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Transition Metal-Catalyzed Enantioselective Ring-Opening Reactions: Innovations in Organic Transformations

The Lautens group focuses on novel transition-metal-mediated organic transformations aiming to efficiently construct pharmaceutical compounds or biologically active natural products. Projects cover catalyst-controlled asymmetric transformations and controlled tandem processes. Research includes C-H bond activation, heterocycles via tandem catalysis, enantioselective desymmetrization, and total synthesis.

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Transition Metal-Catalyzed Enantioselective Ring-Opening Reactions: Innovations in Organic Transformations

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  1. Literature Seminar 2010.05.22 刘媛媛

  2. Ref: Acc. Chem. Res. 2003, 36, 48-58 J. AM. CHEM. SOC. 2003, 125, 14884-14892 PNAS. 2004, 101, 5455–5460 Transition Metal-Catalyzed Enantioselective Ring-Opening Reactions of Aza- and Oxabicyclic Alkenes by Mark Lautens

  3. Mark Lautens University of Toronto Professor NSERC/Merck-Frosst Industrial Research Chair AstraZeneca Professor of Organic Chemistry Department of ChemistryDavenport Chemical Laboratories 80 St. George St. University of Toronto Toronto, Ontario M5S 3H6

  4. Mark Lautens

  5. Mark Lautens

  6. Research The Lautens group is focused on the investigation and development of novel transition-metal-mediated organic transformations. Some projects include catalyst-controlled asymmetric transformations while others focus on controlled tandem or domino processes. Of particular interest are reactions which can efficiently construct frameworks of pharmaceutical compounds or fragments of biologically-active natural products.

  7. Research-Mark Lautens 1. C-H Bond Activation 2. Heterocycles via Tandem Catalysis 3. Enantioselective Desymmetrization 4. Total Synthesis

  8. 1. C-H Bond Activation Palladium-Catalyzed Domino Reactions with C-H Bonds: Synthesis of Substituted Carbocycles and Heterocycles using Strained Alkene Shuttles

  9. 1. C-H Bond Activation Palladium-Catalyzed Domino Reactions with C-H Bonds: Synthesis of Substituted Carbocycles and Heterocycles using Strained Alkene Shuttles

  10. Research-Mark Lautens 1. C-H Bond Activation 2. Heterocycles via Tandem Catalysis 3. Enantioselective Desymmetrization 4. Total Synthesis

  11. 2. Heterocycles via Tandem Catalysis The tandem process displays high versatility: Suzuki, Heck, and Sonogashira couplings, as well as direct arylation can be used orthogonally to carbon-nitrogen bond formation under palladium-catalyzed conditions to create a diverse set of 2-substituted indoles, and a wide range of functionality is tolerated at all positions of the benzenoid ring.

  12. 2. Heterocycles via Tandem Catalysis

  13. 2. Heterocycles via Tandem Catalysis

  14. Research-Mark Lautens 1. C-H Bond Activation 2. Heterocycles via Tandem Catalysis 3. Enantioselective Desymmetrization 4. Total Synthesis

  15. 4. Total Synthesis

  16. Research-Mark Lautens 1. C-H Bond Activation 2. Heterocycles via Tandem Catalysis 3. Enantioselective Desymmetrization 4. Total Synthesis

  17. 3. Enantioselective Desymmetrization Desymmetrization―an achiral or meso molecule to yield enantiomerically enriched products 1. an achiral molecule 2. meso molecule

  18. Ring-Opening Reaction Enantioselective Desymmetrization of meso molecule

  19. Background 1. easy to prepare starting compounds 2. Desymmetrization without ring opening

  20. Background 3. The first report appeared in 1995 by Moinet and Fiaud

  21. Mark Lautens' work―Asymmetric Ring Opening 1. Nickel-Catalyzed Asymmetric Ring Opening of Oxabicyclic Alkenes with Hydride Nucleophile 2. Palladium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Alkyl Nucleophiles B. Aza- and Oxabicyclic Alkenes with Arylboronic Acids 3. Rhodium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Heteroatom Nucleophiles B. Oxabicyclic Alkenes with Aryl- and Alkenylboronic Acids C. Azabicyclic Alkenes with Amine Nucleophiles D. Diazabicycles versus Hydroarylation

  22. t-Bu CuCNLi or t-BuLi/MgBr as a source of hydride 2 2 2 1. Nickel-Catalyzed/Oxabicyclic Alkenes with Hydride Nucleophile inefficient and unselective Ref: Tetrahedron Lett. 1991, 32, 4827-4830

  23. Addition of Ni(COD) 2 1. Nickel-Catalyzed/Oxabicyclic Alkenes with Hydride Nucleophile Change to DIBAL-H was used as a Lewis acidic source of hydride Addition of chiral ligands the rate of addition of DIBAL-H: slower and higher ee

  24. 1. Nickel-Catalyzed/Oxabicyclic Alkenes with Hydride Nucleophile extended to more sensitive substrates: select solvent and consider the electronic effects move to more difficult systems-[3.2.1] oxabicycles: increase temperature Application: total synthesis

  25. Mark Lautens' work―Asymmetric Ring Opening 1. Nickel-Catalyzed Asymmetric Ring Opening of Oxabicyclic Alkenes with Hydride Nucleophile 2. Palladium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Alkyl Nucleophiles B. Aza- and Oxabicyclic Alkenes with Arylboronic Acids 3. Rhodium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Heteroatom Nucleophiles B. Oxabicyclic Alkenes with Aryl- and Alkenylboronic Acids C. Azabicyclic Alkenes with Amine Nucleophiles D. Diazabicycles versus Hydroarylation

  26. 2A. Palladium-Catalyzed/Oxabicyclic Alkenes with Alkyl Nucleophiles by Caple and co-workers In 1971 the first class of nucleophiles shown to induce ring opening of oxabicyclic systems. able to achieve the first example the first example of an asymmetric ring opening

  27. 2A. Palladium-Catalyzed/Oxabicyclic Alkenes with Alkyl Nucleophiles survey of various catalyst systems dimethylzinc Addition of chiral ligands larger nucleophiles

  28. 2A. Palladium-Catalyzed/Oxabicyclic Alkenes with Alkyl Nucleophiles extended substrates: select solvent, chiral ligands and temperature extended substrates: study of various additives

  29. 2A. Palladium-Catalyzed/Oxabicyclic Alkenes with Alkyl Nucleophiles analyze 1. Pd/coordination followed by cleavage from a л-allylpalladium species mechanistic possibilities 2. carbopalladation followed by β-oxygen elimination enantioselective carbometalation key experiment 1: trapping of the carbometalated intermediates no reaction without any additive key experiment 2: form cationic palladium

  30. 2A. Palladium-Catalyzed/Oxabicyclic Alkenes with Alkyl Nucleophiles cationic alkylpalladium(II) species propose mechanism: enantioselective carbopalladation β-oxygen elimination

  31. 2A. Palladium-Catalyzed/Oxabicyclic Alkenes with Alkyl Nucleophiles total synthesis

  32. Mark Lautens' work―Asymmetric Ring Opening 1. Nickel-Catalyzed Asymmetric Ring Opening of Oxabicyclic Alkenes with Hydride Nucleophile 2. Palladium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Alkyl Nucleophiles B. Aza- and Oxabicyclic Alkenes with Arylboronic Acids 3. Rhodium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Heteroatom Nucleophiles B. Oxabicyclic Alkenes with Aryl- and Alkenylboronic Acids C. Azabicyclic Alkenes with Amine Nucleophiles D. Diazabicycles versus Hydroarylation

  33. 2B. Palladium-Catalyzed/Aza- and Oxabicyclic Alkenes with Arylboronic Acids

  34. Mark Lautens' work―Asymmetric Ring Opening 1. Nickel-Catalyzed Asymmetric Ring Opening of Oxabicyclic Alkenes with Hydride Nucleophile 2. Palladium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Alkyl Nucleophiles B. Aza- and Oxabicyclic Alkenes with Arylboronic Acids 3. Rhodium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Heteroatom Nucleophiles B. Oxabicyclic Alkenes with Aryl- and Alkenylboronic Acids C. Azabicyclic Alkenes with Amine Nucleophiles D. Diazabicycles versus Hydroarylation

  35. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles In 1973 report by Hogeveen and Middelkoop yield >70% able to achieve it: by modifying reaction conditions find optimal catalytic systems

  36. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles typically >80% yield and >95% ee face extend this system to other nucleophile classes problems 1. anilines were found to efficiently induce ring opening, but the enantioselectivity was poor ? 2. aliphatic amine was acting as a poison was demonstrated

  37. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles Luckly In addition 2-aminotetralin core is an important structural motif in medicinal chemistry pyrrolidine can do it both a protic and a halide source are important both a protic and a halide source are important find out the Halide Effects on reactivity and enantioselectivity

  38. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles

  39. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles find out the Halide Effects on reactivity find out the Halide Effects on enantioselectivity

  40. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles Application of Halide Effects in the Development of a General Process

  41. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles Application of Halide Effects in the Development of a General Process Sulfur Nucleophiles

  42. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles side products can also form in the absence of catalyst Suppression of this background reaction could be achieved by controlling the rate of substrate addition and/or addition of a radical inhibitor galvinoxyl in 92% yield and 94% ee

  43. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles Scope of Aryl Thiol Ring Opening Reactions Scope of Aliphatic Thiol Ring Opening Reactions

  44. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles Competition Studies between Unreactive Nucleophiles and Thiophenol Empirically, a competent thiol nucleophile in this desymmetrization reaction requires a pKa less than 16 but greater than 5.10 This correlation between reactivity and S-H bond strength may be indic

  45. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles Failed Application of Halide Effects in the Development of a General Process Less reactive oxabicyclo[2.2.1]heptenes higher reaction temperatures and more concentrated reaction conditions

  46. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles Application of Halide Effects in the Development of a General Process Substances contained Halide effect on reactivity and enantioselectivity

  47. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles propose mechanism

  48. 3A. Rhodium-Catalyzed/Oxabicyclic Alkenes with Heteroatom Nucleophiles Catalyst Loading Studies

  49. Mark Lautens' work―Asymmetric Ring Opening 1. Nickel-Catalyzed Asymmetric Ring Opening of Oxabicyclic Alkenes with Hydride Nucleophile 2. Palladium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Alkyl Nucleophiles B. Aza- and Oxabicyclic Alkenes with Arylboronic Acids 3. Rhodium-Catalyzed Asymmetric Ring Opening A. Oxabicyclic Alkenes with Heteroatom Nucleophiles B. Oxabicyclic Alkenes with Aryl- and Alkenylboronic Acids C. Azabicyclic Alkenes with Amine Nucleophiles D. Diazabicycles versus Hydroarylation

  50. 3B. Rhodium-Catalyzed/Oxabicyclic Alkenes with Aryl- and Alkenylboronic Acids Tremendous success has been recently achieved in the rhodium-catalyzed asymmetric 1,4-conjugate addition of organoboronic acids to electron-deficient olefins Ref: Synlett 2001, 879-887 obtain opposite-cleaved compounds to that of reactions with heteroatom nucleophiles despite the use of the same catalyst

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