asymmetric synthesis of axially chiral compounds by ... · enantioselective synthesis of axially...

3

OMOM

HC CH+OMOM

20 mol % Ni(acac)280 mol % PPh340 mol % DIBAL-H

THF, rt

66%

O

O

O

O

OMOM

CO2Me

HC CH+ OMOMCO2Me

20 mol % Ni(acac)280 mol % PPh340 mol % DIBAL-H

THF, rt

94%

2

Scheme 2. Nickel-catalyzed [2+2+2] cycloaddition of an aryl diyne with acetylene

Scheme 1. Nickel-catalyzed [2+2+2] cycloaddition of an aryl monoyne with two acetylenes

1. IntroductionAxially chiral biaryls are the important key structures

of useful chiral ligands and catalysts,1 and biologically active compounds.2 Asymmetric cross-coupling reactions have been investigated for their catalytic enantioselective synthesis, but this approach suffers from low efficiency due to the difficulty of the sterically demanding aryl-aryl

bond formation.3 As a conceptually new approach, the asymmetric aromatic ring construction by the transition-metal-catalyzed [2+2+2] cycloaddition reactions4 has been reported since seminal three reports in 2004.5,6 In 1999, Sato, Mori, and co-worker reported two types of the nickel-catalyzed non-asymmetric [2+2+2] cycloaddition

Abstract: This research article discloses rhodium(I)-catalyzed enantioselective [2+2+2] cycloaddition reactions to produce axially chiral biaryls, developed by our research group. The use of cationic rhodium(I)/axially biaryl bisphosphine complexes as catalysts realized the highly efficient enantioselective biaryl synthesis. Additionally, the enantioselective synthesis of axially chiral compounds with non-biaryl axial chirality and the diastereoselective biaryl synthesis are also disclosed.Keywords: asymmetric catalysis, axial chirality, biaryls, rhodium, [2+2+2] cycloaddition

Asymmetric Synthesis of Axially Chiral Compounds by Rhodium(I)-Catalyzed [2+2+2] Cycloaddition

Ken TanakaDepartment of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1-S1-9 Ookayama, Meguro-ku, Tokyo 152-8550, JapanE-mail: [email protected]

No. 179 l 50th Anniversary issue 2018 TCIMAIL

4

to produce functionalized biaryls.7 One was the [2+2+2] cycloaddition of an aryl-substituted monoyne with two acetylenes, leading to a biaryl ester (Scheme 1), and the other was the [2+2+2] cycloaddition of an aryl-substituted and ester-linked 1,6-diyne with acetylene, leading to a biaryl lactone (Scheme 2).7

In 2002, McDonald and Smolentsev reported the novel synthesis of an oligo-p-phenylene by the RhCl(PPh3)3-catalyzed [2+2+2] cycloaddition of a hexayne with three propargyl alcohols (Scheme 3). The thus introduced dihydrofuran and alcohol functional groups increased the solubility of the oligo-p-phenylene.8

These pioneering works clearly demonstrated the utility of the transition-metal-catalyzed [2+2+2] cycloaddition for the synthesis of the functionalized biaryls, while asymmetric variants of these reactions were not accomplished.9

2. Enantioselective Synthesis of Axially Chiral Biaryls

2.1. Reactions Involving Aryl Diynes In 2003, our research group discovered that cationic rhodium(I) complexes with axially chiral biaryl bisphosphine ligands, especially H8-BINAP, exhibit remarkably high catalytic activity for chemo- and regioselective [2+2+2] cycloaddition of two different monoynes.10,11 In 2004, this new chiral catalyst was successfully applied to the asymmetric aromatic ring construction by the [2+2+2] cycloaddition.5c A cationic rhodium(I)/(S)-H8-BINAP complex catalyzed the enantioselective [2+2+2] cycloaddition of electron-deficient ester-linked 1,6-diynes, possessing ortho-substituted phenyl at an alkyne terminus, with propargyl acetate at room temperature to give axially chiral biaryl lactones with high yields and ee values (Scheme 4). In this reaction, sterically demanding regioisomers were generated with high regioselectivity. Interestingly, the reactions of symmetrical internal monoynes, 1,4-diacetoxy-2-butyne and 2-butyne-1,4-diol, afforded the corresponding biaryls with perfect ee values, although the product yields decreased (Scheme 4).

O

O+

R3

OR2

OR2

R1

O

OR1

5 mol%[Rh(cod)2]BF4/(S)-H8-BINAP

CH2Cl2, rt

R3

PPh2

PPh2

(S)-H8-BINAP

O

MeO

OAc

71%, 87% ee

O

O

OAc

80%, 82% ee

O

MeO

OAc

67%, >99% ee

O

ClO

OH

63%, >99% ee

OAc OH

6 mol %RhCl(PPh3)3

2-PrOH/THF (1:1)reflux

O

O

O

+

O

O

OHOH2C

CH2OH CH2OH

OH

78%

3

Scheme 4. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of aryl diynes with monoynes

Scheme 3. Oligo-p-phenylene synthesis by RhCl(PPh3)3-catalyzed [2+2+2] cycloaddition

TCIMAIL 50th Anniversary issue 2018 l No. 179

5

Unfortunately, the above our report was the third example of the atroposelective [2+2+2] cycloaddition. In 2004, Gutnov, Heller, and co-workers reported the first example of the atroposelective biaryl synthesis by the transition-metal-catalyzed [2+2+2] cycloaddition.5a They reported that a cobalt(I)/chiral cyclopentadiene complex is able to catalyze the enantioselective [2+2+2]

cycloaddition of an aryl-substituted 1,7-diyne with nitriles, leading to axially chiral aryl pyridines (Scheme 5).

In 2004, Shibata and co-workers reported the second example of the atroposelective biaryl synthesis by using an iridium(I)/chiral bisphosphine complex as a catalyst.5b They reported that a neutral iridium(I)/(S,S)-

10 mol%[Rh(cod)2]BF4/

(S)-SEGPHOS

CH2Cl2, rt

O

O

O

OR

RR

R

+

PPh2

PPh2

(S)-SEGPHOS

O

O

O

O

O

On-Pr

n-PrMe

Me

75%, dl/meso = 6:197% ee

O

O

Me

Me

70%, dl/meso = 2:197% ee

OMe

OMe

O

O

71%, dl/meso = 3:185% ee

OMe

OMe

OMe N

R N

R

OMe+

1 mol %chiral [CpRCo(cod)]

THF, hv, –20 – 20 °C

74–88%, 82–93% eeR = Ph, Me, t-Bu

Co

chiral [CpRCo(cod)]

Z

OR

OR

ZOROR

+

[IrCl(cod)]2/2(S,S)-Me-duphos

(1–20 mol% Ir)

xylene, 100 °C

72–97%dl/meso = 91:9–>99:1

95–>99% ee

Z = O, NTs, CH2, C(CO2Et)2,cis-CH=CH

R = Me, MOM, THP, TBS

P

P

Me

(S,S)-Me-Duphos

Me

Me

Me

21

Scheme 7. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of diaryl diynes with monoynes

Scheme 5. Cobalt-catalyzed atroposelective [2+2+2] cycloaddition of an aryl diyne with nitriles

Scheme 6. Iridium-catalyzed atroposelective [2+2+2] cycloaddition of diaryl diynes with monoynes


6

P(O)R32

OMe

R1

R2+ZR1

R2

P(O)R32

OMe

Z5 mol %[Rh(cod)2]BF4/(R)-H8-BINAP

CH2Cl2, rt

P(O)(OEt)2

OMe

Me

Me

O

>99%, 97% ee>99%, 96% ee (1 mol % Rh)

P(O)(OEt)2

OMe

Me

Me

>99%, 97% ee

P(O)Ph2

OMe

Me

Me

O

92%, 91% ee

P(O)Cy2

OMe

Me

Me

O

>99%, 95% ee

P(O)(OEt)2

OMe

Ph

Me

O

80%, 86% ee

P(O)(OEt)2

OMe

PhO

73%, 96% ee

CO2R1

CO2R1

R1O2C

R1O2C

CO2R1

CO2R1R1O2C

R1O2C

OAc

OAc+

R2 R2

5 mol %[Rh(cod)2]BF4/(S)-H8-BINAP

CH2Cl2, rt

CO2EtCO2EtEtO2C

EtO2COAc

Me

80%, 93% ee

CO2EtCO2EtEtO2C

EtO2COAc

Br

80%, 93% ee

CO2MeCO2MeMeO2C

MeO2COAc

89%, 95% ee

Scheme 9. Rhodium-catalyzed atroposelective synthesis of biaryl phosphorus compounds

Scheme 8. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of two monoynes with aryl monoynes

Me-Duphos complex is able to catalyze the diastereo- and enantioselective [2+2+2] cycloaddition of 1,6-diynes, possessing two ortho-substituted aryl groups at alkyne termini, with monoynes, leading to axially chiral 1,4-teraryls (Scheme 6). It should be noted that the desired axially chiral 1,4-teraryls are obtained with near-perfect diastereo- and enantioselectivity.

The atroposelective synthesis of axially chiral 1,4-teraryls having anthraquinone structures was achieved by using a cationic rhodium(I)/(S)-SEGPHOS® complex as a catalyst.12 The reactions of electron-deficient 1,2-bis(arylpropiolyl)benzenes and various electron-rich monoynes proceeded at room temperature to give 1,4-teraryls in good yields with good diastereo- and enantioselectivity (Scheme 7).

2.2. Reactions Involving Aryl Monoynes The high catalytic activity of the cationic rhodium(I)/axially biaryl bisphosphine catalysts allowed the use of sterically demanding and less reactive aryl monoynes instead of aryl diynes in the atroposelective [2+2+2] cycloaddition. The cationic rhodium(I)/(S)-H8-BINAP complex was able to catalyze the atroposelective [2+2+2] cycloaddition of acetyloxymethyl substituted aryl monoynes with two dialkyl acetylenedicarboxylates at room temperature to give the corresponding axially chiral biaryls with high yields and ee values (Scheme 8).13

Not only acetyloxymethyl substituted aryl monoynes but also phosphorus substituted aryl monoynes could be employed for the rhodium(I)-catalyzed atroposelective [2+2+2] cycloaddition. The reactions of electron-rich 1,6-diynes with electron-deficient alkynylphosphonates or alkynylphosphine oxides proceeded at room temperature


7

to give the corresponding biaryl phosphorus compounds with high yields and ee values (Scheme 9).14,15 Furthermore, excellent regioselectivity was observed when using unsymmetrical 1,6-diynes (Scheme 9).14 As the catalytic activity of this rhodium catalyst is very high, the reaction could be carried out even with 1 mol % of the catalyst without erosion of the product yield and ee value (Scheme 9).14

The atroposelective synthesis of axially chiral hydroxycarboxylic acid derivatives was also accomplished with high yields and ee values by the cationic rhodium(I)/(S)-BINAP complex-catalyzed [2+2+2] cycloaddition of α ,ω-diynes with 2-alkoxynaphthalene-derived alkynylesters (Scheme 10).16 Additionally, an axially chiral 1,3-teraryl was synthesized with good ee value by using (S)-SEGPHOS® as a ligand (Scheme 10).16

2.3. Double Cycloaddition Leading to C2-Symmetric Biaryls

C2-symmetric axially chiral biaryls are more important than unsymmetric chiral biaryls as basic skeletons of chiral ligands and catalysts. For the atroposelective synthesis of the C2-symmetric axially chiral biaryls, the rhodium(I)-catalyzed enantioselective double [2+2+2] cycloaddition of symmetric tetraynes with monoynes was examined. Pleasingly, the enantioselective double [2+2+2] cycloaddition of electron-rich tetraynes with two electron-deficient monoynes proceeded at room temperature to give the desired C2-symmetric axially chiral biaryl diesters with varying yields and ee values by using a cationic rhodium(I)/(S)-SEGPHOS® complex as a catalyst (Scheme 11).17

5 mol %[Rh(cod)2]BF4/

(S)-SEGPHOS

CH2Cl2, rt+

E = H, CO2MeR = H, Me

24–52%, 69–98% ee

R

R

O

O

E

CO2Me

CO2Me

OCO2Me

O

R

R

E

E

PPh2

PPh2

(S)-BINAP


(S)-BINAP

CH2Cl2, rtCO2R2

OR3

R1

Me+ZR1

Me

CO2R2

OR3

Z

>99%, 96% ee 95%, 91% ee >99%, 90% ee

CO2i-Pr

OMe

Me

Me

TsN

93%, 97% ee 90%, 74% ee 64%, 87% eeLigand = (S)-SEGPHOS

CO2i-PrMe

OMe

OMe

TsN

CO2i-Pr

OMe

Me

Me

CO2i-Pr

O

Me

Me

O

OMe

CO2i-Pr

OMe

Me

Me

O

CO2i-Pr

OMe

Ph

Me

O

Scheme 11. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of tetraynes with two monoynes

Scheme 10. Rhodium-catalyzed atroposelective synthesis of biaryl esters


8

PAr2

PAr2

(R)-tol-BINAP(Ar = 4-MeC6H4)

Ph2(O)PO

O

O

OP(O)Ph2

10 mol %[Rh(cod)2]BF4/(R)-tol-BINAP

R = P(O)Ph2 55%, 97% eeR = P(O)Ph2 91%, >99% eeR = PPh2 89%, >99% ee

CH2Cl2, rt

recrystallization

SiHCl3, Me2NC6H5

O

O

RR

O

O

CO2R

RO2C

CO2R

RO2C

OAc

OAc

Z

Z


(S)-SEGPHOS

CH2Cl2, rt+

OAc

OAc

CO2RZ

CO2R

Z = C(CO2Me)2, R = Et: 59%, >99% eeZ = CH2, R = Me: 30%, >99% ee

+ZMe

Me Me

P(O)(OEt)2

P(O)(OEt)2

P(O)(OEt)2

P(O)(OEt)2

Z

Me

Z

Me

Me

65–81%, >99% eeZ = O, NTs, NSO2(4-BrC6H4)

1–5 mol %[Rh(cod)2]BF4/

(R)-SEGPHOS

CH2Cl2, rt

+TsNMe

Me Me

CO2Et

CO2Et

CO2EtCO2Et

TsN

Me

TsN

Me

Me

54%, 98% ee


(R)-SEGPHOS

CH2Cl2, rt

Scheme 15. Enantioselective synthesis of an axially chiral biaryl bisphosphine via the rhodium-catalyzed [2+2+2] cycloaddition of a hexayne

Scheme 12. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of two 1,6-diynes with a 1,3-diyne

Scheme 13. Rhodium-catalyzed atroposelective synthesis of biaryl diphosphorus compounds

Scheme 14. Rhodium-catalyzed atroposelective synthesis of biaryl diesters

The cationic rhodium(I)/(S)-SEGPHOS® catalyst was also capable of catalyzing the enantioselective double [2+2+2] cycloaddit ion of two electron-deficient 1,6-diynes with electron-rich 1,3-diynes. The corresponding C2-symmetric axially chiral biaryls were obtained at room temperature with perfect enantioselectivity, although the yields were moderate (Scheme 12).17

The synthetically very useful C2-symmetric axially chiral biaryl phosphorus compounds could be synthesized by the rhodium(I)-catalyzed enantioselective double

[2+2+2] cycloaddition. The [2+2+2] cycloaddition of 1,6-diynes with a phosphonate-substituted 1,3-butadiyne proceeded at room temperature by using the cationic rhodium(I)/(R)-SEGPHOS® catalyst to give C2-symmetric axially chiral biaryl diphosphonates in good yields with perfect enantioselectivity (Scheme 13).18–20 The catalytic activity of this rhodium catalyst is very high so that the reaction could be carried out even with 1 mol % of the catalyst. A C2-symmetric axially chiral biaryl dicarboxylate could also be synthesized by using an ester-substituted 1,3-butadiyne instead of the phosphonate-substituted 1,3-butadiyne (Scheme 14).18


9

U n f o r t u n a t e l y , i n t h e a b o v e r h o d i u m ( I ) -catalyzed enantioselective intermolecular double [2+2+2] cycloaddition, a phosphine oxide-substituted 1,3-butadiyne could not be employed. In order to overcome this limitation, we designed the entropically favorable completely intramolecular double [2+2+2] cycloaddit ion. The [2+2+2] cycloaddit ion of a diphenylphosphinoyl-substituted hexayne in the presence of the cationic rhodium(I)/(R)-tol-BINAP catalyst proceeded at room temperature to give a C2-symmetric axially chiral biaryl bisphosphine oxide in moderate yield with high enantioselectivity (Scheme 15).21,22 Subsequent recrystallization and reduction of this bisphosphine oxide furnished the corresponding enantiopure bisphosphine (Scheme 15), which could be used as an effective chiral ligand for the rhodium(I)-catalyzed asymmetric hydrogenation and cycloaddition.21

3. Enantioselective Synthesis of Axially Chiral Hetero Biaryls

In the axially chiral biaryl synthesis through the [2+2+2] cycloaddition between aryl-substituted α,ω-diynes and monoynes, the use of isocyanates instead of monoynes furnished axially chiral 6-aryl-2-pyridones in high yields with high regio- and enantioselectivity (Scheme 16).23,24 In this reaction, the use of 2-halophenyl-substituted 1,6-diynes as a coupling partner and sterically demanding DTBM-SEGPHOS® as a ligand is crucial to attaining the high enantio- and regioselectivity.

On the other hand, the reactions of internal α,ω-diynes and ortho-substituted phenyl isocyanates in the presence of the cationic rhodium(I)/(R)-BINAP catalyst proceeded at room temperature to give enantioenriched N-aryl-2-

+ZMe

MeN O

R

ZMe

MeN

•O

R


(R)-BINAP

CH2Cl2, rt

N Oi-Pr

Me

Me

41%, 67% ee

MeO2CCO2Me

N OOMe

Me

Me

92%, 58% ee

MeO2CCO2Me

N OCl

Me

Me

78%, 56% ee

MeO2CCO2Me

N OBr

Me

Me

27%, 87% ee

MeO2CCO2Me

N OOMe

Me

Me

72%, 68% ee

MeOH2CCH2OMe

N OOMe

Me

Me

67%, 55% ee

Z

N•

O

R2

+


(R)-DTBM-SEGPHOS

CH2Cl2, –20 °C

R1

N

O

R1

Z

R2

PAr2

PAr2

O

O

O

O

(R)-DTBM-SEGPHOS

(Ar = 4-MeO-3,5-t-Bu2C6H2)

N

O

Cln-C8H17

75%, 90% ee

N

O

ClBn

81%, 87% ee

N

O

BrBn

83%, 85% ee

N

O

ClBn

89%, 92% ee

MeO2C

MeO2C

Scheme 17. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of diynes with aryl isocyanates

Scheme 16. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of aryl diynes with isocyanates


10

+N

CO2Et

N

CO2Et

E

O

O

Ph

PhE

76%, 98% ee


(S)-SEGPHOS

CH2Cl2, rtE

O

Ph

EO

Ph

E = CO2Me

10 mol %[Rh(cod)2]BF4/(S)-H8-BINAP

Z

R1

+

N

COR3

NZ

COR3

R2

R2

CH2Cl2, rt

R1

N

CO2Et

Me

Cl

93%, 98% ee 74%, 94% ee

80%, 99% ee

N

COR3

Me

Cl

85%, 76% ee

EtO2C

EtO2C

EtO2CEtO2C

EtO2C

EtO2C

N

COMe

Me

Cl

EtO2CEtO2C

EtO2C

EtO2C

N

COR3

Me

Br

EtO2CEtO2C

EtO2C

EtO2C

Scheme 18. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of an aryl diyne with a nitrile

Scheme 19. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of haloaryl diynes with nitriles

pyridones with axially chiral C–N bonds (Scheme 17).25,26 Phenyl isocyanates bearing coordinating substituents such as 2-methoxy and 2-chloro groups smoothly reacted with α,ω-diynes to give the corresponding N-aryl-2-pyridones in high yields, while ee values were moderate. Although the reaction of sterically demanding and coordinating 2-bromophenyl isocyanate with a 1,6-diyne was sluggish, the highest enantioselectivity was observed.

Not only axially chiral 2-pyridones but also axially chiral pyridines could be synthesized atroposelectively by the rhodium(I)-catalyzed [2+2+2] cycloaddition. The reaction of a 1,6-diyne, possessing a pentasubstituted phenyl at an alkyne terminus, with ethyl cyanoacetate in the presence of the cationic rhodium(I)/(S)-SEGPHOS®

catalyst afforded an axially chiral arylpyridine as a

single regioisomer in good yield with excellent ee value (Scheme 18).17

Axially chiral 3-(2-halophenyl)pyridines were successfully synthesized at room temperature in high yields with excellent ee values by the cationic rhodium(I)/(S)-H8-BINAP complex-catalyzed enantioselective [2+2+2] cycloaddition of ortho-halophenyl substituted α,ω-diynes with electron-deficient nitriles (Scheme 19).27 The ee values of the products derived from 1,7-diynes were higher than that from a 1,6-diyne. As with the reactions of ary-substituted 1,6-diynes and isocyanates, the use of 2-halophenyl-substituted 1,6-diynes as a coupling partner is crucial to attaining the high enantio- and regioselectivity.


11

+

38%, 98% ee

Me

Me

O

O N

CO2Et

N

N

CO2EtCO2Et

O

O

Me

Me


(R)-SEGPHOS

CH2Cl2, rt

Scheme 20. Rhodium-catalyzed atroposelective [2+2+2] cycloaddition of a tetrayne with two nitriles

In the axially chiral biaryl synthesis through the double [2+2+2] cycloaddition shown in Scheme 11, the use of ethyl cyanoacetate instead of monoynes furnished the corresponding C2-symmetric axially chiral pyridine with excellent enantioselectivity, although the yield of the desired C2-symmetric product was low due to the formation of undesired regioisomers (Scheme 20).17

Not only axially chiral P-P compounds but also axially chiral P-N compounds could be synthesized atroposelectively by the rhodium(I)-catalyzed [2+2+2]

cycloaddition. The reaction of a 1,6-diyne with a diphenylphosphinoyl-substituted isoquinolinyl acetylene proceeded at 80 °C by using the cationic rhodium(I)/(R)-H8-BINAP catalyst to give a diphenylphosphinoyl-substituted axially chiral 1-arylisoquinoline with high yield and ee value (Scheme 21).28 This product was derivatized to the corresponding axially chiral P-N ligand and isoquinoline N-oxide without racemization (Scheme 21), which could be used in the rhodium(I)-catalyzed hydroboration and the Lewis base-catalyzed allylation, respectively.28

P(O)Ph2

Me

TsNMe

Me

5 mol %[Rh(cod)2]BF4/(R)-H8-BINAP

(CH2Cl)2, 80 °C

88%, 95% ee

N

P(O)Ph2

+ MeMe

Me

P(O)Ph2

Me

MeMe

PPh2

Me

MeMe

HSiCl3Et3N mCPBA

N

N N+O–

TsN

TsN TsN

74%, 95% ee 78%, 95% ee

Scheme 21. Rhodium-catalyzed atroposelective synthesis of aryl isoquinoline derivatives


12


Ligand

CH2Cl2, rt+Z

Me

Me

NR12O

R2

NR12

Me

O

Z

Me

R2

R1 = i-Pr: 92%, >99% eeR1 = Et: 94%, >99% eeR1 = Me: 90%, >99% eeLigand = (S)-SEGPHOS

NR12

Me

O

Me

>99%, >99% eeLigand = (S)-BINAP

Ni-Pr2

Me

O

Me

96%, >99% eeLigand = (S)-BINAP

Ni-Pr2

Me

O

Me

Me

OMe

Me Me

Me

Me

BnO2CCO2Bn

BnO2CCO2Bn

BnO2CCO2Bn

81%, >99% eeLigand = (S)-SEGPHOS

Ni-Pr2

Me

O

O

Me

Me

OMe

Me

Z +

NSiMe3

R1

N

SiMe3

R1R3

O

R2

Z

R1

R1

O

R210 mol %

[Rh(cod)2]BF4/(S)-xyl-BINAP

CH2Cl2, rt

R3

N

SiMe3Me

Me

O

Ph

29%, 97% ee

MeO2CCO2Me

N

SiMe3Me

Me

O

PhPh

MeO2CCO2Me

79%, 97% ee

N

SiMe3

O

Et

Et

O

PhPh

62%, 96% ee

Ph

PAr2

PAr2

(R)-xyl-BINAP(Ar = 3,5-Me2C6H4)

Scheme 23. Rhodium-catalyzed atroposelective synthesis of benzamides

Scheme 22. Rhodium-catalyzed atroposelective synthesis of anilides

4. Enantioselective Synthesis of Axially Chiral Anilides and Benzamides

Anilides bearing a sterically demanding ortho-substituent are known to exist as atropisomers due to the high rotational barrier around the aryl-nitrogen single bond.29 We anticipated that the [2+2+2] cycloaddition of internal 1,6-diynes with readily prepared trimethylsilylynamides would afford sterically demanding trimethylsilyl-substituted anilides having

chiral C–N axis. Pleasingly, the desired axially chiral anilides were obtained at room temperature with high ee values by using a cationic rhodium(I)/(S)-xyl-BINAP complex as a catalyst, although the product yields highly depend on the substrates used (Scheme 22).30,31


13

2,6-Disubstituted N,N-dialkylbenzamides are also known to exist as atropisomers due to the high rotational barrier around the aryl-carbonyl single bond.32 This non-biaryl axial chirality could also be constructed atroposelectively by the rhodium(I)-catalyzed [2+2+2] cycloaddition. The reaction of internal 1,6-diynes with N,N-dialkylalkynylamides in the presence of the cationic rhodium(I)/(S)-SEGPHOS® or (S)-BINAP catalyst proceeded at room temperature to give the desired axially chiral benzamides in excellent yields with perfect enantioselectivity (Scheme 23).33

The simultaneous construction of both the aryl-carbonyl and aryl-aryl axial chirality was accomplished with excellent diastereo- and enantioselectivity by the cationic rhodium(I)/(S)-BINAP complex-catalyzed [2+2+2] cycloaddition of N,N-dialkylalkynylamide, bearing a 2-bromophenyl group at an alkyne terminus, with an internal 1,6-diyne (Scheme 24).33

5. Enantioselective Synthesis of Axially Chiral Spiranes

C2-Symmetric heterospiranes with the stable axial chirality are valuable structures for efficient chiral ligands because heteroatoms containing chiral spiranes readily coordinate with many metals to form well-defined chiral chelate complexes.34 The rhodium(I)-catalyzed [2+2+2] cycloaddition was successfully applied to the atroposelective spirane synthesis. The cationic rhodium(I)/(R)-SEGPHOS® or (R)-H8-BINAP complex-catalyzed intramolecular double [2+2+2] cycloaddition of bis-diynenitriles afforded enantioenriched C2-symmetric spirobipyridine ligands, although the product ee values were moderate (Scheme 25).35


Ligand

CH2Cl2, rt

NC

NC

Z

Z

O

O

R

R

ZZ

N

N

O

O

R

R

N

N

O

O

Ph

Ph

N

N

O

O

N

N

O

O

Me

Me

N

N

O

O

Ph

Ph

99%, 64% ee

Ligand = (R)-SEGPHOS98%, 49% ee

Ligand = (R)-H8-BINAP

70%, 47% eeLigand = (R)-H8-BINAP

90%, 45% eeLigand = (R)-H8-BINAP


(S)-BINAP

CH2Cl2, rt+O

Me

Me

Ni-Pr2O

86%, d.r. = >50:1, >99% ee

Br

Ni-Pr2O

O

MeBr

Me

Scheme 25. Rhodium-catalyzed atroposelective synthesis of spirobipyridines

Scheme 24. Rhodium-catalyzed diastereo- and enantioselective synthesis of a biarylamide


14

10 mol %[Rh(cod)2]BF4

(S)-BINAP

CH2Cl2, rtOO

Ph

Me

n-Bu

Me

O

n-Bu

O

R

83%single diastereomer

O

O

Ph

HPh

n-Bu

n-Bu

O

O

H

Me

Me

R2

OR2

O

Me Me

R1

R1

R2

OR2

O

R1

R1

or

O

O

R2

5–10 mol %[Rh(nbd)2]BF4/

dppp

+

Me

Me

CH2Cl2, rt

R1

R1

Me Me

CO2Me

OCO2Me

O

Me

Me

69%

Me Me

O

O

Me

Me

41%

Me MeCO2Me

OCO2Me

O

44%

Me MeOH

OH

Scheme 27. Rhodium-catalyzed diastereoselective [2+2+2] cycloaddition of a chiral hexayne

Scheme 26. Rhodium-catalyzed diastereoselective [2+2+2] cycloaddition of chiral tetraynes with two monoynes

6. Diastereoselective Synthesis of Axially Chiral Biaryls

The chirality transfer from centrochirality to axial chirality is also an attractive strategy for the asymmetric synthesis of biaryls, if the chiral compounds with centrochirality are readily available. Thus, we designed the diastereoselective double [2+2+2] cycloaddition of chiral tetraynes, derived from commercially available (R)-3-butyn-2-ol, with functionalized monoynes as shown in Scheme 26.36 Pleasingly, the desired reactions proceeded at room temperature by using a cationic rhodium(I)/dppp® complex as a catalyst to give the corresponding C2-symmetric axially chiral biaryls with perfect diastereoselecivity. Interestingly, the reactions with methyl propiolate afforded biaryls, possessing large dihedral angles, exclusively. On the contrary, that with propargyl alcohol afforded a biaryl, possessing small dihedral angle, exclusively.

The asymmetric synthesis of a configurationally stable oxygen-linked Geländer-type p-terphenyl has also been achieved in the cationic rhodium(I)/BINAP complex-catalyzed diastereoselective intramolecular double [2+2+2] cycloaddition of a chiral hexayne, derived from commercially available (R)-3-butyn-2-ol (Scheme 27).37 Centrochirality of the chiral hexayne perfectly induced the axial chirality to give the Geländer-type p-terphenyl as a single stereoisomer.

7. Conclusion This research article disclosed the rhodium(I)-catalyzed atroposelective [2+2+2] cycloaddition, developed in our research group, for the synthesis of axially chiral compounds including biaryls, hetero biaryls, teraryls, anilides, benzamides, and spiranes.38 We established that cationic rhodium(I)/axially chiral biaryl bisphosphine complexes are highly active and selective catalysts for a wide variety of the atroposelective [2+2+2] cycloaddition. In this catalyst system, the combination of electron-rich alkynes and electron-deficient unsaturated compounds (alkynes, ni tr i les , and isocyanates) is important to realize the highly chemoselective in te rmolecular cyc loaddi t ion . With respec t to stereoselectivity, the introduction of the coordinating functional groups to the substrates is important. Especially, electron-deficient and highly coordinating alkynylphosphonates and alkynylamides are the best-suited coupling partners, the use of which realized excellent chemo- and stereoselectivity. The present rhodium(I) catalyst system allows in situ generation of active catalysts from stable and commercially available rhodium(I)/diene complexes and axially chiral bisphosphine ligands. This feature is advantageous for catalyst tuning and convenient handling. The further development of new catalysts and reactions are waiting for the application to the synthesis of novel functional molecules.


15

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5405. b) T. Hayashi, Acc. Chem. Res. 2000, 33, 354.[2] G. Bringmann, C. Günther, M. Ochse, O. Schupp, S.

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[4] For selected recent reviews on the transition-metal-catalyzed [2+2+2] cycloaddition, see: a) S. Beeck, H. A. Wegner, Synlett 2017, 28, 1018. b) G. Domínguez, J. Pérez-Castells, Chem. Eur. J. 2016, 22, 6720. c) M. Amatore, C. Aubert, Eur. J. Org. Chem. 2015, 265. d) Y. Satoh, Y. Obora, Eur. J. Org. Chem. 2015, 5041. e) Transition-Metal-Mediated Aromatic Ring Construction, ed. by K. Tanaka, Wiley, Hoboken, 2013, part 1. f) N. Weding, M. Hapke, Chem. Soc. Rev. 2011, 40, 4525. g) G. Domínguez, J. Pérez-Castells, Chem. Soc. Rev. 2011, 40, 3430. h) B. R. Galan, T. Rovis, Angew. Chem. Int. Ed. 2009, 48, 2830. i) K. Tanaka, Chem. Asian J. 2009, 4, 508. j) J. A. Varela, C. Saá, Synlett 2008, 2571. k) T. Shibata, K. Tsuchikama, Org. Biomol. Chem. 2008, 6, 1317.

[5] a) A. Gutnov, B. Heller, C. Fischer, H.-J. Drexler, A. Spannenberg, B. Sundermann, C. Sundermann, Angew. Chem. Int. Ed. 2004, 43, 3795. b) T. Shibata, T. Fujimoto, K. Yokota, K. Takagi, J. Am. Chem. Soc. 2004, 126, 8382. c) K. Tanaka, G. Nishida. A. Wada, K. Noguchi, Angew. Chem. Int. Ed. 2004, 43, 6510.

[6] For a review of the atroposelective biaryl synthesis by the transition-metal-catalyzed [2+2+2] cycloaddition, see: K. Tanaka, Chem. Asian J. 2009, 4, 508.

[7] Y. Sato, K. Ohashi, M. Mori, Tetrahedron Lett. 1999, 40, 5231.

[8] F. E. McDonald, V. Smolentsev, Org. Lett. 2002, 4, 745.[9] a) Y. Sato, T. Nishimata, M. Mori, J. Org. Chem. 1994, 59,

6133. b) I. G. Stará, I. Starý, A. Kollárovič, F. Teplý, S. Vyskocil, D. Saman, Tetrahedron Lett. 1999, 40, 1993.

[10] a) K. Tanaka, K. Shirasaka, Org. Lett. 2003, 5, 4697. b) K. Tanaka, K. Toyoda, A. Wada, K. Shirasaka, M. Hirano, Chem. Eur. J. 2005, 11, 1145.

[11] For reviews of the rhodium(I)-catalyzed [2+2+2] cycloaddition for the synthesis of substituted benzenes, see: a) K. Tanaka, Y. Kimura, K. Murayama, Bull. Chem. Soc. Jpn. 2015, 88, 375. b) Y. Shibata, K. Tanaka, in Transition-Metal-Mediated Aromatic Ring Construction, ed. by K. Tanaka, Wiley, Hoboken, 2013, Chap. 4. c) Y. Shibata, K. Tanaka, Synthesis 2012, 44, 323. d) K. Tanaka, Synlett 2007, 1977. e) M. Fujiwara, I. Ojima, in Modern Rhodium-Catalyzed Organic Reactions, ed. by P. A. Evans, Wiley-VCH, Weinheim, 2005, Chap. 7.

[12] K. Tanaka, T. Suda, K. Noguchi, M. Hirano, J. Org. Chem. 2007, 72, 2243.

[13] K. Tanaka, G. Nishida, M. Ogino, M. Hirano, K. Noguchi, Org. Lett. 2005, 7, 3119.

[14] G. Nishida, K. Noguchi, M. Hirano, K. Tanaka, Angew. Chem. Int. Ed. 2007, 46, 3951.

[15] For the enantioselective synthesis of an axially chiral biaryl phosphine sulfide by the rhodium(I)-catalyzed [2+2+2] cycloaddition, see; A. Kondoh, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2007, 129, 6996.

[16] S. Ogaki, Y. Shibata, K. Noguchi, K. Tanaka, J. Org. Chem. 2011, 76, 1926.

[17] G. Nishida, N. Suzuki, K. Noguchi, K. Tanaka, Org. Lett. 2006, 8, 3489.

[18] G. Nishida, S. Ogaki, Y. Yusa, T. Yokozawa, K. Noguchi, K. Tanaka, Org. Lett. 2008, 10, 2849.

[19] For other examples of the synthesis of biaryl bisphosphine ligands via the rhodium(I)-catalyzed double [2+2+2] cycloaddition, see: a) S. Doherty, J. G. Knight, C. H. Smyth, R. W. Harrington, W. Clegg, Org. Lett. 2007, 9, 4925. b) S. Doherty, C. H. Smyth, R. W. Harrington, W. Clegg, Organometallics 2008, 27, 4837.

[20] For the enantioselective synthesis of chiral tetraphenylenes by the rhodium(I)-catalyzed double [2+2+2] cycloaddition, see: T. Shibata, T. Chiba, H. Hirashima, Y. Ueno, K. Endo, Angew. Chem. Int. Ed. 2009, 48, 8066.

[21] F. Mori, N. Fukawa, K. Noguchi, K. Tanaka, Org. Lett. 2011, 13, 362.

[22] For another example of the rhodium(I)-catalyzed atroposelective [2+2+2] cycloaddition of hexaynes, see: T. Shibata, T. Chiba, H. Hirashima, Y. Ueno, K. Endo, Heteroatom Chem. 2011, 22, 363.

[23] K. Tanaka, A. Wada, K. Noguchi, Org. Lett. 2005, 7, 4737.[24] For a review of the rhodium(I)-catalyzed [2+2+2]

cycloaddition for the synthesis of substituted heterocycles, see: K. Tanaka, Heterocycles 2012, 85, 1017.

[25] K. Tanaka, Y. Takahashi, T. Suda, M. Hirano, Synlett 2008, 1724.

[26] Rhodium(I) -ca ta lyzed a t ropose lec t ive [2+2+2] cycloaddition reactions of diynes with ortho-substituted phenyl isocyanates using chiral counter anions were reported. See: a) M. Augé, M. Barbazanges, A. T. Tran, A. Simonneau, P. Elley, H. Amouri, C. Aubert, L. Fensterbank, V. Gandon, M. Malacria, J. Moussa, C. Ollivier, Chem. Commun. 2013, 49, 7833. b) M. Augé, A. Feraldi-Xypolia, M. Barbazanges, C. Aubert, L. Fensterbank, V. Gandon, E. Kolodziej, C. Ollivier, Org. Lett. 2015, 17, 3754.

[27] K. Kashima, K. Teraoka, H. Uekusa, Y. Shibata, K. Tanaka, Org. Lett. 2016, 18, 2170.

[28] N. Sakiyama, D. Hojo, K. Noguchi, K. Tanaka, Chem. Eur. J. 2011, 16, 1428.

[29] For selected examples of the asymmetric synthesis of axially chiral anilides, see: a) T. Hata, H. Koide, N. Taniguchi, M. Uemura, Org. Lett. 2000, 2, 1907. b) O. Kitagawa, M. Kohriyama, T. Taguchi, J. Org. Chem. 2002, 67, 8682. c) J. Terauchi, D. P. Curran, Tetrahedron: Asymmetry 2003, 14, 587. d) D. J. Bennett, P. L. Pickering, N. S. Simpkins, Chem. Commun. 2004, 1392. e) O. Kitagawa, M. Takahashi, M. Yoshikawa, T. Taguchi, J. Am. Chem. Soc. 2005, 127, 3676. f) S. Brandes, M. Bella, A. Kjærsgaard, K. A. Jørgensen, Angew. Chem. Int. Ed. 2006, 45, 1147. g) K. Kamikawa, S. Kinoshita, H. Matsuzaka, S. Uemura, Org. Lett. 2006, 8, 1097. h) S. Shirakawa, K. Liu and K. Maruoka, J. Am. Chem. Soc. 2012, 134, 916.


16

[30] a) K. Tanaka, K. Takeishi, K. Noguchi, J. Am. Chem. Soc. 2006, 128, 4586. b) K. Tanaka, K. Takeishi, Synthesis 2007, 2920.

[31] The diastereo- and enantioselective construction of both the C–C and C–N axial chirality by the rhodium(I)-catalyzed [2+2+2] cycloaddition was reported. See: R. P. Hsung, R. Figueroa, W. L. Johnson, Org. Lett. 2007, 9, 3969.

[32] For selected examples of the asymmetric synthesis of axially chiral benzamides, see: a) S. Thayumanavan, P. Beak, D. P. Curran, Tetrahedron Lett. 1996, 37, 2899. b) H. Koide, M. Uemura, Chem. Commun. 1998, 2483. c) J. Clayden, L. W. Lai, Angew. Chem. Int. Ed. 1999, 38, 2556. d) R. Rios, C. Jimeno, P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc. 2002, 124, 10272. e) V. Chan, J. G. Kim, C. Jimeno, P. J. Carroll, P. J. Walsh, Org. Lett. 2004, 6, 2051. f) R. Miyaji, Y. Wada, A. Matsumoto, K. Asano, S. Matsubara, Beil. J. Org. Chem. 2017, 13, 1518.

[33] T. Suda, K. Noguchi, M. Hirano, K. Tanaka, Chem. Eur. J. 2008, 14, 6593.

[34] For selected early examples, see: a) A. S. C. Chan, W. Hu, C.-C. Pai, C.-P. Lau, Y. Jiang, A. Mi, M. Yan, J. Sun, R. Lou, J. Deng, J. Am. Chem. Soc. 1997, 119, 9570. b) M. A. Arai, T. Arai, H. Sasai, Org. Lett. 1999, 1, 1795. c) M. A. Arai, M. Kuraishi, T. Arai, H. Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907. d) Y. Fu, J.-H. Xie, A.-G. Hu, H. Zhou, L.-X. Wang, Q.-L. Zhou, Chem. Commun. 2002, 480. e) A.-G. Hu, Y. Fu, J.-H. Xie, H. Zhou, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed. 2002, 41, 2348. f) J.-H. Xie, L.-X. Wang, Y. Fu, S.-F. Zhu, B.-M. Fan, H.-F. Duan, Q.-L. Zhou, J. Am. Chem. Soc. 2003, 125, 4404.

[35] A. Wada, K. Noguchi, M. Hirano, K. Tanaka, Org. Lett. 2007, 9, 1295.

[36] A. Mori, T, Araki, K. Noguchi, K. Tanaka, Eur. J. Org. Chem. 2013, 6774.

[37] Y. Kimura, Y. Shibata, K. Tanaka, Chem. Lett. 2018, 47, 806.

[38] Recently, the enantioselective synthesis of axially chiral tribenzothiepin derivatives by the rhodium(I)-catalyzed [2+2+2] cycloaddition was reported. See: Y. Tahara, R. Matsubara, A. Mitake, T. Sato, K. S. Kanyiva, T. Shibata, Angew. Chem. Int. Ed. 2016, 55, 4552.

[39] SEGPHOS® is a registered trademark of TAKASAGO INTERNATIONAL CORPORATION. dppp® is a registered trademark of HOKKO CHEMICAL INDUSTRY CO., LTD.

Ken TanakaProfessor, DrDepartment of Chemical Science and Engineering, Tokyo Institute of Technology

Ken Tanaka obtained his bachelor’s degree (1990) from The University of Tokyo under the supervision of Professor Atsushi Ishizu and his master’s degree (1993) from The University of Tokyo under the supervision of Professor Koichi Narasaka. He joined Mitsubishi Chemical Corporation in 1993. During his organic process research at Mitsubishi, he obtained his doctor’s degree (1998) from The University of Tokyo under the supervision of Professor Takeshi Kitahara and had been working as a post-doctoral fellow at Massachusetts Institute of Technology under the supervision of Professor Gregory C. Fu (Nov 1999–Dec 2001). After going back to Mitsubishi, he moved to Tokyo University of Agriculture and Technology as an associate professor in Oct 2002. He promoted to a full professor in Apr 2009. In Apr 2014, he moved to Tokyo Institute of Technology as a full professor. His research is focused on the development of novel transition-metal-catalyzed reactions and their application to organic synthesis.

Author Information


17

TCI Related Products

Metal Complexes

Phosphine Ligands

2

ONi

OCH3

CH3

xH2O.

PPh2

PPh2O

O

O

O

P

Rh2

BF4

PAr2

PAr2Ar=

Me

Me

BF4Rh

PAr2

PAr2O

O

O

O

tBu

tBu

Ar= OMe

PAr2

PAr2Ar= Me

P CH2CH2CH2 P

P Rh

3

Cl

PPh2

PPh2O

O

O

O

PPh2

PPh2

IrCl

IrCl

PAr2

PAr2Ar=

Me

Me

Bis(2,4-pentanedionato)nickel(II) Hydrate

(= Ni(acac)2)25g, 100g, 500g

[N0096]

(S)-(-)-SEGPHOS®

200mg, 1g[S0929]

Triphenylphosphine25g, 100g, 500g

[T0519]

Bis[η-(2,5-norbornadiene)]rhodium(I) Tetrafluoroborate (= [Rh(nbd)2]BF4)

100mg[B2091]

(R)-(+)-XylBINAP200mg, 1g

[X0070]

Tris(triphenylphosphine)rhodium(I)Chloride (= RhCl(PPh3)3)

1g, 5g[T0931]

(R)-(+)-SEGPHOS®

200mg, 1g[S0930]

(S)-(-)-BINAP1g, 5g

[B1405]

Chloro(1,5-cyclooctadiene)iridium(I) Dimer(= [IrCl(cod)2])

250mg, 1g[C1807]

(S)-(-)-XylBINAP200mg, 1g

[X0071]

Bis(1,5-cyclooctadiene)rhodium(I) Tetrafluoroborate(= [Rh(cod)2]BF4)

100mg, 1g[B3961]

(R)-(-)-DTBM-SEGPHOS®

200mg, 1g[D4501]

(R)-(+)-TolBINAP1g, 5g

[T3152]

1,3-Bis(diphenylphosphino)propane (= dppp®)5g, 25g[B1138]


asymmetric synthesis of axially chiral compounds by ... · enantioselective synthesis of axially...

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