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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. Asymmetric Reactions Necessity of chemistry Natural Product Synthesis Pharmaceutical Synthesis

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

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

  3. Ligand Modification Substrate Modification Reaction Conditions Sterics Electronics Functionality Size Sterics Electronics Functionality Solvent Additives Temperature Metal Salts 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. Organometallics1995, 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. Ligand Modification Substrate Modification Reaction Conditions Sterics Electronics Functionality Size Sterics Electronics Functionality Solvent Additives Temperature Metal Salts Enantioselectivity Focus Enantioselectivity

  9. 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

  10. 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

  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. 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

  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. 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

  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

  20. 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. 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

  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

  25. 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. 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

  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 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

  31. 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.pdf

  34. (20S)-Camptothecin Retroanalysis Curran, D.P.; Josien, H.; Ko, S.B.; Bom, D. Chem. Eur. J. 1998, 4, 67-83

  35. (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. 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

  44. 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 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

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