Recent Advances in Asymmetric

Transfer Hydrogenation

Adam M. Azman

8 March 2007

1

Chiral Secondary Alcohols and Amines

•

Chiral secondary alcohols and amines prevalent

•

Important as intermediates

Me

Me

Me

O

Me

3

Si

Me

Me

Me

HO

Me

3

Si

Me

Me

Me

H

H

HO

H

or

Me

Me

Me

H

H

H

2

C

(−)-β-cubebene

(−)-cubebol

MeO

MeO

N

H

N

Me

H

H

HN

OH

tubulosine

O

N

H

Me

CF

3

HCl

fluoxetine hydrochloride

(Prozac)

HO

OH

OMe

Me

H

N

NHCHO

(R,R)-formoterol

Fürstner, A.; Hannen, P. Chem. Eur. J., 2006, 12, 3006-3019.

Hett, R.; Fang, Q. K.; Gao, Y.; Hong, Y.; Butler, H. T.; Nie, X.; Wald, S. Tetrahedron Lett., 1997, 38, 1125-1128.

2

Formation of Chiral Secondary Alcohols

•

Addition to aldehyde

–

Organometallic Nucleophile

–

Aldol

N

O

•

Epoxide opening

•

Asymmetric carbonyl/imine reduction

Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett., 1968, 18, 2199-2204.

Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.

J. Org. Chem.

, 2001, 66, 895-902.

R

S

O

Me

L

3

Ti

H

O

R

1

N

O

R

S

O

OH

R

1

"Evans Syn" Product

O

MeLi

Me

OH

Alexakis, A.; Vrancken, E.; Mangeney, P.; Chemla, F.

J. Chem. Soc. Perkin Trans. I

, 2000, 3352.3353.

Ph

Me

O

Ph

(S)

Me

OH

[RuCl

2

(p-cymene)]

2

(1S,2S)-N -(p-toluenesulfonyl)-1,2-

diphenylethylenediamine

i

PrOH, KOH

Hashiguchi, S.; Fujii, A.; Takehara, K.; Ikariya, T.; Noyori, R.

J. Am. Chem. Soc.

, 1995, 117, 7562-7563.

•

Asymmetric alkene oxidation

–

Hydroboration

–

Dihydroxylation

OsO

4

NMO

O

O

O

Me

Me

OH

O

O

O

Me

Me

OH

OH

OH

O

O

O

O

Me
Me

Me
Me

H

H

Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S.; Bennett, F.; Taylor, I. D.

J. Chem. Soc. Perkin Trans. I

, 1986, 5, 815-812.

Still, W. C.; Kempf, D.; Hauck, P. Tetrahedron Lett., 1986, 27, 2727-2730.

H

O

R

s

R

L

SnBu

3

OH

R

s

R

L

Felkin-Ahn Product

Me

OH

Me

Me

OH

Me

OH

Me

Me

BH

3

•THF

3

Reduction of C=X π-Bond

•

Meerwein-Ponndorf-Verley Reduction

–

Discovered in 1920s

–

Commonly aluminum or boron metal center

–

Metal-isopropoxide or -alkyl group as reducing agent

•

Metal-based reductions

–

NaBH

4

discovered in 1942 by Brown

–

LiAlH

4

discovered in 1945 by Bond

–

Dissolving metal reduction

•

Transition metal mediated reduction

–

Pioneered by Noyori

•

Asymmetric Transfer Hydrogenation

–

Ru, Rh, Ir hydrides

–

η

6

-arene and diamine ligands

–

No hydrogen atmosphere

–

Isopropanol or formic acid/triethylamine as
stochiometric reducing agent

R

R'

O

O

H

Al

i

PrO

O

i

Pr

R

R'

O

O

H

Al

i

PrO

O

i

Pr

R

R'

OH

O

Ph

2

P

P

Ph

2

Ru

N

H

2

H

2

N

Ph

Ph

Cl

Cl

(S)-BINAP/(S,S)-DPEN-Ru(II) Catalyst

Ar

R

O

H

2

Ru-catalyst

base

Ar

R

OH

Ponndorf, W. Z.; Angew. Chem., 1926, 39, 138.

Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc., 1995, 117, 2675-2676.

Ph

Me

O

Ph

(S)

Me

OH

[RuCl

2

(p-cymene)]

2

(1S,2S)-N-(p-toluenesulfonyl)-1,2-

diphenylethylenediamine

i

PrOH, KOH

Hashiguchi, S.; Fujii, A.; Takehara, K.; Ikariya, T.; Noyori, R.

J. Am. Chem. Soc.

, 1995, 117, 7562-7563.

Schlesinger, H. I.; Brown, H. C.; Hoekstra, H. R.; Rapp, L. R. J. Am. Chem. Soc., 1953, 75, 199.

Finholt, A. E.; Bond, A. C. Jr.; Schlesinger, H. I. J. Am. Chem. Soc., 1947, 69, 1199.

Barton, D. H. R. J. Chem. Soc., 1953, 1027-1040.

4

Outline

• Mechanism and scope of asymmetric transfer hydrogenation

• Pro-atropisomeric phosphine ligands

• Amino acid-based ligands

• Dendrimer-bound diamine ligands

• Asymmetric transfer hydrogenation in water

• Asymmetric transfer hydrogenation in ionic liquids

5

Mechanism of ATH

•

Several gas-phase computational studies indicate concerted pathway

NTs

Ru

H

2

N

R

R

H

R

1

O

R

2

NTs

Ru

N

R

R

H

O

H

H

R

1

OH

R

2

*

NTs

Ru

HN

R

R

OH

NTs

Ru

N

R

R

H

O

R

2

R

1

H

H

O

NTs

Ru

H

2

N

R

R

Cl

KOH

Ru

Cl

Cl

Cl

Cl

Ru

(S)(S)

R

H

2

N

NHTs

R

HCl

HCl

Samec, J. S. M.; Bäckvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev., 2006, 35, 237-248.

Ph

Me

O

Ph

(S)

Me

OH

[RuCl

2

(p-cymene)]

2

(1S,2S)-N-(p-toluenesulfonyl)-1,2-

diphenylethylenediamine

i

PrOH, KOH

substrate:catalyst ~200:1

6

Mechanism of ATH

•

Solution phase computational study suggests role of solvent in reduction

Ru

H

O

HN

H

C

O

H

H

1.79 Å

1.32 Å

1.31 Å

1.04 Å

2.51 Å

Ru

H

O

HN

H

C

O

H

H

H

3

C

O H

1.92 Å

1.27 Å

1.34 Å

1.40 Å

1.24 Å

2.02 Å

1.04 Å

Ru

H

O

HN

H

C

O

H

H

H

3

C

O

H

2.06 Å

1.14 Å

1.42 Å

1.02 Å

1.75 Å

1.65 Å

1.11 Å

Ru

H

O

HN

H

C

O

H

H

H

3

C

O

H

H

O

CH

3

1.14 Å

1.42 Å
1.04 Å

1.28 Å

1.27 Å

1.95 Å

1.06 Å

0.00 ps

0.69 ps

0.99 ps

1.08 ps

Handgraaf, J.-W.; Meijer, E. J. J. Am. Chem. Soc. ASAP.

7

Sources of Hydrogen

•

Isopropanol

– Oxidation yields acetone
– Transfer hydrogenation is reversible
– After extended reaction times,

stereoselectivity erodes

•

Formic acid/triethylamine

– Oxidation yields carbon dioxide
– Evolution of carbon dioxide renders

reaction irreversible

– Allows for increase in reaction

concentration

Samec, J. S. M.; Bäckvall, J.-E.; Andersson, P. G.;

Brandt, P. Chem. Soc. Rev., 2006, 35, 237-248.

Koike, T. ;Ikariya, T. Adv. Synth. Catal., 2004, 346, 37-41.

NTs

Ru

H

2

N

R

R

H

R

1

O

R

2

NTs

Ru

N

R

R

H

O

H

H

R

1

OH

R

2

*

NTs

Ru

HN

R

R

OH

NTs

Ru

N

R

R

H

O

R

2

R

1

H

H

O

NTs

Ru

H

2

N

R

R

H

R

1

O

R

2

NTs

Ru

N

R

R

O

O

H

H

R

1

OH

R

2

*

NTs

Ru

HN

R

R

HO

O

H

NTs

Ru

N

R

R

H

O

R

2

R

1

H

H

C

O

O

H

8

Origin of Stereoselectivity

•

Some influence from chiral diamine ligand

•

Significant contribution from arene ligand

– CH-π interaction stabilizes otherwise more-congested transition state

H

Ru

O

N

H

H

R

O

H

H

H

H

H

H

H

H

Ru

O

N

H

H

O

R

H

H

H

H

H

H

H

Addition to Si

face of carbonyl

Addition to Re

face of carbonyl

H

H

Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem. Int. Ed., 2001, 40, 2818-2821.

vs.

9

Scope of ATH

•

Mainly aryl-alkyl ketones (alkyl-alkynyl ketones)

– Alkyl group

•

Large functional group tolerance (-Cl, -OH, -CN, -N

2

, -NO

2

, -NHBOC)

•

Not sterically bulky

– Aryl group

•

High oxidation potential prefered

•

o-

Subtituted difficult

•

Electron withdrawing groups erode stereoselectivity

•

Heteroaromatic groups tolerated

Noyori, R.; Hashiguchi, S. Acc. Chem. Res., 1997, 30, 97-102.

Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett., 2000, 41, 9277-9280.

Me

O

i

PrOH - 53% yield, 72% ee

HCOOH/NEt

3

- >99% yield, 97% ee

MeO

n = 1
i

PrOH - 45% yield, 91% ee

HCOOH/NEt

3

- >99% yield, 99% ee

n = 2
i

PrOH - 65% yield, 97% ee

HCOOH/NEt

3

- >99% yield, 99% ee

O

n

R

O

R = Me

>99% yield, 98% ee

R = Et

96% yield, 97% ee

R = iPr

41% yield, 83% ee

R = tBu

<1% yield

Me

O

100% yield, 86% ee

O

2

N

Me

O

R = Me

53% yield, 91% ee

R = OMe 24% yield, 89% ee

R

N

Me

O

2-acetylpyridine

99% yield, 91% ee

3-acetylpyridine

99% yield, 89% ee

4-acetylpyridine

99% yield, 92% ee

10

Scope of ATH

•

Diketones and β-keto esters

– 1,2-diketone: alkyl ketone preferential at low temp
– 1,3-diketone: symmetrical Æ anti-diol in high ee; unsymmetrical Æ low ee
– β-Keto ester: ketone reduced over ester

•

Imines

– Protic solvents not tolerated
– Cyclic imines more selective than acyclic (except phosphinylimines)
– More reactive than ketones

Ph

O

Ph

O

Ph

O

Me

O

10 °C

87% yield

92% ee

Ph

O

Me

OH

40 °C

78% yield

95% ee

Ph

OH

Me

OH

anti

:sy n - 98.6:1.4

100% yield, >99% ee

MeO

MeO

N

Me

>99% yield

95% ee

NBn

Me

72% yield

77% ee

N

Me

99% ee

P

Ph

O

Ph

Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikaria, T. Org. Lett., 1999, 1, 1119-1121.

Koike, T.; Murata, K.; Ikariya, T. Org. Lett., 2000, 2, 3833-3836.

Cossy, J.; Eustache, F.; Dalko, P. I. Tetrahedron Lett., 2001, 42, 5005-5007.

Everaere, K.; Morteux, A.; Carpentier, J.-F. Adv. Synth. Catal., 2003, 345, 67-77.

Noyori, R.; Hashiguchi, S. Acc. Chem. Res., 1997, 30, 97-102.

Gladiali, S.; Alberico, E. Chem. Soc. Rev., 35, 226-236.

O

O

O

O

anti

:sy n = 95:5

85% yield

Ph

O

O

Me

ant i

:sy n = 56:42

79% yield

Ph

O

O

OEt

Me

O

O

OtBu

99% yield

94% ee

99% yield

68% ee

11

Outline

• Mechanism and scope of asymmetric transfer hydrogenation

• Pro-atropisomeric phosphine ligands

• Amino acid-based ligands

• Dendrimer-bound diamine ligands

• Asymmetric transfer hydrogenation in water

• Asymmetric transfer hydrogenation in ionic liquids

12

Pro-atropisomeric Phosphine Ligand

•

Noyori received 2001 Nobel Prize for H

2

hydrogenation

•

Utilizes optically pure BINAP ligands

•

BINAP can be resolved into pure (+) and (-) enantiomers due to high barrier
of rotation about the aryl-aryl bond (atropisomeric)

Ph

2

P

P

Ph

2

Ru

N

H

2

H

2

N

Ph

Ph

Cl

Cl

(S)-BINAP/(S,S)-DPEN-Ru(II) Catalyst

Ar

R

O

H

2

Ru catalyst

base

Ar

Me

OH

(R)

PAr

2

PAr

2

(S)-BINAP

Noyori, R.; Asymmetric Catalysis: Science and Opportunities. Nobel Lecture, 8 December 2001.

13

Pro-atropisomeric Phosphine Ligand

•

BIPHEP and DPBP have significantly lower barriers of rotation (tropisomeric
or pro-atropisomeric)

– Optically pure isomers cannot be isolated in solution
– Benzophenone (and derivatives) forms enantiomers in solid state

PAr

2

PAr

2

(S)-BINAP

PAr

2

PAr

2

BIPHEP

O

PAr

2

PAr

2

DPBP

PPh

2

O

PPh

2

Ph

2

P

O

PPh

2

(P)-Conformation

(M)-Conformation

Jing, Q.; Sandoval, C.; Wang, Z.; Ding, K. Eur. J. Org. Chem., 2006, 3606-3616.

14

(From M enantiomer)

Ru

Ph

2

P

N

H

2

Cl

H

N

P

Ph

2

Ph

Ph

O

Pro-atropisomeric Phosphine Ligand

•

Complexing DPBP to metal with diamine ligand forces single diastereomer
of metal complex

Jing, Q.; Sandoval, C.; Wang, Z.; Ding, K. Eur. J. Org. Chem., 2006, 3606-3616.

15

Pro-atropisomeric Phosphine Ligand

•

BINAP not conducive to ATH

•

Pro-atropisomeric DPBP successful for ATH – First pro-atropisomeric
phosphine used in ATH

•

Catalyst for alkyl-alkyl reductions?

Mikami, K.; Wakabayashi, K.; Yusa, Y.; Aikawa, K. Chem. Commun., 2006, 2365-2367.

Noyori, R.; Hashiguchi, S. Acc. Chem. Res., 1997, 30, 97-102.

O

O

O

O

Ligand

= (R)-BINAP

98 % conv. 72 % ee

Ligand

= DPBP

>99 % conv. 99 % ee

Ligand

= (R)-BINAP

61 % conv. 57 % ee

Ligand

= DPBP

99 % conv. 99 % ee

Ligand

= (R)-BINAP

97 % conv. 68 % ee

Ligand

= DPBP

95 % conv. 91 % ee

Ligand

= (R)-BINAP

96 % conv. 71 % ee

Ligand

= DPBP

97 % conv. 89 % ee

R

Me

O

R

Me

OH

Rh-catalyst, ligand, (S,S)-DPEN

KOtBu, iPrOH, rt, 24 h

Rh

Rh-Catalyst

PAr

2

PAr

2

(R)-BINAP

O

PAr

2

PAr

2

DPBP

(S)

(S)

H

2

N

Ph

Ph

H

2

N

+

SbF

6

-

(S,S)-DPEN

Noyori's Catalyst

95% conv. 97% ee

Noyori's Catalyst

53% conv. 91% ee

Noyori's Catalyst

92% conv., 93% ee

NTs

Ru

H

2

N

Ph

Ph

Cl

(R) (R)

Noyori's Catalyst

(R)

16

Outline

• Mechanism and scope of asymmetric transfer hydrogenation

• Pro-atropisomeric phosphine ligands

• Amino acid-based ligands

• Dendrimer-bound diamine ligands

• Asymmetric transfer hydrogenation in water

• Asymmetric transfer hydrogenation in ionic liquids

17

Amino Acid-Based Ligands

•

Initially, amido-oxazoline ligands were targeted

•

Poor yield, stereoselectivity in ATH

•

Noticed synthetic precursor provided better selectivity than target

N

O

O

N

HN

R

1

O

Me

Me

O

HN

R

2

R

1

R

2

N

O

O

N

HN

R

1

O

Me

Me

O

HN

R

2

R

1

R

2

R

1

NHBoc

N

H

O

R

2

OH

Pastor, I. M.; Västilä, P.; Adolfsson, H. Chem. Commun., 2002, 2046-2047.

18

Amino Acid-Based Ligands

•

Boc group & free hydroxyl group crucial

•

Amino acid stereocenter more important than amino alcohol stereocenter

•

1-amino-2-alcohols catalyze ATH with similar yield and ee

Pastor, I. M.; Västilä, P.; Adolfsson, H. Chem. Eur. J., 2003, 9, 4031-4045.

Bøgevig, A.; Pastor, I. M.; Adolfsson, H. Chem. Eur. J., 2004, 10, 294-302.

(S)

Me

OH

(S)

Me

BocHN

N

H

O

(S)

Ph

Me

O

Ru-catalyst, ligand

NaOH, iPrOH

Ru

Cl

Cl

Cl

Cl

Ru-Catalyst

Ru

91% Conversion, 94% ee

OH

(S)

Me

BocHN

N

H

O

(R)

Ph

OH

95% Conversion, 93% ee

19

Amino Acid-Based Ligands

•

Ru(II)(η

6

-arene) complexes known to facilitate peptide formation

•

Provides template to form ligand in situ, form catalyst in situ, and conduct
ATH in one pot

Ru

H

2

N

Cl

O

O

H

2

N

OMe

O

R

2

-HCl

Ru

HN

H

2

N

O

O

R

2

O

OMe

-MeOH

Ru

N

H

2

N

O

O

R

2

O

R

1

R

1

R

1

Ru

Cl

Cl

Cl

Cl

Ru

H

2

N

OH

O

R

1

-HCl

(S)

NHBoc

Me

O

O

NO

2

H

2

N

(S)

Me

OH

1) iPrOH, Δ, 1h

2) iPrONa, Ru-catalyst,

ketone
i

PrOH, rt, 1h

(S)

Me

OH

Ketone (R=)

Conversion (%)

ee

(%)

R

H

85

97

m

-Me

83

97

o

-F

90

92

m

-OMe

86

97

3,5-OMe

82

97

3,4,5-OMe

45

99

Ru

Cl

Cl

Cl

Cl

Ru

Ru-Catalyst

Haas, K.; Beck, W. Eur. J. Inorg. Chem., 2001, 2485-2488.

Västilä, P.; Wettergren, J.; Adolfsson, H. Chem. Commun., 2005, 4039-4041.

20

Amino Acid-Based Ligands

•

Mechanism elusive for several years

•

Key clues:

– Necessity of NH

Boc

, N

H

C(O)R, O

H

groups

– 3 equivalents of base necessary

– Additives

• Strong Lewis acid additives (Sc(OTf)

3

, Ti(OiPr)

4

) have negative effect on reactivity

• NaCl or KCl additive - similar to nonadditive reactions

• LiCl - higher stereoselectivity (also LiBr, LiI, LiClO

4

, LiOAc)

– Replacing NaOiPr with LiOiPr as base (no additive) increased stereoselectivity to

the same extent as LiCl additive

– No additive effect of LiCl with traditional transfer hydrogenation systems

Västilä, P.; Zaitsev, A. B.; Wettergren, J.; Privalov, T.; Adolfsson, H. Chem. Eur. J., 2006, 12, 3218-3225.

R

1

NHBoc

N

H

O

R

2

OH

21

Amino Acid-Based Ligands

•

Proposed mechanism:

•

Lithium ion activates and directs incoming ketone

•

Smaller lithium ion forms tighter transition state

•

Crown ethers erode stereoselectivity

•

CH-π interactions not as important

Ru

N

O

N

H

Me

O

H

O

OtBu

Me

OLi

H

O

Ph

Ph

O

H

LiO

Ru

N

H

N

O

Me

O

H

O

OtBu

Me

Li

H

H

O

Li O

Ru

H

N

N

Me

R

H

O

OtBu

Me

O

Me

Västilä, P.; Zaitsev, A. B.; Wettergren, J.; Privalov, T.; Adolfsson, H. Chem. Eur. J., 2006, 12, 3218-3225.

22

Amino Acid-Based Ligands

•

Previously, other product stereoisomer obtained through un-natural amino acid ligand

•

Modification from amide to thioamide, removal of alcohol reverses stereoselectivity

NHBoc

(S)

OH

O

1) N-methylmorpholine

i

-BuOC(O)Cl, -15 °C, 1h

2)

rt, 3 h, THF

BocHN

(S)

N

O

( S)

H

Lawesson's Reagent

THF, 60 °C, 8h

BocHN

(S)

N

S

( S)

H

97%

77%

H

2

N

(S)

Me

Ph

Me

Ph

Me

Ph

Pastor, I. M.; Västilä, P.; Adolfsson, H. Chem. Eur. J., 2003, 9, 4031-4045.

Zaitsev, A. B.; Adolfsson, H. Org. Lett., 2006, 8, 5129-5132.

Me

O

Ru-catalyst, ligand

NaOH, iPrOH

Me

OH

*

Ru

Cl

Cl

Cl

Cl

Ru

Ru-Catalyst

NH

2

(S)

Me

O

N

H

(R)

Ph

OH

NH

2

(R)

Me

O

N

H

(S)

Ph

OH

Ligand A

Ligand B

Ligand A - 95% yield, 93% ee (S)

Ligand B - 91% yield, 93% ee (R)

23

Amino Acid-Based Ligands

R

2

O

R

1

Rh-catalyst, ligand

LiCl, iPrONa, iPrOH

R

2

OH

R

1

*

Rh

Cl

Cl

Cl

Cl

Rh

NHBoc

(S)

N

H

S

(S)

Ph

NHBoc

(S)

Me

N

H

O

( R)

OH

Ru

Cl

Cl

Cl

Cl

Ru

Ph

Me

O

O

O

Me

O

Me

Me

Me

MeO

Catalyst A: 95% yield, 93% ee, (S)

Catalyst B: 88% yield, 95% ee, (R)

Catalyst A: 91% yield, 95% ee, (S)

Catalyst B: 88% yield, 96% ee, (R)

Catalyst A: 53% yield, 86% ee, (S)

Catalyst B: 61% yield, 97% ee, (R)

Catalyst A: 63% yield, 95% ee, (S)

Catalyst B: 56% yield, 91% ee, (R)

Catalyst A

Catalyst B

Pastor, I. M.; Västilä, P.; Adolfsson, H. Chem. Eur. J., 2003, 9, 4031-4045.

Zaitsev, A. B.; Adolfsson, H. Org. Lett., 2006, 8, 5129-5132.

24

Outline

• Mechanism and scope of asymmetric transfer hydrogenation

• Pro-atropisomeric phosphine ligands

• Amino acid-based ligands

• Dendrimer-bound diamine ligands

• Asymmetric transfer hydrogenation in water

• Asymmetric transfer hydrogenation in ionic liquids

25

Recoverable Diamine Ligands

•

Recoverable systems important with expensive or toxic heavy metal
complexes

•

Immobilization on supporting apparatus can allow for recovery

•

For ATH, two classes of dendrimers initially tested

Chen, Y.-C.; Wu, T.-F.; Deng, J.; Liu, H.; Jiang, Y.-Z.-, Choi, M. C. K.; Chan, A. S. C. Chem. Commun, 2001, 1488-1489.

Chen, Y.-C.; Wu, T.-F.; Deng, J.; Liu, H.; Xin, C.; Zhu, J.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. J. Org. Chem., 2002, 67, 5301-5306

(S)(S)

H

2

N

HN

S

H

N C

O

O

O

O

O

O

O

O

O

n = 3

Ph

O

Me

Ru-catalyst, ligand

HCOOH/NEt

3

, CH

2

Cl

2

Ph

(S)

OH

Me

Run #

t (h) Conversion (%) ee (%)

1

20

98

96.5

2

20

92

96.6

3

25

87

96.8

4

30

85

96.7

5

40

73

96.3

6

40

52

87

Ru

Cl

Cl

Cl

Cl

Ru

Ru-Catalyst

O

R

2

R

1

Ru-catalyst, ligand

HCOOH/NEt

3

, CH

2

Cl

2

(R)

OH

R

2

R

1

R

1

t (h) Conversion (%) ee (%)

o

-Cl

24

> 99

95.5

p

-tBu

55

98

96.3

R

2

H
H

H

CH

2

C(O)Ph

72

70

>99

H

(CH

2

)

4

C(O)Ph

72

67

>99

Ru

Cl

Cl

Cl

Cl

Ru

Ru-Catalyst

O

O

O

O

C

CCH

2

NH

O

HN

O

O

O

O

CCH

2

NH

O

CCH

2

NH

CCH

2

NH

O

N

H

N

H

N

H

S

S

S

HN

O

O

HN

O

O

HN

O

O

(R)

Ph

( R)

Ph

H

2

N

(R)

Ph

(R)

Ph

H

2

N

(R)

Ph

(R)

Ph

H

2

N

O

O

O

O

Ph

Ph

Ph

Ph

26

Recoverable Diamine Ligands

•

Late-stage tunability of ligand/dendrimer compatible with varying nature of
ketone substrates

•

Recovery procedure:

–

Remove CH

2

Cl

2

in vacuo

–

Precipitate dendrimer with MeOH

–

Filter

Liu, W.; Cui, X.; Cun, L.; Zhu, J.; Deng, J. Tetrahedron: Asymmetry, 2005, 16, 2525-2530.

O

O

O

Ph

Ph

NH

2

NH

2

O

O

O

Ph

Ph

n

n

*

*

Ar

SO

2

Cl, (iPr)

2

NEt

CH

2

Cl

2

, 0 °C - rt

O

O

O

Ph

Ph

NH

NH

2

O

O

O

Ph

Ph

n

n

*

*

SO

2

Ar

Ph

O

Me

Ru-catalyst, ligand

HCOOH/NEt

3

, CH

2

Cl

2

, rt

Ph

OH

Me

*

n

Configuration

Ar

time (h)

Conversion (%)

ee

(%)

Configuration

0

4-CH

3

C

6

H

4

(R,R)

20

95

96.8

R

1

4-CH

3

C

6

H

4

(R,R)

20

>99

96.6

R

2

4-CH

3

C

6

H

4

(R,R)

20

97.1

96.1

R

(95.4, 90.2, 83.7, 71.2) (97.5, 97.2, 97.5, 97.0)

3

4-CH

3

C

6

H

4

(R,R)

20

75

94.6

R

2

2,4,6-Et

3

-C

6

H

2

(S,S)

20

93.0

91.7

S

2

2,4,6-iPr

3

-C

6

H

2

(S,S)

20

91.7

92.8

S

2

1-naphthyl

(S,S)

20

>99

96.3

S

Ru

Cl

Cl

Cl

Cl

Ru

Ru-Catalyst

27

Recoverable Diamine Ligands

•

Minimize organic solvent – run ATH in water

– Switch to 1,2-diaminocyclohexane-based ligands and Cp* rhodium catalyst

system

•

Recovery procedure:

– Add hexanes
– Remove organic layer
– Add HCOOH to pH ~7

(R)(R)

H

2

N

S

H

N C

O

O

O

O

O

HN

O

Me

R

Catalyst, ligand

"H

2

"-source Solvent

Catalyst

"H

2

"-source

Solvent

R

Conversion (%)

ee

(%)

(R)

OH

Me

R

Ru

HCOOH/NEt

3

CH

2

Cl

2

H

>99

94

Ru

HCOONa

H

2

O

H

>99

88

Rh

HCOONa

H

2

O

H

>99

96

Rh

HCOONa

H

2

O

p

-OMe

95

94

Rh

HCOONa

H

2

O

o

-OMe

>99

81

(>99, 98, 99, 85, 97) (96, 95, 94, 95, 95, 95)

O

99% Conversion

97% ee

N

Me

O

70% Yield

91% ee

97% Yield

72% ee

94% Yield

52% ee

OEt

O

O

Ph

Me

O

Ru

Cl

Cl

Cl

Cl

Ru

Ru-Catalyst

Rh

Cl

Cl

Cl

Cl

Rh

Rh-Catalyst

BnO

OBn

OBn

BnO

Ligand

Jiang, L.; Wu, T.-F.; Chen, Y.-C.; Zhu, J.; Deng, J. Org. Biomol. Chem., 2006, 4, 3319-3324.

28

Outline

• Mechanism and scope of asymmetric transfer hydrogenation

• Pro-atropisomeric phosphine ligands

• Amino acid-based ligands

• Dendrimer-bound diamine ligands

• Asymmetric transfer hydrogenation in water

• Asymmetric transfer hydrogenation in ionic liquids

29

ATH in Water

• Increases atom economy and environmental friendliness

– Often no organic solvents during reaction

• Allows for ease of product separation, possibility of

catalyst recyclability

– Distillation or extraction

• Vigorously dried solvents and substrates not necessary

30

ATH in Water – Early Work

•

Bujoli group reported phosphonate-substituted diamine ligands with rhodium
metal-catalyzed ATH

•

High conversions (~ 95%), moderate ee (34-60%), cosolvent needed,
catalyst preparation under inert atmosphere

(R)

(R)

NH

NH

Me

Me

(HO)

2

P

(HO)

2

P

O

O

(S)

(S)

NH

NH

Me

Me

(HO)

2

P

(HO)

2

P

O

O

Maillet, C.; Praveen, T.; Janvier, P.; Minguet, S.; Evain, M.; Saluzzo, C.; Tommasion, M. L.; Bujoli, B. J. Org. Chem., 2002, 67, 8191-8196.

Me

O

Rh-catalyst, ligand

t

BuOK, 1:1 H

2

O:iPrOH

(S)

Me

OH

95% yield

46% ee

Rh

Cl
Cl Rh

(R)

(R)

NH

NH

Me

Me

(HO)

2

P

(HO)

2

P

O

O

Rh-Catalyst

Ligand

31

ATH in Water - Advances

•

Deng group developed o-sulfonated ligands with ruthenium catalyst and
HCOONa as hydrogen source

•

Purification difficult

(R)

(R)

NH

2

NH

2

1) 50% SO

3

oleum

0 °C - rt, 22 h

2) BaCO

3

(R)

(R)

NH

2

NH

2

SO

3

-

SO

3

-

Ba

2

+

TsCl, NaOH/SDS

H

2

O/CH

2

Cl

2

, 0 °C - rt, 24 h

then Na

2

SO

4

(R)

(R)

NHTs

NH

2

SO

3

Na

SO

3

Na

C

12

H

25

OSO

3

Na

SDS =

68%

72%

Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett., 2003,5, 2103-2106.

32

ATH in Water - Advances

•

Recyclability possible – retention of stereoselectivity, loss of conversion
(99% Æ 75%)

•

Surfactant required for satisfactory conversion

Ru

Cl

Cl

Cl

Cl

Ru

O

R

R

Yield (%) ee (%)

p

-Me

94

94

p

-F

88

92

O

n

n

Yield (%) ee (%)

1

66

83

2

21

98

O

R

R Yield (%) ee (%)

87

94

58

84

Br

H

NO

2

Ru-catalyst, ligand

H

2

O, HCO

2

Na, SDS

R

1

R

2

O

R

1

R

2

OH

NHTs

NH

2

(R)

(R)

SO

3

Na

SO

3

Na

Ru-Catalyst

Ligand

C

12

H

25

OSO

3

Na

SDS

(R)

Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett., 2003,5, 2103-2106.

33

ATH in Water – Recent Work

•

Shift to o-amine ligand and Cp* rhodium catalyst allows for increased yields,
stereoselectivities, and scope over previous work

•

Surfactant no longer necessary

R

1

R

2

O

Rh-catalyst, ligand

HCOONa, H

2

O

R

1

R

2

OH

NHTs

NH

2

(S)

(S)

NH

2

NH

2

Ligand

Rh-catalyst

O

R

2

R

1

R

1

R

2

Yield (%) ee (%)

p

-OMe

H

92

96

o

-OMe

H

90

88

p

-F

H

94

95

p-

Br

H

92

94

H

Br

91

97

p

-NO

2

Br

82

90

O

88% yield

97% ee

S

Me

O

90% yield

98% ee

Rh

Cl

Cl

Cl

Cl

Rh

(S)

Li, L.; Wu, J.; Wang, F.; Liao, J.; Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Green Chem., 2007,9, 23-25.

34

2-Bromo-1-arylethanols

•

Key intermediates in syntheses of β-adrenergic receptor agonists

•

Agonists used as bronchodilators in asthmatics

•

Non-aqueous synthesis by ATH previously hampered

O

Br

(R)

OH

Br

Ru-catalyst, ligand

HCOOH/NEt

3

, 28 °C

Ru

Cl

Cl

Cl

Cl

Ru-Catalyst

Ru

NHTs

NH

2

(R)

(R)

Ligand

O

OCHO

0%

73%

Cross, D. J.; Kenny, J. A.; Houson, I.; Campbell, L.; Walsgrove, T.; Wills, M. Tetrahedron: Asymmetry, 2001, 12, 1801-1806.

35

2-Bromo-1-arylethanols

•

Changing to aqueous system allows for reduction

Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett., 2003,5, 2103-2106.

Wang, F.; Liu, H.; Cun, L.; Zhu, J.; Deng, J.; Jiang, Y. J. Org. Chem., 2005, 70, 9424-9429.

Li, L.; Wu, J.; Wang, F.; Liao, J.; Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Green Chem., 2007,9, 23-25.

(R)

OH

Br

R

1

R

2

R

3

R

1

R

2

R

3

Yield (%)

ee

(%)

Surfactant

H

H

H

SDS

87

94

H

H

SDS

47

92

OBn

H

H

H

2:1 SDS:CTAB

97

98

H

OMe

H

2:1 SDS:CTAB

80

90

NO

2

OBn

2:1 SDS:CTAB

H

87

93

H

H

H

−

91

97

H

OMe

H

−

70

96

OBn

H

OBn

−

82

95

O

Br

R

1

R

2

R

3

catalyst, ligand

Surfactant, HCOONa, H

2

O

CH

2

Cl

2

cosolvent

Rh

Cl

Cl

Cl

Cl

Rh

NHTs

NH

2

(R)

(R)

R

4

R

4

Ligand

Rh-Catalyst

Catalyst Ligand

Ru

Cl

Cl

Cl

Cl

Ru-Catalyst

C

12

H

25

OSO

3

Na

SDS

Ru

C

16

H

33

N

Me

Me

Me

Br

-

CTAB

A - R

4

= SO

3

Na

B - R

4

= H

C - R

4

= NH

2

Ru

A

Ru

A

Rh

B

Rh

B

Rh

B

Rh

C

Rh

C

Rh

C

36

(R,R)-Formoterol

•

Long-acting, β

2

-agonist

•

Bronchodilator in treatment of patients with asthma and chronic bronchitis

•

(R,R)-enantiomer more active than other 3 possible stereoisomers

Wilkinson, H. S.; Tanoury, G. J.; Wald, S. A.; Senanayake, C. H. Org. Process Res. Dev., 2002, 6, 146-148.

Li, L.; Wu, J.; Wang, F.; Liao, J.; Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Green Chem., 2007,9, 23-25.

O

Br

BnO

BH

3

-diethylaniline,

(R,S)-aminoindanol

THF

(R)

OH

Br

BnO

NO

2

NO

2

O

Br

BnO

Rh-catalyst, ligand

2:1 SDS:CTAB, HCOONa, H

2

O

(R)

OH

Br

BnO

87% yield, 93% ee

2.3 kg, 80% yield, 88% ee

Rh

Cl

Cl

Cl

Cl

Rh

NHTs

NH

2

(R)

(R)

Ligand

Rh-Catalyst

NO

2

NO

2

HO

OH

OMe

Me

H

N

NHCHO

(R,R)-formoterol

37

(R,R)-Formoterol

OH

Br

BnO

MeOH, aq NaOH

98%

BnO

O

OMe

BnHN

Me

1) neat, 90 °C

2) PtO

2

, H

2

3) HCOOH

BnO

OH

OMe

Me

Bn

N

NHCHO

NO

2

NO

2

1) Pd-C, H

2

, EtOH

2)

L

-tartaric acid, iPrOH

85%

HO

OH

OMe

Me

H

N

NHCHO

(R,R)-formoterol

45%, 3 steps

+

Hett, R.; Fang, Q. K.; Gao, Y.; Hong, Y.; Butler, H. T.; Nie, X.; Wald, S. Tetrahedron Lett., 1997, 38, 1125-1128.

38

ATH in Water - Imines

•

Noyori reported ATH of imines not conducive to protic solvents

•

Deng achieved reduction in water with o-sulfonated diamine ligands

– Acyclic imines unsuccessful

•

Recovery procedure

–

Extract (3x) with 1:1 Et

2

O:hexanes

–

Add 1 eq. HCOOH

–

Ready for reuse

MeO

MeO

N

R

R

Yield (%)

ee

(%)

Me

97

95

Et

68

92

i

Pr

90

90

MeO

MeO

S

N

R

Yield (%)

ee

(%)

Me

97

65

t

Bu

95

94

O

O

R

97

94
94

95
96

94

85

94

Recycle

Experiments

MeO

MeO

N

+

R

Bn

R

Yield (%)

ee

(%)

Me

85

90

Ph

94

95

N

R

Ru-catalyst, ligand, CTAB

HCOONa, H

2

O, 28 °C

NH

R

C

16

H

33

N

Me

Me

Me

Br

-

CTAB

NHTs

NH

2

(R)

(R)

SO

3

Na

SO

3

Na

Ru-Catalyst

Ligand

Ru

Cl

Cl

Cl

Cl

Ru

( S)

Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun., 2006,1766-1768.

39

Outline

• Mechanism and scope of asymmetric transfer hydrogenation

• Pro-atropisomeric phosphine ligands

• Amino acid-based ligands

• Dendrimer-bound diamine ligands

• Asymmetric transfer hydrogenation in water

• Asymmetric transfer hydrogenation in ionic liquids

40

ATH in Ionic Liquids

• Ionic liquid: salt of organic cation with melting point near

ambient temperature

• Can stabilize/immobilize transition metal catalysts
• Negligible vapor pressure
• Tunable miscibility
• Easy recyclability

N

N

Me

BF

4

-

Me

[bmim][BF

4

] =

butylmethylimidazolium tetrafluoroborate

41

ATH in Ionic Liquids

•

Synthesis of ionic liquid-supported precursor

H

2

N

Cl

NHTs

Ph

Ph

Ru

N

N

Me

Me

Cl

N

N

Me

Me

toluene, 110 °C

1)

2) NaBF

4

, CH

2

Cl

2

N

N

BF

4

-

Me

Me

RuCl

3

MeOH, 80 °C

BF

4

-

BF

4

-

Ru

Cl

Cl

Cl

Ru

Cl

N

N

Me

Me

Ph

NHTs

H

2

N

Ph

DMF, rt

N

N

Me

Me

BF

4

-

Geldbach, T. J.; Dyson, P. J. J. Am. Chem. Soc., 2004, 126, 8114-8115.

42

ATH in Ionic Liquids

•

Recovery procedure:

–

Extract – Et

2

O or hexanes

–

Wash – water

–

Dry in vacuo

H

2

N

Cl

NHTs

Ph

Ph

Ru

(R)

(R)

Me

O

catalyst, [bmmim][PF

6

]

HCOOH/NEt

3

, 40 °C, 24 h

(R)

Me

OH

Cycle #

Catalyst A

(% yield,

% ee)

Catalyst B

(% yield,

% ee)

1

>99%, 99% >99%, 99%

2

>99%, 99% >99%, 99%

3

>99%, 99%

80%, 99%

4

99%, 99%

45%, 99%

5

96%, 99%

H

2

N

Cl

NHTs

Ph

Ph

Ru

(R)

(R)

BF

4

-

N

N

Me

Me

Catalyst A

Catalyst B

Cycle #

R =

Conversion (%)

ee

(%)

1

o

-Me

72%

97%

2

p

-Cl

99%

95%

3

H

99%

99%

4

H

98%

99%

1

Acetophenone

99%

97%

2

Tetralone

99%

97%

3

Benzaldehyde

90%

N/A

N

N

Me

Me

n

Bu

PF

6

-

[bmmim][PF

6

]

Geldbach, T. J.; Dyson, P. J. J. Am. Chem. Soc., 2004, 126, 8114-8115.

43

ATH in Ionic Liquids

•

Library of ionic liquids screened

– Hydrophilic ILs inhibit reaction
– Hydrophobic ILs slow reaction, but good ee

Joerger, J.-M.; Paris, J.-M.; Vaultier, M. Arkivoc, 2006, 152-160.

Me

O

Ionic

Liquid

Cycle #

Time (h) Conversion (%)

ee

(%)

[bmim][PF

6

]

1

31

97

96

2

50

92

95

3

95

46

89

[bmim][BF

4

]

40

<1

-

[bmim][MeSO

4

]

48

19

85

[emim][OTf]

24

0

-

Hydrophilic

Ionic Liquids

[bmim][NTf

2

]

1

27

98

96

2

21

58

96

[tmba][NTf

2

]

1

26

98

97

2

41

99

97

3

94

99

97

4

50

56

96

Hydrophobic

Ionic Liquids

(S)

Me

OH

catalyst, ionic liquid

HCOOH/NEt

3

N

N

Me

n

Bu

BF

4

-

[bmim][BF

4

]

N

N

Me

Et

[emim][OTf]

-

O

CF

3

S

O

O

N

+

Me

Me

Me

n

Bu

N

-

CF

3

S

O

O

F

3

C

S

O

O

[tmba][NTf

2

]

H

2

N

Cl

NHTs

Ph

Ph

Ru

(S)

(S)

Catalyst

44

Conclusions

• Role of solvent in transition state may be significant
• Pro-atropisomeric phosphine ligands can impart

stereocontrol

• Ligands based on naturally-occurring amino acids

suitable for ATH

• Catalyst can be recovered and reused
• ATH can be run in water or ionic liquid

• Future directions:

– Increase substrate:catalyst ratio
– Expand scope
– Improve recoverability further

45

Acknowledgments

Acknowledgments

•

Professor Crimmins

•

Crimmins Group Members

•

UNC Chemistry