1
High-Throughput Catalysis
MacMillan Group Meeting
Oct. 22, 2008
Jay Conrad
2
Enantioslective Catalysis and the Chemical Industry
■ Bulk chemical prcesses already make use of "Green" homogeneous catalysis
e.g. hydroformylation - carbonylation - oxidation
■ In fine chemicals have been slow to adopt new technologies
e.g. pharmaceuticals - agrochemicals - dyestuffs - flavours - fragrences
H.U. Blaser Chem. Commun. 2003, 293.
3
Enantioselective Catalysis and Fine Chemicals
■ Difficulties impletmenting catalytic technologies
Problems with homogeneous catalysis: loading - leaching - cost - TIME
"Cannot spend years to develop a reaction that may not make it to production." - H.U. Blaser (Solvias)
Really need to develope enantioselective catalysis - Chiral drugs onthe market in 1992 58%, 2006 75%.
However developement time is especially problematic for enantioselective catalysis.
■ Fine Chemical Research and developement
clock is ticking on patents
Time for
enantioselective
catalysis?
H. U. Blaser Appl. Catal. 2001, 221, 119.
4
High-Throughput Catalysis
! Why it takes so long, consider all the moving parts of a catalytic reaction:
metal (amine)
counterion (co-cat)
ligand
ancillary ligand
metal / ligand ratio
prep method
substrate/cat ratio
reactant
solvent
temperature
pressure
concentration
substrate/reactant ratio
rate of addition
pH
additives - acids, bases, salts
10 trials for each variable = 1017 combinations
From lead discovery to an
optimized prcoess can be very
time intensive
J. de Vries Eur. J. Org. Chem. 2003, 799.
5
The Trial and Error Component to Developing Chemsitry
! Nobel prize winner acknowledges role luck/trial and error
"Since acheiving about 95% ee only involves energy differences of about 2 kcal, which is no
more than the barrier encountered in a simple rotatation of ethane, it is unlikely that before the
fact one can predict what kind of ligand structures will be effective."
- W. S. Knowles Acc. Chem. Res. 1983, 16, 106.
! In 25 years we still face the same challenges in the design of chemical reactions
"Success in developing new and highly enantioselective catalysts depends
upon design, experience, intuition, trial and error and/or serendipity."
- M. Reetz Angew. Chem. Int. Ed. Eng. 2008, 47, 2556.
! To attack these problems researchers have adopted high-throughput methods
6
High-Throughput Catalysis
■ Traditional optimization - Serial
1 Reaction
One shot at the target - reload
precise and accurate
but slow turnaround
■ High-Throughput - Parallel
Many Reactions
lower precisions and
accuracy but many more
chances of hitting the target
7
High-Throughput Catalysis
! What is high-throughput catalysis?
evaluation of large numbers of
experiments
reaction
optimization
combinatorial
approaches to
reaction design
Reviews:
M. Reetz Angew. Chem. Int. Ed. Eng. 2001, 40, 284.
A. F. Volpe Jr. Appl. Catal. A 2001, 221, 23.
S. Brase Synthesis, 2001, 1431.
K. Ding Chem. Eur. J. 2004, 10, 2872.
R. Paciello Chem. Rev. 2006, 106, 2912.
M. Reetz Angew. Chem. Int. Ed. Eng. 2008, 47, 2556.
catalyst or ligand
discovery
8
High-Throughput Catalysis
■ Requirements for HT catalysis
Hardware: Robots, parallel reactors
Fast analysis
Libraries of ligands / catalyst
Software for data handling
■ Typical workflow for HT catalysis
9
Important Early Examples
! C-H Activation
CO2(L-Men)
CO2(L-Men)
CO2(L-Men)
N2
catalyst
N
O
O
N
O
DDQ oxidation
N
O
O
O
Previous best: Cu(OTf)2 - BOX
64% yield 2.3:1 dr
"M"
CO2(L-Men)
CO2(L-Men)
BOX:
M
M
H
N
H
Me
O
N
O
O
N
O
O
Me
Ph
O
Sulikowski J. Org. Chem. 1995, 60, 2326. Review: Davies Nature 2008, 451, 417.
N
Ph
10
Important Early Examples
! Evaluation of ligands, solvent and metals for C-H Activation
Me
Me
O
O
N
O
Ph
N
Ph
Ph
O
N
Ph
N
Ph
Ph
N
N
Ligands
H
O
N
N
H
iPr
iPr
AgSbF6
Sc(OTf)3
Cu(OTf)2
OH
N
O
N
N
tBu
H
tBu
tBu
HO
tBu
H
[Rh(nbd)]BPh4
Metals
THF
MeCN
CHCl3
MePh
Solvents
AuCl(SMe2)
La(OTf)3
Yb(OTf)3
= 96 experiments
Burgess Angew. Chem. Int. Ed. Engl. 1996, 35, 220
11
Important Early Examples
! New catalysts identified
CO2(L-Men)
CO2(L-Men)
CO2(L-Men)
N2
catalyst
N
O
O
N
O
DDQ oxidation
N
O
O
Previous best: Cu(OTf)2 CH2Cl2
64% yield 2.3:1 dr
Me
O
N
Ph
61% yield 4.4:1 dr
Me
O
Me
O
N
Ph
75% yield
Me
O
N
Ph
AgSbF6 THF
Cu(OTf)2 THF
Me
Me
O
N
O
N
Ph
3.5:1 dr
Ph
- The same ligand was found to give better dr
- Silver at the time was rarely used
- First silver catalyzed C-H insertion
N
Ph
O
12
Important Early Examples
! Notable features and comments from the Burgess paper
First use of microtiter 96 well plate for catalyst developement - long used in biology
Advantages of high-throughput catalysis outlined:
- highly efficient method for catalyst evaluation
- parallel format encourages the trial of a wider range of conditions
- increases chemists ability to be creative
- the potential for rapid optimization of industrial processes is outlined
- one reaction per well is the only efficient way to evaluate catalyst
13
Chiral Catalysts for the Strecker Reaction
! Jacobsen - parallel synthetic ligand libraries
O
catalyst
N
TBSCN
F3C
N
H
CN
TFA
! Modifed Schiff bases were prepared in a combinatorial fashion on a solid support
R
R
O
N
R
M
Linker1
amino acid
Linker2
O
R
N
N
M
R
Solid support
tridentate Schiff base complex
E. N. Jacobsen J. Am. Chem. Soc. 1996, 118, 8983.
E. N. Jacobsen J. Am. Chem. Soc. 1998, 120, 4901.
O
R
14
Chiral Catalysts for the Strecker Reaction
■ The initial catalyst screen
the ligand itself is better than the metal complexes!
15
Chiral Catalysts for the Strecker Reaction
■ Optimization of the urea and thiourea catalysts
Ph
R
H
N
O
N
H
S R
R
N
H
N
Ph
tBu
H
N
O
HO
S
N
H
N
H
N
HO
X
OMe
tBu
tBu
80% ee
■ a new class of catalysts discovered
■ many new applications
■ major advance in H-bonding catalysis
■ showcase of combinatorial catalyst design
16
Polyolefin Catalyst Discovery
! Polyolefin production is a 100 billion-dollar industry
catalyst
R
n
R
polyolefin
myriad applications
!-olefin
feedstock chemical
! Mechanism: Polymer growth by alkene 1,2-insertion with chain migration
P
M
M
P
M
P
17
Polyolefin Catalyst Discovery
! Highly active single-site catalysts been developed for over 50 years
1957 - Ziegler/Natta catalysts
1980 - Kaminsky
1963 - Nobel Prize
TiCl4
or
Cl
Ti
O Al
Me
Cl
MAO additive
increases activty
+ AlEt3
1986 - Jordan no activator
1985 - Britzinger ansa metallocenes
Me
Zr
THF
Cl
B(C6F5)4
highly active can now do polypropylene
Ti
Cl
syndiotactic polymers
L. Cavallo, F. Piemontesi Chem. Rev. 2000,100, 1253.
G. Fink, R. Muelhaupt, H. H. Brintzinger Ziegler Catalysts, Springer, Berlin, 1995.
18
Polyolefin Catalyst Discovery
! Catalysts aggressively patented - need new structures for industrial processes
New ligand designs:
N
Me
N
Ti
Me2Si
R
P
Cl
N
M
Cl
N
Me
P
tBu
Constrained geometry
(Dow)
Me
Ti
N
Me
R
Phosphoramides
(Nova)
McConville
New Metals:
R
Ar
R
N
CH3
Pd
R
N
sol
Ar
1995 - Brookhart
R
Me
N
tBu
Al
N
Me-B(C6F5)4
R
1997 - Jordan
N
Me
Al
O
MeB(C6F5)4
1999 - Gibson
19
Polyolefin Catalyst Discovery
■ Can a new catalyst for α-olefin polymerization be rapidly discovered and optimized?
Target: linear low-density polyethylene by ethlyene/octene copolymerization
catalyst ?
hex
hex
LLDPE
Workplan:
Dow Chemicals / Symyx: V. Murphy J. Am. Chem. Soc. 2003, 125, 4306.
20
Polyolefin Catalyst Discovery
■ A library of 24 ligands is used to make a series of novle catalysts
L
M(CH2Ph)4
XH
L
M(CH2Ph)4
- PhCH3
X
M = Zr, Hf
21
Polyolefin Catalyst Discovery
■ Primary discovery workflow
■ Zr results
known ligands for Zr polymerization
TMS
H
N
N
H
N
N
New ligand
NH
O
22
Polyolefin Catalyst Discovery
■ Hf results - a new, highly active polyolefin catalyst
23
Polyolefin Catalyst Discovery
! 2nd Screen - Focused library of ligands with Hf
Change condtions to commercially relevant copolymerization conditons
- higher temperature 130 °C
- larger scale (15 mL) high pressure batch reactors
Me
Me
NH
O Me
Me
original hit
New ligand library:
R1
NH
O
R2
R1
NH
O
R2
96 amino - ether type ligands
R1
NH
O
R2
24
Polyolefin Catalyst Discovery
■ 2nd Screen - Focused library of ligands with Hf
Hf(CH2Ph)4
ligand
hex
100 psi
250 uL
AliBu3
[Me2PhNH][B(C6F5)4]
hex
25
Polyolefin Catalyst Discovery
! Final results - one gallon batch reactor
catalyst
hex
450 psi
250 g
AliBu3
[Me2PhNH][B(C6F5)4]
hex
130 °C
isoparafin solvent
Dow Production Catalyst
Me2Si
Ti
N
O
Me
Me
Optimized Catalyst
Initial Lead
Me
Mes
O
CH2Ph
N
Hf
CH2Ph
N
Hf
CH2Ph
CH2Ph
tBu
CH2Ph
CH2Ph
activity
(g polymer/umol cat)
52.30
7.56
13.76
Mw
59 500
97 000
181 000
2.0
3.0
2.8
0.912
0.910
0.917
Mw/Mn
density (g/mL)
26
Polyolefin Catalyst Discovery
! What about polymer tacticity?
catalyst
Me
Me
Me
! Added value high performance plastics
Ph
Ph
Ph
Ph
Ph
Ph
Ph
atactic
syndiotactic
brittle
low melting
50 c / lb
(styrofoam cups)
Dow - Questra
tough crystaline
high melting
$3 / lb
Ph
27
Polyolefin Catalyst Discovery
! Catalyst controls polymer microstructure
Ph
C2
Zr
Me
Ph
M
Me
H
M
Ph
Me
M
Ph
Me
Ph
Zr
Me
Me
enantiotopic
Britzinger 1985, Chem Rev
Ph
isotactic
homotopic
C1
Me
M
Ph
H
Me
M
Ph
Me
M
Ph
Me
Ph
Ph
syndiotactic
28
Polyolefin Catalyst Discovery
■ Isotactic catalyst developement over the last 30 years
■ Current state of the art
Me
Me
Me
Si
Zr
Me
29
Polyolefin Catalyst Discovery
■ Isotactic catalyst developement - 39 ligand screen
dramatically
influences
performances
Hf(NMe2)4
R1
R3
+ AlMe3 / [Ph3C][B(C6F5)4]
NH
N
R2
Me
75 °C toluene
V. Murphy, J. C. Stevens, V. Busico Angew. Int. Ed. Engl. 2006, 45, 3278.
Me
Me
polypropylene
30
Polyolefin Catalyst Discovery
■ NMR provides a qualitative measure of isotacticity
for a polymer remarkably regular - very few polymer irregularities
31
Polyolefin Catalyst Discovery
! Two new catalysts identified
Me2N
Hf(NMe2)4
NH
NMe2
Hf
10 AlMe3
N
N
N
- 2 NHMe2
Me
Me
Me
also:
Hf
-2 Al2Me5(NMe2)
Me
Hf
N
N
N
N
! Mechanistic model: metallocene mimic
Me
Me
Hf
isotactic
polypropylene
P
Hf
Me
32
Polyolefin Catalyst Discovery
! Hold on, how do you get isotactic polymer from a C1 symmetric ligand ?
C1-symmetric the ligand should give rise to enantiotopic binding sites
N
Hf
N
Me
Me
Hf
P
Me
Me
enantiotopic
Me
syndiotactic
! The twisting of the ligand makes the coordination sites pseudo-homotopic
Me
Hf
P
Hf
P
Me
C1 ligand with diasterotopic binding sites
behaves like a C2 symmetric - homotopic
Me
Me
isotactic
33
Polyolefin Catalyst Discovery
! Comparison of new catalysts to highly developed industry standard metallocene
Me
Me
Me
Hf
Hf
Me
Me
N
N
Me
Si
Zr
Me
N
N
Me
6.9 bar propene, 10 equiv Al(iBu)2H, [Me2PhNH][B(C6F5)4], 90 °C
Productivity TOF
kg polymer / mmol cat / min
9.2
1.9
0.3
Mw [kDa]
95
300
710
Mw/Mn
2.0
2.1
3.2
Tm (°C)
142
127
141
> 300 desired
> 150 desired
34
Polyolefin Catalyst Discovery
! In just 4 years a new catalyst for isotactic polypropylene production has been realized
Me
Me
Hf
N
N
Ph
! robust solution catalyst operating above 100 °C
! isotactic
! high Mw polypropylene
! Tm 150 °C
! now in produciton at Dow, trade name Versify
35
Industrial Scale Hydrogenation
! Each process uses different ligand reflecting substrate specificty and IP restrictions
MeO
CHO2H
NHAc
NHAc
AcO
OH
95% ee
Monsanto 1 t/y
L-dopa Parkinson drug
97% ee
Takasago 300 t/y
(citronellol - Vitamon E)
CO2H
83% ee
Enichem 15 t/y
(aspartame sweetner)
Me
MeO
P
P
PPh2
OMe
Ph
PPh2
99% ee
Degussa-Huls 10 kg
Me
N
N
PPh2
PPh2
Ph2P
Ph
NBn
Ph2P
eniphos
dipamp
deguphos
binap
PCy2
O
N
O
N
Et
NHtBu
Me
97% ee
Lonza > 200 kg
pharmaceutical intermediate
Fe PPh2
H
josiphos
H. U. Blaser Appl. Catal. A 2001, 221, 119.
36
Catalyst Design and the Hydrogenation Mechanism
■ Halpern discovered this behavior in asymmetric hydrogenation
O
Ph
Me
Ph2
P
sol
Rh
MeO
HN
Me
O
Me
P
Ph2
-2 sol
Me
MeO2C
Ph2
P
Rh
Me
P
Ph2
sol
Me
NH
Ph
Me
O
Me
Ph2 MeO C
2
P
Rh
P
Ph2
(chiraphos)
Ph
NH
O
Me
diastereoisomers
major isomer > 10:1
NMR and X-ray
J. Halpern J. Am. Chem. Soc. 1980, 102, 5952.
J. Halpern Science 1982, 217, 401.
J. Halpern J. Am. Chem. Soc. 1987, 109, 1746.
37
Halpern Hydrogenation Mechanism
Me
Me
MeO2C
Ph2
P
Rh
NH
Ph
P
Ph2
K
Me
Me
O
Me
Ph2 MeO C
2
P
Rh
P
Ph2
major
kmaj
NH
+ 1.4 kcal/mol
O
Me
minor
Oxidative addition of H2
(rate determining step)
kmin
= 580
kmaj
H2
R
H
Ph
P
NH
Rh
Ph
P
!!G = 3.7 kcal/mol
kmin
H
Ph
R
H
NH
Rh
Me
P
O
H
H2
O
P
Me
1,2 insertion
R
H
P
NH
Rh
Ph
P
Ph
R
H
NH
Rh
P
Me
P
O
O
Me
reductive elimination
O
MeO
Bn
minor
O
dechelation
H
N
Me
O
H
N
MeO
Bn
Me
O
major 96% ee, > 50:1
38
Catalyst Design and the Curtin Hammett Principle
K
k1
C
A
major
minor
k2
B
D
TS2
G
TS1
!G1
!!G
!G2
A
!G
C
B
D
The design of a suitable (enantioselective) catalyst becomes diffiuclt as the exact
reaction pathway can depend on more reactive transient intermediates (A)
! The reaction outcome depends on !!G
! The equilibrium constant between the intermediates does not impact the reaction outcome
! Energies involved are 2-3 kcal/mol, current DFT has an error of about 1-5 kcal/mol
! While ligands can be cleverly designed, optimization is ultimately empirical
39
Hydrogenation at Merck and High-Throughput Optimizaiton
■ Parallel pressure reactors enabled the evaluation of many ligands
C. S. Shultz, S. W. Krska Acc. Chem. Res. 2007, 40, 1320
40
Hydrogenation at Merck and High-Throughput Optimizaiton
! Conditions and ligand otimization in cooperation with Solvias led to a commercial process
tBu
P
tBu
Me
0.32 mol %
Fe PPh2
CF3
CF3
F
N
N
NH2
F
F
O
N
F
0.15 mol % [Rh(cod)Cl]2
50 °C, 150 psi H2
N
N
NH2
F
MeOH, 18 h
N
O
F
sitagliptin (DPP-4 inhibitor)
Treatment for type II diabetes
FDA approved in October 2006
Just 6 months to reach 100 kg scale
20 MT has been produced to date
C. S. Shultz, S. W. Krska Acc. Chem. Res. 2007, 40, 1320
>95%, 95% ee
41
Monodentate Phosphoramidites as Ligands for Hydrogenation
■ 3 groups independently reported enantioselcetive catalysis mediated by phosphoramidites
O
O
O
P
OR
O
P
NR
M. Reetz Angew. Chem. Int. Ed. Engl. 2000, 112, 4047.
P. G. Pringle Chem. Commun. 2000, 961.
J. G. de Vries, B. Feringa J. Am. Chem. Soc. 2000, 122, 11539.
phosphite
phosphoramidite
■ In some cases monodentate ligands are faster and more selective than bidentate
O
NHAc
HO
Me
Et
B. L. Feringa, J. G. de Vries Acc. Chem. Res. 2007, 40, 1267.
42
Optimization of Hydrogenation by Combinatorial Ligand Libraries
■ In situ formation of ligands from phosphites and amines
O
P
O
Cl
R2
H
N
NEt3
R1
R1
O
P
O
NEt3·HCl
N
R2
■ Instant catalyst libraries from combiinatorial ligand - metal constructs
43
Optimization of Hydrogenation by Combinatorial Ligand Libraries
■ Hydrogentation screening results - substrate specificity towards ligand R1 and R2
■ For both substrates a highly efficient and selective ligand was found: >90%, >90% ee
44
Unexpected Results in Monodentate Phosphoramidate Mediated Catalysis
! Use of 2 equiv of one ligand results in moderate to high selectivity
O
MeO
H2
O
NHAc
NHAc
MeO
Me
O
La
O
[RhLaLa]BF4
P
tBu
92% ee
O
Lb
O
[RhLbLb]BF4
P
OMe
77% ee
! Not the average of the two ligands' selectivities, MLaLb faster and more selective
2 MLaLb
MLaLa + MLbLb
[RhLaLb]BF4
M. Reetz Angew. Chem. Int. ed. Eng. 2003, 42, 790.
98% ee
45
Rate Acceleration of Mixed Ligand Systems
■ Hetero-combination of matched S,S ligands provides faster rates of hydrogenation
O
O
O
O
M. Reetz Angew. Chem. Int. Ed. Engl. 2006, 45, 1412.
P
P
CH3
tBu
1a
1b
46
Even More Unexpected: Achiral Ligands Amplify Selectivity
! Higher selectivities werefound by using mixtures of ligands
O
NHAc
MeO
O
H2
NHAc
MeO
Me
[RhLaLb]BF4
98% ee
[RhLaLa]BF4
75% ee
[RhLbLb]BF4
0% ee
! Not the average of the two ligands' selectivities, MLaLb faster and more selective
2 MLaLb
MLaLa + MLbLb
1
16
La
O
O
P
OMe
1
Lb
O
O
P
OMe
Achiral
M. Reetz Angew. Chem. Int. ed. Eng. 2005, 44, 2959.
47
Achiral Ligand Adopts Matched Case
! Comparing Combinations of different chiral to achiral phosphites
O
[RhLL]BF4
NHAc
MeO
Me
Case 1: Matched
Case 2: Mis-matched
O
O
O
O
P
O
tBu
O
P
O
tBu
O
P
OMe
100%
98% ee
P
OMe
84%
40% ee
100%
98% ee
Achiral
Case 3: Fluxinal
O
O
P
tBu
O
O
P
mis-matched
OMe
O
O
P
matched
OMe
48
High-Throughput Developement of a Mixed Ligand Hydrogenation Process
! DSM Pharma makes AliskirenTM a renin inhibitor via a hydrogenation process
MeO
O
CO2H
MeO
Me
MeO
hydrogenation
MeO
Me
Me
OH
Me
H Me
N
H2N
MeO
O
O
MeO
Me
CONH2
O
Me
Me
AliskirenTM - Novartis
Goals: Reduce cost and stay within time-to-market window
J. de Vries Org. Proc. Res. Dev. 2007, 11, 585.
CO2H
Me
Me
49
High-Throughput Developement of a Mixed Ligand Hydrogenation Process
■ Initial study: monophos and additives
2
O
Me
P
O
N
Me
monophos
MeO
O
MeO
CO2H
Me
Me
[Rh(cod)2]BF4
additive
H2
MeO
O
MeO
CO2H
Me
Me
50
High-Throughput Developement of a Mixed Ligand Hydrogenation Process
! Instant ligand library optimization with PPh3 additive
Me
O
R
P
Cl
H
O
96 amines
N
R
Me
Me
O
2
R
P
O
N
R
Me
MeO
O
MeO
MeO
CO2H
Me
Me
PPh3
H2
[Rh(cod)2]BF4
O
MeO
CO2H
Me
Me
51
High-Throughput Developement of a Mixed Ligand Hydrogenation Process
■ Instant ligand library optimization with PPh3 additive
Me
O
O
Me
R
P
N
R
52
High-Throughput Developement of a Mixed Ligand Hydrogenation Process
■ Instant ligand library optimization with PPh3 additive
Me
O
O
Me
R
P
N
R
53
High-Throughput Developement of a Mixed Ligand Hydrogenation Process
! The final process
Me
O
2
O
MeO
O
P
N
P
CO2H
Me
Me
MeO
Me
Me
80 bar H2
IPA/H2O (80/20)
0.02 mol % [Rh(cod)2]BF4
MeO
O
MeO
CO2H
Me
Me
100 %
90% ee
TON 5000
TOF 1800/h
TON > 10,000 possible
50 g substrate
3
54
Catalyst Design by Self-Assembly
! Combinatorial method for the design of new bidentate ligands
N
N
A
N
H
N
H
O
Piv
N
N
N
Do
Piv
H
N
O
O
N
H
H
H
N
N
Do
M
H
O
T
Do
N
Do
N
Me
modular ligands
DNA Base pairs
Ligands:
self assembled catalyst
O
R
Piv
N
H
N
P
Ar
Piv
Ph
N
P
N
H
H
O
P
O
R
B. Breit J. Am. Chem. Soc. 2006, 128, 4188.
N
O
R
R
O
55
Catalyst Design by Self-Assembly
! Highly enantioselective ligand system found for hydrogenation
[Rh(COD)2]BF4
La / L b
H2
O
MeO
O
N
H
Me
CH2Cl2
Me
MeO
O
O
N
H
Me
TON 1000
99% ee
100% conv
Best ligand combination:
O
Piv
N
N
H
H
O
N
P
O
Rh
P
O
O
(Control reactions showed the
heterocombination to be superior to
homocombinations of either ligand)
56
Self-Assembled Supramolecular Catalysts
! 3-aminochromanes are found in many natural products
NHMs
O
NC
EtO2C
O
OH
H
N
N
OH
MK-0499
SR 58611A
! Hydrogenation of enamides of this type is difficult
H
N
Me
H
N
Rh-L
O
Me
O
Ph
O
O
P
N
O
P
S
N
PPh2
PPh2
O
Ph
J. Ferringa
J. Org. Chem. 2005, 70, 943.
94% conv
34% ee
J. Ferringa
Org. Lett. 2004, 6, 1433.
40% conv
34% ee
C. Bruneau
Adv. Syn. Catal. 2003, 345, 230.
94% conv (Ru)
80% ee
57
Self-Assembled Supramolecular Catalysts
■ Self asembled catalyst designed to solve the difficult hydrogenation of enamide
Ligand library generated by self assembly of a
suoramolecular porphyrin structure - supraphos
J. N. H. Reek Angew. Chem. Int. Ed. Engl. 2006, 45, 1223.
Review: B. Breit Angew. Chem. Int. Ed. Engl. 2005, 44, 6816.
58
Self-Assembled Supramolecular Catalysts
■ Modular ligands increases the accessible structural diversity
59
Self-Assembled Supramolecular Catalysts
H
N
Me
O
[Rh(cod)2]BF4
Supraphos
H
N
Me
O
H2
L2 - L'1
100% conv, 94% ee
O
O
Rh
Ph2
P
P
N
O
N
N
Zn
Ph
Supraphos
All control reactions led to eroded selectivity - Binap 60% ee
Ph
N
N
Ph
60
New Methods for High-Throughput Screening
■ Mass spectrometric evaluation of catalysts by microscopic reversibility
Me
O
N
microscopic retro DA
O
Bn
N
(S )
Bn
Me
N
Me
O
Pr
Me
N
H
375 m/z
Si
Me
Me
Pr
HCl
O
1 h 50 °C
Me
O
N
(R )
Bu
pseudoenantiomers
with different mass
Bn
N
Me
389 m/z
Me
Re
Bu
changing Bu and Pr
gives the same result
Mass labelled catalyst
A. Pfaltz Angew. Chem. Int. Ed. Engl. 2008, 47, 3360.
61
New Methods for High-Throughput Screening
■ Determining relative catalyst enantioselectivity from microscopic reverse DA
O
Pr
(S )
O
(R )
catalyst pool
1 h 50 °C
Bu
With any new and exciting
experiments more
questions are raised
can yield be addressed - a funciton of ionization potential
will this be a general method
how many catalysts can be done at once? mass overlap
does this method account for Halpern type systems?
62
Conclusions
! HT techniques have impacted several fields of chemistry and industry
! HT/combinatorial catalysis is not anti-intellectual
! The goal of performing greater numbers of experiments increase creativity and chances of success
! So far, HT in fine chemicals is typically 100's not 1000's - enantioselective quality over quantity
! Impressive discoveries have been made: H-bonding, Hf polymerization, non-linear effects
! HT has enabled enantioselective catalysis to be adopted in fine chemical production