Recent Advances in Asymmetric Transfer · PDF fileMeO MeO N H N Me H H HN OH tubulosine O N H...

Recent Advances in Asymmetric Transfer Hydrogenation

Adam M. Azman8 March 2007

1

Chiral Secondary Alcohols and Amines• Chiral secondary alcohols and amines prevalent

• Important as intermediates

Me

Me Me

O

Me3Si

Me

Me Me

HO

Me3Si

Me

MeMe

HHHO H

or

Me

MeMe

HHH2C

(−)-β-cubebene(−)-cubebol

MeO

MeON

HN

MeH

H

HN

OH

tubulosine

O

NH

Me

CF3

HCl

fluoxetine hydrochloride(Prozac)

HO

OH

OMeMe

HN

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

NO

• 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 OMe

L3Ti

H

O

R1NO

R

S O OH

R1

"Evans Syn" Product

O MeLiMe

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

[RuCl2(p-cymene)]2(1S,2S)-N -(p-toluenesulfonyl)-1,2-

diphenylethylenediamine

iPrOH, KOH

Hashiguchi, S.; Fujii, A.; Takehara, K.; Ikariya, T.; Noyori, R.J. Am. Chem. Soc., 1995, 117, 7562-7563.

• Asymmetric alkene oxidation– Hydroboration

– Dihydroxylation

OsO4NMO

O

OO

MeMe

OHO

OO

MeMe

OHOH

OH

O

O

O

O

MeMe

MeMe

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

Rs

RL SnBu3

OH

Rs

RL

Felkin-Ahn ProductMe

OH

MeMe

OH

Me

OHMe

MeBH3•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– NaBH4 discovered in 1942 by Brown– LiAlH4 discovered in 1945 by Bond– Dissolving metal reduction

• Transition metal mediated reduction– Pioneered by Noyori

• Asymmetric Transfer Hydrogenation– Ru, Rh, Ir hydrides– η6-arene and diamine ligands– No hydrogen atmosphere– Isopropanol or formic acid/triethylamine as

stochiometric reducing agent

R R'

O O

H

Al

iPrO OiPr

R R'

O O

H

Al

iPrO OiPr

R R'

OH O Ph2P

PPh2

RuNH2

H2N Ph

Ph

Cl

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

Ar R

OH2

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

[RuCl2(p-cymene)]2(1S,2S)-N-(p-toluenesulfonyl)-1,2-


iPrOH, 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

NTsRu

H2N

R R

H

R1

O

R2

NTsRu

N

R R

H

O HH

R1

OH

R2*

NTsRu

HN

R R

OH

NTsRu

N

R R

H

O

R2R1

HH

O

NTsRu

H2N

R R

ClKOH

RuCl

Cl Cl

ClRu

(S)(S)

R

H2N 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

[RuCl2(p-cymene)]2(1S,2S)-N-(p-toluenesulfonyl)-1,2-


iPrOH, KOH

substrate:catalyst ~200:1

6

Mechanism of ATH• Solution phase computational study suggests role of solvent in reduction

Ru H

OHN

H CO

H

H

1.79 Å

1.32 Å

1.31 Å

1.04 Å 2.51 Å

Ru H

OHN

HC

O

H

H

H3C

O H

1.92 Å1.27 Å

1.34 Å1.40 Å

1.24 Å

2.02 Å

1.04 Å

RuH

OHN

HC

O

H

H

H3C

O H

2.06 Å

1.14 Å

1.42 Å1.02 Å

1.75 Å

1.65 Å

1.11 Å

RuH

OHN

HC

O

H

H

H3C

OH

H

O

CH3

1.14 Å

1.42 Å1.04 Å

1.28 Å

1.27 Å1.95 Å

1.06 Å

0.00 ps0.69 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.

NTsRu

H2N

R R

H

R1

O

R2

NTsRu

N

R R

H

OH

H

R1

OH

R2*

NTsRu

HN

R R

OH

NTsRu

N

R R

H

O

R2R1

HH

O

NTsRu

H2N

R R

H

R1

O

R2

NTsRu

N

R R

O

OH

H

R1

OH

R2*

NTsRu

HN

R R

HO

O

H

NTsRu

N

R R

H

O

R2R1

HH

CO

OH

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

RuO

NH

H RO

HH

H HH

H

H

H

RuO

NH

H O

R

HH

H HH

H

H

Addition to Siface of carbonyl

Addition to Reface 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, -N2, -NO2, -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

iPrOH - 53% yield, 72% eeHCOOH/NEt3 - >99% yield, 97% ee

MeO

n = 1iPrOH - 45% yield, 91% eeHCOOH/NEt3 - >99% yield, 99% ee

n = 2iPrOH - 65% yield, 97% eeHCOOH/NEt3 - >99% yield, 99% ee

O

nR

O

R = Me >99% yield, 98% eeR = Et 96% yield, 97% eeR = iPr 41% yield, 83% eeR = tBu <1% yield

Me

O

100% yield, 86% ee

O2N

Me

O

R = Me 53% yield, 91% eeR = OMe 24% yield, 89% ee

RN

Me

O

2-acetylpyridine99% yield, 91% ee



10

Scope of ATH• Diketones and β-keto esters

– 1,2-diketone: alkyl ketone preferential at low temp– 1,3-diketone: symmetrical anti-diol in high ee; unsymmetrical 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

OPh

OPh

OMe

O

10 °C

87% yield92% ee

Ph

OMe

OH

40 °C

78% yield95% ee

Ph

OHMe

OH

anti :syn - 98.6:1.4100% yield, >99% ee

MeO

MeON

Me

>99% yield95% ee

NBn

Me

72% yield77% ee

N

Me

99% ee

PPh

OPh

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.

OO O

O

anti :syn = 95:585% yield

Ph

O O

Me

ant i:syn = 56:4279% yield

Ph

O O

OEt Me

O O

OtBu

99% yield94% ee

99% yield68% ee

11







12

Pro-atropisomeric Phosphine Ligand• Noyori received 2001 Nobel Prize for H2 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)

Ph2P

PPh2

RuNH2

H2N Ph

Ph

Cl

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

Ar R

OH2

Ru catalyst

base Ar Me

OH

(R)

PAr2

PAr2

(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

PAr2

PAr2

(S)-BINAP

PAr2PAr2

BIPHEP

OPAr2

PAr2

DPBP

PPh2

O PPh2

Ph2P

OPPh2

(P)-Conformation (M)-Conformation

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

14

(From M enantiomer)

Ru

Ph2P

NH2

Cl

HN

PPh2

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.

OO OO

Ligand = (R)-BINAP98 % conv. 72 % ee

Ligand = DPBP>99 % conv. 99 % ee


Ligand = DPBP99 % conv. 99 % ee





R Me

O

R Me

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

KOtBu, iPrOH, rt, 24 h

Rh

Rh-Catalyst

PAr2PAr2

(R)-BINAP

OPAr2

PAr2

DPBP

(S)(S)

H2N Ph

PhH2N

+

SbF6-

(S,S)-DPEN

Noyori's Catalyst95% conv. 97% ee

Noyori's Catalyst53% conv. 91% ee

Noyori's Catalyst92% conv., 93% ee

NTsRu

H2N

Ph Ph

Cl

(R) (R)

Noyori's Catalyst

(R)

16







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

R1O

MeMe

OHN

R2

R1

R2

N

O

O

N

HN

R1O

MeMe

OHN

R2

R1

R2

R1

NHBoc

NH

O R2

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

BocHNNH

O

(S)Ph

Me

ORu-catalyst, ligand

NaOH, iPrOH

RuCl

Cl Cl

Cl

Ru-Catalyst

Ru

91% Conversion, 94% ee

OH

(S)Me

BocHN

NH

O

(R)

Ph

OH

95% Conversion, 93% ee

19

Amino Acid-Based Ligands• Ru(II)(η6-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

H2NCl O

O

H2NOMe

O

R2

-HCl

Ru

HNH2N O

OR2

OOMe

-MeOH

Ru

NH2N O

OR2

OR1R1 R1

RuCl

Cl Cl

ClRu

H2NOH

O

R1

-HCl

(S)

NHBoc

MeO

O

NO2

H2N (S)Me

OH

1) iPrOH, Δ, 1h

2) iPrONa, Ru-catalyst,ketoneiPrOH, rt, 1h

(S) Me

OH

Ketone (R=) Conversion (%) ee (%)

R

H 85 97m-Me 83 97o-F 90 92

m-OMe 86 973,5-OMe 82 97

3,4,5-OMe 45 99

RuCl

Cl Cl

ClRu

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 NHBoc, NHC(O)R, OH 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, LiClO4, 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.

R1

NHBoc

NH

O R2

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

NO NH

MeO

HO

OtBuMe

OLi

H

O

Ph Ph

OHLiO

Ru

NH N

OMe

OH

O

OtBuMeLi

H H

O Li O

RuH

N

NMe

R HO

OtBuMe

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-methylmorpholinei-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%H2N (S) Me

PhMe

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

ORu-catalyst, ligand

NaOH, iPrOHMe

OH

* RuCl

Cl Cl

ClRu

Ru-Catalyst

NH2

(S)MeO

NH

(R)

Ph

OH NH2

(R)MeO

NH

(S)

Ph

OH

Ligand A Ligand BLigand A - 95% yield, 93% ee (S)Ligand B - 91% yield, 93% ee (R)

23

Amino Acid-Based Ligands

R2

O

R1

Rh-catalyst, ligand

LiCl, iPrONa, iPrOHR2

OH

R1*

RhCl

Cl Cl

ClRh NHBoc

(S) NH

S

(S)

Ph

NHBoc(S)

MeNH

O

( R)

OH

RuCl

Cl Cl

ClRu

Ph

Me

O O O

Me

O

Me Me

Me MeOCatalyst 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 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







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)

H2N HN SHN C

OO

O

O

O

O

O

O

On = 3

Ph

O

Me

Ru-catalyst, ligand

HCOOH/NEt3, CH2Cl2 Ph (S)

OH

Me

Run # t (h) Conversion (%) ee (%)1 20 98 96.52 20 92 96.63 25 87 96.84 30 85 96.75 40 73 96.36 40 52 87

RuCl

Cl Cl

ClRu

Ru-Catalyst

O

R2R1

Ru-catalyst, ligand

HCOOH/NEt3, CH2Cl2(R)

OH

R2R1

R1 t (h) Conversion (%) ee (%)

o-Cl 24 > 99 95.5p-tBu 55 98 96.3

R2

HH

H CH2C(O)Ph 72 70 >99H (CH2)4C(O)Ph 72 67 >99

RuCl

Cl Cl

ClRu

Ru-Catalyst

O

OO

OCCCH2NHO

HNO

O O

O

CCH2NH

OCCH2NH

CCH2NHO

NH

NH

NH

S

S

S

HNO

O

HNO

O

HNO

O

(R)Ph

( R)

Ph

H2N

(R)Ph

(R)

Ph

H2N

(R)Ph

(R)

Ph

H2NO

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 CH2Cl2 in vacuo– Precipitate dendrimer with MeOH– Filter

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

O

OO

Ph

Ph

NH2

NH2

O

OO

Ph

Ph

n

n

**

ArSO2Cl, (iPr)2NEt

CH2Cl2, 0 °C - rt

O

OO

Ph

Ph

NH

NH2

O

OO

Ph

Ph

n

n

**

SO2Ar

Ph

O

Me

Ru-catalyst, ligand

HCOOH/NEt3, CH2Cl2, rt Ph

OH

Me*

n ConfigurationAr time (h) Conversion (%) ee (%) Configuration

0 4-CH3C6H4 (R,R) 20 95 96.8 R1 4-CH3C6H4 (R,R) 20 >99 96.6 R2 4-CH3C6H4 (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-CH3C6H4 (R,R) 20 75 94.6 R2 2,4,6-Et3-C6H2 (S,S) 20 93.0 91.7 S2 2,4,6-iPr3-C6H2 (S,S) 20 91.7 92.8 S2 1-naphthyl (S,S) 20 >99 96.3 S

RuCl

Cl Cl

ClRu

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)

H2N SHN C

OO

O

O

O

HN

O

MeR

Catalyst, ligand

"H2"-source Solvent

Catalyst "H2"-source Solvent R Conversion (%) ee (%)

(R)

OH

MeR

Ru HCOOH/NEt3 CH2Cl2 H >99 94

Ru HCOONa H2O H >99 88

Rh HCOONa H2O H >99 96

Rh HCOONa H2O p-OMe 95 94Rh HCOONa H2O o-OMe >99 81

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

O

99% Conversion97% ee

NMe

O

70% Yield91% ee

97% Yield72% ee

94% Yield52% ee

OEt

OO

Ph Me

ORu

Cl

Cl Cl

ClRu

Ru-Catalyst

RhCl

Cl Cl

ClRh

Rh-Catalyst

BnO

OBn

OBnBnO

Ligand

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

28







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)2P

(HO)2PO

O

(S)(S)

NH

NH

Me

Me(HO)2P

(HO)2PO

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

ORh-catalyst, ligand

tBuOK, 1:1 H2O:iPrOH(S) Me

OH

95% yield46% ee

Rh ClCl Rh (R)(R)

NH

NH

Me

Me(HO)2P

(HO)2PO

ORh-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)

NH2

NH2

1) 50% SO3 oleum0 °C - rt, 22 h

2) BaCO3

(R)(R)

NH2

NH2

SO3-

SO3-

Ba2+

TsCl, NaOH/SDSH2O/CH2Cl2, 0 °C - rt, 24 h

then Na2SO4(R)(R)

NHTs

NH2

SO3Na

SO3Na

C12H25OSO3NaSDS =

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% 75%)

• Surfactant required for satisfactory conversion

RuCl

Cl Cl

ClRu

O

R

R Yield (%) ee (%)p-Me 94 94p-F 88 92

O

n

n Yield (%) ee (%)1 66 832 21 98

O

R

R Yield (%) ee (%)87 9458 84

Br

HNO2

Ru-catalyst, ligand

H2O, HCO2Na, SDSR1 R2

O

R1 R2

OH

NHTs

NH2(R)(R)

SO3Na

SO3Na

Ru-Catalyst Ligand

C12H25OSO3Na

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

R1 R2

O Rh-catalyst, ligand

HCOONa, H2O R1 R2

OH

NHTs

NH2(S)

(S)

NH2

NH2

LigandRh-catalyst

OR2

R1

R1 R2 Yield (%) ee (%)

p-OMe H 92 96o-OMe H 90 88

p-F H 94 95p-Br H 92 94

H Br 91 97p-NO2 Br 82 90

O

88% yield97% ee

SMe

O

90% yield98% ee

RhCl

Cl Cl

ClRh

(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

OBr

(R)

OHBrRu-catalyst, ligand

HCOOH/NEt3, 28 °C

RuCl

Cl Cl

Cl

Ru-Catalyst

Ru NHTs

NH2(R)

(R)

Ligand

OOCHO

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)

OHBrR1

R2

R3

R1 R2 R3 Yield (%) ee(%)Surfactant

H H H SDS 87 94H H SDS 47 92OBn

H H H 2:1 SDS:CTAB 97 98H OMe H 2:1 SDS:CTAB 80 90

NO2 OBn 2:1 SDS:CTABH 87 93

H H H − 91 97H OMe H − 70 96

OBn H OBn − 82 95

OBrR1

R2

R3

catalyst, ligand

Surfactant, HCOONa, H2O

CH2Cl2cosolvent

RhCl

Cl Cl

ClRh

NHTs

NH2(R)

(R)

R4

R4

Ligand

Rh-CatalystCatalyst Ligand

RuCl

Cl Cl

Cl

Ru-Catalyst

C12H25OSO3Na

SDS

Ru

C16H33N

MeMe

Me

Br-

CTABA - R4 = SO3NaB - R4 = HC - R4 = NH2

Ru ARu A

Rh BRh BRh B

Rh CRh CRh C

36

(R,R)-Formoterol

• Long-acting, β2-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.

OBr

BnO

BH3-diethylaniline,(R,S)-aminoindanol

THF(R)

OHBr

BnONO2 NO2

OBr

BnO

Rh-catalyst, ligand

2:1 SDS:CTAB, HCOONa, H2O(R)

OHBr

BnO

87% yield, 93% ee

2.3 kg, 80% yield, 88% ee RhCl

Cl Cl

ClRh NHTs

NH2(R)

(R)

LigandRh-Catalyst

NO2 NO2

HO

OH

OMeMe

HN

NHCHO

(R,R)-formoterol

37

(R,R)-Formoterol

OHBr

BnO

MeOH, aq NaOH

98%BnO

O

OMe

BnHN

Me

1) neat, 90 °C

2) PtO2, H23) HCOOH

BnO

OH

OMeMe

BnN

NHCHO

NO2 NO2

1) Pd-C, H2, EtOH

2) L-tartaric acid, iPrOH85% HO

OH

OMeMe

HN

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 Et2O:hexanes– Add 1 eq. HCOOH– Ready for reuse

MeO

MeON

R

R Yield (%) ee (%)Me 97 95Et 68 92iPr 90 90

MeO

MeO SN

R Yield (%) ee (%)Me 97 65tBu 95 94

O O

R

97 949495

96 9485 94

RecycleExperiments

MeO

MeON+

RBn

R Yield (%) ee (%)Me 85 90Ph 94 95

N

R

Ru-catalyst, ligand, CTAB

HCOONa, H2O, 28 °C

NH

R

C16H33N

MeMe

Me

Br-

CTAB

NHTs

NH2(R)

(R)

SO3Na

SO3Na

Ru-Catalyst Ligand

RuCl

Cl Cl

ClRu

(S)

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

39







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

NN Me

BF4-

Me

[bmim][BF4] =butylmethylimidazolium tetraf luoroborate

41

ATH in Ionic Liquids• Synthesis of ionic liquid-supported precursor

H2NCl NHTs

PhPh

RuN NMe

Me

ClNNMe

Me

toluene, 110 °C

1)

2) NaBF4, CH2Cl2

N N

BF4-

MeMe

RuCl3

MeOH, 80 °C

BF4-

BF4-

RuCl Cl

ClRu

Cl

NNMe

Me Ph

NHTsH2N

Ph

DMF, rt

N NMe

Me

BF4-

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

42

ATH in Ionic Liquids

• Recovery procedure:– Extract – Et2O or hexanes– Wash – water– Dry in vacuo

H2NCl NHTs

PhPh

Ru

(R)

(R)

Me

Ocatalyst, [bmmim][PF6]

HCOOH/NEt3, 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%

H2NCl NHTs

PhPh

Ru

(R)

(R)BF4

-

N NMe

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

NNMe

Me

nBu

PF6-

[bmmim][PF6]

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

IonicLiquid

Cycle # Time (h) Conversion (%) ee (%)

[bmim][PF6] 1 31 97 962 50 92 953 95 46 89

[bmim][BF4] 40 <1 -[bmim][MeSO4] 48 19 85

[emim][OTf] 24 0 -

HydrophilicIonic Liquids

[bmim][NTf2] 1 27 98 962 21 58 96

[tmba][NTf2] 1 26 98 972 41 99 973 94 99 974 50 56 96

HydrophobicIonic Liquids

(S) Me

OHcatalyst, ionic liquid

HCOOH/NEt3

NNMe nBu

BF4-

[bmim][BF4]

NNMe Et

[emim][OTf ]

-O CF3SO

O

N+

Me

Me

Me

nBu

N-

CF3S

O

O

F3CS

O

O

[tmba][NTf2]

H2NCl NHTs

PhPh

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

AcknowledgmentsAcknowledgments

• Professor Crimmins• Crimmins Group Members• UNC Chemistry

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