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The Total Synthesis of Phalarine : Racemic and Enantiopure Routes

The Total Synthesis of Phalarine : Racemic and Enantiopure Routes. Anthony Pianosi CHM 8256S December 9, 2010. Where Does Phalarine Come From?. Phalaris coerulescens (Blue Canary Grass). Colgate and colleagues isolated phalarine in 1999

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The Total Synthesis of Phalarine : Racemic and Enantiopure Routes

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  1. The Total Synthesis of Phalarine:Racemic and Enantiopure Routes Anthony Pianosi CHM 8256S December 9, 2010

  2. Where Does Phalarine Come From? Phalariscoerulescens (Blue Canary Grass) • Colgate and colleagues isolated phalarine in 1999 • currently, no promising biological activity known • possesses a novel furanobisindole alkaloid structure Phytochemistry1999, 51, 153-157

  3. Structure of Phalarine C3 C2 • novel furanobisindole alkaloid structure • two stereocenters: C2 and C3 • gramine-related moiety (EF) interlocked with • carboline-related subunit (ABC) via ring (D) Phytochemistry1999, 51, 153-157 Pure Appl. Chem.2010, 82, 1735-1748

  4. Propeller-Like Interlocking C3 C3 C2 C2 C2 C3

  5. Danishefsky Attempts A Total Synthesis • structural novelty draws attention • of Danishefsky’s lab • began synthesis of phalarine with • model studies Samuel J. Danishefsky Li, C.; Chan, C.; Heimann, A.; Danishefsky, S. J. Angew. Chem. Int. Ed.2007, 46, 1448-1450

  6. Retrosynthesis

  7. Initial Model Study Tetrahedron Lett. 2006, 47, 4839-4841

  8. Reasons For Incorrect Regiochemistry Tetrahedron Lett. 2006, 47, 4839-4841

  9. Reasoning For Second Model Study Tetrahedron Lett. 2006, 47, 4839-4841

  10. Second Model Study Tetrahedron Lett. 2006, 47, 4839-4841

  11. Reasons For Undesired Product Tetrahedron Lett. 2006, 47, 4839-4841

  12. Attempt atReordering of Bond Formation C3 C2 SEQUENCE FOR BOND FORMATION 1. C C between carbolineC2and aryl moiety 2. C O at carbolineC3 Angew. Chem. Int. Ed.2007, 46, 1448-1450

  13. Retrosynthesis

  14. Retrosynthesis

  15. Synthesis of AzaspiroOxindole Angew. Chem. Int. Ed.2007, 46, 1448-1450

  16. Formation of C2-Aryl Bond Angew. Chem. Int. Ed.2007, 46, 1448-1450

  17. Rearrangement Unsuccessful Angew. Chem. Int. Ed.2007, 46, 1448-1450

  18. Reasons for Failed Rearrangement Reasons: 1. urethane-bound methylene has low propensity for migration 2. hydrogen bonding ( ) would restrict rotation Pure Appl. Chem.2010, 82, 1735-1748

  19. Reasons for Failed Rearrangement 1. urethane-bound methylene has low propensity for migration Pure Appl. Chem.2010, 82, 1735-1748

  20. Reasons for Failed Rearrangement 2. hydrogen bonding ( ) would restrict rotation Pure Appl. Chem.2010, 82, 1735-1748

  21. What’s Next?.....Improve Migratory Tendency 1. Replace urethane with an N-methyl function REASONS: N-METHYL IS ELECTRON DONATING HIGHER LIKELYHOOD OF MIGRATION Pure Appl. Chem.2010, 82, 1735-1748

  22. What’s Next?.....Remove Hydrogen Bonding 2. Incorporate an activating tosyl (Ts) function REASONS: ELIMINATES HYDROGEN BONDING PERMITS FREE ROTATION Pure Appl. Chem.2010, 82, 1735-1748

  23. Preparation of New Substrate Angew. Chem. Int. Ed.2007, 46, 1448-1450

  24. Preparation of New Substrate Angew. Chem. Int. Ed.2007, 46, 1448-1450

  25. Rearrangement Achieved Angew. Chem. Int. Ed.2007, 46, 1448-1450

  26. Phalarine’s Core Synthesized Result: - appropriate activating functions allow for desired rearrangement - can proceed with the total synthesis of phalarine Angew. Chem. Int. Ed.2007, 46, 1448-1450

  27. Introduction of Amine Angew. Chem. Int. Ed.2007, 46, 1448-1450

  28. GassmanOxindole Synthesis Angew. Chem. Int. Ed.2007, 46, 1448-1450

  29. Completion of Racemic Synthesis Angew. Chem. Int. Ed.2007, 46, 1448-1450

  30. Important Mechanistic Questions Remain - concerning the pathway of the key skeletal rearrangement…. RECALL - at this point, two possible pathways present themselves…. Pure Appl. Chem.2010, 82, 1735-1748

  31. ? Pure Appl. Chem.2010, 82, 1735-1748

  32. Wagner-Meerwein Gives Single Enantiomer Pure Appl. Chem.2010, 82, 1735-1748

  33. Retro-Mannich Gives Achiral Intermediate Pure Appl. Chem.2010, 82, 1735-1748

  34. Achiral Intermediate Leads to Racemate Pure Appl. Chem.2010, 82, 1735-1748

  35. Why Is This Important? CORRECT MECHANISTIC INSIGHTS LEAD TO….. NATURAL ENANTIOMER OF PHALARINE

  36. Initiate Synthesis With Single Enantiomer Pure Appl. Chem.2010, 82, 1735-1748

  37. EnantiopureOxindole Pure Appl. Chem.2010, 82, 1735-1748

  38. Racemization During Cyclization Pure Appl. Chem.2010, 82, 1735-1748

  39. Rules Out Wagner-Meerwein Pathway

  40. Retro-Mannich Then Pictet-Spengler

  41. Pictet-Spengler Reaction Mechanism Chem. Rev.1995, 95, 1797-1842

  42. Pictet-Spengler Reaction Mechanism Chem. Rev.1995, 95, 1797-1842

  43. ?

  44. Retro-Mannich Cleavage Problems • retro-Mannich cleavage step was preventing progress towards • enantiopurephalarine • at this point, Danishefsky and colleagues investigated an • alternative to the chemistry described earlier J. Am. Chem. Soc.2010, 132, 8506-8512 Pure Appl. Chem.2010, 82, 1735-1748

  45. Build a New Indole System C3 C2 suitable aromatic structure at C2 2. ethylamino group at C3 REASONS: 1. determine feasibility of achiral intermediate develop further insights into the mechanism of the Pictet-Spengler reaction J. Am. Chem. Soc.2010, 132, 8506-8512 Pure Appl. Chem.2010, 82, 1735-1748

  46. Synthesizing New Indole J. Am. Chem. Soc.2010, 132, 8506-8512 Pure Appl. Chem.2010, 82, 1735-1748

  47. Synthesizing New Indole J. Am. Chem. Soc.2010, 132, 8506-8512 Pure Appl. Chem.2010, 82, 1735-1748

  48. Pictet-Spengler Attempt Successful J. Am. Chem. Soc.2010, 132, 8506-8512 Pure Appl. Chem.2010, 82, 1735-1748

  49. Achiral Intermediate is Feasible C3 C2 BUT………….MECHANISTIC UNCERTAINTY REMAINS! CYCLIZATION AT C2 OR CYCLIZATION AT C3 J. Am. Chem. Soc.2010, 132, 8506-8512 Pure Appl. Chem.2010, 82, 1735-1748

  50. What is the Minimum Rearrangement Criteria? RECALL Pure Appl. Chem.2010, 82, 1735-1748

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