J O H N S O N M A T T H E YJ O H N S O N M A T T H E Y
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Phosphorous Phosphorous LigandsLigands in Homogenous in Homogenous CatalysisCatalysis
ChemsourceChemsource Symposium 14Symposium 14thth June 2006June 2006
William HemsWilliam Hems
[email protected]@matthey .com.com
Objectives
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Brief overview of industrial homogeneous asymmetric catalysis (….a little biased towards hydrogenation....)
and
discussion of some practical problems and opportunities for industrial applications
From the viewpoint of a catalyst and technology company: Johnson Matthey Catalysts, Catalysis and ChiralTechnologies
The growing market for enantioselective catalysis
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The request for single isomer products is driven by:
• Superior performance of single isomers
• Regulatory requirements
Fine chemicals, pharmaceutical intermediates, agrochemicals, vitamins, flavour and fragrances:
• Small scale / high value products
• Multi-step synthesis, usually in batch equipment
• Time to market critical (for pharmaceuticals)
Synthesis of Synthesis of enantiopureenantiopure moleculesmolecules
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Separation of Separation of enantiomersenantiomers
classical resolution (crystallisation of classical resolution (crystallisation of diastereoisomersdiastereoisomers))
chromatographic technology (simulated moving bed)chromatographic technology (simulated moving bed)
Synthesis from Synthesis from chiralchiral poolpool
EnantioselectiveEnantioselective synthesissynthesis
chiralchiral auxiliariesauxiliaries
biocatalysisbiocatalysis
asymmetric catalysisasymmetric catalysis
Advantages of asymmetric catalysisAdvantages of asymmetric catalysis
• No loss of one No loss of one enantiomerenantiomer (as for separation/classic (as for separation/classic resolution)resolution)
•• No loss of No loss of chiralchiral auxiliary (as for auxiliary (as for enantioselectiveenantioselectivesynthesis)synthesis)
•• Easier, cleaner, more efficient industrial processes Easier, cleaner, more efficient industrial processes (volume efficiency / catalyst separation / possible (volume efficiency / catalyst separation / possible catalyst recycling)catalyst recycling)
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Asymmetric HydrogenationAsymmetric Hydrogenation
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Hydrogenation of alkenes Hydrogenation of alkenes -- Wilkinson’s Wilkinson’s CatalystCatalyst
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(R3P)3RhCl
H-C-C-H
(R3P)2RhCl
RhPP
Cl
RhP
ClC
PS
HC H
H2
RhP
ClH
P
H- R3P
Alkene
Monsanto: synthesis of L-DOPAKnowles and Horner reported in 1968 the first homogeneously catalysed asymmetric hydrogenation of olefines with Rh-chiral monophosphines
Kagan devised in 1971 the bidentate ligand DIOP
P
PPh
MeO
Ph
MeO
= DIPAMP
PPh2
PPh2
O
O= DIOP
HO2C NHCOMe
MeOOAc
Rh-DIPAMP+
H2 HO2C NHCOMe
MeOOAc
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Knowles group at Monsanto developed the asymmetric hydrogenation of the intermediate for L-Dopa, 95% ee, TON 20,000, TOF 1,000, scale 1 t / y
Takasago: synthesis of L-Menthol
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In 1980 Noyori introduced BINAP as ligand for asymmetric hydrogenation
Asymmetric isomerisation of allyl amine catalysed by BINAP-Rh developed for Tagasako.
Intermediate for L-menthol produced in > 1000 t per year (TON: 400,000, TOF 440, 97% ee).
Li, Et2NH
NEt2 NEt2
Rh-(S)-BINAP
CHO
H3O+
OHOH
ZnBr2H2, Ni
myrcene
(R)-citronellalisopulegolL-menthol
BINAP in asymmetric hydrogenation
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BINAP-Ru-carboxylate complexes reduce unsaturated acids and allylic alcohols
Takasago, intermediate for Vitamin E (Ru-BINAP, 300t/y, TON 50,000,97%ee),
BINAP-Ru-halide complexes reduce ketoesters
Takasago, NCS Technologies Takasago (dynamic kinetic resolution(up to TON 20,000, 98% ee, multi 100 Kg) 100t/y, 97% ee, 94%de)
OH OH
R
OCOOR'
R
OHCOOR' R
O
COOR'NHCOPh R
OH
COOR'NHCOPh
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BINAP-type ligands are indispensable tools for asymmetric catalysis
PPh2PPh2
MeOMeO
Cl
Cl
PPh2PPh2
MeOMeO
MeO-BIPHEP (Roche)
Cl-MeO-BIPHEP (Bayer)
N
N
PPh2PPh2
MeOMeO
OMe
OMe
S
S
PPh2
PPh2
TMBTP (Sannicolo /Chemi)
P-Phos(Chan / Johnson Matthey)
PPh2PPh2
Hexaphemp (Chirotech / Dow)
PPh2PPh2
O
O
Bibfup (Bayer)
S
S
PPh2
PPh2
BITIANAP
PPh2PPh2
PPh2PPh2
O
OO
O
Seguphos H8-BINAP (Takasago)
Some applications of BINAP analogues
Roche: TON 10-100,000, TOF -10,000, > 98% ee
R OH R OH
Ru-MeO-BIPHEP
COOH
F
COOH
F
Ru-MeO-BIPHEPRoche: TON 1,000, TOF 400, 94% ee, multi 10 Kg
OCOOR'
OHCOOR'Cl Cl
Ru-TMBTP Chemi: intermediate for carnitine, TON 20,000, TOF 15,000, 97% ee
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Chemi: TON 20,000, TOF 6,600, 92% ee, multi 100 Kg
COOH Ru-TMBTPF3C
COOHF3C
...Not only success stories….Catalytic synthesis of (S)-Naproxen
COOH COOH
Hydroxycarboxylation Pd /BINAPO
HydroformylationRh / phosphites(Union Carbide)
Hydrogenation Ru / BINAP
(Takasago, Monsanto)
HydrocyanationNi / phosphinites (DuPont)
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No catalytic approach could compete with the original resolution strategy:
• optimised resolution with recycling of unwanted enantiomer (Syntex)
• starting materials for catalytic reactions are expensive
• some catalytic transformations are not yet efficient enough and further enantioenrichment is required
Synthesis of aminoacids viaasymmetric hydrogenation
In 1990 the problem of the hydrogenation of E/Z mixtures was solved by the introduction of bidentate phospholanes (DuPhos, BPE) by M. Burk at DuPont
P
P= Me-DuPhos
HO2C NHCOMe HO2C NHCOMe
Rh-DuPhos +R R
H2
E / Z mixture
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Chirotech: various dehydroaminoacids hydrogenated in multi 10 Kg batches, TON > 1,000, >98 % ee, often in combination with biocatalyticdeacetylation
M. Burk Acc. Chem. Res. 2000, 362
….. More phospholane ligands ...
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P
P
Me
Me
Me
Me
P
P
Me
Me
Me
Me
OO
OO
P
P
Me
Me
Me
Me
OBn
OBn
OBn
OBn
P
P
MeOOMeOMe
MeO
BASPHOSBASF
P
P
Me
Me
P
P
Me
Me
Me
MeO
O
O
P
P
Me
Me
Me
MeS P
P
Me
Me
Me
MeS
Me
Me
Me-DuPHOSDUPONT
Me-KetalPhosCHIRAL QUEST
RoPHOSSOLVIAS/BASF
MalphosDEGUSSA
"P-Chiral"PFIZER
UlluPHOSCHEMI
ButiPHOSCIBA - SOLVIAS
These ligands are functionally equivalent to DuPHOSand fall outside the scope of DuPont patents
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Ligands based on the ferrocenebackbone
Fe
Josiphos(Ciba/Solvias)
BoPhoz(Eastman)
Fe
PAr2
PAr2
PPh2NR
PPh2Fe PAr2
R
PAr2
RR = CONR2 JAFAPhos (Aventis/Johnson Matthey)
Fe PAr2PAr2
R R
TaniaPhos (Solvias)
Fe PAr2PAr2
MandyPhos (Solvias)
Fe
P
P
FerroTANE(Chirotech)
Fe
P
P
f-Binaphane(Chiral Quest)
Ciba/Syngenta/Solvias: synthesis of (S)-Metolachlor
FeN
OMeHN
OMeIr-Josiphos
PR2
R'2P
= JosiphosH2
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Intermediate for an herbicide, >100,000 t/y, 80% ee, TON 2,000,000, TOF 400,000
Critical factors:
moderate enantioselectivity requirement
Identification of appropriate additives
development of a family of ligands
commitment to >10 years reasearch
The history of Metolachlor chiral switch:
H.U. Blaser Adv.Synth.Catal. 2002, 17
LigandsLigands for asymmetric for asymmetric hydrogenation: new trendshydrogenation: new trends
• Monodentate ligands are being “rediscovered”• Phosphites, phosphonites, phosphoroamidates are used • as cheap alternative ligands
Fe
Phosphonites (Reetz)
PO
O
O
OP
O
OP NR2
O
OP OR
MonoPhos(Feringa, DSM)
Monophosphites(Reetz, Bayer)
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Will the reduced cost of the ligand compensate for the reduced activity?
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R O
Cl
Ru
Cl
N
N
P
P R OH
i-PrOH, base, H2 e.e. >98%
PAr2
PAr2 NH2
NH2
OMe
MeO
NH2
NH2
Ar = Ph (R)-BINAP
Ar = p-CH3-C6H4 (R)-Tol-BINAP
Ar = 3,5-(CH3)2-C6H3 (R)-Xylyl-BINAP
(S)-DAIPEN
Phosphine: Diamine:
(S,S)-DPEN
Ketone Hydrogenation TechnologyKetone Hydrogenation Technology
Original work by Noyori (1995):Original work by Noyori (1995):
Noyori, Nobel lecture, Noyori, Nobel lecture, Angew.Chem.Int.Ed.Angew.Chem.Int.Ed. 20022002, 2008, 2008
Noyori Noyori et al. Angew.Chem.Int.Ed.et al. Angew.Chem.Int.Ed. 20012001, 40, 40
Scope and Potential of Ketone Scope and Potential of Ketone Hydrogenation TechnologyHydrogenation Technology
HOOH
SOH
OH
OH Cl
O
OH
NOHOH
CF3
OH
H3CO
OH
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The reaction has excellent industrial applicability:The reaction has excellent industrial applicability:
High selectivity (>98% ee), activity (TON up to100,000) and broHigh selectivity (>98% ee), activity (TON up to100,000) and broad scopead scope
It can be applied to existing processes without changes in the It can be applied to existing processes without changes in the synthetic synthetic strategystrategy
New Ligands for Ketone HydrogenationNew Ligands for Ketone Hydrogenation
PR2
PR2
Ru
Cl
Cl
N
N
MeOMeO
OMe
OMe
H2N
NH2
Main focus for the Main focus for the development of new development of new catalysts has been, so far, catalysts has been, so far, the phosphine ligand.the phosphine ligand.
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New Ligands for Ketone Hydrogenation New Ligands for Ketone Hydrogenation ––Part IPart I
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PhanephosPhanephos--RuRu--DPEN is more active than DPEN is more active than BINAP complexes and activated more BINAP complexes and activated more quickly TON up to 100,000 and TOF up to 60 quickly TON up to 100,000 and TOF up to 60 secsec--1 1
PR2
PR2
H2N
NH2
Ru
Cl
Cl
R
PR2
PR2
H2N
NH2
Ru
Cl
Cl
N
N
MeOMeO
OMe
OMe
XylXyl--PP--Phos and PPhos and P--PhosPhos--RuRu--DPEN are DPEN are competitive with BINAP complexes and competitive with BINAP complexes and do not require expensive diamines. TON do not require expensive diamines. TON up to 100,000up to 100,000
Phanephos: M. BurkPhanephos: M. Burk et al Org. Lett.et al Org. Lett. 20002000, 4173, 4173
Paraphos: JM CCT Paraphos: JM CCT Org. LettOrg. Lett 20042004, 1927 , 1927
A. ChanA. Chan et al J.Org.Chem.et al J.Org.Chem. 20022002, 7908, 7908
A. ChanA. Chan et al Eur.J.Chem.et al Eur.J.Chem. 20032003, 2963, 2963
New Ligands for Ketone Hydrogenation New Ligands for Ketone Hydrogenation ––Part IIPart II
P
P R1
H2N
NH2
R2Ru
Cl
Cl
X
X
PhPh
Ph Ph
R34,4’4,4’--Disubstituted BINAP provide a Disubstituted BINAP provide a suitable chiral pocket even without Xyl suitable chiral pocket even without Xyl substituents. TON of up to 1,000,000substituents. TON of up to 1,000,000
W. LinW. Lin et al., Org. Lett.et al., Org. Lett. 20042004, 2937, 2937
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P
P
H2N
NH2
Ru
Cl
Cl
Ar
Ar
Ar
Ar
3
3
Bulky aromatic monophosphine Bulky aromatic monophosphine ligands give activity and selectivity ligands give activity and selectivity comparable with the best bidentate comparable with the best bidentate ligandsligands
DingDing et al., Adv.Synth.Catal. et al., Adv.Synth.Catal. 20052005, , 11931193
New Diamine Ligands for Ketone New Diamine Ligands for Ketone HydrogenationHydrogenation
PR2
PR2
Ru
Cl
Cl
N
N
MeOMeO
OMe
OMe
H2N
NH2
Diamines different from 1,2 diamines Diamines different from 1,2 diamines will change the orientation of the Nwill change the orientation of the N--H H group and will open the opportunity to group and will open the opportunity to further catalyst tuningfurther catalyst tuning
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Ketone hydrogenation mechanism studied by Noyori Ketone hydrogenation mechanism studied by Noyori et al.,et al., J.Am.Chem.Soc.J.Am.Chem.Soc. 20032003, 13490, 13490
New Focus on the Amine LigandNew Focus on the Amine Ligand
P
P
H2N
SRu
Cl
Cl
PhPh
Ph Ph
HH
Aminothioethers combined with BICP Aminothioethers combined with BICP give high selectivity in ngive high selectivity in n--BuOH, TON up to BuOH, TON up to 10001000
D. Ager, D. GenovD. Ager, D. GenovAngew.Chem.Int.Ed. Angew.Chem.Int.Ed. 20042004, 2816, 2816
P
P
N
NH2
Ru
Cl
Cl
TolTol
TolTol
The use of aminomethylpyridine makes The use of aminomethylpyridine makes possible the reduction of aliphatic tpossible the reduction of aliphatic t--Butyl Butyl ketones in EtOH, TON up to 100,000ketones in EtOH, TON up to 100,000
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R. NoyoriR. Noyori et al J.Am.Chem.Soc. et al J.Am.Chem.Soc. 20052005, , 82888288
1,3 1,3 ––Diamines: [XylDiamines: [Xyl--PP--Phos RuClPhos RuCl22 DPPN]DPPN]
P
PRu
Cl
Cl
N
N
MeOMeO
OMe
OMe
H2N
NH2
XylXyl
XylXyl
[(S)-Xyl-P-Phos RuCl2 (R,R)-DPPN]
O ONH2 NH2
(R,R)-DPPN
G. Grasa, A. Zanotti, W. Hems, G. Grasa, A. Zanotti, W. Hems, Journal of Journal of Organometallic Chemistry, in print.Organometallic Chemistry, in print.
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1,3 1,3 ––Diamines: [XylDiamines: [Xyl--PP--Phos RuClPhos RuCl22 DPPN]DPPN]
O OH S/C 10,000/1, catalyst, i-PrOH, t-BuOK 2.5%,
10 bar hydrogen95% e.e.
OH
93% e.e.
OH
97% e.e.
OH
96% e.e.
OH
86% e.e.
F3C
CF3
MeO
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The properties of the DPPN are broadly similar to the analogous The properties of the DPPN are broadly similar to the analogous DPEN catalysts.DPEN catalysts.
XylXyl--Phos gives better selectivity than PPhos gives better selectivity than P--Phos.Phos.
Strong matching/mismatching effect.Strong matching/mismatching effect.
Rates and enantioselectivity make the DPPN catalyst a useful Rates and enantioselectivity make the DPPN catalyst a useful addition to ketone hydrogenation technology but no significant addition to ketone hydrogenation technology but no significant advantages are obtained over the DPEN ligandadvantages are obtained over the DPEN ligand
1,3 1,3 ––Diamines: [XylDiamines: [Xyl--PP--Phos RuClPhos RuCl22 DPPN]DPPN]
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1,41,4--Diamines: [PDiamines: [P--Phos RuClPhos RuCl22 (DAMTar)](DAMTar)]
PPh2
PPh2
Ru
Cl
Cl
N
N
MeOMeO
OMe
OMe
H2N
NH2
OO
H
H
O
OH
H
H2N
H2N MeOOC
MeOOC
O
OH
H
G.Grasa, A. Zanotti, J. Medlock, G.Grasa, A. Zanotti, J. Medlock, W. Hems, W. Hems, Org. Lett., Org. Lett., 20052005,, 14491449
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Hydrogenation of AcetophenoneHydrogenation of AcetophenoneO OH S/C 1,000/1, catalyst,
i-PrOH, t-BuOK 2.5%,
10 bar hydrogen, RT
(R)(R)--PP--Phos / (R,R) 1,4Phos / (R,R) 1,4--diamine : 75 % e.e. (R)diamine : 75 % e.e. (R)
(S)(S)--PP--Phos / (R,R) 1,4Phos / (R,R) 1,4--diamine : 81% e.e. (S)diamine : 81% e.e. (S)
(R)(R)--XylXyl--PP--Phos / (R,R) 1,4 diamine : 55% e.e. (S)Phos / (R,R) 1,4 diamine : 55% e.e. (S)
(S)(S)--XylXyl--PP--Phos / (R,R) 1,4 diamine : 51% e.e. (R)Phos / (R,R) 1,4 diamine : 51% e.e. (R)
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PP--Phos better that XylPhos better that Xyl--PP--PhosPhos
Limited matching/mismatching of phosphine/diamine ligandsLimited matching/mismatching of phosphine/diamine ligands
Moderate results obtained on acetophenone but higher selectivitModerate results obtained on acetophenone but higher selectivity with 2y with 2--MeOMeO--acetophenone (93%ee)acetophenone (93%ee)
Hydrogenation of IsoHydrogenation of Iso--ButyrophenoneButyrophenoneO OH
S/C 1,000/1, catalyst, i-PrOH, t-BuOK 2.5%,
10 bar hydrogen
(S)(S)--PP--Phos / (R,R) 1,4Phos / (R,R) 1,4--diamine : 97 % e.e. (S)diamine : 97 % e.e. (S)
(S)(S)--PP--Phos / (S,S) 1,4Phos / (S,S) 1,4--diamine : 95% e.e. (S)diamine : 95% e.e. (S)
(S)(S)--PP--Phos / (rac) 1,4 diamine : 96% e.e. (S)Phos / (rac) 1,4 diamine : 96% e.e. (S)Catalyst with Catalyst with racemic diamine !racemic diamine !
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Changing the ring size imparts new properties to the catalyst:Changing the ring size imparts new properties to the catalyst:
Enhanced stereocontrol by the phosphine ligandEnhanced stereocontrol by the phosphine ligand
Rate acceleration vs. DPEN catalystRate acceleration vs. DPEN catalyst
1,41,4--Diamines: [BINAP RuClDiamines: [BINAP RuCl2 2 IPHAN]IPHAN]
PAr2
PAr2
Ru
Cl
Cl
H2N
NH2
R
R
O
OHydrogenation of tetralone Hydrogenation of tetralone with BINAP / 1,4with BINAP / 1,4--diaminesdiamines
Dynamic kinetic resolution Dynamic kinetic resolution is possibleis possible
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R. Noyori R. Noyori et al.et al. Org. Lett.,Org. Lett., 20042004, 2681, 2681
Hydrogenation of Cyclic KetonesHydrogenation of Cyclic KetonesO OHS/C 1,000/1 - 55,000/1
i-PrOH, t-BuOK,
9-50 bar hydrogen 92-99% e.e.
R RR' R'
((SS))--XylXyl--BINAP RuClBINAP RuCl22 ((RR))--IPHAN: tetralone and 7IPHAN: tetralone and 7--substituted tetralonessubstituted tetralones
((SS))--TolTol--BINAP RuClBINAP RuCl22 ((RR))--IPHAN: 4,5 and 6IPHAN: 4,5 and 6--substituted tetralonessubstituted tetralones
Dynamic kinetic resolution is possibleDynamic kinetic resolution is possibleO OH S/C 500/1
i-PrOH, t-BuOK,
10 bar hydrogen, RT 96-98% e.e.
R R
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((SS))--XylXyl--PP--Phos RuClPhos RuCl22 ((RR))--DAMTar: tetralone and 6DAMTar: tetralone and 6--MeOMeO--tetralonetetralone
1,41,4--diamine ligands are complementary to 1,2diamine ligands are complementary to 1,2--diamine diamine ligandsligands
The catalysts bearing 1,4The catalysts bearing 1,4--diamines are practically useful diamines are practically useful and expand the range of substrates for asymmetric and expand the range of substrates for asymmetric hydrogenation.hydrogenation.
The different ring sizes in the The different ring sizes in the RuRu--diaminesdiamines impart different impart different properties to the catalystproperties to the catalyst
(P(P--Phos) and (BINAP) RuClPhos) and (BINAP) RuCl22(1,4(1,4––Diamines)Diamines)
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Where next?Where next?
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Process and developmentProcess and development
Understanding of the factors that govern the reactivity of theUnderstanding of the factors that govern the reactivity of thecatalystcatalyst
Creativity in testing new combination of ligandsCreativity in testing new combination of ligands
The goals:The goals:
Application on scale of the existing asymmetric hydrogenationsApplication on scale of the existing asymmetric hydrogenations
Application to new substrates and transformationsApplication to new substrates and transformations
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AcknowledgementsAcknowledgements
Neil Caplan, Beatriz Dominguez, Alan Dyke, Gabriela Grasa, MicheNeil Caplan, Beatriz Dominguez, Alan Dyke, Gabriela Grasa, Michelle Groarke, William Hems, lle Groarke, William Hems, Laleh Jafarpour, Jacques LeLaleh Jafarpour, Jacques Le--Paih, Jonathan Medlock, Hans Nedden, Paih, Jonathan Medlock, Hans Nedden, Andreas Seger, Antonio Zanotti. Andreas Seger, Antonio Zanotti.
