+ All Categories
Home > Documents > Myers The Noyori Asymmetric Hydrogenation Reaction Chem...

Myers The Noyori Asymmetric Hydrogenation Reaction Chem...

Date post: 17-Mar-2018
Category:
Upload: hadieu
View: 244 times
Download: 5 times
Share this document with a friend
11
PPh 2 PPh 2 PPh 2 PPh 2 O CH 3 OCH 3 O RuCl 2 [(R)-BINAP] (0.05 mol %) OH OH OH CH 3 OCH 3 O (S)-(–)-BINAP OCH 3 CH 3 O HO H 2 [(R)-BINAP]RuCl(CH 3 O)(CH 3 OH) 2 2 CH 3 OH CH 3 OH CH 3 O O OCH 3 CH 3 CH 3 [(R)-BINAP]RuHCl(CH 3 OH) 2 [(R)-BINAP]RuCl 2 (CH 3 OH) 2 O O CH 3 OCH 3 [(R)-BINAP](CH 3 OH)ClRu RuCl 2 [(R)-BINAP]–Ru H 2 (100 atm) CH 3 OH, 23 °C H 2 HCl 2 CH 3 OH CH 3 OH O OCH 3 CH 3 CH 3 CH 3 OCH 3 O O O O CH 3 OCH 3 [(R)-BINAP]HClRu CH 3 OH 2 CH 3 OH 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: H 2 (100 atm) CH 3 OH, 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]RuCl 2 } 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
Transcript
Page 1: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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

Page 2: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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

Page 3: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

• 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

Page 4: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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

Page 5: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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

Page 6: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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

Page 7: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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

Page 8: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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

Page 9: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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

Page 10: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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.

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

Page 11: Myers The Noyori Asymmetric Hydrogenation Reaction Chem …faculty.chemistry.harvard.edu/files/myers/files/18-noyori... · Myers The Noyori Asymmetric Hydrogenation Reaction Chem

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.

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.

2. H2, Pd/C aq. HCl, MeOH

82%

H3N t-Bu H3N t-Bu

11


Recommended