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Who Am I

The Development of Metal Catalyzed, One-Step Approaches to α-Amino Acids, Pyrroles and α-Substituted Amides 21/09/2011 Yingdong Lu. Who Am I. In Canada. PDF supervisor Dr. C. Crudden Queen’s University. Ph.D supervisor Dr. B. Arndtsen McGill University. Direct Synthesis.

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Who Am I

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  1. The Development of Metal Catalyzed, One-Step Approaches to α-Amino Acids, Pyrroles and α-Substituted Amides21/09/2011Yingdong Lu

  2. Who Am I

  3. In Canada PDF supervisor Dr. C. Crudden Queen’s University Ph.D supervisor Dr. B. Arndtsen McGill University

  4. Direct Synthesis Can complex molecules be constructed directly from simple building blocks, via the mechanistic design of new metal catalyzed reactions? Efficient, Green, Diversified Target Products

  5. A One Pot Synthesis of Münchnones Dhawan, R., Dghaym, R. and Arndtsen, B. A. JACS2003,125,1474

  6. Münchnone Chemistry Typical Münchnone Synthesis: Potts, K. In . 1,3-Dipolar Cycloaddition Chemistry, Padwa, A. Ed. ; Wiley: New York, 1984: Vol.2 p.1

  7. Previous Work

  8. Request from Organic Synthesis • Scale up failed: no more than 1 mmol of reagents • My answer: Need a new catalytic system • How? • Kinetic study to figure out mechanism

  9. Mechanism Rate α [iminium], [Pd], [CO] fast An e-rich and bulky ligand is need to accelerate Oxidative addition and CO coordination

  10. Though phosphine ligand accelerate the oxidative addtion, it slow the CO coordination step

  11. Ligand Effect

  12. higher reaction rate of both oxidative addition and CO coordination was achieved

  13. Large scale Münchnone synthesis (multigram) • Pd loading lower to 0.1% • Milder reaction condition (room temperature)

  14. Application: Lipitor Synthesis

  15. With Benzyl Protected Product

  16. Limitations of N-acyl Iminium Salt Intermediates • Limitation of Substituents R1 and R2 can not be e-withdrawing or bulky R3 can not be enolizable (non-alkyl) • Stability of starting materials

  17. Useα-Alkoxy Amides as N-acyl Iminium Precusor? • Stability • Easily synthesized • Easily diversified • Challenge: activation of the ether C-O bond

  18. Oxidative Addition Ethers to Pd ???

  19. Oxidative Addition Ethers to Pd ??? C-O bond is too strong to oxidative addition to Pd0 , adding Lewis acid might weak the C-O bond and help the oxidative addition

  20. Oxidative Addition to Pd with the Assistance of Lewis Acids

  21. Pd Catalyzed Amidoester Synthesis

  22. Pd Catalyzed Amidoester Synthesis BF3 is too strong Lewis acid for this reaction we need something milder

  23. Pd Catalyzed Amidoester Synthesis We can carbonylate the C-O bond and generate products that can not be synthesized through imines and acid chlorides

  24. Diversity Lu, Y., Arndtsen, B. A. Org. Lett. 2007, 4395

  25. Directly Activate C-O Bond Without Lewis Acid Problems with the current system: • The Lewis acid is expensive • Limited functionality Solution: Activate the C-O directly without Lewis Acids. How: • Weaken/polarize C-O bond • Design better a catalyst

  26. Carbonylation Without Lewis Acids

  27. Ligand Scanning Making a more electron rich catalyst allows for efficient C-O activation

  28. Direct Lewis Acid-Free Carbonylation

  29. Pyrrole Synthesis

  30. Pyrrole Synthesis Compared to PhOH, PyOH is a much weaker nucleophile.

  31. Diversity Lu, Y., Arndtsen, B. A. Angew. Chem. Inter. Ed, 2008, 5430

  32. Importance of Asymmetric Synthesis • Biological importance DNA, protein, amino acids…. • Pharmaceutical importance

  33. Asymmetric Synthesis • Start with chiral starting materials • Chiral auxiliaries • Chiral resolution • Asymmetric catalysis

  34. Asymmetric Alkynylation Black, D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org. Chem.2008 73, 1906

  35. A Less “Synthetic” Source of Chirality? a-Amino Acids Peptides

  36. Idea: Tunable, Hydrogen Bonding Metal Catalysis

  37. Alkynylation of Imines

  38. Chiral Bronsted Acids in Asymmetric Catalysis

  39. Chiral Bronsted Acid Catalyzed Alkynylation of Imines

  40. Proposed Mechanism

  41. Initial Attempt

  42. Scanning of Amino Acids

  43. Proposed Mechanism Tune the phosphine ligands could affect the enantioselectivity

  44. Scanning of Ligands

  45. Diversity Lu, Y., Johnstone, T. C. Arndtsen, B. A. JACS, 2009, 11284

  46. Pyrrole Synthesis • Found in a wide range of natural products and • pharmaceuticals • Antibacterial, antiviral (HIV-1), antiinflammatants, • ntioxidants,cytokine inhibitors, etc.

  47. Existing Pyrrole Syntheses Paal-Knorr Condensation Gevorgyan JACS 2001, 123, 2074 Luh JACS, 2000, 122, 4992 Murahashi Org Lett 2001, 3, 421

  48. An Indole Synthesis Le Corre,M; Hercouet, A; Le Baron, H. Journal of the Chemical Society, Chemical Communications1981,1, 14-15.

  49. Idea

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