Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

Reviews: Mechanism:
1/n {[(R)-BINAP]RuCl2}n
Noyori, R. Angew. Chem. Int. Ed. 2013, 52, 79–92. • Catalytic cycle:
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
OCH3
Original Report by the Noyori Group: O
HCl
CH3OH O
[(R)-BINAP]RuHCl(CH3OH)2 CH3
H2
H2 (100 atm) 2 CH3OH
O O RuCl2[(R)-BINAP] (0.05 mol %) OH O
OCH3
CH3 OCH3 CH3 OCH3 O
CH3OH, 36 h, 100 °C
[(R)-BINAP]RuCl(CH3O)(CH3OH)2 [(R)-BINAP]HClRu
96%, >99% ee O
OCH3 CH3
O
OCH3
HO O
Noyori, R., Okhuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akuragawa, S. CH3OH
CH3 [(R)-BINAP](CH3OH)ClRu
J. Am. Chem. Soc. 1987, 109, 5856–5858.
2 CH3OH 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,

prepared from the relatively inexpensive (±)-1,1'-bi-2-naphthol. pp. 56–82.

• 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

OH PPh2 PPh2 ruled out.

+
OH PPh2 PPh2

H2 (100 atm)
O O RuCl2[(R)-BINAP]–Ru OH O
(±)-1,1'-Bi-2-naphthol (R)-(+)-BINAP (S)-(–)-BINAP
CH3 OCH3 CH3OH, 23 °C CH3 OCH3
20% 20% CH3 CH3 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

1
Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115
• The use of a deuterated substrate provides further evidence that the reduction proceeds • 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 H2 (100 atm) OH O
O RuBr2[(R)-BINAP] O Cl
OCH3 OCH3 P P
D NHAc D NHAc Ru (R)-BINAP OH O
O CH2Cl2 O
O O
H CH3 OCH3

CH3 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 Cl
P P
the phenyl rings attached to phosphorous to adopt the conformation depicted here (the napthyl OH O
Ru (R)-BINAP
rings are omitted for clarity). O O
H CH3 OCH3

CH3O CH3 (S) !-hydroxy ester

axial

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

Reaction Conditions:
Ru(OCOCH3)2[(S)-BINAP]

• 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 DMF, 100 ºC
1/ [RuCl2(benzene)]2 + (R)-BINAP (R)-BINAP-Ru(II)
2
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

2
Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115
• The procedure involving in situ catalyst generation was found to be much more reliable. Also, • These conditions have been improved on even further, with milder reaction conditions and

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

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

O O Ru–(R)-BINAP (0.05 mol %) OH O
H2 (4 atm), (R)-BINAP
O O [C6H6RuCl]2 (0.05 mol %) OH O CH3 Ot-Bu CH3 Ot-Bu
CH3OH, 40 °C, 8 h
BnO BnO
OEt EtOH, 100 °C, 6 h OEt 97%, >97% ee
(10.0 kg) (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
King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57,
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, 6689–6691.

but not terminal olefins.

• Reduction of !-keto esters has been achieved at 1 atm of hydrogen using a catalyst
H2 (50 psi)
prepared in situ from BINAP, (COD)Ru(2-methylallyl)2, and HBr, all of which are
O O Ru–(S)-BINAP (0.2 mol %) OH O
CH3 CH3 commercially available. No special reaction apparatus is necessary for this procedure;
OCH3 CH3OH, 80 °C, 6 h OCH3
however, the catalyst loading is unusually high.

90%, 98% ee

H H2 (1 atm)
O O Ru–(S)-BINAP (2 mol %) OH O
N CH3 CH3
OCH3 OCH3
acetone, 50 °C, 3.5 h
CH3 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. Lenoir, J. Y. Tetrahedron Lett. 1995, 36, 4801–4804.
Taber, D. F.; Deker, P. B.; Silverberg, L. J. J. Org. Chem. 1992, 57, 5990–5994.
Andrew Haidle, Fan Liu

3
Myers 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
secondary alcohol with high yields and high enantioselectivities. NHBoc

H2 (100 atm) syn

O O RuBr2[BINAP] (0.18 mol %)
OH O OH
X X X Ph OEt
R R R EtOH, 23 °C, 145 h
NHBoc
OH O
OH H2 O H2 OH
Ph OEt
R X (R)-BINAP–Ru R X (S)-BINAP–Ru R X NHBoc
OH O OH
X X X anti
R R R

X = OR, NR2

configuration of BINAP % yield syn : anti

• The authors propose that the heteroatom is necessary because the substrate must function as a R 98 >99:1

bidentate ligand for Ru. 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.
X
P
• The (R)-BINAP case represents a stereochemically
P Ru O OCH3
O
matched case, while the (S)-BINAP catalyzed case H
H
• Example: has to override the inherent syn selectivity of the Bn NHBoc

substrate: H

1. H2 (100 atm) proposed T.S.

RuCl2[(S)-BINAP] (0.1 mol%)
O O
EtOH, 30 °C, 100 h
OEt
CH3 O
2. AcOH, toluene, reflux • Analysis of the results show that for this substrate, catalyst control is >32:1, while the
O
H3C
94%, 99.5% ee substrate control is only 3:1.

Okhuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509–5512. Nishi, T.; Kitamura, M.; Okhuma, T.; Noyori, R. Tetrahedron Lett. 1988, 29, 6327–6330.

Andrew Haidle, Fan Liu

4
Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115
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 OH O OH O
O OH H2 (100 atm)
H2 (100 atm) O
CH3 OCH3 CH3 OCH3 CH3 OCH3
HO HO HO RuBr2[(R)-BINAP]
CH3 RuCl2[(R)-BINAP] CH3 CH3 CH3 CH3 CH3
EtOH
1:1
kS/kR = 64

50.5%, 92% ee 49.5%, 92% ee

O O H2 (100 atm) HO O HO O
H H
OCH3 [RuCl(PhH)((R)-BINAP)]Cl OCH3 OCH3
• An inherent drawback to kinetic resolution is the fact that the maximum yield is 50% of
(0.09 mol %)
enantiopure material.
99 : 1
Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1993,
pp. 56–82.
• The preference for one diastereomer over the other can be rationalized by examining the likely
• Epimerizing systems can give rise to a dynamic kinetic resolution, where the maximum theoretical
transition states for carbonyl reduction. If the reduction of the !-amino compound, below right, is
yield is 100%.
carried out in methanol instead of dichloromethane, the diastereoselectivity drops from

99 : 1 to 82 : 18.

O O H2 (100 atm) OH O
RuBr2[(R)-BINAP] (0.4 mol %)
CH3 OCH3 CH3 OCH3 X X
NHAc P P H3C
CH2Cl2, 15 °C, 50 h NHAc Ru O
P OCH3 Ru O O H
99%, 98% ee O P
O
kS,R H H N CH3
kinv kinv H
CH3 H
O
O O H2 (100 atm) OH O P,P = (R)-BINAP
P,P = (R)-BINAP
RuBr2[(R)-BINAP] (0.4 mol %)
CH3 OCH3 CH3 OCH3
NHAc CH2Cl2, 15 °C, 50 h NHAc
Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.;
1%, >90% ee
kR,R
Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134–9135.

• To achieve yields approaching 100%, isomerization must be rapid relative to reduction

• A detailed mathematical model of the dynamic kinetic resolution process has been
(kinv > kS,R and kR,R).
published.

Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.;
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144–152.
Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134–9135.
Andrew Haidle

5
Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115
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.

Ar2 Cl H2
P N
H2 (60 psi) OCH3
O O OH O trans-RuCl2[(R)-xylbinap][(R)-diapen] = Ru
(R,R)-i-Pr-BPE-RuBr2 (0.2 mol %) H
P Cl N
CH3 OCH3 CH3 OCH3 Ar2 H2 i-Pr
CH3OH : H2O (9 : 1), 35 ºC
Ar = 3,5-(CH3)2-C6H3
100%, 99.3% ee

H2 (8 atm)
i-Pr i-Pr
(R, R)-Ru catalyst (0.05 mol %)
(R,R)-i-Pr-BPE = P P O CH3 OH CH3
t-BuOK (0.8 mol %)
N N
i-Pr i-Pr
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

been developed. • This method allows for a practical synthesis of the antidepressent (R)-fluoxetine without the need
for any chromatographic separations.

H2 (8 atm)
H2 (50 psi)
O O (S)-[2.2]-PHANEPHOS-Ru(TFA)2 (0.6 mol %) OH O (S,S)-Ru catalyst (0.01 mol %)
O OH
CH3 OCH3 CH3 t-BuOK (0.1 mol %) CH3
CH3 OCH3 Bu4NI (5 mol %) N N
CH3OH : H2O, –5 °C, 18 h CH3 i-PrOH, 25 °C, 5 h CH3

100%, 96% ee
96 %, 97.5 % ee

PPh2 CF3
(S)-[2.2]-PHANEPHOS =
PPh2 O
H
N • HCl
CH3

Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998,
Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510–6511.
39, 4441–4444. Andrew Haidle

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Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115
Other Ligands and Other Substrates: • Seminal reports on the use of ruthenium based catalysts for the asymmetric reduction of ketones
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 O
F O Ru[(R)-Xyl-BINAP][(R)-diapen]Cl2 F O

F O (0.1 mol%) F OH
[(S,S)-iPr-DuPhos Ru(TFA)2] (0.02 mol%)
O O K2CO3, i-PrOH, THF
H2 (150 psi), MeOH H
OH OH S S
O O N N
OMOM OMOM
i-Pr
(R)-3-furoic acid F3C CF3 99% ee F3C CF3
P >98% ee
i-Pr
(S,S)-iPr-DuPhos = i-Pr
P
O
i-Pr MeO OMe F O
P(Xyl)2
F O
P(Xyl)2 N
i-Pr NH2
NH2 S
Johnson, N. B.; Lennon, I. C.; Moran, P. H.; Ramsden, J. A. Acc. Chem. Res. 2007, 40, 1291–1299. N
(R)-Xyl-BINAP (R)-diapen OMOM
F3C CF3
• A reduction of an !,"-unsaturated cabroxylic acid using (R)-[2.2]-PHANEPHOS enabled the large-
scale synthesis of the integrin inhibitor JNJ-26076713: Chen, C.-Y.; Reamer, R. A.; Chilenski, J. R.; McWilliams, C. J. Org. Lett. 2003, 5, 5039–5042.

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

O Ru[(S)-PhanePhos][(R,R)-DPEN] OH
CO2Et KOtBu, H2 (150 psi) CO2Et
S S
N i-PrOH, 40 ºC N
1. Ru(COD)(CF2CO2)2 (0.1 mol%) CH3 CH3
(R)-[2.2]-PHANEPHOS 93.4% ee
CO2H CO2H
N H2 (10 bar), 40 ºC N
Boc Boc
N 86% ee, >99% conversion N
2. precipitation from toluene Ph NH2
PPh2
71%, >99% ee

PPh2 Ph NH2

O
(S)-PhanePhos (R,R)-DPEN S
NHCH3•HCl

Kinney, W. A.; Teleha, C. A.; Thompson, A. S.; Newport, M.; Hansen, K.; Ballentine, S.; Ghosh, S.; (S)-duloxetine
Mahan, A. Grasa, G.; Zanotti-Gerosa, A.; Dinegen, J.; Schubert, C.; Zhou, Y.; Leo, G. C.;
Hems, W.; Rossen, K.; Reichert, D.; Kohler, K.; Perea, J. J. US Patent 0272390, 2005
McComsey, D. F.; Santulli, R. J.; Maryanoff, B. E. J. Org. Chem. 2008, 73, 2302–2310. Joseph Tucker

7
Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115
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 RuCl2[(S)-BINAP] (0.1 mol %) OH O

CH3 OEt CH3 OEt

Dowex-50 resin
H2 (110 atm) EtOH, 130 °C, 10 h
O O OH O
[RuCl2((S)-BINAP)]2•Et3N (0.2 mol %) 94%, 94% ee
BnO Ot-Bu BnO Ot-Bu
CH3OH, 45 °C, 24 h

76%, 96% ee CH3

S
N(CH3)2
N O CH3
CH3
O OH CH3 O
CH3
O HO H2N CH3
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.;

Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753–1765. Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237–12254.

H2 (50 psi) H2 (1500 psi)

O O OH O
Ru–(S)-BINAP (0.2 mol %) O O [RuCl(PhH)((R)-BINAP)]Cl (0.09 mol %) HO O
OCH3 OCH3 H
CH3OH, 80 °C, 6 h OCH3 CH2Cl2, 50 °C, 70 h OCH3

CH3 CH3 84%, 98% ee CH3 CH3 99%, 93% ee

CH3
O
OH O
H O
O CH3
HO O CH3
CH3
H CH3
CH3
N
(+)-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. Andrew Haidle

8
Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115
O O
H2 (100 atm)
OH O L-DOPA: First Industrial Application of Asymmetric Hydrogenation
Ru2Cl4[(S)-BINAP]•Et3N (1 mol %)
PMBO OCH3 PMBO OCH3
CH3OH, 23 °C, 70 h OH
OAc OAc
90%, >95% ee HO
H3CO [Rh(cod)(R,R-dipamp)]BF4 H3CO

CH3O CH3
H OH NH2 CO2H
CH3O O AcNH CO2H AcNH CO2H
O
H3C L-DOPA
O N FK506
CH3 H
O
OH O
H
OCH3
O
CH3 CH3 H3CO P
OH

• Although the chirality of the "-hydroxy ester is lost in the final product, it is used to set two other H3CO P
stereocenters.

LDA (2.5 equiv)

OH O OH O
allyl bromide (3.5 equiv) (R,R)-DiPAMP
PMBO OCH3 PMBO OCH3
THF, –78 °C ! 0 °C, 4 h

90 %

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

• Chelation control and steric shielding explain the
H
high diastereoselectivity of the allylation reaction.
Fráter, G.; Müller, U.; Günther, W. Tetrahedron 1984, 40, 1269–1277. X–R'
Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1984, 63, 109–120.
O
R Li
O • This is the first successful industrial application of a homogeneous catalytic asymmetric
H 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.

CH3 SnPh3 (1.8 equiv)

PMBO O PMBO OH • Knowles was awarded the 2002 Nobel Prize in Chemistry for this discovery.
(4:1 trans:cis)
O H O
BF3•OEt (1.1 equiv) CH3
I 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

9
Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115
Mechanism: Application in Industry

• (R)-Warfarin synthesis:

H A • An asymmetric hydrogenation was employed in the synthesis of (R)-warfarin, one of the most
X substrate with
P Sol X chelating group X commonly prescribed oral anticoagulant drugs in North America.
product Rh
H * P Sol
• Enantiomeric excess could be improved from 88% to 98% ee by recrystallization.
solvate complex
A
P X Rh(cod)OTf (0.1 mol%)
A Rh
* P O O O CH3 (S,S)-Et-DuPhos O O O CH3
P X H
Rh
* P Sol catalyst-substrate
H MeOH, i-PrOH
complex
ONa Ph H2 (4 bar), 25 oC ONa Ph
Rh-catalyzed Hydrogenation
>98%, 88% ee (R)-warfarin
(unsaturated mechanism)
H2
reductive oxidative addition
elimination
Robinson, A.; Li, H.-Y.; Feaster, J. Tetrahedron Lett. 1996, 37, 8321–8324.

H A
H A • Sitagliptin:
P X
Rh
* P
P
Rh
X • Sitagliptin (Januvia!) is a potent and selective DPP IV inhibitor for the treatment of type 2 diabetes
H
Sol
H migratory * P
mellitus.
insertion dihydride
Rh-alkyl monohydride • The second-generation process route involves the hydrogenation of an unprotected "-
complex
(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
F
Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633. F
NH2 O F
[RhCl(cod)]2 (0.15 mol%) NH2 O
N N
N N N
• The solvate complex, catalyst-substrate complex, and Rh-alkyl monohydride complexes have all F N (S,R)-tBu-JOSIPHOS N
(0.155 mol%) F N
been observed and characterized. CF3
H2 (17 bar), NH4Cl CF3
MeOH, 50 oC 98%, 95% ee
• Enantioselectivity is highly dependent on temperature and H2 pressure. (>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. 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.;
Halpern, J. Science 1982, 217, 401–407. 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
Myers The Noyori Asymmetric Hydrogenation Reaction 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 NH2
CN CN
(0.0037 mol%)
i-Pr i-Pr i-Pr

CO2– H2 (3.5 bar) CO2– CO2H

MeOH, 25 oC
H3N t-Bu H3N t-Bu
98%, 98% ee Lyrica!

• Rh-catalyzed asymmetric hydrogenation replaced an enzymatic resolution

t-Bu t-Bu (lower cost of reagents, waste reduction and higher throughput)
P P
H3C t-Bu
• Trichickenfootphos (TCFP) is a P-chiral phosphine designed and
developed at Pfizer that allowed for high turnover numbers (> 27000) and
(S)-TCFP
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 [Rh(cod)((R,R)-Et-DUPHOS)]BF4 O
N CO2CH3 (5 mol%) N CO2CH3
NHCbz H2 (3 bar), MeOH, 48 oC, 80% NHCbz
BnO BnO

83% ee
(>96% ee after recrystalization)

Zn, aq. NH4Cl N CO2CH3 1. LiOH, THF, H2O N CO2H

THF, 92% NHCbz 2. H2, Pd/C NH2

BnO aq. HCl, MeOH HO
82% L-azatyrosine

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

Danica Rankic

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