18-noyori_asymmetric_hydrogenation_reaction.pdf

1. PPh2
PPh2
PPh2
PPh2
O
CH3 OCH3
O RuCl2[(R)-BINAP] (0.05 mol %)
OH
OH
OH
CH3 OCH3
O
(S)-(–)-BINAP
OCH3
CH3
O
HO
H2
[(R)-BINAP]RuCl(CH3O)(CH3OH)2
2 CH3OH
CH3OH
CH3
O O
OCH3
CH3 CH3
[(R)-BINAP]RuHCl(CH3OH)2
[(R)-BINAP]RuCl2(CH3OH)2
O
O
CH3
OCH3
[(R)-BINAP](CH3OH)ClRu
RuCl2[(R)-BINAP]–Ru
H2 (100 atm)
CH3OH, 23 °C
H2
HCl
2 CH3OH
CH3
OH O
OCH3
CH3 CH3
CH3
OCH3
O
O
O
O
CH3
OCH3
[(R)-BINAP]HClRu
CH3OH
2 CH3OH
Chem 115
The Noyori Asymmetric Hydrogenation Reaction
Myers
Reviews:
Noyori, R. Angew. Chem. Int. Ed. 2013, 52, 79–92.
Kitamura, M.; Nakatsuka, H. Chem. Commun. 2011, 47, 842–846.
Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40–73.
Original Report by the Noyori Group:
H2 (100 atm)
CH3OH, 36 h, 100 °C
96%, >99% ee
Noyori, R., Okhuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akuragawa, S.
J. Am. Chem. Soc. 1987, 109, 5856–5858.
Mechanism:
(±)-1,1'-Bi-2-naphthol (R)-(+)-BINAP
20%
20%
Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth. 1989, 67, 20–32.
• Catalytic cycle:
1/n {[(R)-BINAP]RuCl2}n
Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1993,
pp. 56–82.
Andrew Haidle
• Both enantiomers of BINAP are commercially available. Alternatively, both enantiomers can be
+
prepared from the relatively inexpensive (±)-1,1'-bi-2-naphthol.
99%, 96% ee
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
ruled out.
Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345–350.
•
Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3069.
1

2. Ru
Cl
H
O O
P
P
OCH3
CH3
Ru
Cl
H
O O
P
P
CH3
CH3O
CH3 OCH3
O
OH
CH3 OCH3
O
OH
(R) !-hydroxy ester
(S) !-hydroxy ester
• Of the two possible diastereomeric transition states for complexes with (R)-BINAP shown
below, the one leading to the (R) !-hydroxy ester allows the approach of the ketone at an
unhindered quadrant (as represented by the light lower left quadrant of the circle).
(R)-BINAP
(R)-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.
Kitamura, M.; Tokunaga, M.; Okhuma, T; Noyori, R. Org. Synth. 1993, 71, 1–13.
Andrew Haidle, Fan Liu
P Ru P
• A crystal structure of Ru(OCOCH3)2[(S)-BINAP] revealed that the rigid BINAP backbone forces
the phenyl rings attached to phosphorous to adopt the conformation depicted here (the napthyl
rings are omitted for clarity).
• The two protruding equatorial P-phenyl groups allow a coordinating ligand access to only two
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.
Ohta, T.; Takaya, H.; Noyori, R. Inorg. Chem. 1988, 27, 566–569.
Ru(OCOCH3)2[(S)-BINAP]
O
O
OCH3
O
O
NHAc
D
O
O
OCH3
O
OH
NHAc
D
CH2Cl2
RuBr2[(R)-BINAP]
H2 (100 atm)
• The use of a deuterated substrate provides further evidence that the reduction proceeds
through the keto tautomer. Enolization is rapid, so the deuterium is lost quickly. However,
when the reaction was stopped at 1.3% conversion, the hydroxy ester product retained
80% of the deuterium at C-2, and no deuterium was incorporated at C-3.
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.
axial
equatorial
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
1/2 [RuCl2(benzene)]2 + (R)-BINAP
DMF, 100 ºC
(R)-BINAP-Ru(II)
2

3. • These conditions have been improved on even further, with milder reaction conditions and
lower catalyst loadings.
• 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
may be a result of low levels of basic impurities. Note that the acid-sensitive t-Bu ester is
King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57,
6689–6691.
CH3 Ot-Bu
O O
CH3 Ot-Bu
OH O
H2 (50 psi), HCl (0.1 mol%)
Ru–(R)-BINAP (0.05 mol %)
CH3OH, 40 °C, 8 h
97%, >97% ee
not cleaved under these conditions.
Andrew Haidle, Fan Liu
O O
OEt
BnO
OH O
OEt
BnO
H2 (4 atm), (R)-BINAP
[C6H6RuCl]2 (0.05 mol %)
EtOH, 100 °C, 6 h
96%, 97–98% ee
• The procedure involving in situ catalyst generation was found to be much more reliable. Also,
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.
Beck, G.; Jendralla, H.; Kesseler, K. Synthesis 1995, 1014–1018.
• 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,
but not terminal olefins.
O O
OCH3
OH O
OCH3
CH3 CH3
N
CH3
CH3
H
H2 (50 psi)
Ru–(S)-BINAP (0.2 mol %)
CH3OH, 80 °C, 6 h
90%, 98% ee
(–)-Indolizidine 223AB
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.
• Reduction of !-keto esters has been achieved at 1 atm of hydrogen using a catalyst
prepared in situ from BINAP, (COD)Ru(2-methylallyl)2, and HBr, all of which are
commercially available. No special reaction apparatus is necessary for this procedure;
however, the catalyst loading is unusually high.
OCH3
O O
CH3 OCH3
OH O
CH3
H2 (1 atm)
Ru–(S)-BINAP (2 mol %)
acetone, 50 °C, 3.5 h
100%, 99% ee
Genet, J. P.; Ratovelomanana-Vidal, V.; Caño de Andrade, M. C.; Pfister, X.; Guerreiro, P.;
Lenoir, J. Y. Tetrahedron Lett. 1995, 36, 4801–4804.
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
(10.0 kg) (9.7 kg)
3

4. CH3
O
O
OEt
RuCl2[(S)-BINAP] (0.1 mol%)
O
O
H3C
1. H2 (100 atm)
EtOH, 30 °C, 100 h
2. AcOH, toluene, reflux
94%, 99.5% ee
• Example:
Okhuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509–5512.
• Chiral substrates:
OEt
O O
NHBoc
OEt
OH O
NHBoc
OEt
OH O
NHBoc
RuBr2[BINAP] (0.18 mol %)
Ph
Ph
Ph
syn
anti
H2 (100 atm)
EtOH, 23 °C, 145 h
configuration of BINAP % yield syn : anti
S
98
96
>99:1
9:91
• The (R)-BINAP case represents a stereochemically
substrate:
matched case, while the (S)-BINAP catalyzed case
has to override the inherent syn selectivity of the
• Analysis of the results show that for this substrate, catalyst control is >32:1, while the
substrate control is only 3:1.
Nishi, T.; Kitamura, M.; Okhuma, T.; Noyori, R. Tetrahedron Lett. 1988, 29, 6327–6330.
Substrates:
• !-Keto esters are typically the best substrates. However, nearly any substrate that has an
ether or amine separated from a ketone by 1–3 carbons will be reduced to the corresponding
R
O
X
H2 H2
(S)-BINAP–Ru
(R)-BINAP–Ru
X = OR, NR2
secondary alcohol with high yields and high enantioselectivities.
• The authors propose that the heteroatom is necessary because the substrate must function as a
bidentate ligand for Ru.
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.
Andrew Haidle, Fan Liu
proposed T.S.
R
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
R
O
R
O
X
X
R
OH
X
R
OH
R
OH
X
X
R
OH
X
R
OH
R
OH
X
X
O
O OCH3
H
Ru
H
P
P
X
Bn NHBoc
H
4

5. Dynamic Kinetic Resolution:
• Kinetic resolution of enantiomers occurs when the chiral catalyst reacts with one enantiomer much
more rapidly than the other.
CH3
HO
O
EtOH
CH3
HO
OH
CH3
HO
O
H2 (100 atm)
RuCl2[(R)-BINAP]
50.5%, 92% ee 49.5%, 92% ee
kS/kR = 64
• An inherent drawback to kinetic resolution is the fact that the maximum yield is 50% of
enantiopure material.
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%.
CH3 OCH3
O O
NHAc
CH3 OCH3
O O
NHAc
CH3 OCH3
OH O
NHAc
CH3 OCH3
OH O
NHAc
RuBr2[(R)-BINAP] (0.4 mol %)
H2 (100 atm)
CH2Cl2, 15 °C, 50 h
99%, 98% ee
1%, >90% ee
RuBr2[(R)-BINAP] (0.4 mol %)
H2 (100 atm)
CH2Cl2, 15 °C, 50 h
kinv
kinv
kS,R
kR,R
• 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.
Andrew Haidle
• The stereochemistry of the secondary alcohol is determined by the choice of catalyst, but
the stereochemistry at the !-position is substrate dependent.
CH3 OCH3
O O
CH3
CH3 OCH3
OH O
CH3
CH3 OCH3
OH O
CH3
O
OCH3
O HO
OCH3
O HO
OCH3
O
H
H
RuBr2[(R)-BINAP]
H2 (100 atm)
H2 (100 atm)
[RuCl(PhH)((R)-BINAP)]Cl
(0.09 mol %)
1 : 1
99 : 1
O
O OCH3
H
Ru
H
P
P
O
CH3
O O
N
Ru
H
P
P H3C
H
O
CH3
H
• 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.
P,P = (R)-BINAP
P,P = (R)-BINAP
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.
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
•
X X
5

6. Cl
Cl
Ar2
P
P
Ar2
Ru
H2
N
N
H2
OCH3
OCH3
H
i-Pr
CH3 OCH3
O
O
CH3 OCH3
O
O
Bu4NI (5 mol %)
CH3 OCH3
O
OH
P P
i-Pr
i-Pr
i-Pr
i-Pr
CH3 OCH3
O
OH
PPh2
PPh2
O
N
CH3
O
O
N
CH3
CH3
O
N
CH3
H
CF3
OH
N
CH3
CH3
OH
N
CH3
O
Other Ligands:
• Burk's 1,2-bis(trans-2,5-diisopropylphospholano)ethane (i-Pr-BPE) is a useful ligand for the
reduction of many !-keto esters, and the reaction conditions are milder than those originally
reported by Noyori.
(R,R)-i-Pr-BPE =
(R,R)-i-Pr-BPE-RuBr2 (0.2 mol %)
H2 (60 psi)
CH3OH : H2O (9 : 1), 35 ºC
100%, 99.3% ee
Burk, M. J.; Harper, T. G. P.; Kalberg, C. S. J. Am. Chem. Soc. 1995, 117, 4423–4424.
(S)-[2.2]-PHANEPHOS =
H2 (50 psi)
CH3OH : H2O, –5 °C, 18 h
100%, 96% ee
(S)-[2.2]-PHANEPHOS-Ru(TFA)2 (0.6 mol %)
Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998,
39, 4441–4444.
• Using the [2.2]-PHANEPHOS ligand, mild, neutral conditions for the reduction of !-keto esters have
been developed.
Andrew Haidle
Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510–6511.
• Noyori has discovered a Ru–based catalyst, trans-RuCl2[(R)-xylbinap][(R)-diapen], that efficiently
reduces "-, !-, and #-amino ketones in a highly enantioselective fashion under mild conditions.
trans-RuCl2[(R)-xylbinap][(R)-diapen] =
(R, R)-Ru catalyst (0.05 mol %)
t-BuOK (0.8 mol %)
H2 (8 atm)
i-PrOH, 25 °C
96 %, 99.8 % ee
• 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.
• This method allows for a practical synthesis of the antidepressent (R)-fluoxetine without the need
for any chromatographic separations.
(S,S)-Ru catalyst (0.01 mol %)
t-BuOK (0.1 mol %)
H2 (8 atm)
i-PrOH, 25 °C, 5 h
96 %, 97.5 % ee
• HCl
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
Ar = 3,5-(CH3)2-C6H3
6

7. Other Ligands and Other Substrates:
Joseph Tucker
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
Johnson, N. B.; Lennon, I. C.; Moran, P. H.; Ramsden, J. A. Acc. Chem. Res. 2007, 40, 1291–1299.
• Ru catalysts have been applied to asymmetric reduction of acrylate derivatives.
• Production of 3-furoic acid using (S,S)-i-Pr-DuPhos:
O
O
OH
O
O
OH
H
(R)-3-furoic acid
>98% ee
P
P
i-Pr
i-Pr
i-Pr
i-Pr
[(S,S)-iPr-DuPhos Ru(TFA)2] (0.02 mol%)
H2 (150 psi), MeOH
(S,S)-iPr-DuPhos =
N
CO2H
N
Boc
Ru(COD)(CF2CO2)2 (0.1 mol%)
(R)-[2.2]-PHANEPHOS
H2 (10 bar), 40 ºC
N
CO2H
N
Boc
A reduction of an !,"-unsaturated cabroxylic acid using (R)-[2.2]-PHANEPHOS enabled the large-
scale synthesis of the integrin inhibitor JNJ-26076713:
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.
•
86% ee, >99% conversion
1.
2. precipitation from toluene
71%, >99% ee
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.
(R)-Xyl-BINAP
P(Xyl)2
P(Xyl)2
NH2
OMe
MeO
(R)-diapen
O
O
F
F O
N
S
F3C CF3
OMOM
O
O
F
F
N
S
F3C CF3
OMOM
OH
Ru[(R)-Xyl-BINAP][(R)-diapen]Cl2
(0.1 mol%)
K2CO3, i-PrOH, THF
99% ee
O
O
F
F
N
S
F3C CF3
OMOM
N
O
Chen, C.-Y.; Reamer, R. A.; Chilenski, J. R.; McWilliams, C. J. Org. Lett. 2003, 5, 5039–5042.
•
Application to the synthesis of a PDE-IV inhibitor:
•
NH2
i-Pr
A similar system was used in the production of the antidepressant, (S)-duloxetine.
S
O
N
CO2Et
CH3
S
N
CO2Et
CH3
OH
S
NHCH3•HCl
O
(S)-duloxetine
NH2
NH2
Ph
Ph
(S)-PhanePhos (R,R)-DPEN
Ru[(S)-PhanePhos][(R,R)-DPEN]
KOtBu, H2 (150 psi)
i-PrOH, 40 ºC
93.4% ee
•
PPh2
PPh2
Hems, W.; Rossen, K.; Reichert, D.; Kohler, K.; Perea, J. J. US Patent 0272390, 2005
7

8. OH OH OH
O
CH3
CH3
O OH
CH3
OH OH
HO
CH3
HO
H
H
O
CH3
O
OH
H2 (50 psi)
Ru–(S)-BINAP (0.2 mol %)
CH3OH, 80 °C, 6 h
84%, 98% ee
(+)-Brefeldin A
Ot-Bu
O
O
BnO
OCH3
O O
CH3
CH3
OCH3
OH O
CH3
CH3
Ot-Bu
O
OH
BnO
O O
OCH3
CH3
O O
OEt
[RuCl(PhH)((R)-BINAP)]Cl (0.09 mol %)
RuCl2[(S)-BINAP] (0.1 mol %)
O O CH3
O
O
N
S
CH3
CH3
N(CH3)2
H2N
CH3
CH3
O
O
O
CH3
CH3
CH3
CH3
CH3
N
CH3
OH O
OEt
HO O
OCH3
H
H2 (200 psi)
Dowex-50 resin
EtOH, 130 °C, 10 h
94%, 94% ee
Pateamine A
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.
H2 (1500 psi)
CH2Cl2, 50 °C, 70 h
99%, 93% ee
Heathcock, C. H.; Kath, J. C.; Ruggeri, R. B. J. Org. Chem. 1995, 60, 1120–1130. Andrew Haidle
(–)-Roxaticin
[RuCl2((S)-BINAP)]2•Et3N (0.2 mol %)
H2 (110 atm)
CH3OH, 45 °C, 24 h
76%, 96% ee
• In all of the examples, the carbonyl carbon that is initally reduced is circled in the final product.
Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753–1765.
Taber, D. F.; Silverberg, L. J.; Robinson, E. D. J. Am. Chem. Soc. 1991, 113, 6639–6645.
(+)-Codaphniphylline
Examples in Total Synthesis:
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
8

9. SnPh3
(1.8 equiv)
(4:1 trans:cis)
O
H
O
I
PMBO
OCH3
O
O
PMBO
OCH3
O
OH
PMBO
O O
O
O
O
N
CH3
CH3
OCH3
OH
H
H
OH
H
CH3O
CH3O
CH3
O
H3C
OH
CH3
EtO
O
O
Li
R
H
BF3•OEt (1.1 equiv)
OCH3
O
OH
PMBO
OH
O
I
PMBO
CH3
OCH3
O
OH
PMBO
Andrew Haidle, Danica Rankic
Ru2Cl4[(S)-BINAP]•Et3N (1 mol %)
H2 (100 atm)
CH3OH, 23 °C, 70 h
90%, >95% ee
Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J. Am.
Chem. Soc. 1990, 112, 5583–5601.
LDA (2.5 equiv)
allyl bromide (3.5 equiv)
THF, –78 °C ! 0 °C, 4 h
90 %
X–R'
CH2Cl2, –78 °C, 100 min
54%, >97% dr
(5:1 diastereomeric mixture)
(67% maximum yield for major diastereomer)
• Although the chirality of the "-hydroxy ester is lost in the final product, it is used to set two other
stereocenters.
• Chelation control and steric shielding explain the
high diastereoselectivity of the allylation reaction.
Fráter, G.; Müller, U.; Günther, W. Tetrahedron 1984, 40, 1269–1277.
Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1984, 63, 109–120.
H
CH3
FK506
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
[Rh(cod)(R,R-dipamp)]BF4
H3CO
OAc
CO2H
AcNH
H3CO
OAc
CO2H
AcNH
P
P
H3CO
(R,R)-DiPAMP
L-DOPA: First Industrial Application of Asymmetric Hydrogenation
HO
OH
CO2H
NH2
This is the first successful industrial application of a homogeneous catalytic asymmetric
hydrogenation.
• (S)-3',4'-dihydroxyphenylalanine (L-DOPA) is used in the treatment of Parkinson's disease.
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.
• Knowles was awarded the 2002 Nobel Prize in Chemistry for this discovery.
Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998–2007.
Knowles, W. S. Adv. Synth. Catal. 2003, 345, 3–13.
H3CO
L-DOPA
•
•
9

10. Danica Rankic
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
Mechanism:
P
P
Rh
Sol
Sol
*
solvate complex
P
P
Rh
X
*
catalyst-substrate
complex
P
H
Rh
X
*
dihydride
complex
P
H
P
P
Rh
X
*
Sol
H
H
Rh-alkyl monohydride
P
P
Rh
Sol
X
*
H
X
substrate with
chelating group X
migratory
insertion
H2 oxidative addition
reductive
elimination
X
H
H
product
Rh-catalyzed Hydrogenation
(unsaturated mechanism)
A
A
A
A
A
Evidence suggests that Rh-catalyzed hydrogenations operate through a mechanism by which
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.
Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633.
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.
•
The solvate complex, catalyst-substrate complex, and Rh-alkyl monohydride complexes have all
been observed and characterized.
Enantioselectivity is highly dependent on temperature and H2 pressure.
Halpern, J. Science 1982, 217, 401–407.
•
•
•
MeOH, i-PrOH
O
ONa
CH3
O O
Ph H2 (4 bar), 25 oC
Rh(cod)OTf (0.1 mol%)
(S,S)-Et-DuPhos
(R)-warfarin
>98%, 88% ee
(R)-Warfarin synthesis:
O
ONa
CH3
O O
Ph
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.
Robinson, A.; Li, H.-Y.; Feaster, J. Tetrahedron Lett. 1996, 37, 8321–8324.
Application in Industry
•
•
•
Sitagliptin:
NH2
N
O
N
N
N
CF3
F
F
F
NH2
N
O
N
N
N
CF3
F
F
F
[RhCl(cod)]2 (0.15 mol%)
(S,R)-tBu-JOSIPHOS
(0.155 mol%)
H2 (17 bar), NH4Cl
MeOH, 50 oC 98%, 95% ee
(>99.9% ee after recrystalization)
Sitagliptin (Januvia!) is a potent and selective DPP IV inhibitor for the treatment of type 2 diabetes
mellitus.
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.
•
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.
Hydrogenation occurs through the imine tautomer.
•
•
•
•
H
10

11. Danica Rankic
The Noyori Asymmetric Hydrogenation Reaction
Myers Chem 115
CN
i-Pr
[Rh(cod)((S)-TCFP)]BF4
(0.0037 mol%)
H2 (3.5 bar)
MeOH, 25 oC
CN
i-Pr
CO2
– CO2
–
98%, 98% ee
i-Pr
CO2H
Lyrica!
NH2
P
P
H3C
t-Bu
t-Bu
t-Bu
(S)-TCFP
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-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.
•
N
O
CO2CH3
NHCbz
BnO
Anti-tumor antibiotic L-azatyrosine:
[Rh(cod)((R,R)-Et-DUPHOS)]BF4
(5 mol%)
H2 (3 bar), MeOH, 48 oC, 80%
N
O
CO2CH3
NHCbz
BnO
83% ee
(>96% ee after recrystalization)
L-azatyrosine
Zn, aq. NH4Cl
THF, 92%
N CO2CH3
NHCbz
BnO
1. LiOH, THF, H2O N CO2H
NH2
HO
Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 3, 3157–3159.
An N-oxide was found to be necessary to prevent catalyst inhibition through pyridine coordination.
•
•
•
2. H2, Pd/C
aq. HCl, MeOH
82%
H3N t-Bu H3N t-Bu
11