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NMR Prediction and its Use to Determine the Structure of Hexacyclinol

NMR Prediction and its Use to Determine the Structure of Hexacyclinol. Dec. 18, 2008. Structure Elucidation. NMR is an extremely powerful tool for structural elucidation but it is still up to the chemist to interpret this data and derive structural information.

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NMR Prediction and its Use to Determine the Structure of Hexacyclinol

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  1. NMR Prediction and its Use to Determine the Structure of Hexacyclinol Dec. 18, 2008

  2. Structure Elucidation NMR is an extremely powerful tool for structural elucidation but it is still up to the chemist to interpret this data and derive structural information. DFT is becoming a powerful tool and can be used to calculate the chemical shift values of several nuclei for complex molecules. 1H, 13C, 15N, 17O, 31P 1H, 13C, 15N, 17O, 31P Cimino, P.; Gomez-Paloma, L.; Duca, D.; Riccio, R.; Bifulco, G. Magn. Reson. Chem.2004, 42, S26

  3. Structure Elucidation ChemDraw NMR Predictor

  4. NMR Prediction in the Literature Structure of the GHIJKLM Domain of Maitotoxin Originally Proposed Stereochemistry Reversed Stereochemistry at C51 - C52 Reversed Stereochemistry at C50 - C55 Nicolaou, K. C.; Frederick, M. O. Angew. Chem. Int. Ed.2007, 46, 5278.

  5. Hexacyclinol The Journal of Antibiotics Published September, 2002 Gräfe’s Proposed Structure: UdoGräfe Hans-Knöll-Institute for Natural Products Research Schlegel, B.; Härtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gräfe, U.; Dörfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814.

  6. Isolation and Structure Elucidation of Hexacyclinol • Isolated from basidiospores of the mushroom Panusrudis strain HKI 0254 • Antiproliferative metabolite • Potent inhibitor of L-929 and K-562 cells Structure elucidated by MS, IR, 1H and 13C NMR, DEPT, COSY, HMQC, HMBC and NOESY Schlegel, B.; Härtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gräfe, U.; Dörfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814.

  7. Proposed Structure of Hexacyclinol Schlegel, B.; Härtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gräfe, U.; Dörfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814.

  8. Proposed Structure of Hexacyclinol Schlegel, B.; Härtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gräfe, U.; Dörfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814.

  9. The First Total Synthesis of Hexacyclinol AngewandteChemie International Edition Published Online Feb 9, 2006 James J. La Clair Xenobe Research Institute Hexacyclinol La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769.

  10. The First Total Synthesis of Hexacyclinol Key Step: [2+2+2] Cycloaddition with Singlet O2 37 Linear Step Synthesis 0.9 % Overall Yield 42 Linear Step Synthesis 0.06 % Overall Yield La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769.

  11. Biological Activity of Intermediates La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769.

  12. La Clair’s Synthesis of Hexacyclinol La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769

  13. La Clair’s Synthesis of Hexacyclinol La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769

  14. La Clair’s Synthesis of Hexacyclinol La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769

  15. La Clair’s Synthesis of Hexacyclinol La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769

  16. La Clair’s Synthesis of Hexacyclinol La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769

  17. La Clair’s Synthesis of Hexacyclinol La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769

  18. La Clair’s Synthesis of Hexacyclinol La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769

  19. 1H NMR Spectrum of Synthetic Hexacyclinol Note: CDCl3 Signal @ 7.5 ppm La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769

  20. Key Steps in La Clair’s Synthesis La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769.

  21. Key Steps in La Clair’s Synthesis Complete inversion of hindered tertiary alcohol viaMitsunobu-type conditions La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769.

  22. Mechanism of Mitsunobu-type Inversion of Tertiary Alcohol Possible Intermediate La Clair, J. J. Angew. Chem. Int. Ed.2006, 45, 2769.

  23. Rychnovsky’s Structural Revision Organic Letters Published Online Jun 1, 2006 Scott D. Rychnovsky University of California - Irvine “Recently, a provocative synthesis of hexacyclinol was reported, and interest in the paper triggered my reexamination of the original structure assignment” Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  24. Principles of Nuclear Magnetic Resonance • Each nucleus has a magnetic moment arising from its angular momentum. • When placed in a magnetic field, the nuclei precess around the axis of • the applied magnetic field, Bo with a “Larmor Frequency”, νL. Atkins, P.; de Paula, J. Physical Chemistry, 4th ed.; W. H. Freeman and Co.: New York, 2002

  25. Principles of Nuclear Magnetic Resonance This frequency will depend on the local magnetic field of each nucleus. σ is known as the Shielding Constant. In order to compare NMR spectra, chemists use the Chemical Shift (δ)to compare the shielding constant of a nucleus with a reference value. δ = σ - σref γBo γBo νL = (1 - σ) νL = 2π 2π Atkins, P.; de Paula, J. Physical Chemistry, 4th ed.; W. H. Freeman and Co.: New York, 2002

  26. Introduction to NMR Calculations Step 1: Geometry optimization to identify an energy minimum Cimino, P.; Gomez-Paloma, L.; Duca, D.; Riccio, R.; Bifulco, G. Magn. Reson. Chem. 2004, 42, S26

  27. Introduction to NMR Calculations Step 2: Perform single-point chemical shift calculations σ is an electronic property that can be accessed by quantum chemical calculation for every nucleus Gauge-Including Atomic Orbital (GIAO) method Chemical Shift δ is then calculated based on a suitable reference. Cimino, P.; Gomez-Paloma, L.; Duca, D.; Riccio, R.; Bifulco, G. Magn. Reson. Chem.2004, 42, S26 Modern Methods and Algorithms of Quantum Chemistry, Grotendorst, J.; ed. John von Neumann Institute for Computing: Jülich, 2000, p. 541

  28. Rychnovsky’s NMR Prediction Method Step 1: Lowest energy conformation identified using Monte Carlo MMFF Step 2: The energy of the optimized species was recalculated using the HF/3-21G method Step 3: The 13C NMR shifts were calculated by GIAO using the mPW1PW91/6-31G(d,p) DFT method The calculations took approximately 12h of CPU time and were performed on an inexpensive Linux computer with a 3.06 GHz Intel Pentium 4 processor. Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  29. Validating Bifulco’s Method Using Structurally Similar Molecules Each compound’s structure is conformationally rigid and has been confirmed by X-ray analysis Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  30. Rychnovsky’s NMR Prediction Model Studies Average Δδ = 1.9 ppm Maximum Δδ = 3.8 ppm Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  31. Rychnovsky’s NMR Prediction Model Studies Average Δδ = 1.1 ppm Maximum Δδ = 3.7 ppm Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  32. Rychnovsky’s NMR Prediction Model Studies Average Δδ = 1.5 ppm Maximum Δδ = 3.8 ppm Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  33. Rychnovsky’s Structural Revision Average Δδ = 6.8 ppm Maximum Δδ = 22.0 ppm Average Δδ = 6.8 ppm Maximum Δδ = 22.0 ppm Predicted 13C NMR shifts for Gräfe’s structure of Hexacyclinol do not fit well with experimental data Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  34. What is the Correct Structure of Hexacyclinol? Could Hexacyclinol be an artifact of the isolation of Panepophenanthrin? Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  35. Hexacyclinol = Isolation Artifact of Panepophenanthrin?? Panepophenanthrin Hexacyclinol? Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  36. Revised Structure of Hexacyclinol Stereochemistry? Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  37. Revised Structure of Hexacyclinol Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  38. Revised Structure of Hexacyclinol Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  39. Rychnovsky’s Revised Structure of Hexacyclinol C9 and C12 do not fit well with experimental shifts Average Δδ = 4.2 ppm Maximum Δδ = 18.5 ppm Average Δδ = 4.2 ppm Maximum Δδ = 18.5 ppm C9’s calculated shift is ~ 17 ppm too low while C12 is ~ 18 ppm too high. Possible HMQC misassignment in isolation paper? Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  40. Rychnovsky’s Revised Structure of Hexacyclinol C12 C9 C12 C9 ? H9, H12 C9’s calculated shift is ~ 17 ppm too low while C12 is ~ 18 ppm too high. Possible HMQC misassignment in isolation paper? Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  41. Rychnovsky’s Revised Structure of Hexacyclinol C2 and C5 still do not fit well with experimental shifts Average Δδ = 2.9 ppm Maximum Δδ = 9.5 ppm Average Δδ = 2.9 ppm Maximum Δδ = 9.5 ppm Getting better, but can we make the prediction even more accurate? Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  42. Revised Structure of Hexacyclinol The Karplus Equation J3 = A(cos2φ) + B(cosφ) + C Lowest calculated energy conformation shows these H’s have a dihedral angle of 65º J3 = 10.1 Hz suggests a dihedral angle closer to 180º Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  43. Revised Structure of Hexacyclinol There is another conformer 1.6 kcal/mol higher in energy with a H4-H5 dihedral angle of 159º Average Δδ = 1.8 ppm Maximum Δδ = 5.2 ppm Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  44. Revised vs. Originally Proposed Hexacyclinol Average Δδ = 1.8 ppm Maximum Δδ = 5.2 ppm Average Δδ = 6.8 ppm Maximum Δδ = 22.0 ppm Rychnovsky, S. D. Org. Lett.2006, 8, 2895

  45. Two Proposed Structures for Hexacyclinol Gräfe’s Proposed Structure of Hexacyclinol Rychnovsky’s Proposed Structure of Hexacyclinol Synthetically confirmed by La Clair Supported by NMR Prediction No synthetic corroboration

  46. Porco’s Synthesis of the Revised Structure of Hexacyclinol AngewandteChemie International Edition Received July 18, 2006 Published Online July 27, 2006 John A. Porco Jr. Boston University “In light of our prior synthesis of Panepophenanthrin and access to the natural product as well as chiral, nonracemicepoxyquinol monomer precursors, we initiated studies to prepare the revised structure of Hexacyclinol.” Porco, J. A.; Su, S.; Lei, X.; Bardham, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790

  47. Hexacyclinol = Isolation Artifact of Panepophenanthrin? Panepophenanthrin Hexacyclinol? Rychnovsky, S. D.; Org. Lett.2006, 8, 2895

  48. Hexacyclinol From Acid-Catalyzed Rearrangement of Panepophenanthrin? Attempted validation of Rychnovsky’s hypothesis Panepophenanthrin Hemi-acetal “locks” the structure and prevents ring opening The revised Hexacyclinol could not have come from Panepophenanthrin directly, but they might share a common biosynthetic intermediate Porco, J. A.; Su, S.; Lei, X.; Bardham, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790

  49. Panepophenanthrinvia [4+2] Dimerization Panepophenanthrin Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913

  50. Total Synthesis of Panepophenantrin via Spontaneous [4+2] Dimerization 80 % Dimerization reaches 80% after standing neat for 24 h. Could Hexacyclinol be formed from a similar epoxyquinol monomer intermediate? Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913

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