dual enantioselectivity inducing a single chiral ligand to reverse a reaction s enantioselectivity n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Dual Enantioselectivity: Inducing a Single Chiral Ligand to Reverse a Reaction’s Enantioselectivity PowerPoint Presentation
Download Presentation
Dual Enantioselectivity: Inducing a Single Chiral Ligand to Reverse a Reaction’s Enantioselectivity

Loading in 2 Seconds...

play fullscreen
1 / 45

Dual Enantioselectivity: Inducing a Single Chiral Ligand to Reverse a Reaction’s Enantioselectivity - PowerPoint PPT Presentation


  • 162 Views
  • Uploaded on

Dual Enantioselectivity: Inducing a Single Chiral Ligand to Reverse a Reaction’s Enantioselectivity. James Hrovat Stahl Research Group February 15, 2007. Determining Enantioselectivity. Asymmetric Reactions Necessity of chemistry Natural Product Synthesis Pharmaceutical Synthesis

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Dual Enantioselectivity: Inducing a Single Chiral Ligand to Reverse a Reaction’s Enantioselectivity' - valentina


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
dual enantioselectivity inducing a single chiral ligand to reverse a reaction s enantioselectivity

Dual Enantioselectivity:Inducing a Single Chiral Ligand to Reverse a Reaction’s Enantioselectivity

James Hrovat

Stahl Research Group

February 15, 2007

determining enantioselectivity
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.aspx

reaction optimizations

Ligand

Modification

Substrate

Modification

Reaction

Conditions

Sterics

Electronics

Functionality

Size

Sterics

Electronics

Functionality

Solvent

Additives

Temperature

Metal Salts

Reaction Optimizations

Enantioselectivity

substrate modification
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

ligand modification
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. Organometallics1995, 14, 5486-5487

reaction modification
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??
drastic effect by minor changes
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

enantioselectivity focus

Ligand

Modification

Substrate

Modification

Reaction

Conditions

Sterics

Electronics

Functionality

Size

Sterics

Electronics

Functionality

Solvent

Additives

Temperature

Metal Salts

Enantioselectivity Focus

Enantioselectivity

reaction scope
Reaction Scope
  • Cycloadditions:
    • [4+2] Diels-Alder
    • [4+2] Hetero Diels-Alder
    • 1,3-Dipolar Cycloaddition
    • [4+1] 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

today s scope
Today’s Scope
  • [4+2] 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
ln catalyzed diels alder
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

ln catalyzed diels alder1
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

slide13

Re site

Si site

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

recalling the modifications
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
1 3 dipolar cycloadditions
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

slide16

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

slide17

A

Si face

C

Re face

D

Re face

B

Si face

Dark Blue: Oxizolidinone

Green: α,β-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

mapping out selectivity
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

recalling the modifications1
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
ynone aldol
Ynone Aldol

Trost, B.M.; Fettes, A.; Shireman, B.T.; J. Am. Chem. Soc.2004, 126, 2660-2661

binding preference
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

probing the reaction

100

80

60

Yield (%)

Unmodified Rxn

40

Modified Rxn

20

0

0

2

4

6

8

10

12

Time (h)

80

40

ee (%)

0

-40

-80

0

0.75

1.25

3

6

10.75

Time (h)

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

regeneration of catalyst
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

recalling the modifications2
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
alkyl addition to aldehydes
Alkyl Addition to Aldehydes

Soai, K.; Lutz, F.; Igarashi, T.; Kawasaki, T. J. Am. Chem. Soc.2005, 127, 12206-12207

determining the catalyst
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

regeneration of catalyst1
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

ligand ratio effects

100

Stage 1

Stage 2

50

Observed ee

0

-50

-100

20

18

16

14

12

10

8

6

2

Chiral Ligand (mol%)

Achiral LIgand (20%-Chiral%)

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

simplified catalytic structures
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

recalling the modifications3
Recalling the Modifications
  • Reactive insitu catalyst is generated
    • Product incorporation into new catalyst
  • Achiral ligand reverses intial enantioselectivity
    • At a specific ratio of chiral:achiral 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

cyanosilylation of ketones
Cyanosilylation of Ketones

Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc.2000, 122, 7412-7413

solvent screen
Solvent Screen

Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc.2000, 122, 7412-7413

applying methodology
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.pdf

20 s camptothecin retroanalysis
(20S)-Camptothecin Retroanalysis

Curran, D.P.; Josien, H.; Ko, S.B.; Bom, D. Chem. Eur. J. 1998, 4, 67-83

20 s camptothecin retroanalysis1
(20S)-Camptothecin Retroanalysis

Curran, D.P.; Josien, H.; Ko, S.B.; Bom, D. Chem. Eur. J. 1998, 4, 67-83

comparing retrons
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

a few hurdles
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

a few hurdles1
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

reversing selectivity
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

switching enantioselectivity
Switching Enantioselectivity

Shibasaki, M. et al. J. Am. Chem. Soc.2001, 123, 9908-9909

retron synthesis
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

recalling the modifications4
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
overview

Reaction Parameters

Additive Effects

Variation of

Metal Salt

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

Reversing

Enantioselectivity

  • Decrease Temp:
    • Increase ee
  • Increase Temp:
    • Increase ee
  • Changing of Mechanism
  • Counter Ion Effects
why it matters
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
acknowledgements
Acknowledgements:

Shannon Stahl

Stahl Group

Akiko K Hrovat

Practice Talk Attendees:

Jamie Ellis

Dr. Tetsuya Hamada

Dr. Justin Hoerter

Lauren Huffman

Megan Jacobson

Amanda King

Dr. Vasily Kotov

Dr. Guosheng Liu

David Michaelis

Brian Popp

Michelle Rogers

Chris Scarborough

Nickeisha Stephenson

Xuan Ye

Lani McCartney

Joel Broussard

Emily Blamer