up to 96% ee

[Cu(MeCN)4]BF4(R,R)-5,8-TMS-QuinoxP*

n n

Scheme 32. Direct enantio-convergent transformation of racemicsubstrates catalyzed by Cu(I)–(R,R)-5,8-TMS-QuinoxP* com-plex.


‘,6-empirical rule was not applicable to the entirelyflat four-membered chelate cycle with no distinctquasi-axial and equatorial groups, although thecomplex afforded (R)-configuration products withexcellent enantiomeric excesses. Another attemptedexplanation was made by applying the Halpern–Brown mechanism, which is also known as theunsaturated mechanism, the major/minor concept,or the anti-lock-and-key mechanism.109)–117) How-ever, not only the origin and the sense of theenantioselection but also the observed very highenantioselectivities could not be reasonably explainedby the mechanism. These discrepancies are the mainreasons why we initiated our mechanistic studies ofthe rhodium-catalyzed asymmetric hydrogenation.

To detect the reaction intermediates and toexamine their reactivities, we began our multinuclearNMR study with the use of complex 25a. Fortu-

nately, complex 25a was sufficiently soluble indeuteriomethanol even at a very low temperature,and the spectral data obtained could be analyzedwithout difficulty owing to its simple molecularstructure.

Our experimental findings and a plausibleenantioselection mechanism including the catalyticcycle are shown in Scheme 33.118) One of theimportant findings is that solvate complex 47generated from catalyst precursor 25a reactedreversibly with H2 at a low temperature to givediastereomeric dihydride intermediates 48a and 48bin approximately 10:1 ratio; these are the firstobservable Rh dihydrides with a bisphosphine ligand.These dihydrides reacted with probing substrateMAC very rapidly at !90 °C to give monohydridecomplex 52 detected by NMR measurement. Thereaction was considered to proceed through 49, 50,

P

PRh+

Met-Bu

t-Bu

Me

H2

S: CD3OD

P

PRh+

Met-Bu

t-Bu

MeS

S

P

PRh+

Me t-Bu

t-Bu

Me

S

HH

S

P

PRh+

Me t-Bu

t-Bu

Me

HH

O

MeNH

H

PhX

X = CO2Me

P

PRh+

Me t-Bu

t-Bu

Me

SH

O

MeNH

Ph

CO2Me

P

PRh+

Me t-Bu

t-Bu

Me

OH

O

OMe

NH

Ph

Me

H2

25a

PhCO2Me

NHAcMAC

PhCO2Me

NHAc

–90 °C

SRh

> –50 °C

P

PRh+

Met-Bu

t-Bu

Me H Ph

NH

Me

OOMe

O

Re

P

PRh+

Met-Bu

t-Bu

Me NH

PhOH

SiO

OMe

Me+

ca. 10:1

MAC

S

P

PRh+

Me t-Bu

t-Bu

Me

HH

O

Me

HN

Ph

CO2Me

S

P

PRh+

Me t-Bu

t-Bu

Me

S

HS

H

+

ca. 10:1

47b45a45

48a 48b

49

50

51

52

H2 (2 atm)–80 °C, 1 h

53

–90 °C

very fast

Scheme 33. Plausible catalytic cycle for the asymmetric hydrogenation of MAC with [Rh((S,S)-t-Bu-BisP*)(nbd)]BF4.


and 51. Thus, the amide oxygen atom of MACcoordinated to the rhodium atom at the trans to theRh–H bond to form complex 49, and subsequently,the carbon–carbon double bond moved to the Rh–Hbond, leading to the transition state 50. Themigratory insertion of the alkene into the Rh–Hbond afforded monohydride complex 51, which inturn isomerized into a more stable monohydride 52.At temperatures above !50 °C, 52 underwentreductive elimination to afford hydrogenation prod-uct 53 with 99% ee and solvate complex 47.

On the other hand, solvate complex 47 reactedwith MAC to form Rh-alkene complexes 54a and54b in the ratio of approximately 10:1. Thesediastereomeric complexes were allowed to react withH2 (2 atm) at !80 °C for 1 h to give monohydride 52,which was detected by NMR measurement alongwith the signals of solvate complex 47 and dihydrides48a and 48b. At the temperatures higher than!50 °C, it was converted into the hydrogenationproduct 53 with 97% ee (R). The absolute config-uration of the product corresponded to that of si-coordinated minor complex 54b, and this hydro-genation followed seemingly the Halpern–Brownmechanism. However, this transformation proceededat a relatively higher temperature and required alonger reaction time than the reaction of thedihydride complexes 48a and 48b with MAC.Therefore, it is reasonable to consider that the alkenecomplexes 54a and 54b exist in a resting state andare not directly subjected to hydrogenation; theyreversibly dissociate into the solvate complex 47 andsubstrate MAC and eventually furnished 52 via thedihydride pathway.

We consider that the enantioselection would bedetermined at the association step to form hexacoor-dinated Rh(III) dihydride complex 50. Among theeight possible stereoisomers of the transition statestructure, only 50 as the most favorable transitionstate satisfies the following steric and electronicrequirements:1. A chelate ring is formed, avoiding steric

repulsion with the bulky t-butyl group of theligand.

2. The carbon–carbon double bond is parallel tothe Rh–H bond trans to the Rh–P bond.

3. The ,-carbon of the ester binds to the Rh atomduring the migratory insertion.The origin of the very high enantioselectivity is

responsible for the multiple factors for lowering thetransition state energy. This enantioselection mech-anism is analogous to that of enzyme reactions, even

though the catalyst is not a macromolecule similar toan enzyme. It is also worth mentioning that therelationship between the catalyst structure and theproduct chirality can be reasonably explained byconsidering transition state structure 50.

To confirm the dihydride mechanism, we stud-ied the reactivities of tetracoordinated Rh(I)-alkenechelating complexes toward H2 using other electron-rich P-chiral phosphine ligands (R,R)-t-Bu-MiniPHOS, (R)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane (Trichikenfootphos:TCFP), (R,R)-BenzP*, etc. Scheme 34 shows anexample of the studies based on low-temperatureNMR measurements and DFT computations.119) Inthis case, TCFP–Rh solvate complex reacted withMAC to provide alkene complexes 55a and 55b inapproximately 1:1 ratio, and no distinct major/minorconcentrations were observed. A significant findingis that both the re- and si-coordinated alkenecomplexes 55a and 55b reacted with H2 at !78 °Cto give the same (R)-enantiomer product in 97% ee.The NMR monitoring and extensive DFT computa-tions led us to conclude that the hydrogenation of55a and 55b does not occur directly, but is precededby the dissociation of the double bond to result in themore reactive species 56. Semi-dissociated species56 reacts with H2 to give non-chelating Rh(III)-dihydride complex 57, which undergoes migratoryinsertion via transition state 58 to generate mono-hydride 59. Finally, 59 is converted into product 53via reductive elimination. It is noted that transitionstate 58 closely resembles 50 and the observed veryhigh enantioselectivities would be responsible for theabove-described steric and electronic effects.

In addition to the example mentioned above, themechanisms of the Rh-catalyzed asymmetric hydro-genation of many functionalized alkenes, such as O-dehydroamino acid derivatives, enamides, and ,,O-unsaturated phosphonates, were studied using notonly (S,S)-t-Bu-BisP* but also other several P-chiralbisphosphine ligands. In all cases, the resulting highenantioselectivity and stereochemical outcome (Ror S) were reasonably explained by considering thedihydride pathway. In addition, the absolute config-uration of the product could be predicted byconsidering the transition structure in the associationand migratory insertion step. Furthermore, theproposed catalytic cycle and the enantioselectionmechanism would be crucial for the design of newchiral ligands and catalysts. More details aredescribed in original papers65)–67),85),120)–126) and re-views.127)–129)


6. Conclusions

A new method for the synthesis of enantiopureP-chiral phosphine ligands has been established byutilizing the characteristic properties of phosphine–boranes. A rationally designed P-chiral phosphineligand, t-Bu-BisP*, was synthesized in 1998, and itsvery high enantioinduction ability was demonstratedin the Rh-catalyzed asymmetric hydrogenation offunctionalized alkenes. The discovery of the t-Bu-BisP* ligand ushered in a revival of P-chiralphosphine ligands in asymmetric catalysis, and manyP-chiral ligands have been synthesized and success-fully applied in a variety of transition-metal-cata-lyzed asymmetric reactions. In particular, TangPhos,DuanPhos, BIBOP, and QuinoxP* have foundwidespread use in both academia and industry owingto their exceedingly high enantioinduction abilityand superior catalytic efficiency.

Structurally simple P-chiral phosphine ligands,such as BisP*, TCFP, and BenzP*, have beenemployed in the mechanistic studies of the Rh-catalyzed asymmetric hydrogenation of enamidesand related substrates. It has been suggested thatthe hydrogenation proceeds through the dihydride

pathway and the enantioselection is determined bythe formation of the octahedral Rh(III) dihydridecomplex and the subsequent migratory insertionstep. Furthermore, the absolute configuration of theproducts can be predicted by considering the multi-ple stereoregulating factors at the transition state.

Asymmetric catalysis is undoubtedly one of themost environmentally benign and economical meth-ods for the production of enantiomerically pure orenriched high value-added compounds. I believe thatP-chiral phosphine ligands along with many otherbackbone chirality ligands will play a vital role in thefurther development of the sophisticated and trulyuseful catalytic synthetic transformations.

Acknowledgments

The work described in this review was carriedout at Chiba University and Nippon ChemicalIndustrial Co., Ltd., where many coworkers wereengaged in these studies. I deeply thank all collab-orators, whose names appear in the Referencessection. My sincere appreciation also goes to theMinistry of Education, Culture, Sports, Science andTechnology of Japan for the financial support in theform of a Grant-in-Aid for Scientific Research.

P

PRh+

t-Bu

Me

t-BuO

t-Bu

MeO2C

H

NH

Me

P

PRh+

t-Bu

Me

t-BuO

t-Bu

H

MeO2CNH

MePh

Ph

P

PRh+

t-Bu

Me

t-BuO

t-Bu

HN

Me

OH

Me

CO2Me

HPh

P

P

t-Bu

Me

t-BuH

t-BuO

H

O

Me

NH

CO2Me

Ph

H

H2

H

Me

P

PRh+

t-Bu

Me

t-Bu

H

t-Bu

H

O

Me

N

X Ph

H

P

PRh+

t-Bu

Me

t-Bu

O

t-Bu

H

O

Me

N

Ph

H

CO2Me

H

Me CO2MePhNHCOMe

97% ee

ca. 1:1

(catalytic conditions:>99% ee)

Rh

X = CO2Me

55a 55b

56 57

9585

53

H

Scheme 34. (Color online) Reaction of [Rh((R)-TCFP)]–MAC complexes with H2 leading to the hydrogenation product.


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(Received July 29, 2021; accepted Aug. 30, 2021)


Profile

Tsuneo Imamoto was born in 1942 in Shizuoka Prefecture, Japan. After graduatingfrom Shizuoka University, he proceeded to study physical organic chemistry under thesupervision of Professor Yasuhide Yukawa at Osaka University and obtained his Ph.D.degree in 1972. After postdoctoral work under the direction of Professor TeruakiMukaiyama at Tokyo Institute of Technology, he was appointed an assistant professor atOsaka University in 1973. In 1975, he moved to Wayne State University in Detroit,Michigan, where he studied organophosphorus chemistry and asymmetric synthesis as apostdoctoral fellow under Professor Carl R. Johnson. In 1978, he joined the researchgroup of Professor Mukaiyama at the University of Tokyo, and in 1980, he moved toChiba University where he worked as an assistant professor. He was promoted toassociate professor in 1987 and professor in 1993, and he retired from Chiba University in 2008. Currently, he is aprofessor emeritus and a grand fellow of Chiba University. He worked as a research consultant of Nippon ChemicalIndustrial Co., Ltd. (2008–2020) and was a visiting professor of Shanghai Jiao Tong University (2009–2018). Since2020, he has been working as a visiting professor of Hokkaido University. His research interests lie in the areasof synthetic methodology, organoelement chemistry, asymmetric catalysis, and organic reaction mechanism. Hepioneered the use of phosphine–boranes for the synthesis of phosphine ligands and invented cerium(III)-modifiedorganometallic reagents, which have found widespread use in the efficient addition reactions of carbonylcompounds. He is a recipient of the Synthetic Organic Chemistry Award (Academic Division), Japan (1997); theRare Earth Society Award, Japan (2001); the Prize for Science and Technology by the Ministry of Education,Culture, Sports, Science and Technology (2008); the Synthetic Organic Chemistry Award (Technology Division),Japan (2013); and the Ryoji Noyori Prize (2020).


synthesis and applications of high-performance p-chiral

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