Dual Enantioselectivity: Inducing a Single Chiral Ligand to Reverse a Reactions Enantioselectivity

1
Dual EnantioselectivityInducing a Single Chiral
Ligand to Reverse a Reactions Enantioselectivity

• James Hrovat
• Stahl Research Group
• February 15, 2007

2
Determining Enantioselectivity

• Asymmetric Reactions
• Necessity of chemistry
• Natural Product Synthesis
• Pharmaceutical Synthesis
• Methodology Studies
• Requirements
• Substrate Generalization
• Readily Available Chiral Sources
• Mild Reaction Conditions

http//www.pfizeroncology.com/products/camptosar.a
spx
3
Reaction Optimizations
Enantioselectivity
4
Substrate Modification

• Sterics
• Maximize/Minimize Interactions
• Electronics
• Electron rich vs. Electron poor
• Functionality
• Hydrogen bonding

• Advantages
• Customizing the Reaction for Selectivity
• Limitations
• Modifying the Substrate is Not Optimal

Shibasaki, M. Hamashima, Y. Kanai, M. J. Am.
Chem. Soc., 2000, 122, 7412-7413 Shibasaki, M.,
et al. J. Am. Chem. Soc. 2001, 123, 9908-9909

5
Ligand Modification

• Sterics
• Maximize/Minimize Interactions
• Electronics
• Electron-Rich vs. Electron-Poor
• Functionality
• Hydrogen Bonding
• Chelation Properties
• Size
• Metallocycle Formation

• Advantages
• Customizing for Enantioselectivity
• Limitations
• Expensive
• Time Consuming

Uemera, S. Nishibayashi, Y. Segawa, K. Ohe, K.
Organometallics 1995, 14, 5486-5487
6
Reaction Modification

• Solvent Changes
• Temperature Modifications
• Addition of Additives
• Non-Chiral Reagents
• Inorganic/Organic Bases
• Molecular Sieves
• Metal Salts
• Catalyst Precursors

• Advantages
• Cost Effective
• Immediate Modifications
• Limitations
• How Much Screening Is Necessary?
• Is It Enough??

7
Drastic Effect by Minor Changes
Aged Refluxing for 10 minutes and standing
for 24 hours
Mosher, H.S. Yamaguchi, S. J. Org. Chem. 1973,
38, 1870-1877
8
Enantioselectivity Focus
Enantioselectivity
9
Reaction Scope

• Cycloadditions
• 42 Diels-Alder
• 42 Hetero Diels-Alder
• 1,3-Dipolar Cycloaddition
• 41 Cycloaddition
• Michael Additions
• Aldol Reactions
• Ene Reactions
• Hydrogenation of Alkenes
• Hydroformylation

• Alkylation of Aldehydes
• Allylations
• Heck Coupling
• Suzuki Coupling
• Elimination Reactions
• Silylations
• Hydrocyanation
• Henry Reactions

Sibi, M. Liu, M. Curr. Org. Chem., 2001, 5,
719-755 Zanoni, G. Frnzini, M. Giannini, E.
Castronovo, F. Vidari, G. Chem. Soc. Rev. 2003,
3, 115-129 Kim, Y.H. Acc. Chem. Res. 2001, 37,
2922-2959
10
Todays Scope

• 42 Diels-Alder
• Ytterbium Salt and BINOL
• 1,3-Dipolar Cycloadditions of Nitrones
• Magnesium Salt and Phenyl BOX
• Carbonyl Transformations
• Zn-Ynone Aldol
• Zn-Alkyl Addition
• Synthesis of (20S)-Camptothein Retron
• Glucose Derived Ligand
• Reversal of Original Optimized Enantioselectivity

11
Ln Catalyzed Diels-Alder
Kobayashi, S. Hachiya, I. Ishitani, H. Araki,
M. Tetrahedron Lett. 1993, 34, 4535-4538 Kobayashi
, S. Ishintani, H. J. Am. Chem. Soc. 1994, 116,
4083-4084
12
Ln Catalyzed Diels-Alder
Kobayashi, S. Hachiya, I. Ishitani, H. Araki,
M. Tetrahedron Lett. 1993, 34, 4535-4538 Kobayashi
, S. Ishintani, H. J. Am. Chem. Soc. 1994, 116,
4083-4084
13
Additive binds the Si site leaving only the Re
site available for substrate binding
Kobayashi, S. Hachiya, I. Ishitani, H. Araki,
M. Tetrahedron Lett. 1993, 34, 4535-4538 Kobayashi
, S. Ishintani, H. J. Am. Chem. Soc. 1994, 116,
4083-4084
14
Recalling the Modifications

• Additive effects
• Tertiary amine was necessary for good
  enantioselectivity
• Second additive was able to block more reactive
  site
• Reaction was forced to less reactive site of the
  catalyst
• What did not change
• Substrate
• Reagent
• Metal salt
• Solvent
• Temperature

15
1,3-Dipolar Cycloadditions
Desimoni, G. Gaita, G. Mortoni, A., Righetti,
P. Tetrahedron Lett. 1999, 40, 2001-2004 Jørgensen
, K.A. Gothelf, K.V. Hazell, R.G. J. Org. Chem.
1998, 63, 5483-5488
16
Desimoni, G. Gaita, G. Mortoni, A., Righetti,
P. Tetrahedron Lett. 1999, 40, 2001-2004 Jørgensen
, K.A. Gothelf, K.V. Hazell, R.G. J. Org. Chem.
1998, 63, 5483-5488
17
Dark Blue Oxizolidinone Green
a,ß-Unsaturated Purple Ligand Top Face
Re Bottom Face Si
endo-Re calculated as the lowest TS
Desimoni, G. Gaita, G. Mortoni, A., Righetti,
P. Tetrahedron Lett. 1999, 40, 2001-2004 Jørgensen
, K.A. Gothelf, K.V. Hazell, R.G. J. Org. Chem.
1998, 63, 5483-5488 Jørgensen, K.A. Gothelf,
K.V. Hazell, R.G. J. Org. Chem. 1996, 61, 346-355
18
Mapping Out Selectivity

• Similar Effects have been seen in Cu2, Zn2, and
  Sc3 catalyzed reactions
• Molecular Sieves are more than just drying
  reagents

Desimoni, G. Gaita, G. Mortoni, A., Righetti,
P. Tetrahedron Lett. 1999, 40, 2001-2004 Jørgensen
, K.A. Gothelf, K.V. Hazell, R.G. J. Org. Chem.
1998, 63, 5483-5488 Ohta, T. et al. J. Organomet.
Chem. 2000, 603, 6-12 Jørgensen, K.A Gothelf,
K.V. Chem. Commun. 2000, 1449-1458
19
Recalling the Modifications

• Counter ion of metal salt has a strong influence
  on enantioselectivity
• Coordination influence geometry
• Molecular sieves influence enantioselectivity
• Binding at the surface forces geometric
  constraints on the catalyst
• Substrate binding is affected by cis binding of
  molecular sieves
• Multiple ways to the same product enantiomer
• What did not change
• Substrate
• Reagent
• Solvent
• Chiral Ligand
• Metal

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Ynone Aldol
Trost, B.M. Fettes, A. Shireman, B.T. J. Am.
Chem. Soc. 2004, 126, 2660-2661
21
Binding Preference
Proposed Active Catalyst Alkynylation of Aryl
Aldehydes

• Re-site leads to major product

Trost, B.M. Fettes, A. Shireman, B. J. Am.
Chem. Soc. 2004, 126, 2660-2661 Trost, B.M.
Weiss, A., Wangelin, A. J. Am. Chem. Soc. 2006,
128, 8-9
22
Probing the Reaction
Rxn Cond. Standard Reaction Conditions 5 mol
Zn 2.5 mol Chiral Ligand Modified Rxn.
Cond. 5 mol Zn 2.5 mol Chiral Ligand, 2.5
mol Aldol Product
Trost, B.M. Fettes, A. Shireman, B. J. Am.
Chem. Soc. 2004, 126, 2660-2661
23
Regeneration of Catalyst

• Regeneration of initial catalyst does not occur
• New insitu catalyst is generated
• Incorporates alkoxide product into structure

Trost, B.M. Fettes, A. Shireman, B. J. Am.
Chem. Soc. 2004, 126, 2660-2661 Trost, 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 Effect
• Raising temperature increases ee
• Lowering temperature reversed ee
• Solvent Optimization
• What did not change
• Catalyst Precursor
• Chiral Ligand
• Substrate
• Reagent

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Alkyl Addition to Aldehydes
Soai, K. Lutz, F. Igarashi, T. Kawasaki, T. J.
Am. Chem. Soc. 2005, 127, 12206-12207
26
Determining the Catalyst

• 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 reaction
• Stage 1 Measure the selectivity of the initial
  catalyst
• Stage 2 Probe catalyst components

Soai, K. Lutz, F. Igarashi, T. Kawasaki, T. J.
Am. Chem. Soc. 2005, 127, 12206-12207
27
Regeneration of Catalyst

• Regeneration of initial catalyst does not occur
• New insitu catalyst is generated
• Incorporates alkoxide product into structure

Trost, B.M. Fettes, A. Shireman, B. J. Am.
Chem. Soc. 2004, 126, 2660-2661 Trost, B.M.
Weiss, A., Wangelin, A. J. Am. Chem. Soc. 2006,
128, 8-9
28
Ligand Ratio Effects
Stage 1 Catalyst Zn(OiPr)4, Chiral Ligand,
Achiral Ligand Stage 2 Catalyst Zn(OiPr)4,
Chiral Ligand, Achiral Ligand, Aldol Product
Soai, K. Lutz, F. Igarashi, T. Kawasaki, T. J.
Am. Chem. Soc. 2005, 127, 12206-12207
29
Simplified Catalytic Structures
Structure of insitu catalyst is currently unknown
Auto Catalytic Nature of the System takes over
enantioselectivity
Soai, K. Lutz, F. Igarashi, T. Kawasaki, T. J.
Am. Chem. Soc. 2005, 127, 12206-12207 Blackmond,
D.G. Buono, F.G. J. Am. Chem. Soc., 2003 125,
8978-8979 Blackmond, D.G. Buono, F.G., Iwamura,
H. Angew. Chem. Int. Ed. 2003, 43, 2900-2103
30
Recalling the Modifications

• Reactive insitu catalyst is generated
• Product incorporation into new catalyst
• Achiral ligand reverses intial enantioselectivity
• At a specific ratio of chiralachiral ligand,
  selectivity reverses
• What did not change
• Substrate
• Catalyst Precursor
• Chiral Ligand
• Solvent
• Temperature

Enantioselectivity of 38-85 ee has been observed
with 1 mol chiral initiator (0.1 ee)
Soai, K. et. al. J. Am. Chem. Soc. 1998, 120,
12157-12158
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Cyanosilylation of Ketones
Shibasaki, M. Hamashima, Y. Kanai, M. J. Am.
Chem. Soc. 2000, 122, 7412-7413
32
Solvent Screen
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 Agent
• Isolated from Camptotheca acuminata
• Wall and Wani (1966)
• Pfizer Camptosar
• 1st Quarter 2006 212 million (worldwide)
• (20R)-Camptothecin
• 10-200 Times Less Active

Wall, M.E. Wani, W.C. Natschke, S.M. Nicholas,
A.W. J. Med. Chem. 1996, 29, 1553-1555 http//www.
pfizer.com/pfizer/download/news/2006q1_earnfin4.pd
f
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(20S)-Camptothecin Retroanalysis
Curran, D.P. Josien, H. Ko, S.B. Bom, D. Chem.
Eur. J. 1998, 4, 67-83
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(20S)-Camptothecin Retroanalysis
Curran, D.P. Josien, H. Ko, S.B. Bom, D. Chem.
Eur. J. 1998, 4, 67-83
36
Comparing Retrons
Curran Retrons
Shibasaki Retrons
Curran, D.P. Josien, H. Ko, S.B. Bom, D. Chem.
Eur. J. 1998, 4, 67-83 Shibasaki, M. et al. J.
Am. Chem. Soc. 2001, 123, 9908-9909
37
A Few Hurdles

• Problems
• Reaction Optimized for
• (R)-Cyanosilylation Product
• Ligand Synthesis Uses
• D-Glucose Precursor
• L-Glucose is Needed
• Ligand Synthesis
• High-Yielding Reactions
• Straight-Forward

D-Glucose 0.16/g. L-Glucose 62.50/g
38
A Few Hurdles

• Problems
• Reaction Optimized For the
• (R)-Cyanosilylation Product
• Ligand Synthesis Uses
• D-Glucose Precursor
• L-Glucose is Needed
• Ligand Synthesis
• High-Yielding Reactions
• Straight-Forward

D-Glucose 0.16/g. L-Glucose 62.50/g
39
Reversing Selectivity
Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123,
9908-9909 Shibasaki, M. Hamashima, Y. Kanai, M.
J. Am. Chem. Soc. 2000, 122, 7412-7413
40
Switching Enantioselectivity
Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123,
9908-9909
41
Retron Synthesis
Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123,
9908-9909 Curran, D.P. Josien, H. Ko, S.B.
Bom, D. Chem. Eur. J. 1998, 4, 67-83
42
Recalling the Modifications

• Variation of metal salt
• Ti and Sm have different mechanisms for cyano
  delivery
• Reverses enantioselectivity
• Needed new optimizations for different mechanism
• New metal to ligand ratio
• Solvent variation
• Temperature variations
• What did not change
• Substrate
• Reagent
• Chiral Ligand

43
Overview
Reversing Enantioselectivity

• Blocking Reactive Site
• Geometric Constraints
• Generation of New Catalytic Complex

• Decrease Temp
• Increase ee
• Increase Temp
• Increase ee

• Changing of Mechanism
• Counter Ion Effects

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Why it matters

• Optimization for all asymmetric reactions
• Focusing on reaction conditions instead of ligand
  and substrate
• Reaction characteristics
• Autocatalysis
• Mechanistic pathway
• Expands the scope of a chiral ligand
• Long ligand synthesis
• Expensive starting materials
• Commercial availability of chiral ligands

45
Acknowledgements

• Shannon Stahl
• Stahl Group
• Akiko K Hrovat

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