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The Combinatorial Approach toAsymmetric Hydrogenation.
Johannes G. de Vries
DSM Pharma Chemicals
and
U ivers roni n
IASOC 2004, IschiaUnlirnited.
1. DSM. A century of changes.
2. Homogeneous catalysis for fine chemicals
3. HTE approach; ligand libraries
4. MonoPhosTMligandsfor asymmerichydrogenation5. Instant Ligand Libraries6. Mechanism
7. The wedding between homogeneous catalysis &biocatalysis
DSM Pharma Chemicals Unlimited.
Evolutionife Science
ProductsPerformanceMaterials
Sustainability
Customer intimacy
Competences 11
mechanical technology
chemical technology
chemistry
polymer technologymaterial science
adv. organic chemistry
biotechnology
DSM Pharma Chemicals Unlimited.
DSM 2002 DSM 2003
Total sales - € 7 bn
Specialties from - 50% to > 80%
DSM Pharma Chemicals Unlimited.
Important technolo~ies
- Asymmetric hydrogenation (olefins, ketones, imines, enamides)- Asymmetric transfer hydrogenation (ketones)- Asymmetric epoxidation- Aromatic substitution
-Heck-Suzuki/Negishi-Sonogashira-Amination-Cyanation
-CO chemistry (hydroformylation, carbonylation, amidocarbonylation)-Isomerisation and racemisation-Oxidation
- benzylic and allylicoxidation- alcoholsto aldehydes or acids- olefins to epoxides
DSM Pharma Chemicals Unlimited.
. Nobel prize winning chemistry
.. Several hundred ligands known
" Many thousands examples on lab-scale
Till about 5 years ago the use of this technology for the production offine chemicals was scarce.
Why?Reviews
H.U. Blaser, F. Spindlerand M. Studer, Appl. Cata/.: A GeneraI, 2001, 221,119.
J.G. de Vries in Encyclopedia of Catalysis, I. Horvath, ed. 2003, Voi 3, P 295.
DSM Pharma Chemicals Unlimited. 15M
1. Time to market constraints in pharmaceuticals productionleads to very short development time
2. Competing technologies
3. Cost
. Cost of metal (Rh or Ru)
. Cost of ligand
. Activity of the catalyst.
. Stability of the catalyst
. Recovery or recyclability
4. Availability of catalysts on short notice
5. Patents and high cost of licensing
6. Reliability, real or perceived
DSM Pharma Chemicals Unlimited.
Goal: Find catalytic solution for customer requests within 3 weeks
Requirements:. Hardware
. Endeavor (8 high pressure reactors)
. Two proprietary reactors for high pressure (96 and 28 vessels)
. HTE Ana/ysis. GC
. HPLC (including chiral HPLC)
. Flow-NMR
. Libraries of ligands
Review: J.G. de Vries and A.H. M. de Vries, Eur. J. Org. Chem., 2003, 799-811.
Review Ligand libraries: C. Gennari, U. Piarulli, Chem. Rev. 2003, 103,3071.
. Libraries of phosphine ligands are not easy to prepare.
. Phosphoramidites on the contrary are easily prepared in 2 steps:
. Diversity from both diol and amine part.
. Chirality from BINOl or TADDOl skeleton or chiral amine.
. Very successful in copper catalysed asymmetric 1,4 addition ofEt2Zn to cyclic enones (B. Feringa et al, RUG)
. Not known for asymmetric hydrogenation!
DSM Pharma Chemicals Unlimited.
(OH
* +OH (
°,
PCl3 * O/P-CI ~NH/Base
...RR'NH +CI, ,R
PCI3 P-NC( 'R'
* (OH
OH
*(OH +HMPT~ (°, ~
OH * P-N(M
RR'NH
0/ eh cat.tetrazole
DSM Pharma Chemicals Unlimited.
DSMPharma Chemicals Unlimited.
R
M. van den Berg, A.J. Minnaard, E.P. Schudde, J. van Esch, A.H.M. deVries, J.G. de Vries and B.L. Feringa, J.Am. Chem. Soc. , 2000, 122, 11539.
WO 02/04466
DSM Pharma Chemicals Unlimited.
Entrv Solvent Temp e.e.
1. CH30H RT
2. CH2CI2 RT 95%
3. CH2CI2 5°C
4. THF RT 93%
5. Acetone RT 92%
6. PrOCH2CH2OH RT 77%
Entrv R R' Solvent e.e. (RT) e.e (O°C)
1. Ph Me CH2CI2 95% 97%
2. Ph H EtOAc 97%
3. H Me EtOAc >99%
4. H H EtOAc >99%
rAYYG~2R' e!jh (~pq)2tI13P4J~MPQPPh~S.Af'y'G02fR'
R~ NHAc H2'GH2GI2 ~ NHAc
M. van den Berg et al., Adv. Synth. Catal. 2003, 345, 308-322.
DSM Pharma Chemicals Unlimited.
.. MonoPhos can be prepared in a single step from commerciallyavailable SINOL (Compare with DUPHOS: 6 steps).
.. MonoPhos is an order of magnitude cheaper than currentlyavailable bisphosphines.
.. The hydrogenation rate can be increased by increasing the H2pressure without loss in enantioselectivity!
.. At S/C ratio of 2000 fuIl conversion in 2 h at 10 bar.
. Method of choice for asymmetric olefin hydrogenation.
.. Large library of ligands available.
DSM Pharma Chemicals Unlimited.DSM
R R Solvent e.e. (RT) e.e. (O°C)
1. H Me CH2CI2 95% 97%
2. 3-MeO H CH2CI2 97%
3. 4- Ph Me CH2CI2 95%
4. 4-0Ac, 3-0Me Me EtOAc 94% 98%
5. 4-Ac Me CH2CI2 99%
MonoPhos
H. Bernsmann et al., submitted to JOC
DSM Pharma Chemicals Unlimited.
o O
~oMeR
.. Synthesis of precursors: ZIE mixtures with predominantly Z
.. Asymmetric hydrogenation of E is facile.
.. Asymmetric hydrogenation of Z is difficult. For R = aryl so far onlya few successful catalyst systems known: Ru-BINAPO, Tangphos(x. Zhanget al.)
.. Two strategies can be developed:
.. find good ligand for Z
.. synthesis of only E(See: D. Heller et al. Angew. Chem. Int. Ed. 2003, 42, 913)
DSM Pharma Chemicals Unlimited.
L
D. Pena et al,J. Am. Chem. Soc.,2002, 124, 14552-3.
Unlimited.
'# What happens if you mix ligands?
RhL1L1
DSM Pharma Chemicals Unlìmited.
Substrate Ligand Solvent e.e.
E- R = CH3 MonoPhos CH2CI2 95%
E- R = CH3 1 CH2CI2 99%
z- R = CH 2 iPrOH 95%3Z- R = Ph 2 iPrOH 92%
~ R'O, /
P-N0/ \
(S)-1, R' = Me, R2= R3= H(S)-3, R' = R2= Me, R3= H(S)-4, R' = Me, R2= H, R3= Br(S)-5, R' = Bn, R2= R3= H
NHAc
R~C02Et
R2
"'-
O, )-PhP-N
0/ H50
g&I/-o /
'P-N/ \y O
~ I (S)-2
90
80
~: 70
60
(S,R)-6 e ntry 9 10 11
DSM Pharma Chemicals 7 = 6 +1; 8 = 6 + 2; etc.Unlimited.
" ...works! (D. Pena et al. Org. Biomol. Chem., 2003, 1,1087.).
" From NMR: Almost exclusive formation of mixed complex in caseof e.e. enhancement.
" Most tested combinations gave lower enantioselectivity than thehomo-catalysts.
" Significantly increases the scope of asymmetric hydrogenation.
" Aiso shown to work with monodentate phosphites. (M.Reetz et al.Angew. Chem. Int. Ed. 2003,42,790.)
DSM Pharma Chemicals Unlimited.
" They can ali be synthesized in 1-2 steps
" Other applications besides hydrogenation: Asymmetric Heck,hydroarylation, hydrosilylation, allylic substitution.
DSM Pharma Chemicals Unlimited.
.. So far ligand libraries have been made manually. Each ligandsynthesised and purified separately.
.. Can we make ligands in a robot?
" What about purification?
Metal
Precursors
I(
OHChiral diols *
OH
JPhosphorus - Parall~l I-
Source SyntheslZer
(pC13,HMPT...) tR1"
Amines NH
R(
.1 ParallelReactors
(Fast) I-Analysis
Library("ane vesse~
ane compOlmd")
t HitsProchiralSubstrate
.. ~ 96 wells microplateI \ 2mL,Oleophobicfilter
-O~ I Orbtrt1/~er I
(°,/P-CI°
R)R2NH ..
Et3N
96 wells microplateCollectingplate
Parallel
-+Filtration
11111111
Metal
precursor==
Substrate D- Array 0196 vials (1OmL)
DSM Pharma Chemicals
~CO;,CH3V NHAc
IRh(COD);,]BF4' Ugand
H2 6 bar, 1h
Converslon
90-100
0-10 40-50 80-9060-7020-30
-
..Parallel Reactor
ligand E.e.
<50 85-9055-60 65-70 75-80
NHAc
ÀC02CH3
[Rh(CODhJBF 41 Ligand.H26 bar, 1h
ConversionLigand
E.e.
0-10 20-30 40-50 60-70 80-90
Purified ligands Libraryligands
Ligand Conv.(%)
Ee
(%)
Conv
(%)
Ee
(%)
NEt2 8 46 11 41
Piperidine 11
NH-a-MeBenz
96
NHiPr 100
DSM Pharma Chemicals
55 7 43
94 51 88
95 95 92
Unlimited.
.. This HTE approach enables a very fast synthesis of a widerange of phosphoramidites and their screening in asymmetricolefin hydrogenation of
.. Aiso less easy accessible N-H ligands can be tested.
.. E.e's are slightly lower than for the conventional reaction.However, the order is representative.
.. Can also be applied to other monodentate ligand fanilies
.. Can also be applied in other catalytic chemistry (C-C bondformation)
L. Lefort, J.A.F. Boogers, A.H.M. de Vries and J.G. de Vries, Org Lett, 2004
DSM Pharma Chemicals Unlimited.
~C02CH3 [Rh (COD}zt BF4-/Ligandal0J NHAc~C02CH3l0J NHAc
Rate dependence on Monophos/Rh ratio
100
20
-+-1 eq.
--1.5eq.
2 eq.
3 eq.
80c:o'iij 60....Q)
1: 40oCJ
o
o 2
time (h)
3 4
DSM Pharma Chemicals Unlimited.
~ ~ C02CH3 [Rh (COD)2r BF4-/Ligand
~ NHAc .H
~C02CH3~ NHAc
E.e dependence on MonoPhos/Rh ratio
-+--1 equi
-1.5equi
2 equi
1,5 2
time (h)
2,5 3
DSM Pharma Chemicals Unlimited.
-AsymmetricAmplification!
-More than 1ligandon rhodium?
DSM Pharma Chemicals Unlimited.
100
80
60Q)Q)
40
20
O
1
LR" / O)NHRh -!
L( ~C02H
If the "racemic"catalystisslowerthan theenantiopurecatalyststhe e.e. will be higherthanexpected;positiveasymmetricamplification.
1l
LR" / O)NHRh -!
L( ~C02H
If the "racemic"catalystis faster thantheenantiopurecatalysts:e.e. willbe lowerthanexpected;negativeasymmetricamplification.
1l
Ls" o)Rh' NH
L( ~ C02H
This experimentprovesthe existenceof RhL2'
Sut... ... .
DSM Pharma Chemicals Unlimited.
DSM Pharma Chemicals
. ..it does not rule out the
existenceof catalyticallyactiveRhL.
.NMR, MS and kineticstudiesneeded.
Unlimited.
LR" / ONH
ONH
Rh
L( :::c--- C02H
/Rh
1l L( C02H
LR" / ONH
ONH
Rh
/ C02HLs
/
1lRh
L( C02H
Ls" / ONHRh
L( C02H
Experiment with 5 mol% Rh followed over time with ES-MS (cationic mode):
After 30 min: RhL2(nbd), RhL2(Substrate), RhL3' RhL3(Substrate)
After 60 min: RhL2(nbd), RhL2(Substrate), RhL3' RhL4
After 120 min: RhL2(Substrate), RhL3' RhL4
-No RhL derived complexes found
-RhL3and RhL4cannot lead to products
-From results with mixtures of ligands: Only RhLz(not RhL) is an activecatalyst!
- A large part of the rhodium is tied up in inproductive complexes.
DSM Pharma Chemicals Unlimitèd.
~,I
l
193K
~ 211K
221 K
232 K
~- 243 K
254K
242 Hz
b bb b
39Hz(\b
b
b
b
239 Hz
221 Hz
f\f\
a a
c c
PPMT
143,0T
142.0T
141.0T
140.0l
139.0T
138.0T
137.0T
138.0T
135.0T
134,0T
133.0T
132.0T
1310T
130.0l
129.0
Coordination sites of
I the cyclooctadiene,CODomitted for clarity
Rh
Coordination sites ofthe cyclooctadiene,CODomitted for clarity
@ Transition metal catalysed reactions very good for:. Hydrogenation. c-c bondformation. Oxidation
@ Enzymes are very good in:. Hydrolytic reactions. Chiral induction
. Enormous diversity readily available in large numbers!
@ Can we wed the best properties of both?
@ Prior art: Whitesides and Ward (biotin linkedcatalysed bound to Avidin)
DSMPharma Chemicals Unlimited.
@ Combine homogeneous catalysts that are good inhydrogenation and hydroformylation with anenzymel
@ Enzyme-Ligand-Metal@ Unfavourable weight ratio demands highly active
catalyst
@ Catalyst needs to be stable in aqueous environment@ Attachment at single position in enzyme for
reproducibility.
@ Start: Papain plus rhodium/phosphite complexes
@ Enzyme-S-linker-O-P(ORhRh-(COD)BF 4
DSM Pharma Chemicals Unlimited.
DSMPharma Chemicals Unlimited.
DSM Pharma Chemicals Unlimited.
t o .~N02HNJoN IIDZ)fwe($4~
)o
(50 J.!M)
~N02N-o1:;=9000 at 404 nrn
0,25
-= 0,15~~
~ 0,1
0,05
0,2
-+- LinkerC- Cofactor4C
-Papain- Papain+5%Dioxane
°° 200 400 600 800
t (sec)
DSM Pharma Chemicals Unlimited.
After treatment of the ligated enzyme with [Rh(COD)2]BF4andpurification only a single Rh is bound to the enzyme!
ESI-IVIS
500000
450000
400000
350000
300000
250000
200000
150000
100000
50000
o23400
HydrolyzedHO '- ---~-.--ilRh'~
I'
p"'-- ---
""",inli?
Pap-Phos + HzO
23600 24200 246002440023800 24000
DSM Pharma Chemicals Unlimited.DSM
==(C02MeNHAc
.. Product N-Ac-Ala-OH is racemic
.. Native papain reacted with Rh-precursor and purified inthe sa me manner shows no reactivity.
.. Next step: other enzymes and substrates.
Lavinia Panella, unpublished results
DSM Pharma Chemicals Unlimited.
. Monodentate phosphoramidites are excellent ligands forenantioselective olefin hydrogenation.
. Monophos is at least an order of magnitude cheaper thanexisting bisphosphine ligands.
. A library of 96 phosphoramidite ligands can be made in a singleday and screened in catalysis the next day.
. MonophosTM and other phosphoramiditesare available inresearch quantities via STREM
. Combination of transition metal catalysts with enzymes is apromising new field.
DSM Pharma Chemicals Unlimitèd.
DSM-GeleenAndré de Vries
Jeroen BoogersCharlotte WillansLaurent Lefort
Sjoerd van de WalMath Boesten
Universitv of GroninQen
Michel vd BergAdri Minnaard
Ben L. FeringaDiego PenaLavinia PanellaDick Janssen
Marco Fraaije
IFOK
Detlef Heller
Financial support: DSM, University of Groningen,Dutch Science Foundation Combichem program,EU (RTN Network Combichem)
Unlimifed.DSM