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Misassigned Natural Products and the Role of Chemical Synthesis in Modern Structure Ilucidation: Total Synthesis of (+)-Hexacyclinol Jolaine Savoie, 18.

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Presentation on theme: "Misassigned Natural Products and the Role of Chemical Synthesis in Modern Structure Ilucidation: Total Synthesis of (+)-Hexacyclinol Jolaine Savoie, 18."— Presentation transcript:

1 Misassigned Natural Products and the Role of Chemical Synthesis in Modern Structure Ilucidation: Total Synthesis of (+)-Hexacyclinol Jolaine Savoie, 18 Mars 2008 Department of Chemistry, Université de Montréal, C.P Station Downtown, Montréal, Québec, H3C 3J7, Canada

2 Summary 1. Introduction 2. The state of modern structure elucidation  Total synthesis of (+)-hexacyclinol by La Clair  Formation of endoperoxides  Stability endoperoxides  Using the endoperoxide as a synthetic intermediate  Total synthesis of (+)-hexacyclinol by Porco & Rychnovsky 3. Conclusion

3 Molecules of Mistaken Identity & Total Synthesis K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, Structural Hypotheses What’ s the Role of Total Synthesis Today? Before World War II  Degradation  Derivatization Today  Multidimensional NMR Spectroscopy  High-Resolution Mass Spectroscopy  X-Ray Crystallography  Scale up for biological testing  Structural assignment

4 Molecules of Mistaken Identity & Total Synthesis A CLASSICAL MISASSIGNMENT: Wieland and Windaus, two researchers in Germany, won the Nobel Prize in Chemistry in because of the proposed structure of cholesterol K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44,

5 Molecules of Mistaken Identity & Total Synthesis Number of inaccuracies in the core structure was revealed in 1932 by Bernal, who obtained on X-Ray cristal structure of ergosterol. Structure of Ergosterol (1932) Verified by X-Ray Crystal Analysis Correct Structure of Cholesterol (1932) K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44,

6 Molecules of Mistaken Identity & Total Synthesis In 1962, Büchi and his colleagues at the Massachussetts Institute of Technology (MIT), obtaining synthetic material that fully corresponded to authentic patchouli alcohol. K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44,

7 Molecules of Mistaken Identity & Total Synthesis In 1963, Dunitz and his colleagues at Eidgenössische Technische Hochschule Zürich, used the X-Ray Crystal Analysis of patchouli alcohol and reassigned the structure. K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44,

8 Molecules of Mistaken Identity & Total Synthesis Surprisingly, the examples outlined in the Nicolaou’s review cover virtually every compound class : stereods, terpenes, indole alkaloids and peptides and encompass molecules of all sizes and levels of stereochemical complexity. K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, Proposed Structure Method Original Assignment Revised Structure Basis for Revision Verified By Total Synthesis

9 Why do so many errors occur? Molecules of Mistaken Identity & Total Synthesis The answer from Nicolaou is : The number of errors simply reflects the fact that every method of assignment has its weaknesses, some of which can not be resolved even if every tool for structural elucidation is also applied. X-Ray Crystal Analysis  Does not reveal the hydrogen atoms (discern between O and N)  Confuse the identity of atoms within certain functional groups (cyano vs diazo) High –Resolution Mass Spectroscopy  Ionisation (Fast –Atom Bombardment (FAB) vs Electron Spray Ionisation (ESI) IR Spectroscopy  Structural information K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44,

10 Total Synthesis of (+)-Hexacyclinol: La Clair 1. Introduction 2. The state of modern structure elucidation  Total synthesis of (+)-hexacyclinol by La Clair  Formation of endoperoxides  Stability endoperoxides  Using the endoperoxide as a synthetic intermediate  Total synthesis of (+)-hexacyclinol by Porco & Rychnovsky 3. Conclusion

11 Story of (+)-Hexacyclinol Panus Rudis Biological Data  Isolated by Gräfe and co-workers, in  From basidiospores collected from Panus Rudis (Mushrooms growing on dead wood).  Biosynthesis of hexacyclinol occurs via the terpenoid pathway.  Moderate antibiotic activity.  Showed an antiproliferative effect.  Inhibitory activity against (P. Falciparum). (antimalariale)

12 Story of (+)-Hexacyclinol  German fungal cultures provided a strain of P. rudis that was able to do the biosynthesis of 1, 2 and 3.  Retrocycloaddition of 1 and 2 released oxygen to afford 3.  [2+2+2] cycloaddition of 3 with singlet O2 returned to a mixture of 1 and 2.

13 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Retrosynthetic Analysis for Hexacyclinol

14 Total Synthesis of (+)-Hexacyclinol: La Clair Retrosynthetic Analysis for Hexacyclinol: Jolaine

15 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Cyclization Via SN 2 Isomerisation

16 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Cyclization Via Mitsunobu Reaction

17 Total Synthesis of (+)-Hexacyclinol: La Clair D. Picq, I. Drivas, G. Carret, D. Anker, Tetrahedron, 1985, 41,13, , J. Attaghrai, D. Picq, D. Anker, Carbohydr. Res. 1987, 159,159 Kinetic Resolution of Epoxyde Synthesis of Precursor 18

18 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Combination of 14 & 18 follow by Mitsunobu (1:4,5) Since 19a didn’t react, that result suggested that the C6-carbinol was too hindered to form the required alkoxyphosphonium intermediate.

19 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Tandem Ring Opening & Closing Via Cleavage MOM Group Cyclization

20 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Ring Closing via Aldol Reaction Ring opening via esterification Thermolysis

21 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Intermolecular Cyclization Via Julia-Kocienski Olefination  -Thiolation

22 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Mechanism Tandem Hydrolysis &  -Elimination Ring Opening

23 Total Synthesis of (+)-Hexacyclinol: La Clair J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, Cycloadditon [2+2+2] Allylic Oxidation Julia-Kocienski Olefination (8:1) 0,6% for 37 steps

24 Total Synthesis of (+)-Hexacyclinol: La Clair Natural Synthetic  D = 131,5 o c= 0,40,  D = 130,5 o c= 0,403

25 Endoperoxide 1. Introduction 2. The state of modern structure elucidation  Total synthesis of (+)-hexacyclinol by La Clair  Formation of endoperoxides  Stability of endoperoxides  Using the endoperoxide as a synthetic intermediate  Total synthesis of (+)-hexacyclinol by Porco & Rychnovsky 3. Conclusion

26 Endoperoxides : Natural Products & Pharmaceuticals T.C.T. Chang, M. Roseblum, J. Org. Chem., 1981, 46, P. M. O’Neill, S. L. Rawe, R. C. Storr, S. A. Ward, G. H. Posnet, Tetrahedron Lett., 2005, 46,

27 Endoperoxides : Formation J. S. Yadav, R. Satheesh Babu, G. Sabitha, Tetrahedron lett., 2003, 44, Direct Nucleophilic Attack on O 2

28 Endoperoxide : Formation Thebaine is known to produce exclusively the adduct resulting from cycloaddition on the less hindered face of the diene P. M. O’Neill, S. L. Rawe, R. C. Storr, S. A. Ward, G. H. Posnet, Tetrahedron Lett., 2005, 46, D. Lopez, E. Quinoa, R. Riguera, J. Org. Chem., 2000, 65, 15, Diels-Alder Thebaine

29 Endoperoxide : Formation A. Rostami, Y. Wang, A. M. Arif, R. McDonald, F. G. West, Org. Lett., 2007, 9, 4, Nazarov

30 Endoperoxide : Stability A. M. Szpilman, E. Korshin, H. Rozenberg, M. D. Bachi, J. Org. Chem., 2005, 70, 9, Mukayama Aldol

31 Endoperoxide : Stability F. Grellepois, B. Crousse, D. Bonnet-Delpon, J.-P. Bégué, Org. Lett., 2005, 7, 23, Metathesis

32 Endoperoxide : Stability V. K.-Y. Lo, Y. Liu, M.-K. Wong, C.-M. Che, Org. Lett., 2006, 8, 8, Gold Coupling

33 Endoperoxide : Stability H.-X. Jin, H.-H. Liu, Q. Zhang, Y. Wu, J. Org. Chem., 2005, 70, B. J. Kim, T. Sasaki, J. Org. Chem., 2004, 69, Acetalization Reduction

34 Endoperoxide : Synthetic Utility Mechanism Example Kornblum DeLaMare Rearrangement S. T. Staben, X. Linghu, F. D. Toste, J. Am. Chem. Soc, 2006, 128,

35 Endoperoxide : Synthetic Utility I. Erden, N. Öcal, J. Song, C. Gleason, C. Gärtner, Tetrahedron, 2006, 62, Mechanism Example Endoperoxide Isomerisation: 2-Vinyl-2-Cyclopentenone

36 Endoperoxide : Synthetic Utility B.W. Greatrex, D.K. Taylor, J. Org. Chem, 2004, 69, T. V. Robinson, D. K. Taylor, E. R.T. Tiekink, J. Org. Chem, 2006, 71, 19, Ring Contraction 3,6-Dihydro-1-2-dioxine Epoxy-1-2-dioxine

37 Endoperoxide : Synthetic Utility C. Fattorusso, G. Campiani, B. Catalanotti, M. Persico, N. Basilico, S. Parapini, D. Taramelli, C. Campagnuolo, E. Fattorusso, A. Romano, O. Taglialatela-Scafiati, J. Med. Chem, 2006, 49, 24, T. V. Robinson, D. K. Taylor, E. R.T. Tiekink, J. Org. Chem, 2006, 71, 19, Reduction of Endoperoxide

38 Endoperoxide : Synthetic Utility T. V. Robinson, D. K. Taylor, E. R.T. Tiekink, J. Org. Chem, 2006, 71, 19, Reduction of Endoperoxide

39 Total Synthesis of (+)-Hexacyclinol: Porco & Rychnovsky 1. Introduction 2. The state of modern structure elucidation  Total synthesis of (+)-hexacyclinol by La Clair  Formation of endoperoxides  Stability of endoperoxides  Using the endoperoxides as a synthetic intermediate  Total synthesis of (+)-Hexacyclinol by Porco &Rychnovsky 3. Conclusion

40 Total Synthesis of (+)-Hexacyclinol: Porco & Rychnovsky J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, What is the wrong with the structure of (+)-hexacyclinol ? Proposed a new structure of (+)- hexacyclinol based : 1.On calculated 13 C NMR chemical shift correlation. 2.From an acid catalyzed rearrangement panepophenanthrin. (ubiquitin activating enzyme inhibitor) Gräfre’ s proposed structure La Clair’s synthesis Pabepophenanthrin

41 Total Synthesis of (+)-Hexacyclinol: Porco & Rychnovsky J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, Revised Retrosynthetic Analysis for Hexacyclinol

42 Total Synthesis of (+)-Hexacyclinol: Porco & Rychnovsky Synthesis of Precursor 7 Via Oxidation Reaction A. B. Hughes, M. V. Sargent, J. Chem. Soc. Perkin Trans 1, 1989, 10, X. Lei, R. P. Johnson, J. A. Porco, Jr., Angew. Chem. Int. Ed., 2003, 42, Chelation-controlled reduction was attempted using DiBAL-H or Zn(BH 4 ) 2 to induce the anti- epoxy alcohol, but it’s showed no diastereoselectivity (1:1). In contrast, the reduction with the Super-Hydride cleanly afforded syn-epoxy alcohol.

43 Total Synthesis of (+)-Hexacyclinol: Porco & Rychnovsky 9 introduce via Stille Coupling J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, L. T. Scott, G. J. DeCicco, J. L. Hyun, G. Reinhardt, J. Am. Chem. Soc., 1985, 107, H.X. Zhang, F. Guibé, G. Balavoine, J. Org. Chem., 1990, 55, 1857 Hydrostannylation of propargyl alcohol ( 9)

44 Total Synthesis of (+)-Hexacyclinol: Porco & Rychnovsky J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, Diels-Alder Reaction & S N 2’ substitution/Cyclization 10 partially dimerized upon standing without solvent (25 o C). The Diels-Alder ‘s product was cleanly obtained in 87% yield as a single diastereoisomer. 28% for 11 steps

45 Total Synthesis of (+)-Hexacyclinol: Porco & Rychnovsky J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, X-Ray Crystal Structure Analysis of Synthetic 2 S N 2’ cyclization places the prenyl substituent at C-5 in a pseudo equatorial orientation, which minimizes steric interactions on the envelope conformation of the tetreahydrofuran ring. C-5 position

46 Total synthesis of (+)-Hexacyclinol: Porco & Rychnovsky  D = 133,3 o c= 0,40  D = 130,5 o c= 0,403

47 Total synthesis of (+)-Hexacyclinol: Porco & Rychnovsky

48 Conclusion Porco & Rychnovsky La Clair  D = 133,3 o c= 0,40, MeOH  D = 131,5 o c= 0,40,

49 Conclusion La Clair Porco & Rychnovsky  No 13 C data or experimental protocols in the supporting information.  [  ] D & 1 H NMR similar to the natural product.  Proof on his structure: release of O 2.  Fugal cultures can make hexacyclinol & desoxyhexacyclinol.  [  ] D & 1 H NMR similar to the natural product.  13 C NMR data matched the natural product.  X-Ray Crystal obtained synthetic material (not natural product).  Proposed that hexacyclinol is an artifact obtained during the isolation procedure.  No mention of O 2 release.


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