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Diazonamide A: The Long Story of a Misunderstood Molecule

Diazonamide A: The Long Story of a Misunderstood Molecule. Seminar presented by Elisia Villemure February 14, 2008. The Origin of Diazonamide. Isolated from the colonial ascidian Diazona angulata Collected from the ceilings of caves along the northwest coast of Siquijor

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Diazonamide A: The Long Story of a Misunderstood Molecule

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  1. Diazonamide A: The Long Story of a Misunderstood Molecule Seminar presented by Elisia Villemure February 14, 2008

  2. The Origin of Diazonamide • Isolated from the colonial ascidian Diazona angulata • Collected from the ceilings of caves along the northwest coast of Siquijor Island in the Philippines Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

  3. Why Is this Molecule So Interesting? Over the years, many groups focused their efforts towards the synthesis of Diazonamide A. Only K. C. Nicolaou’s and P. G. Harran’s groups had been able to complete the total synthesis of the molecule. • Diazonamide A has a IC50 of 2-5 nM against 4 human cancer cell lines (Diazonamide A is more potent than Diazonamide B) • Molecule is trapped as a single atropisomer because of its rigidity • Macrolactam unit • Macrocyclic Heterocyclic core • Quaternary center at the center of the molecule Initially proposed structure Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

  4. Structure Determination of Diazonamide A and B Structures determined by William Fenical (Scripps Institution of Oceanography) And Jon Clardy (Cornell University) in 1991 Diazonamide A Diazonamide B Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

  5. Strategy for Structure Elucidation Jaspars, M Nat. Prod. Rep. 1999, 16,241 Pretsch, E.; Toth, G.; Munk, M. E. ; Baddertscher, M. Computer-Aided Structure Elucidation, Wiley-VCH 2002, 279 p.

  6. Evidence of the Presence of an Hemiacetal in Diazonamide A and B Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

  7. Evidence on the Structure of Diazonamide A and B Diazonamide A Diazonamide B Similarity in the 2 structures • 1H, 13C NMR, UV and IR indicate an identical polycyclic nucleus • UV shows evidence of their high degree of unsaturation Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

  8. Evidences on the Structure of Diazonamide A and B Diazonamide A Diazonamide B MS (M + H – H2O): C40H35N6O6Cl2 C35H24N5O5Cl2Br • + 5 Carbons • + 11 Hydrogens • + 1 Nitrogen • + 1 Oxygen • + 1 Bromine An valine extra residue fits the differences in the molecular formula and coincides with NMR assignment Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

  9. Crystal Structure of Diazonamide B Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

  10. First Synthesis by Harran’s Group In 2001, P. G. Harran published the first synthesis of ‘’Diazonamide A’’. Spectroscopic data didn’t match the natural product assignment!!! 24 step synthesis Revision of the structure is proposed! Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4765

  11. Wiedemannic Acid Structural Misassignment in Literature A search in the literature between January 1990 to April 2004 revealed 300 structural revisions of natural products Kinamycin C: (+)-tolyporphin A: Sauer, E., Barriault, L. Org. Lett.2004, 19, 3329 Nicolaou, K. C. Angew. Chem., Int. Ed.2005, 44, 1012

  12. Diazonamide Structure Revision In 2001, P. G. Haran’s group published the structure revision of Diazonamide Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

  13. X-Ray Crystallography Scattered X-Ray Incident X-Ray Atom X-Ray generator Electron cloud Crystal Diffraction pattern Nucleus • Every atom scatters X-Ray differently depending on its size • Hydrogen atoms are almost invisible in X-Ray Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p. Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.

  14. X-Ray Crystallography X-Ray Phasing Fitting Crystal Diffraction patterns Electron density map Atomic model 1- The crystal is mounted in the X-Ray beam and rotated 2- The crystal is irradiated by X-Ray (typical wavelength: 1 Å (0.1 nm)) 3- Multiple diffraction patterns are obtained 4- Phasing :2D images are converted into a 3D model of the density of electrons by mathematic calculations 5- Fitting: Electron density map is converted into a atomic model Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p. Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.

  15. X-Ray Crystallography X-Ray Phasing Fitting Crystal Diffraction patterns Electron density map Atomic model Thermal ellipsoids atomic model: • Represents the probability of finding the electrons around the atom as it vibrates. • High probability = More precise atomic model = Smaller ellipsoids Thermal ellipsoids size: Debye-Waller factor (B-factor): -Accounting for the thermal motion of the atom - Numeric representation of the size of the ellipsoid Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p. Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.

  16. X-Ray Crystallography Collected information • Structure in the space • Stereochemistry • Bond lengths • Bond angles • Debye-Waller factor (B-factor) Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p. Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.

  17. C10 (4.83) C12 (4.83) C8 (4.33) C17 (4.53) C7 (4.49) C11 (5.13) O2 (5.46) O3 (7.42) Diazonamide Structure Revision Natural Diazonamide bicyclic core Typical C–O bond distances: 1.353-1.409 Å Typical C–N bond distances: 1.365-1.411 Å C7–O2 bond length: 1.371 Å C17–O3 bond length: 1.433 Å Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

  18. C10 (4.83) C12 (4.83) C8 (4.33) C17 (4.53) C7 (4.49) C11 (5.13) O2 (5.46) O3 (7.42) Diazonamide Structure Revision Natural Diazonamide bicyclic core • O3 has a large thermal motion compared with O2 • X-Ray analysis of the synthetic Diazonamide B B(eq) : O2 = 6.00 Å2 O3 = 5.35 Å2 The bond length and the B-factor are consistent the hypothesis of O3 being a Nitrogen Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

  19. C10 (4.83) C12 (4.83) C8 (4.33) C17 (4.53) C7 (4.49) C11 (5.13) O2 (5.46) O3 (7.42) Diazonamide Structure Revision Natural Diazonamide bicyclic core In X-Ray, the scattering power of an atom is proportional to its atomic number. Neighboring atoms in the periodic table differ slightly from one another, like O and N Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

  20. Comparison of the Assignments Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770 Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

  21. Diazonamide Structure Revision To be consistent with the molecular formula, C40H35N6O6Cl2, one oxygen atom is missing and there is one extra nitrogen 5 oxygens 7 nitrogens Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

  22. Diazonamide Structure Revision Acid digests of diazonamide A do not produce valine, but indicates the presence of two isopropyl groups • N7 protons are reported as a sharp • one-proton doublet • C37 resonates at 76,9 ppm. Considerably downfield for a typical valine (~62 ppm) These observations are consistent with C37 substituent being an alcohol rather than an amine Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

  23. Diazonamide Structure Revision Dehydrated form of the originally proposed structure Growth inhibition determined for human adenocacinoma OVCAR-3 Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 470

  24. Find the differences! Latervalidated by total synthesis Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12888 Nicolaou, K. C. Angew. Chem., Int. Ed.2002, 41, 3495 Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

  25. Diazonamide A Timeline Discovery Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12888 Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4765 Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Nicolaou, K. C. Angew. Chem., Int. Ed.2002, 41, 3495 Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

  26. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Nicolaou’s Synthetic Strategy Formation of the Heterocyclic core Macrolactamization

  27. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Retrosynthetic Analysis of Diazonamide A

  28. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Retrosynthetic Analysis of Diazonamide A

  29. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Retrosynthetic Analysis of Diazonamide A

  30. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Indole-OxazoleBuilding Block Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 10162

  31. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Indole-OxazoleBuilding Block Li, J. J. Name Reactions in Heterocyclic Chemistry, Wiley-Interscience 2005, 557p.

  32. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Indole-OxazoleBuilding Block Miyaura, N. J. Org. Chem.1995, 60, 7508

  33. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of the Aryl Bromide Coupling Partner

  34. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of the Aryl Bromide Coupling Partner Padwa, A. J. Am Chem. Soc.1975, 97, 1837

  35. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of the Aryl Bromide Coupling Partner

  36. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group

  37. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group Most accessible aldehyde Parikh-Doering oxidation

  38. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group Mixture of 8 diastereomers

  39. Hetero Pinacol Sequence Proposed Mechanism Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

  40. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group Mixture of 4 diastereomers

  41. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group Mixture of 2 diastereomers

  42. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group Mixture of 2 diastereomers

  43. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group Only one diastereomer cyclizes: the desired one

  44. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group Substrate specific: Doesn’t work with other model substrates !!!

  45. Proposed Mechanism for the Oxidation with Pearlman’s Catalyst Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

  46. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group

  47. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group

  48. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12888

  49. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Synthesis of Diazonamide ANicolaou’s Group

  50. Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753 Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897 Overview of Nicolaou’s Group Synthesis • 39 steps synthesis • 31 steps in the longest linear sequence (overall yield: 0.01% !!) • First example of an heteropinacol cyclization cascade in the formation of a macrocycle • Surprising concomitant Reduction/Oxidation reaction using Pearlman’s catalyst

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