18 noyori asymmetric hydrogenation reaction

Myers

Chem 115

The Noyori Asymmetric Hydrogenation Reaction

Reviews:

Mechanism:

Noyori, R. Angew. Chem. Int. Ed. 2013, 52, 79–92.

• Catalytic cycle:

1/n {[(R)-BINAP]RuCl2}n
2 CH3OH

Kitamura, M.; Nakatsuka, H. Chem. Commun. 2011, 47, 842–846.
Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3069.
Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40–73.

[(R)-BINAP]RuCl2(CH3OH)2
H2

Original Report by the Noyori Group:

OCH3
O

HCl
CH3OH

O
[(R)-BINAP]RuHCl(CH3OH)2

H2

CH3
2 CH3OH

H2 (100 atm)
O
CH3

O

OH O

RuCl2[(R)-BINAP] (0.05 mol %)
OCH3

OCH3

OCH3

CH3

CH3OH, 36 h, 100 °C

O
[(R)-BINAP]RuCl(CH3O)(CH3OH)2

96%, >99% ee

[(R)-BINAP]HClRu
O

OCH3

CH3

O
Noyori, R., Okhuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akuragawa, S.
J. Am. Chem. Soc. 1987, 109, 5856–5858.

OCH3

HO

O

CH3
2 CH3OH

CH3OH

[(R)-BINAP](CH3OH)ClRu
O
CH3

• Both enantiomers of BINAP are commercially available. Alternatively, both enantiomers can be

Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1993,
pp. 56–82.

prepared from the relatively inexpensive (±)-1,1'-bi-2-naphthol.

• The reduction of methyl 2,2-dimethyl-3-oxobutanoate proceeds in high yield and with high

enantioselectivity, providing evidence that the reduction proceeds through the keto form of the !-keto
ester. However, pathways that involve hydrogenation of the enol form of other !-keto esters cannot be
PPh2
PPh2

OH
OH

PPh2
PPh2

+

ruled out.

H2 (100 atm)
(±)-1,1'-Bi-2-naphthol

O
(R)-(+)-BINAP
20%

O

RuCl2[(R)-BINAP]–Ru

OCH3
CH3 CH3

CH3OH, 23 °C

(S)-(–)-BINAP
20%

CH3

OH
CH3

O

OCH3
CH3 CH3

99%, 96% ee

Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth. 1989, 67, 20–32.

Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345–350.

Andrew Haidle

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The Noyori Asymmetric Hydrogenation Reaction

• The use of a deuterated substrate provides further evidence that the reduction proceeds

Chem 115

• Of the two possible diastereomeric transition states for complexes with (R)-BINAP shown

through the keto tautomer. Enolization is rapid, so the deuterium is lost quickly. However,

below, the one leading to the (R) !-hydroxy ester allows the approach of the ketone at an

when the reaction was stopped at 1.3% conversion, the hydroxy ester product retained

unhindered quadrant (as represented by the light lower left quadrant of the circle).

80% of the deuterium at C-2, and no deuterium was incorporated at C-3.

O
O
O

O

OCH3

D NHAc

H2 (100 atm)

OH O

RuBr2[(R)-BINAP]

O

CH2Cl2

O

OCH3
D NHAc

P

Cl

P

O

O

CH3

H

CH3

OH O

(R)-BINAP

Ru

OCH3

OCH3

(R) !-hydroxy ester

Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.;
Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134–9135.

• A crystal structure of Ru(OCOCH3)2[(S)-BINAP] revealed that the rigid BINAP backbone forces
P

the phenyl rings attached to phosphorous to adopt the conformation depicted here (the napthyl

Cl

P

Ru
O

rings are omitted for clarity).

CH3

H
CH3O

OH O

(R)-BINAP

O

OCH3

(S) !-hydroxy ester

CH3

axial

equatorial

P Ru P

Ru(OCOCH3)2[(S)-BINAP]

Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36–56.

Reaction Conditions:
• Noyori has published conditions to prepare the active Ru-BINAP catalyst in one step from

commercially available [RuCl2(benzene)]2, and it can be used without a purification step.
Also, the reaction can be run at 4 atm/100 °C or 100 atm/23 °C.

• The two protruding equatorial P-phenyl groups allow a coordinating ligand access to only two

1/

2

[RuCl2(benzene)]2 + (R)-BINAP

DMF, 100 ºC

(R)-BINAP-Ru(II)

quadrants on the accessible face of Ru (the other face is blocked by BINAP's napthyl rings).
This situation is represented by a circle with two black quadrants where no coordination can occur.
Kitamura, M.; Tokunaga, M.; Okhuma, T; Noyori, R. Org. Synth. 1993, 71, 1–13.
Ohta, T.; Takaya, H.; Noyori, R. Inorg. Chem. 1988, 27, 566–569.

Andrew Haidle, Fan Liu

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The Noyori Asymmetric Hydrogenation Reaction

• The procedure involving in situ catalyst generation was found to be much more reliable. Also,

Chem 115

• These conditions have been improved on even further, with milder reaction conditions and
lower catalyst loadings.

reactions with this catalyst were more enantioselective and required less catalyst. The
following reaction was done on a 10-kg scale. Note the benzyl group is not removed.

H2 (50 psi), HCl (0.1 mol%)
O

H2 (4 atm), (R)-BINAP
O

O

BnO

OH O

[C6H6RuCl]2 (0.05 mol %)
OEt

BnO

CH3

OH O

Ru–(R)-BINAP (0.05 mol %)
Ot-Bu

OEt

EtOH, 100 °C, 6 h

(10.0 kg)

O

CH3OH, 40 °C, 8 h

CH3

Ot-Bu

97%, >97% ee

(9.7 kg)
96%, 97–98% ee
• The authors present kinetic data to show the dramatic increase in reaction rate that occurs
in the presence of a catalytic amount of strong acid, and they suggest that failed reactions

Beck, G.; Jendralla, H.; Kesseler, K. Synthesis 1995, 1014–1018.

may be a result of low levels of basic impurities. Note that the acid-sensitive t-Bu ester is
not cleaved under these conditions.

• A simplified, milder set of conditions that also features a catalyst available in one step from

commercially available BINAP and RuCl2•cyclooctadiene has been published. The reaction
proceeds at a sufficiently low H2 pressure (50 psi) to avoid reduction of trisubstituted olefins,

King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57,
6689–6691.

but not terminal olefins.

• Reduction of !-keto esters has been achieved at 1 atm of hydrogen using a catalyst

H2 (50 psi)
O
CH3

O
OCH3

CH3OH, 80 °C, 6 h

prepared in situ from BINAP, (COD)Ru(2-methylallyl)2, and HBr, all of which are

OH O

Ru–(S)-BINAP (0.2 mol %)

commercially available. No special reaction apparatus is necessary for this procedure;

CH3

OCH3

however, the catalyst loading is unusually high.

90%, 98% ee

H

H2 (1 atm)
O

N
CH3

CH3

O

OH O

Ru–(S)-BINAP (2 mol %)
OCH3

CH3
acetone, 50 °C, 3.5 h

OCH3

CH3
100%, 99% ee

(–)-Indolizidine 223AB
Genet, J. P.; Ratovelomanana-Vidal, V.; Caño de Andrade, M. C.; Pfister, X.; Guerreiro, P.;
Taber, D. F.; Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227–4230.
Taber, D. F.; Deker, P. B.; Silverberg, L. J. J. Org. Chem. 1992, 57, 5990–5994.

Lenoir, J. Y. Tetrahedron Lett. 1995, 36, 4801–4804.
Andrew Haidle, Fan Liu

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The Noyori Asymmetric Hydrogenation Reaction

Chem 115

Substrates:
• Chiral substrates:

• !-Keto esters are typically the best substrates. However, nearly any substrate that has an

OH O

ether or amine separated from a ketone by 1–3 carbons will be reduced to the corresponding

Ph

OEt
NHBoc

secondary alcohol with high yields and high enantioselectivities.
H2 (100 atm)
OH

O
X

R
OH

(R)-BINAP–Ru

X

H2

OH

(S)-BINAP–Ru

X

R

R

RuBr2[BINAP] (0.18 mol %)
OEt
EtOH, 23 °C, 145 h

NHBoc

OH O
Ph

X

R

OEt
NHBoc

OH
X

R

syn

OH

O
X

O

Ph

X

R

O

H2

R

OH
X

R

O

anti

X

R

X = OR, NR2

• The authors propose that the heteroatom is necessary because the substrate must function as a
bidentate ligand for Ru.

configuration of BINAP

% yield

syn : anti

R

98

>99:1

S

96

9:91

Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.;
Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629–631.
• The (R)-BINAP case represents a stereochemically
matched case, while the (S)-BINAP catalyzed case
has to override the inherent syn selectivity of the

• Example:

substrate:

RuCl2[(S)-BINAP] (0.1 mol%)
OEt

CH3
O

94%, 99.5% ee

Okhuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509–5512.

OCH3
H

H
Bn

NHBoc
H

O

EtOH, 30 °C, 100 h
2. AcOH, toluene, reflux

O
O

proposed T.S.

1. H2 (100 atm)
O

X
P
P Ru

O
• Analysis of the results show that for this substrate, catalyst control is >32:1, while the
H3C

substrate control is only 3:1.

Nishi, T.; Kitamura, M.; Okhuma, T.; Noyori, R. Tetrahedron Lett. 1988, 29, 6327–6330.
Andrew Haidle, Fan Liu

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Chem 115

The Noyori Asymmetric Hydrogenation Reaction

Dynamic Kinetic Resolution:

• The stereochemistry of the secondary alcohol is determined by the choice of catalyst, but

• Kinetic resolution of enantiomers occurs when the chiral catalyst reacts with one enantiomer much

the stereochemistry at the !-position is substrate dependent.

more rapidly than the other.
O
O

HO

OH

H2 (100 atm)
HO

RuCl2[(R)-BINAP]

CH3

O
HO

CH3

O

CH3

OCH3

RuBr2[(R)-BINAP]

CH3

CH3

OH O

H2 (100 atm)
CH3

OH O
OCH3

CH3

OCH3

CH3

CH3

EtOH
1:1
kS/kR = 64
49.5%, 92% ee

50.5%, 92% ee

O
• An inherent drawback to kinetic resolution is the fact that the maximum yield is 50% of

O

H2 (100 atm)
OCH3

HO

H

HO

O

H

O

OCH3

[RuCl(PhH)((R)-BINAP)]Cl

OCH3

(0.09 mol %)

enantiopure material.

99 : 1

Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1993,
pp. 56–82.
• Epimerizing systems can give rise to a dynamic kinetic resolution, where the maximum theoretical

yield is 100%.

• The preference for one diastereomer over the other can be rationalized by examining the likely

transition states for carbonyl reduction. If the reduction of the !-amino compound, below right, is
carried out in methanol instead of dichloromethane, the diastereoselectivity drops from
99 : 1 to 82 : 18.

O

OCH3
NHAc

CH3

kinv

kinv
O
CH3

H2 (100 atm)

O

O
OCH3
NHAc

RuBr2[(R)-BINAP] (0.4 mol %)

OH O
CH3

CH2Cl2, 15 °C, 50 h

kR,R

Ru

OH O
CH3

P,P = (R)-BINAP

O
O

H

H2 (100 atm)

CH2Cl2, 15 °C, 50 h

P
P

99%, 98% ee

kS,R

RuBr2[(R)-BINAP] (0.4 mol %)

X

OCH3
NHAc

OCH3

X
P
Ru
P

H3C
O
O H
O
N
H
H
CH3

H

CH3
O

P,P = (R)-BINAP

OCH3
NHAc

1%, >90% ee

• To achieve yields approaching 100%, isomerization must be rapid relative to reduction
(kinv > kS,R and kR,R).
Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.;
Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134–9135.

Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.;
Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134–9135.

• A detailed mathematical model of the dynamic kinetic resolution process has been
published.
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144–152.
Andrew Haidle

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Chem 115

The Noyori Asymmetric Hydrogenation Reaction

Other Ligands:

• Noyori has discovered a Ru–based catalyst, trans-RuCl2[(R)-xylbinap][(R)-diapen], that efficiently

• Burk's 1,2-bis(trans-2,5-diisopropylphospholano)ethane (i-Pr-BPE) is a useful ligand for the

reduces "-, !-, and #-amino ketones in a highly enantioselective fashion under mild conditions.

reduction of many !-keto esters, and the reaction conditions are milder than those originally

OCH3

reported by Noyori.

H2 (60 psi)
O

O

CH3

OCH3

CH3OH : H2O (9 : 1), 35 ºC

trans-RuCl2[(R)-xylbinap][(R)-diapen] =

OH O

(R,R)-i-Pr-BPE-RuBr2 (0.2 mol %)

Ar2 Cl H2
N
P
Ru
P Cl N

Ar2
H2

OCH3

CH3

OCH3
H
i-Pr

Ar = 3,5-(CH3)2-C6H3

100%, 99.3% ee
i-Pr

H2 (8 atm)

i-Pr

(R, R)-Ru catalyst (0.05 mol %)
(R,R)-i-Pr-BPE =

P

P

i-Pr

O

i-Pr

CH3
N

OH

t-BuOK (0.8 mol %)

CH3
N

i-PrOH, 25 °C

O

O

96 %, 99.8 % ee

Burk, M. J.; Harper, T. G. P.; Kalberg, C. S. J. Am. Chem. Soc. 1995, 117, 4423–4424.

• The mechanism of this reduction differs from the Ru-BINAP catalyst in that the adjacent nitrogen
is believed not to ligate to the Ru center.
• Using the [2.2]-PHANEPHOS ligand, mild, neutral conditions for the reduction of !-keto esters have
• This method allows for a practical synthesis of the antidepressent (R)-fluoxetine without the need

been developed.

for any chromatographic separations.
H2 (8 atm)

H2 (50 psi)
O

O

CH3

OH O

(S)-[2.2]-PHANEPHOS-Ru(TFA)2 (0.6 mol %)
OCH3

Bu4NI (5 mol %)

CH3

(S,S)-Ru catalyst (0.01 mol %)

O
OCH3

CH3OH : H2O, –5 °C, 18 h
100%, 96% ee

CH3

N

CH3

OH

t-BuOK (0.1 mol %)

CH3
N
CH3

i-PrOH, 25 °C, 5 h
96 %, 97.5 % ee

CF3

PPh2
(S)-[2.2]-PHANEPHOS =
PPh2

Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998,
39, 4441–4444.

O
H
• HCl
N
CH3
Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510–6511.
Andrew Haidle

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Chem 115

The Noyori Asymmetric Hydrogenation Reaction

• Seminal reports on the use of ruthenium based catalysts for the asymmetric reduction of ketones

Other Ligands and Other Substrates:

focused on the use of a chiral diamine in combination with BINAP derived bis-phosphine ligands.

• Ru catalysts have been applied to asymmetric reduction of acrylate derivatives.

• Application to the synthesis of a PDE-IV inhibitor:

• Production of 3-furoic acid using (S,S)-i-Pr-DuPhos:

O
F

[(S,S)-iPr-DuPhos Ru(TFA)2] (0.02 mol%)
H2 (150 psi), MeOH

O

H

F

O

OH

O

O

O

F

OH

S

S
N

OMOM
F3C CF3

(R)-3-furoic acid
>98% ee

P

O

N

O
i-Pr

Ru[(R)-Xyl-BINAP][(R)-diapen]Cl2
(0.1 mol%)
K2CO3, i-PrOH, THF

O

OH

F

OMOM
F3C CF3

99% ee

i-Pr
i-Pr

(S,S)-iPr-DuPhos =
P

O

i-Pr

MeO

OMe

P(Xyl)2
P(Xyl)2

O
F

i-Pr
Johnson, N. B.; Lennon, I. C.; Moran, P. H.; Ramsden, J. A. Acc. Chem. Res. 2007, 40, 1291–1299.

F

N

NH2
NH2

S
N

(R)-diapen

(R)-Xyl-BINAP

O

OMOM
F3C CF3

• A reduction of an !,"-unsaturated cabroxylic acid using (R)-[2.2]-PHANEPHOS enabled the large-

Chen, C.-Y.; Reamer, R. A.; Chilenski, J. R.; McWilliams, C. J. Org. Lett. 2003, 5, 5039–5042.

scale synthesis of the integrin inhibitor JNJ-26076713:

• A similar system was used in the production of the antidepressant, (S)-duloxetine.

Ru[(S)-PhanePhos][(R,R)-DPEN]
KOtBu, H2 (150 psi)
i-PrOH, 40 ºC

O
S
CO2H
Boc

N
N

1. Ru(COD)(CF2CO2)2 (0.1 mol%)
(R)-[2.2]-PHANEPHOS
H2 (10 bar), 40 ºC

CO2Et

N
CH3

CO2Et
N
CH3

93.4% ee

CO2H
Boc

OH
S

N

86% ee, >99% conversion
2. precipitation from toluene
71%, >99% ee

N

PPh2
PPh2

Ph

NH2

Ph

NH2
O

(S)-PhanePhos
Kinney, W. A.; Teleha, C. A.; Thompson, A. S.; Newport, M.; Hansen, K.; Ballentine, S.; Ghosh, S.;
Mahan, A. Grasa, G.; Zanotti-Gerosa, A.; Dinegen, J.; Schubert, C.; Zhou, Y.; Leo, G. C.;
McComsey, D. F.; Santulli, R. J.; Maryanoff, B. E. J. Org. Chem. 2008, 73, 2302–2310.

(R,R)-DPEN

S

NHCH3•HCl

(S)-duloxetine
Hems, W.; Rossen, K.; Reichert, D.; Kohler, K.; Perea, J. J. US Patent 0272390, 2005

Joseph Tucker

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Chem 115

The Noyori Asymmetric Hydrogenation Reaction

Examples in Total Synthesis:

H2 (200 psi)

• In all of the examples, the carbonyl carbon that is initally reduced is circled in the final product.

O

O

CH3
H2 (110 atm)
O

O

BnO

OEt

CH3

OEt

EtOH, 130 °C, 10 h
BnO

CH3OH, 45 °C, 24 h

94%, 94% ee

Ot-Bu
CH3

76%, 96% ee
S

N(CH3)2
N

CH3
O
CH3

O

CH3

CH3 O

OH
O

CH3

OH O

Dowex-50 resin

OH O

[RuCl2((S)-BINAP)]2•Et3N (0.2 mol %)
Ot-Bu

RuCl2[(S)-BINAP] (0.1 mol %)

H2N

HO

CH3
O

O

CH3

CH3
OH OH OH OH OH

Pateamine A

(–)-Roxaticin
Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer, A.;
Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237–12254.

Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753–1765.

O

H2 (50 psi)

O
OCH3

CH3

H2 (1500 psi)

OH O

O

Ru–(S)-BINAP (0.2 mol %)
OCH3

CH3OH, 80 °C, 6 h
84%, 98% ee

CH3

CH3

CH3

[RuCl(PhH)((R)-BINAP)]Cl (0.09 mol %)

O
OCH3

HO

CH2Cl2, 50 °C, 70 h

H

O
OCH3

99%, 93% ee

CH3
O
H

OH

O
O

HO

O

CH3

H

O

CH3

CH3

CH3
N

CH3

(+)-Brefeldin A
(+)-Codaphniphylline
Taber, D. F.; Silverberg, L. J.; Robinson, E. D. J. Am. Chem. Soc. 1991, 113, 6639–6645.
Heathcock, C. H.; Kath, J. C.; Ruggeri, R. B. J. Org. Chem. 1995, 60, 1120–1130.

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The Noyori Asymmetric Hydrogenation Reaction

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O

H2 (100 atm)

O
OCH3

PMBO

L-DOPA: First Industrial Application of Asymmetric Hydrogenation

OH O

Ru2Cl4[(S)-BINAP]•Et3N (1 mol %)

OCH3

PMBO

CH3OH, 23 °C, 70 h

OAc

90%, >95% ee
CH3O
H
CH3O

H3CO

CH3
OH
O

O
O

CO2H

AcNH

CO2H

NH2

CO2H

FK506
O

OH O

H

O
CH3 CH3

OCH3
OH

• Although the chirality of the "-hydroxy ester is lost in the final product, it is used to set two other
stereocenters.
LDA (2.5 equiv)

OH O
PMBO

H3CO

P

H3CO

P

(R,R)-DiPAMP

allyl bromide (3.5 equiv)
OCH3

HO

[Rh(cod)(R,R-dipamp)]BF4 H3CO

AcNH

N
H

CH3

PMBO

OH

OAc

L-DOPA

H3C

OH O

Chem 115

OCH3

THF, –78 °C ! 0 °C, 4 h
90 %

• (S)-3',4'-dihydroxyphenylalanine (L-DOPA) is used in the treatment of Parkinson's disease.

EtO
• Chelation control and steric shielding explain the
high diastereoselectivity of the allylation reaction.

H

R

O

Li
O

X–R'

Fráter, G.; Müller, U.; Günther, W. Tetrahedron 1984, 40, 1269–1277.
Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1984, 63, 109–120.

H

• This is the first successful industrial application of a homogeneous catalytic asymmetric

hydrogenation.
• William Knowles had developed the Rh-catalyzed enantioselective hydrogenation using (R,R)-

DiPAMP as a chiral ligand while working at Monsanto in the late 1970s.

PMBO
O

CH3

O

SnPh3

(1.8 equiv)

PMBO

(4:1 trans:cis)
H

• Knowles was awarded the 2002 Nobel Prize in Chemistry for this discovery.

O
CH3

BF3•OEt (1.1 equiv)
I

OH

CH2Cl2, –78 °C, 100 min

I

(5:1 diastereomeric mixture)
54%, >97% dr
(67% maximum yield for major diastereomer)

Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998–2007.
Knowles, W. S. Adv. Synth. Catal. 2003, 345, 3–13.

Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J. Am.
Chem. Soc. 1990, 112, 5583–5601.

Andrew Haidle, Danica Rankic

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The Noyori Asymmetric Hydrogenation Reaction

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Chem 115

Application in Industry

Mechanism:

• (R)-Warfarin synthesis:

A

H

X
product

P
P

*

H

Rh

Sol
Sol

substrate with
chelating group X

X

• An asymmetric hydrogenation was employed in the synthesis of (R)-warfarin, one of the most

commonly prescribed oral anticoagulant drugs in North America.
• Enantiomeric excess could be improved from 88% to 98% ee by recrystallization.

solvate complex

A
A

*

P
P

Rh

*

H

X
Sol

P
P

Rh

X

Rh(cod)OTf (0.1 mol%)
O

catalyst-substrate
complex

H
Rh-catalyzed Hydrogenation
(unsaturated mechanism)

O O

CH3

ONa Ph

(S,S)-Et-DuPhos

O

MeOH, i-PrOH
H2 (4 bar), 25 oC

ONa Ph

reductive
elimination

CH3

(R)-warfarin

>98%, 88% ee
H2

O O

oxidative addition
Robinson, A.; Li, H.-Y.; Feaster, J. Tetrahedron Lett. 1996, 37, 8321–8324.

H A

*

P
P

Rh

H

X

Sol
H
Rh-alkyl monohydride

migratory
insertion

*

P
H

Rh
P

A

• Sitagliptin:

X

• Sitagliptin (Januvia!) is a potent and selective DPP IV inhibitor for the treatment of type 2 diabetes

mellitus.
dihydride
complex

• The second-generation process route involves the hydrogenation of an unprotected "-

(amino)acrylamide.
• A catalytic amount of NH4Cl is required for high ee and turnover numbers.
• Evidence suggests that Rh-catalyzed hydrogenations operate through a mechanism by which

• Hydrogenation occurs through the imine tautomer.

substrate chelation occurs prior to hydrogen oxidative addition, although recently, studies with bulky

diphosphines have shown that oxidative addition can occur prior to substrate association.
F
Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633.

F

F
NH2 O

• The solvate complex, catalyst-substrate complex, and Rh-alkyl monohydride complexes have all

been observed and characterized.

F

[RhCl(cod)]2 (0.15 mol%)

N

N
N

N
CF3

(S,R)-tBu-JOSIPHOS
(0.155 mol%)
H2 (17 bar), NH4Cl
MeOH, 50 oC

• Enantioselectivity is highly dependent on temperature and H2 pressure.

F

NH2 O
N

N
F

N

N
CF3

98%, 95% ee
(>99.9% ee after recrystalization)

• Curtin-Hammett kinetics is operating under the reaction conditions: the minor diastereomer of the

catalyst-substrate complex undergoes hydrogenation to afford the major enantiomer of product.
Halpern, J. Science 1982, 217, 401–407.

Desai, A. A. Angew. Chem. Int. Ed. 2011, 50, 1974–1976.
Hansen, K. B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.; Rosner, T.;
Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.; Spindler, F.; Malan, C.; Grabowski, E. J. J.;
Armstrong, J. D. J. Am. Chem. Soc. 2009, 131, 8798–8804.
Danica Rankic

10

The Noyori Asymmetric Hydrogenation Reaction

Myers

Chem 115

• Pregabalin:
• Pregabalin (Lyrica!) is an anti-convulsive agent marketed for the treatment of a number of nervous

system disorders, including epilepsy, neuropathic pain, anxiety and social phobia.
[Rh(cod)((S)-TCFP)]BF4
(0.0037 mol%)

CN
i-Pr
CO2–

H2 (3.5 bar)
MeOH, 25 oC

H3N t-Bu

98%, 98% ee

t-Bu t-Bu
P
P
t-Bu

H3C
(S)-TCFP

NH2

CN
i-Pr

i-Pr
CO2–

CO2H

H3N t-Bu

Lyrica!

• Rh-catalyzed asymmetric hydrogenation replaced an enzymatic resolution
(lower cost of reagents, waste reduction and higher throughput)
• Trichickenfootphos (TCFP) is a P-chiral phosphine designed and
developed at Pfizer that allowed for high turnover numbers (> 27000) and
high ee.

Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J. J. Am. Chem. Soc. 2004,
126, 5966–5967.
• Anti-tumor antibiotic L-azatyrosine:
• An N-oxide was found to be necessary to prevent catalyst inhibition through pyridine coordination.

O
N

BnO

CO2CH3

[Rh(cod)((R,R)-Et-DUPHOS)]BF4
(5 mol%)
H2 (3 bar), MeOH, 48 oC, 80%

NHCbz

O
N

CO2CH3
NHCbz

BnO

83% ee
(>96% ee after recrystalization)

Zn, aq. NH4Cl
THF, 92%

N
BnO

CO2CH3
NHCbz

1. LiOH, THF, H2O
2. H2, Pd/C
aq. HCl, MeOH
82%

N
HO

CO2H
NH2

L-azatyrosine

Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 3, 3157–3159.

Danica Rankic

11