myers the noyori asymmetric hydrogenation reaction chem...
TRANSCRIPT
PPh2PPh2
PPh2PPh2
O
CH3 OCH3
O RuCl2[(R)-BINAP] (0.05 mol %)
OHOH
OH
CH3 OCH3
O
(S)-(–)-BINAP
OCH3
CH3
O
HO
H2
[(R)-BINAP]RuCl(CH3O)(CH3OH)2
2 CH3OH
CH3OH
CH3
O O
OCH3CH3 CH3
[(R)-BINAP]RuHCl(CH3OH)2
[(R)-BINAP]RuCl2(CH3OH)2
O
OCH3
OCH3
[(R)-BINAP](CH3OH)ClRu
RuCl2[(R)-BINAP]–RuH2 (100 atm)
CH3OH, 23 °C
H2
HCl
2 CH3OH
CH3
OH O
OCH3CH3 CH3
CH3
OCH3O
O
O
OCH3
OCH3
[(R)-BINAP]HClRu
CH3OH
2 CH3OH
Chem 115The Noyori Asymmetric Hydrogenation ReactionMyersReviews:
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
Ru
Cl
HO O
PP
OCH3CH3
Ru
Cl
HO O
PP
CH3CH3O
CH3 OCH3
OOH
CH3 OCH3
OOH
(R) !-hydroxy ester
(S) !-hydroxy ester
• Of the two possible diastereomeric transition states for complexes with (R)-BINAP shownbelow, the one leading to the (R) !-hydroxy ester allows the approach of the ketone at anunhindered 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
OO
NHAcDO
O
OCH3
OOH
NHAcDCH2Cl2
RuBr2[(R)-BINAP]H2 (100 atm)
• The use of a deuterated substrate provides further evidence that the reduction proceedsthrough 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 ReactionMyers Chem 115
1/2 [RuCl2(benzene)]2 + (R)-BINAPDMF, 100 ºC
(R)-BINAP-Ru(II)
2
• 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 reactionsmay 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 OH2 (50 psi), HCl (0.1 mol%)Ru–(R)-BINAP (0.05 mol %)
CH3OH, 40 °C, 8 h97%, >97% ee
not cleaved under these conditions.
Andrew Haidle, Fan Liu
O O
OEtBnOOH O
OEtBnO
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 reactionproceeds at a sufficiently low H2 pressure (50 psi) to avoid reduction of trisubstituted olefins,
but not terminal olefins.
O O
OCH3
OH O
OCH3CH3 CH3
N
CH3CH3
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 catalystprepared in situ from BINAP, (COD)Ru(2-methylallyl)2, and HBr, all of which arecommercially available. No special reaction apparatus is necessary for this procedure;however, the catalyst loading is unusually high.
OCH3
O OCH3 OCH3
OH OCH3
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 ReactionMyers Chem 115
(10.0 kg) (9.7 kg)
3
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
OX
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 ReactionMyers Chem 115
R
O
R
O
X
X
R
OHX
R
OH
R
OH
X
X
R
OHX
R
OH
R
OH
X
X
OO OCH3
H
Ru
H
PP
X
Bn NHBoc
H
4
Dynamic Kinetic Resolution:
• Kinetic resolution of enantiomers occurs when the chiral catalyst reacts with one enantiomer muchmore rapidly than the other.
CH3HO
O
EtOH
CH3HO
OH
CH3HO
OH2 (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% ofenantiopure 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
NHAcCH3 OCH3
OH O
NHAc
CH3 OCH3
OH O
NHAc
RuBr2[(R)-BINAP] (0.4 mol %)H2 (100 atm)
CH2Cl2, 15 °C, 50 h99%, 98% ee
1%, >90% ee
RuBr2[(R)-BINAP] (0.4 mol %)H2 (100 atm)
CH2Cl2, 15 °C, 50 h
kinvkinvkS,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, butthe 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
OHH
RuBr2[(R)-BINAP]
H2 (100 atm)
H2 (100 atm)
[RuCl(PhH)((R)-BINAP)]Cl(0.09 mol %)
1 : 1
99 : 1
OO OCH3
H
Ru
H
PP
O
CH3
O ON
Ru
H
PP 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)-BINAPP,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 ReactionMyers Chem 115
•
X X
5
Cl
Cl
Ar2P
PAr2
Ru
H2N
NH2
OCH3
OCH3H
i-PrCH3 OCH3
OO
CH3 OCH3
OO
Bu4NI (5 mol %)
CH3 OCH3
OOH
P P
i-Pr
i-Pri-Pr
i-Pr
CH3 OCH3
OOH
PPh2
PPh2
ONCH3
O
O
NCH3
CH3
O
NCH3
H
CF3
OH
NCH3
CH3
OHNCH3
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 originallyreported 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 HaidleOhkuma, 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 efficientlyreduces "-, !-, 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 nitrogenis believed not to ligate to the Ru center.
• This method allows for a practical synthesis of the antidepressent (R)-fluoxetine without the needfor 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 ReactionMyers Chem 115
Ar = 3,5-(CH3)2-C6H3
6
Other Ligands and Other Substrates:
Joseph Tucker
The Noyori Asymmetric Hydrogenation ReactionMyers 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
OHH
(R)-3-furoic acid>98% eeP
P
i-Pr
i-Pri-Pr
i-Pr
[(S,S)-iPr-DuPhos Ru(TFA)2] (0.02 mol%)H2 (150 psi), MeOH
(S,S)-iPr-DuPhos =
N
CO2HN
Boc
Ru(COD)(CF2CO2)2 (0.1 mol%)(R)-[2.2]-PHANEPHOS
H2 (10 bar), 40 ºC
N
CO2HN
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 toluene71%, >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)2P(Xyl)2
NH2
OMeMeO
(R)-diapen
OOF
F O
NS
F3C CF3
OMOM
OOF
F
NS
F3C CF3
OMOM
OH
Ru[(R)-Xyl-BINAP][(R)-diapen]Cl2 (0.1 mol%)
K2CO3, i-PrOH, THF
99% ee
OOF
F
NS
F3C CF3
OMOM
NO
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.
SO
NCO2Et
CH3
S NCO2Et
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
OH OH OH
OCH3
CH3O OH
CH3
OH OH
HO
CH3
HO
H
HO
CH3O
OH
H2 (50 psi)
Ru–(S)-BINAP (0.2 mol %)
CH3OH, 80 °C, 6 h
84%, 98% ee
(+)-Brefeldin A
Ot-Bu
OO
BnO
OCH3
O O
CH3CH3
OCH3
OH O
CH3CH3
Ot-Bu
OOH
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
ON
S
CH3
CH3
N(CH3)2
H2N
CH3
CH3
OO
OCH3
CH3
CH3
CH3CH3
N
CH3
OH O
OEt
HO O
OCH3
H
H2 (200 psi)
Dowex-50 resinEtOH, 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 ReactionMyers Chem 115
8
SnPh3(1.8 equiv)
(4:1 trans:cis)O
HO
I
PMBO
OCH3
OO
PMBO
OCH3
OOH
PMBO
O O
O
O O
N
CH3
CH3
OCH3
OH
H
H
OHHCH3O
CH3O
CH3
O
H3C
OH
CH3
EtOO
OLiR
H
BF3•OEt (1.1 equiv)
OCH3
OOH
PMBO
OH
O
I
PMBO
CH3
OCH3
OOH
PMBO
Andrew Haidle, Danica Rankic
Ru2Cl4[(S)-BINAP]•Et3N (1 mol %)H2 (100 atm)
CH3OH, 23 °C, 70 h90%, >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 thehigh 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 ReactionMyers Chem 115
[Rh(cod)(R,R-dipamp)]BF4H3COOAc
CO2HAcNH
H3COOAc
CO2HAcNH
P
P
H3CO
(R,R)-DiPAMP
L-DOPA: First Industrial Application of Asymmetric Hydrogenation
HOOH
CO2HNH2
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
Danica Rankic
The Noyori Asymmetric Hydrogenation ReactionMyers Chem 115Mechanism:
PP
RhSolSol
*solvate complex
PP
RhX
*
catalyst-substratecomplex
PH
RhX
*dihydridecomplex
P
HPP
RhX
*Sol
H
HRh-alkyl monohydride
PP
RhSolX
*H
Xsubstrate with
chelating group X
migratory insertion
H2 oxidative additionreductive elimination
X
H
H
product
Rh-catalyzed Hydrogenation(unsaturated mechanism)
A
A
AA
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
CH3O 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
CH3O 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
NN
CF3
F
FF
NH2
N
O
N
NN
CF3
F
FF
[RhCl(cod)]2 (0.15 mol%)
(S,R)-tBu-JOSIPHOS (0.155 mol%)
H2 (17 bar), NH4ClMeOH, 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.
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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.
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•
H
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Danica Rankic
The Noyori Asymmetric Hydrogenation ReactionMyers Chem 115
CNi-Pr
[Rh(cod)((S)-TCFP)]BF4(0.0037 mol%)
H2 (3.5 bar)MeOH, 25 oC
CNi-Pr
CO2– CO2
–
98%, 98% ee
i-Pr
CO2H
Lyrica!
NH2
PPH3C
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.
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NO
CO2CH3
NHCbzBnO
Anti-tumor antibiotic L-azatyrosine:
[Rh(cod)((R,R)-Et-DUPHOS)]BF4 (5 mol%)
H2 (3 bar), MeOH, 48 oC, 80%
NO
CO2CH3
NHCbzBnO
83% ee (>96% ee after recrystalization)
L-azatyrosine
Zn, aq. NH4Cl
THF, 92%
N CO2CH3
NHCbzBnO
1. LiOH, THF, H2O N CO2H
NH2HO
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.
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2. H2, Pd/C aq. HCl, MeOH
82%
H3N t-Bu H3N t-Bu
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