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

3 Reaction Optimizations EnantioselectivityEnantioselectivity SubstrateModificationSubstrateModification Sterics Electronics Functionality LigandModificationLigandModification Sterics Electronics Functionality Size ReactionConditionsReactionConditions Solvent Additives Temperature Metal Salts

4 Substrate Modification Sterics Maximize/Minimize Interactions Electronics Electron rich vs. Electron poor Functionality Hydrogen bonding Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc., 2000, 122, Shibasaki, M., et al. J. Am. Chem. Soc. 2001, 123, Advantages: Customizing the Reaction for Selectivity Limitations: Modifying the Substrate is Not Optimal

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,

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 Mosher, H.S.; Yamaguchi, S. J. Org. Chem. 1973, 38, “Aged”: Refluxing for 10 minutes and standing for 24 hours

8 Enantioselectivity Focus EnantioselectivityEnantioselectivity SubstrateModificationSubstrateModification Sterics Electronics Functionality LigandModificationLigandModification Sterics Electronics Functionality Size ReactionConditionsReactionConditions Solvent Additives Temperature Metal Salts

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, Zanoni, G.; Frnzini, M.; Giannini, E.; Castronovo, F.; Vidari, G. Chem. Soc. Rev. 2003, 3, Kim, Y.H. Acc. Chem. Res. 2001, 37,

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 Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron Lett. 1993, 34, Kobayashi, S.; Ishintani, H.; J. Am. Chem. Soc. 1994, 116, Ln Catalyzed Diels-Alder M(OTf) 3 LuYbTmEr Yield (%) endo (%) ee (%)

12 Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron Lett. 1993, 34, Kobayashi, S.; Ishintani, H.; J. Am. Chem. Soc. 1994, 116, Ln Catalyzed Diels-Alder M(OTf) 3 LuYbTmEr Yield (%) endo (%) ee (%)517074

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, Kobayashi, S.; Ishintani, H.; J. Am. Chem. Soc. 1994, 116, Re site

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 CatalystTemp (°C) Time (h) Yield (%) endo/ex o ee (%)Re/S i Mg(ClO 4 ) >9895:548Re Mg(OTf) >9897:386Re MgI to 2020>95100:048Si Desimoni, G.; Gaita, G.; Mortoni, A., Righetti, P. Tetrahedron Lett. 1999, 40, Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1998, 63,

16 CatalystAdditiveTemp (°C) Time (h) Yield (%) endo/exoee (%) (endo) Re/S i Mg(ClO 4 ) 2 4Å M.S.-1515>9870:3070Si Mg(ClO 4 ) >9895:548Re Mg(ClO 4 ) 2 H 2 O (2 eq.)-1548>9896:445Re Mg(OTf) >9897:386Re MgI 2 4Å M.S.-78 to 2020>9573:2782Re MgI to 2020>95100:048Si MgI 2 H 2 O (40%)-78 to 2020>9590:1036Si MgI 2 H 2 O (18%) 4Å M.S. -78 to 2020>9595:536Re Desimoni, G.; Gaita, G.; Mortoni, A., Righetti, P. Tetrahedron Lett. 1999, 40, Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1998, 63,

17 D Re face B Si face C Re face Dark Blue: Oxizolidinone Green: α,β-Unsaturated Purple: Ligand Top Face: Re Bottom Face: Si Desimoni, G.; Gaita, G.; Mortoni, A., Righetti, P. Tetrahedron Lett. 1999, 40, Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1998, 63, Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1996, 61, A Si face endo-Re: calculated as the lowest TS

18 Mapping Out Selectivity Desimoni, G.; Gaita, G.; Mortoni, A., Righetti, P. Tetrahedron Lett. 1999, 40, Jørgensen, K.A.; Gothelf, K.V.; Hazell, R.G. J. Org. Chem. 1998, 63, Ohta, T. et al. J. Organomet. Chem. 2000, 603, 6-12 Jørgensen, K.A; Gothelf, K.V. Chem. Commun. 2000, Similar Effects have been seen in Cu 2+, Zn 2+, and Sc 3+ 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 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 Trost, B.M.; Fettes, A.; Shireman, B.T.; J. Am. Chem. Soc. 2004, 126, Temp. (°C) Time (h)Yield (%)ee (%) Ynone Aldol

21 Solvent Temp. (°C) Time (h)Yield (%)ee (%)R/SR/S Toluene046344R THF R Toluene S THF S Trost, B.M.; Fettes, A.; Shireman, B. J. Am. Chem. Soc. 2004, 126, Trost, B.M.; Weiss, A., Wangelin, A. J. Am. Chem. Soc. 2006, 128, 8-9 Binding Preference Proposed Active Catalyst: Alkynylation of Aryl Aldehydes Re-site leads to major product

22 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 ee (%) Time (h) Time (h) Yield (%) Trost, B.M.; Fettes, A.; Shireman, B. J. Am. Chem. Soc. 2004, 126, Probing the Reaction Unmodified Rxn Modified Rxn

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, 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,

26 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 Stag e Zn( i Pr) 4 (mmol) Aldehyd e (mmol) Ligand (mmol) Determining the Catalyst Soai, K.; Lutz, F.; Igarashi, T.; Kawasaki, T. J. Am. Chem. Soc. 2005, 127,

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, Trost, B.M.; Weiss, A., Wangelin, A. J. Am. Chem. Soc. 2006, 128, 8-9

28 Stage 1 Catalyst: Zn(O i Pr) 4, Chiral Ligand, Achiral Ligand Stage 2 Catalyst: Zn(O i Pr) 4, Chiral Ligand, Achiral Ligand, Aldol Product Ligand Ratio Effects Soai, K.; Lutz, F.; Igarashi, T.; Kawasaki, T. J. Am. Chem. Soc. 2005, 127,

29 Soai, K.; Lutz, F.; Igarashi, T.; Kawasaki, T. J. Am. Chem. Soc. 2005, 127, Blackmond, D.G.; Buono, F.G. J. Am. Chem. Soc., , Blackmond, D.G.; Buono, F.G., Iwamura, H. Angew. Chem. Int. Ed. 2003, 43, Simplified Catalytic Structures Structure of insitu catalyst is currently unknown 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 enantioselectivity At a specific ratio of chiral:achiral ligand, selectivity reverses What did not change: Substrate Catalyst Precursor Chiral Ligand Solvent Temperature Soai, K. et. al. J. Am. Chem. Soc. 1998, 120, Enantioselectivity of 38-85% ee has been observed with 1 mol% chiral initiator (0.1% ee)

31 Cyanosilylation of Ketones Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc. 2000, 122, Catalyst Temp. (°C) Temp (h)Yield (%)ee (%)R/SR/S Et 2 AlCl Yb(O i Pr) S Zr(O i Bu) R Ti(O i Pr) R Ti(O i Pr) R

32 Solvent Screen SolventConc. (M) Temp. (°C) Time (h) Yield (%) ee (%) CH 2 Cl Toluene THF THF Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc. 2000, 122,

33 Applying Methodology Main Goal: Synthetic Application of Methodology Camptothecin: Potent Antitumor Agent Isolated from Camptotheca acuminata Wall and Wani (1966) Pfizer: Camptosar 1 st Quarter 2006: $212 million (worldwide ) (20R)-Camptothecin Times Less Active Wall, M.E.; Wani, W.C.; Natschke, S.M.; Nicholas, A.W. J. Med. Chem. 1996, 29,

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

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

36 Curran Retrons: Shibasaki Retrons: Curran, D.P.; Josien, H.; Ko, S.B.; Bom, D. Chem. Eur. J. 1998, 4, Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123, Comparing Retrons

37 Problems: Reaction Optimized for (R)-Cyanosilylation Product Ligand Synthesis Uses D-Glucose Precursor L-Glucose is Needed Ligand Synthesis High-Yielding Reactions Straight-Forward A Few Hurdles D-Glucose: $0.16/g. L-Glucose: $62.50/g

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

39 Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123, Shibasaki, M.; Hamashima, Y.; Kanai, M. J. Am. Chem. Soc. 2000, 122, Reversing Selectivity Metal Solven t Temp (°C) Ligand/Meta l Ratio Time (h) Yield (%) ee (%) R/SR/S Ti(O i Pr) 4 (10%)THF-301: R Yb(O i Pr) 3 (10%)CH 2 Cl 2 201:129018S Sm(O i Pr) 3 (5%)THF-401.8:128582S Gd(O i Pr) 3 (5%)THF-401.8:12-89S Gd(O i Pr) 3 (5%)THF-402:1292 S

40 Metal Solven t Temp (°C) Ligand/Meta l Ratio Time (h) Yield (%) ee (%) R/SR/S Ti(O i Pr) 4 (10%)THF-301: R Sm(O i Pr) 3 (5%)THF-401:1--20S Sm(O i Pr) 3 (5%)THF-401.8: S Sm(O i Pr) 3 (5%)MeCN-401.8: S Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123, Switching Enantioselectivity

41 Retron Synthesis Shibasaki, M. et al. J. Am. Chem. Soc. 2001, 123, 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 Additive Effects Variation of Metal Salt Reaction Parameters

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 Practice Talk Attendees: Jamie Ellis Dr. Tetsuya Hamada Dr. Justin Hoerter Lauren Huffman Megan Jacobson Amanda King Acknowledgements: Shannon Stahl Stahl Group Akiko K Hrovat Dr. Vasily Kotov Dr. Guosheng Liu David Michaelis Brian Popp Michelle Rogers Chris Scarborough Nickeisha Stephenson Xuan Ye Lani McCartney Joel Broussard Emily Blamer