dual enantioselectivity: inducing a single chiral ligand to reverse a reaction’s...
TRANSCRIPT
Dual Enantioselectivity:Inducing a Single Chiral Ligand to
Reverse a Reaction’s Enantioselectivity
James HrovatStahl Research Group
February 15, 2007
2
Determining Enantioselectivity
Asymmetric ReactionsNecessity of chemistry
Natural Product SynthesisPharmaceutical SynthesisMethodology Studies
Requirements:Substrate GeneralizationReadily Available Chiral SourcesMild Reaction Conditions
N
N
O
O
OHO
OO
N
N
IrinotecanPfizer: Camptosar(CPT-11)
http://www.pfizeroncology.com/products/camptosar.aspx
3
Reaction Optimizations
EnantioselectivityEnantioselectivityEnantioselectivityEnantioselectivity
SubstrateSubstrateModificationModificationSubstrateSubstrate
ModificationModification
StericsElectronics
Functionality
LigandLigandModificationModification
LigandLigandModificationModification
StericsElectronics
FunctionalitySize
ReactionReactionConditionsConditionsReactionReaction
ConditionsConditions
SolventAdditives
TemperatureMetal Salts
4
Substrate Modification
StericsMaximize/Minimize Interactions
Electronics Electron rich vs. Electron poor
FunctionalityHydrogen bonding
O NC OTMS
N
TMS
OMe
OTBS
O
N
TMS
OMe OTBS
TMSO CN
"Chiral Catalyst"
"Chiral Catalyst"
Yield: 85%ee: 92%
Yield: 34%ee: 18%
Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc., 2000, 122, 7412-7413Shibasaki, M., et al. J. Am. Chem. Soc. 2001, 123, 9908-9909
Advantages: Customizing the Reaction for
Selectivity
Limitations: Modifying the Substrate is Not
Optimal
5
Ligand Modification
StericsMaximize/Minimize Interactions
ElectronicsElectron-Rich vs. Electron-Poor
FunctionalityHydrogen BondingChelation Properties
SizeMetallocycle Formation
Advantages:Customizing for Enantioselectivity
Limitations:ExpensiveTime Consuming
Fe
O OH
0.25 %[Rh(cod)Cl]21.3 eq. H2SiPh, Et2O25°C, 15-20 hrs.
0.5% QuantativeYieldee: 91%
NO
Ph
PhPh2P
Uemera, S.; Nishibayashi, Y.; Segawa, K.; Ohe, K. Organometallics 1995, 14, 5486-5487
6
Reaction Modification
Solvent ChangesTemperature ModificationsAddition of Additives
Non-Chiral Reagents
Inorganic/Organic Bases
Molecular Sieves
Metal SaltsCatalyst Precursors
Advantages:Cost EffectiveImmediate Modifications
Limitations:How Much Screening Is Necessary?Is It Enough??
7
Drastic Effect by Minor Changes
O
NPh
Ph OH
OH
''Fresh'' Condition:LiAlH4 (1.56 eq.)Et2O, - 65°C, 12 h
3.6 eq.
82%yield100%conversion68%ee
Mosher, H.S.; Yamaguchi, S. J. Org. Chem. 1973, 38, 1870-1877
O
NPh
Ph OH
OH
"Aged"Condition:LiAlH4 (1.56 eq.)Et2O, 20°C, 24 h
3.6 eq.
40%yield40%Conversion66%ee
“Aged”: Refluxing for 10 minutes and standing for 24 hours
8
Enantioselectivity Focus
EnantioselectivityEnantioselectivityEnantioselectivityEnantioselectivity
SubstrateSubstrateModificationModificationSubstrateSubstrate
ModificationModification
StericsElectronics
Functionality
LigandLigandModificationModification
LigandLigandModificationModification
StericsElectronics
FunctionalitySize
ReactionReactionConditionsConditionsReactionReaction
ConditionsConditions
SolventAdditives
TemperatureMetal Salts
9
Reaction Scope
Cycloadditions:[4+2] Diels-Alder[4+2] Hetero Diels-Alder1,3-Dipolar Cycloaddition[4+1] Cycloaddition
Michael AdditionsAldol ReactionsEne ReactionsHydrogenation of AlkenesHydroformylation
Alkylation of AldehydesAllylationsHeck CouplingSuzuki CouplingElimination Reactions SilylationsHydrocyanationHenry Reactions
Sibi, M.; Liu, M. Curr. Org. Chem., 2001, 5, 719-755Zanoni, G.; Frnzini, M.; Giannini, E.; Castronovo, F.; Vidari, G. Chem. Soc. Rev. 2003, 3, 115-129Kim, Y.H. Acc. Chem. Res. 2001, 37, 2922-2959
10
Today’s Scope
[4+2] Diels-AlderYtterbium Salt and BINOL
1,3-Dipolar Cycloadditions of NitronesMagnesium Salt and Phenyl BOX
Carbonyl TransformationsZn-Ynone Aldol
Zn-Alkyl Addition
Synthesis of (20S)-Camptothein RetronGlucose Derived LigandReversal of Original Optimized Enantioselectivity
11Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron Lett. 1993, 34, 4535-4538Kobayashi, S.; Ishintani, H.; J. Am. Chem. Soc. 1994, 116, 4083-4084
Ln Catalyzed Diels-Alder
M(OTf)3 Lu Yb Tm Er
Yield (%)
60 77 46 24
endo (%)
89 89 86 83
ee (%)93 93 75 69
NO
O O
20 mol%[M-BINOL]4Å, CH2Cl2,0°C, 20 h
O NO
O
O NOO
Si Product Re Product
12Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron Lett. 1993, 34, 4535-4538Kobayashi, S.; Ishintani, H.; J. Am. Chem. Soc. 1994, 116, 4083-4084
Ln Catalyzed Diels-Alder
M(OTf)3 Lu Yb Tm Er
Yield (%) 30 88 72 59
endo (%) 89 89 92 91
ee (%) 51 70 74 74
NO
O O
20 mol%[M-BINOL]4Å, CH2Cl2,0°C, 20 h
O NO
O
O NOO
Si Product Re Product
13
Additive binds the Si site leaving only the Re site available for substrate binding
Si site
Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron Lett. 1993, 34, 4535-4538Kobayashi, S.; Ishintani, H.; J. Am. Chem. Soc. 1994, 116, 4083-4084
Re site
OOH
H
Yb(OTf)3
N
N
OO
Ph
OOH
Ph
14
Recalling the Modifications
Additive effectsTertiary amine was necessary for good enantioselectivity Second additive was able to block more reactive siteReaction was forced to less reactive site of the catalyst
What did not change:SubstrateReagentMetal saltSolventTemperature
15
1,3-Dipolar Cycloadditions
O N
O ONO
H
N
O
N
O
Ph Ph NO
Z
NO
Z
Si site Re Site
10-11%
10 mol%MgX2, CH2Cl21.5 eq. Nitrone
Catalyst
Temp (°C)
Time (h)
Yield (%)
endo/exo
ee (%)
Re/Si
Mg(ClO4)
2 -15 15 >98 95:5 48 Re
Mg(OTf)2 -15 20 >98 97:3 86 Re
MgI2 -78 to 20 20 >95 100:0 48 SiDesimoni, G.; Gaita, G.; Mortoni, A., Righetti, P. Tetrahedron Lett. 1999, 40, 2001-2004Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1998, 63, 5483-5488
16
Catalyst
Additive Temp (°C)
Time (h)
Yield
(%)
endo/exo
ee (%)(endo)
Re/Si
Mg(ClO4)
2
4Å M.S. -15 15 >98 70:30 70 Si
Mg(ClO4)
2
-15 15 >98 95:5 48 Re
Mg(ClO4)
2
H2O (2 eq.)
-15 48 >98 96:4 45 Re
Mg(OTf)2 -15 20 >98 97:3 86 Re
MgI2 4Å M.S. -78 to 20 20 >95 73:27 82 Re
MgI2 -78 to 20 20 >95 100:0 48 Si
MgI2 H2O
(40%)-78 to 20 20 >95 90:10 36 Si
MgI2 H2O
(18%) 4Å M.S.
-78 to 20 20 >95 95:5 36 Re
Desimoni, G.; Gaita, G.; Mortoni, A., Righetti, P. Tetrahedron Lett. 1999, 40, 2001-2004Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1998, 63, 5483-5488
O N
O ONO
H
N
O
N
O
Ph Ph NO
Z
NO
Z
Si site Re Site
10-11%
10 mol%MgX2, CH2Cl21.5 eq. Nitrone
17
DRe face
BSi face
CRe face
O N
O O
Ligand
Dark Blue: Oxizolidinone Green: α,β-Unsaturated Purple: Ligand Top Face: ReBottom Face: Si
Desimoni, G.; Gaita, G.; Mortoni, A., Righetti, P. Tetrahedron Lett. 1999, 40, 2001-2004Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1998, 63, 5483-5488Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1996, 61, 346-355
ASi face
endo-Re: calculated as the lowest TS
18
Mapping Out Selectivity
O N
O ON
O
H
MgI2/MSGoodee
NOPh
PhO
XN
OPh
PhO
X
Mg(OTf)2Goodee
MgI2Poor ee
Mg(ClO4)2/MSModerateee
(3S,4R) (3R,4S)
Desimoni, G.; Gaita, G.; Mortoni, A., Righetti, P. Tetrahedron Lett. 1999, 40, 2001-2004Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1998, 63, 5483-5488Ohta, T. et al. J. Organomet. Chem. 2000, 603, 6-12Jørgensen, K.A; Gothelf, K.V. Chem. Commun. 2000, 1449-1458
Similar Effects have been seen in Cu2+, Zn2+, and Sc3+ catalyzed reactions
Molecular Sieves are more than just drying reagents
19
Recalling the Modifications
Counter ion of metal salt has a strong influence on enantioselectivity
Coordination influence geometryMolecular sieves influence enantioselectivityBinding at the surface forces geometric constraints on the catalystSubstrate binding is affected by cis binding of molecular sieves
Multiple ways to the same product enantiomer
What did not change:SubstrateReagentSolventChiral LigandMetal
20
EtO OEt
O O
SiEt3
(R)EtO OEt
OH O
SiEt3
OH NN
HO PhOHPhPh Ph
5 mol%Zn(Et)24Å, THF
10%
Trost, B.M.; Fettes, A.; Shireman, B.T.; J. Am. Chem. Soc. 2004, 126, 2660-2661
Temp. (°C)
Time (h)Yield (%)
ee (%)
0 7.5 63 84
25 2.5 65 99
Ynone Aldol
21
SolventTemp. (°C)
Time (h)Yield (%)
ee (%)
R/S
Toluene 0 4 63 44 R
THF 0 7.25 61 83 R
Toluene -25 4 27 72 S
THF -25 2 - 69 S
Trost, B.M.; Fettes, A.; Shireman, B. J. Am. Chem. Soc. 2004, 126, 2660-2661Trost, B.M.; Weiss, A., Wangelin, A. J. Am. Chem. Soc. 2006, 128, 8-9
Binding Preference
Proposed Active Catalyst: Alkynylation of Aryl Aldehydes
NN
OPh
OPhPh Ph
O
Zn Zn
ZnR
R
RO
1R
H
O
R1 HNN
OPh
OPhPh Ph
O
Zn Zn
ZnR
R
R
Re-site leads to major product
22
Rxn Cond.:Standard Reaction Conditions5 mol% [Zn]2.5 mol% Chiral Ligand
Modified Rxn. Cond.:5 mol% [Zn]2.5 mol% Chiral Ligand,2.5 mol% Aldol Product
0 0.75 1.25 3 6 10.75
-80
-40
0
40
80
ee (
%)
Time (h)
0
20
40
60
80
100
0 2 4 6 8 10 12Time (h)
Yie
ld (
%)
Trost, B.M.; Fettes, A.; Shireman, B. J. Am. Chem. Soc. 2004, 126, 2660-2661
Probing the Reaction
Unmodified Rxn
Modified Rxn
23
Regeneration of Catalyst
NN
OPhO
PhPh Ph
O
Zn Zn
ZnO
R
RR1RH
NN
OPhO
PhPh Ph
O
Zn Zn
ZnR
R
RZnR2
Zn(R)(Prod)
R=Enol
Regeneration of initial catalyst does not occurNew insitu catalyst is generated
Incorporates alkoxide product into structure
Trost, B.M.; Fettes, A.; Shireman, B. J. Am. Chem. Soc. 2004, 126, 2660-2661Trost, B.M.; Weiss, A., Wangelin, A. J. Am. Chem. Soc. 2006, 128, 8-9
24
Recalling the Modifications
Product is incorporated into new insitu catalyst
Temperature EffectRaising temperature increases eeLowering temperature reversed ee
Solvent Optimization
What did not change:Catalyst PrecursorChiral Ligand SubstrateReagent
25
N
N
O
tBu
N
N
(R)
OH
tBu
Ph
MeHO
NMe2
HO
NBu2
Zn(iPr)2 (2 eq.),
DMNE (20%), hexanes,0°C, 16 hrs.
N
N
O
tBu
N
N
(S)
OH
tBu
Zn(iPr)2 (2 eq.),
DMNE (0.5%), DBAE (20%)hexanes, 0°C, 16 hrs.
Yield=98%ee =98.8%
Yield=95%ee =94.8%
(1S,2R)-N,N-dimethylnorephedrine[DMNE]
N,N-dibutylaminoethanol[DBAE]
Alkyl Addition to Aldehydes
Soai, K.; Lutz, F.; Igarashi, T.; Kawasaki, T. J. Am. Chem. Soc. 2005, 127, 12206-12207
26
N
N
OZniPr
tBu
Stage1 Stage2Zn(iPr)2
Ph
MeHO
NMe2
HO
NBu2
Aldehyde AldehydeZn(iPr)2
Ph
MeiPrZnO
NMe2
iPrZnO
NBu2
What is the role of the achiral ligand?Does the product have a role in the system?
Two stage system to measure source of enatioselectivity of the reactionStage 1: Measure the selectivity of the initial catalystStage 2: Probe catalyst components
Stage
Zn(iPr)4
(mmol)
Aldehyde
(mmol)
Ligand
(mmol)
1 1 .5 0.1
2 1.25 .62 -
Determining the Catalyst
Soai, K.; Lutz, F.; Igarashi, T.; Kawasaki, T. J. Am. Chem. Soc. 2005, 127, 12206-12207
27
Regeneration of Catalyst
NN
OPhO
PhPh Ph
O
Zn Zn
ZnO
R
RR1RH
NN
OPhO
PhPh Ph
O
Zn Zn
ZnR
R
RZnR2
Zn(R)(Prod)
R=Enol
Regeneration of initial catalyst does not occurNew insitu catalyst is generated
Incorporates alkoxide product into structure
Trost, B.M.; Fettes, A.; Shireman, B. J. Am. Chem. Soc. 2004, 126, 2660-2661Trost, B.M.; Weiss, A., Wangelin, A. J. Am. Chem. Soc. 2006, 128, 8-9
28
20 18 16 14 12 10 8 6 2
-100
-50
0
50
100
Ob
serv
ed
ee
Chiral Ligand (mol%)Achiral LIgand (20%-Chiral%)
Stage 1Stage 2
Stage 1 Catalyst: Zn(OiPr)4, Chiral Ligand, Achiral LigandStage 2 Catalyst: Zn(OiPr)4, Chiral Ligand, Achiral Ligand, Aldol Product
Ligand Ratio Effects
Soai, K.; Lutz, F.; Igarashi, T.; Kawasaki, T. J. Am. Chem. Soc. 2005, 127, 12206-12207
29Soai, K.; Lutz, F.; Igarashi, T.; Kawasaki, T. J. Am. Chem. Soc. 2005, 127, 12206-12207Blackmond, D.G.; Buono, F.G. J. Am. Chem. Soc., 2003 125, 8978-8979Blackmond, D.G.; Buono, F.G., Iwamura, H. Angew. Chem. Int. Ed. 2003, 43, 2900-2103
Simplified Catalytic Structures
Structure of insitu catalyst is currently unknown
[Zn]2LACLC
Substrate[Zn] [Zn]3LACLC(Sub)
IntialActiveCatalyst
CatalystRestingState
[Zn]x(LAC)y(LC)z(Prod)x-y-z
LAC: Achiral LigandLC: Chiral Ligand
AutoCatalyst
Auto Catalytic Nature of the System takes over enantioselectivity
30
Recalling the Modifications
Reactive insitu catalyst is generated Product incorporation into new catalyst
Achiral ligand reverses intial enantioselectivityAt a specific ratio of chiral:achiral ligand, selectivity reverses
What did not change:SubstrateCatalyst PrecursorChiral LigandSolventTemperature
Soai, K. et. al. J. Am. Chem. Soc. 1998, 120, 12157-12158
Enantioselectivity of 38-85% ee has been observed with 1 mol% chiral initiator (0.1% ee)
31
Cyanosilylation of Ketones
O NC OTMS
HO
O
O
BnO
Ph2(O)P
10 mol%CatalystCH2Cl2
10%
Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc. 2000, 122, 7412-7413
Catalyst
Temp. (°C)
Temp (h)Yield (%)
ee (%)
R/S
Et2AlCl 20 48 0 - -
Yb(OiPr)3 20 2 90 18 S
Zr(OiBu)4 20 36 52 14 R
Ti(OiPr)4 20 48 78 35 R
Ti(OiPr)4 -20 36 44 73 R
32
Solvent Screen
O NC OTMS10 mol%Ti(OiPr)4
HO
O
O
BnO
Ph2(O)P
10%
SolventConc. (M)
Temp. (°C)
Time (h)Yield (%)
ee (%)
CH2Cl2 0.65 -20 36 44 73
Toluene 0.65 -20 36 40 70
THF 0.65 -20 36 58 83
THF 3 -30 36 85 92
Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc. 2000, 122, 7412-7413
33
Applying Methodology
Main Goal: Synthetic Application of Methodology
Camptothecin: Potent Antitumor AgentIsolated from Camptotheca acuminata
Wall and Wani (1966)
Pfizer: Camptosar 1st Quarter 2006: $212 million (worldwide)
(20R)-Camptothecin10-200 Times Less Active
N
N
O
O
OHO
N
N
O
O
OHO
OO
N
N
(20S)-Camptothecin
IrinotecanPfitzer: Camptosar (CPT-11)
Wall, M.E.; Wani, W.C.; Natschke, S.M.; Nicholas, A.W. J. Med. Chem. 1996, 29, 1553-1555http://www.pfizer.com/pfizer/download/news/2006q1_earnfin4.pdf
34
N
N
O
O
OHO
N
X
O
O
OHO
HN
X
O
O
(20S)-camptothecin
CN
OHO
N
R
OMe
ON
R
OMe
Curran, D.P.; Josien, H.; Ko, S.B.; Bom, D. Chem. Eur. J. 1998, 4, 67-83
(20S)-Camptothecin Retroanalysis
35
1) K3Fe(CN)6 (3 eq.), K2CO3 (3 eq.)CH3SO2NH2 (2 eq.), (DHQD)2- PYR (2.5 mol%)OsO4 (0.5 mol%), 1:1 tBuOH/H2O, 0ºC, 12 hrs.
2) I2 (9 eq.), CaCO3 (2 eq.),10:1 MeOH/H2O, 32 hrs., 20ºC
Yield: 85%ee: 94%
N
N
O
O
OHO
N
X
O
O
OHO
HN
TMS
O
O
(20S)-camptothecin
CN
OHO
N
TMS
OMe
ON
R
OMe
Curran, D.P.; Josien, H.; Ko, S.B.; Bom, D. Chem. Eur. J. 1998, 4, 67-83
(20S)-Camptothecin Retroanalysis
36
HN
X
O
O
OHO
N
R
OMe
O
Curran Retrons:
N
X
OMe
OTBS
O
N
X
OMe
OTBSCN
TMSO
N
X
OMe
O
HOO
Shibasaki Retrons:
Curran, D.P.; Josien, H.; Ko, S.B.; Bom, D. Chem. Eur. J. 1998, 4, 67-83Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123, 9908-9909
Comparing Retrons
37
OOAc
OAcAcO
OPh2(O)P
OHO
HO
11StepsOverall Yield: 44%
$2.70/g.
Problems:Reaction Optimized for
(R)-Cyanosilylation ProductLigand Synthesis Uses
D-Glucose Precursor L-Glucose is Needed
Ligand SynthesisHigh-Yielding ReactionsStraight-Forward
A Few Hurdles
O NCOTMS
N
TMS
OMe
OTBS
O
N
TMS
OMe
OTBS
NC OTMS
(R)
(S)
D-Glucose: $0.16/g.L-Glucose: $62.50/g
38
OOH
OHHO
OH
OH
OPh2(O)P
OHO
HO
14Steps
Problems:Reaction Optimized For the
(R)-Cyanosilylation ProductLigand Synthesis Uses
D-Glucose Precursor L-Glucose is Needed
Ligand SynthesisHigh-Yielding ReactionsStraight-Forward
A Few Hurdles
O NCOTMS
N
TMS
OMe
OTBS
O
N
TMS
OMe
OTBS
NC OTMS
(R)
(S)
D-Glucose: $0.16/g.L-Glucose: $62.50/g
39Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123, 9908-9909Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc. 2000, 122, 7412-7413
O NCOTMS
HO
O
O
BnO
Ph2(O)P
xmol%Ti(OiPr)4
Reversing Selectivity
MetalSolve
ntTemp (°C)
Ligand/Metal Ratio
Time (h)
Yield (%)
ee (%)
R/S
Ti(OiPr)4 (10%) THF -30 1:1 36 85 92 R
Yb(OiPr)3 (10%) CH2Cl2 20 1:1 2 90 18 S
Sm(OiPr)3 (5%) THF -40 1.8:1 2 85 82 S
Gd(OiPr)3 (5%) THF -40 1.8:1 2 - 89 S
Gd(OiPr)3 (5%) THF -40 2:1 2 92 92 S
40
Metal Solvent
Temp (°C)
Ligand/Metal Ratio
Time (h)
Yield (%)
ee (%)
R/S
Ti(OiPr)4
(10%)THF -30 1:1 144 34 18 R
Sm(OiPr)3
(5%)THF -40 1:1 - - 20 S
Sm(OiPr)3
(5%)THF -40 1.8:1 24 92 72 S
Sm(OiPr)3
(5%)MeCN -40 1.8:1 18 98 84 S
N
TMS
OMe
OTBS
O
N
TMS
OMe
OTBSCN
TMSO
Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123, 9908-9909
Switching Enantioselectivity
41
Retron Synthesis
Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123, 9908-9909Curran, D.P.; Josien, H.; Ko, S.B.; Bom, D. Chem. Eur. J. 1998, 4, 67-83
N
TMS I
OMe
OR
N
TMS I
OMe
OR'
HN
I
O
O
O
HN
I
O
O
O
Curran's Synthesis:
Shibasaki's Sythesis:
5 StepsYield: 13%ee: 94%
RecoveredS.M.:Yield: 36%ee: 94%
4StepsYield: 60%ee: 84%
Recrystallization:Yield: 30%ee: >99%
R=Crotyl
R' =TBS
HN
X
O
O
OHO
N
R
OMe
O
42
Recalling the Modifications
Variation of metal salt [Ti] and [Sm] have different mechanisms for cyano deliveryReverses enantioselectivity
Needed new optimizations for different mechanismNew metal to ligand ratio Solvent variationTemperature variations
What did not change:SubstrateReagentChiral Ligand
43
Overview
ReversingEnantioselectivity
Blocking Reactive SiteGeometric ConstraintsGeneration of New Catalytic Complex
Decrease Temp:Increase ee
Increase Temp:Increase ee
Changing of Mechanism
Counter Ion Effects
Additive Effects
Variation of Metal Salt
Reaction Parameters
44
Why it matters
Optimization for all asymmetric reactionsFocusing on reaction conditions instead of ligand and substrate
Reaction characteristicsAutocatalysisMechanistic pathway
Expands the scope of a chiral ligandLong ligand synthesisExpensive starting materialsCommercial availability of chiral ligands
45
Practice Talk Attendees:
Jamie EllisDr. Tetsuya HamadaDr. Justin HoerterLauren Huffman Megan Jacobson Amanda King
Acknowledgements:
Shannon Stahl
Stahl Group
Akiko K Hrovat
Dr. Vasily KotovDr. Guosheng LiuDavid MichaelisBrian PoppMichelle RogersChris Scarborough
Nickeisha Stephenson
Xuan YeLani McCartneyJoel BroussardEmily Blamer