1. - 1 - Anodic Oxidative Cyclizations: Tools for the Synthetic Organic Chemist Mélina Girardin October 19 th 2006

2. - 2 - Presentation overview 1) Introduction to organic electrochemistry - Electrosynthesis cell - Electrode potential - Radical cation reactivity 2) Cyclizations with oxygen nucleophiles 3) Cyclizations with formation of C-C bond 4) Total synthesis of heptemerone B and guanacastepene E

3. - 3 - What is Anodic Oxidation? Electron transfer initiated at an electrode: Electrode potential is the energy for the electron transfer: -Selectivity between electrophores Current is a flow of electrons: It is an heterogeneous reaction: -Reactivity is influenced by the electrode material 1 Faraday (F) = 1 mole of e - -Non-thermal activation of molecules

4. - 4 - What is an Electrosynthesis Cell? The basic setup: a.Beaker, vial, round-bottom flask b.Power supply: domestic or specialized c.Ammeter and voltmeter d.Working electrode: the anode for oxidation e.Auxiliary electrode: the cathode f.Solvent (ROH, MeCN, DCM, THF, etc.) g.Soluble supporting electrolyte (LiClO 4, R 4 N + X - ) h.Agitation d.e.

5. - 5 - Can we Improve the Setup? The options: i.Divided cell with porous disk j.Potensiostat k.Reference electrode l.Inert atmosphere m.Thermoregulation j. k. i.

6. - 6 - The Importance of the Potential Constant current (i 0 ): -Often used -Simple setup -Potential increases Controlled potential (E 0 ): -High selectivity -Need a potensiostat -Current decreases -Used when needed

7. - 7 - RH 2 is an electrophile What is the Reactivity of a Radical Cation? RH 2 · + radical cation is an acid is an oxidizer RH 2 Nu · RH ·

8. - 8 - Kolbe Oxidation of Carboxylic Acids (1849) is an electrophile RH 2 · + radical cation is an acid is an oxidizer RH 2 Nu · RH · is a radical dimerization; chain reaction RH 2

9. - 9 - Kolbe Oxidation of Carboxylic Acids (1849) Asahi (Japan) : 100 tons sebacic acid annually Organic Electrochemistry, 4 th Ed. Lund, H., Hammerich, O., Ed. Marcel Dekker, Inc., New York, 2001, 1391 p.

10. - 10 - Anodic Functionalization of Amino Acids is an electrophile RH 2 · + radical cation is an acid is an oxidizer RH 2 Nu · RH · is a radical - e - dimerization; chain reaction RH + is an acid R is an electrophile RHNu RH 2

11. - 11 - Anodic Functionalization of Amino Acids Shono, T.; Matsumura, Y.; Tsubata, K. Org. Syntheses 1990, Coll. Vol. 7, 307-310

12. - 12 - TEMPO-Mediated Oxidative Resolution is an electrophile RH 2 · + radical cation is an acid is an oxidizer RH 2 Nu · RH · is a radical - e - dimerization; chain reaction RH + is an acid R is an electrophile RHNu mediated electrochemical reaction

13. - 13 - TEMPO-Mediated Oxidative Resolution Kashiwagi, Y.; Yanagisawa, Y.; Kurashima, F.; Anzai, J.; Osa, T.; Bobbitt, J.M. Chem. Commun. 1996, 24, 2745-2746.

14. - 14 - Intramolecular Trapping of Radical Cations is an acid is an electrophile RH 2 · + radical cation is an acid is an oxidizer RH 2 Nu · RH · is a radical - e - dimerization; chain reaction RH + is an acid R is an electrophile RHNu is a radical - e - RH 2 Nu + … is an electrophile RH 2 Nu 2 mediated electrochemical reaction

15. - 15 - General Mechanism for Anodic Cyclizations Umpolung reactivity results in coupling of bis-nucleophiles:

16. - 16 - Oxygen Nucleophiles: Furans/Pyrans Synthesis Sutterer, A.; Moeller, K.D. J. Am. Chem. Soc. 2000, 122, 5636-5637.

17. - 17 - Improving Stereoselectivity Liu, B.; Duan, S.; Sutterer, A.; Moeller, K.D. J. Am. Chem. Soc. 2002, 124, 10101-10111.

18. - 18 - Accounting for the Stereoselectivity? 17 ratio suggests a kinetically controlled cyclization Proof of the independance on enol ether geometry: Liu, B.; Duan, S.; Sutterer, A.; Moeller, K.D. J. Am. Chem. Soc. 2002, 124, 10101-10111. Sterics and stereoelectronic effects ( Bürgi -Dunitz angle):

19. - 19 - A Little More on the Reaction Conditions… -Reticulated Vitreous Carbon anode: chemically inert -Supporting electrolyte (Et 4 NOTs): ionic conductivity -Solvent (MeOH): quenches cationic intermediate -Cosolvent (THF): lowers [MeOH] at the electrode -Base (2,6-lutidine): quenches acidity at the anode -2 Faraday / mole: 2 e /molecule Grahame, D.C. Chem. Rev. 1947, 41, 441-501. -

20. - 20 - A Challenge in Chemoselectivity? Duan, S.; Moeller, K.D. J. Am. Chem. Soc. 2002, 124, 9368-9369.

21. - 21 - Expanding the Methodology to Lactones Brandt, J.D.; Moeller, K.D. Org. Lett. 2005, 7, 3553-3556.

22. - 22 - Possible Mechanism Explaining Solvent Effects Brandt, J.D.; Moeller, K.D. Org. Lett. 2005, 7, 3553-3556.

23. - 23 - Early C-C Bond Formation: Bis Enol Ethers Moeller, K.D.; Tinao, L.V. J. Am. Chem. Soc. 1992, 114, 1033-1041.

24. - 24 - Differentiating the Reactive Moieties Sun, Y.; Moeller, K.D. Tetrahedron Lett. 2002, 43, 7159-7161. Frey, D.A.; Reddy, S.H.K.; Moeller, K.D. J. Org. Chem. 1999, 64, 2805-2813.

25. - 25 - Electron-Rich Phenyls and Over-Oxidation New, D.G.; Tesfai, Z.; Moeller, K.D. J. Org. Chem. 1996, 61, 1578-1598. E 1/2 = 1.40 V E 1/2 = 0.9-1.0V

26. - 26 - Preliminary Results on Furan Cyclization EntryRnYield (%) 1H175 2Me154 3H262 New, D.G.; Tesfai, Z.; Moeller, K.D. J. Org. Chem. 1996, 61, 1578-1598.

27. - 27 - Wright’s Furan Annulation Strategy Whitehead, C.R.; Sessions, H.; Ghiviriga, I.; Wright, D.L. Org. Lett. 2002, 4, 3763-3765.

28. - 28 - Chemical and Electrochemical Oxidations EntryConditionsObservationYield (%) 1CAN, MeCNhydrolysis--- 2Mn(OAc) 3, Et 2 Ohydrolysis--- 3VO(OCH 2 CF 3 )Cl 2 decomposition--- 4Ar 3 NSbCl 6 cyclization68 5carbon anode, i-PrOH, MeCN, 2,6-lutidine, LiOCl 4 cyclization76 Sperry, J.B.; Whitehead, C.R.; Ghiviriga, I.; Walczak, R.M.; Wright, D.L. J. Org. Chem. 2004, 69, 3726-3734.

29. - 29 - Scope of the Methodology Sperry, J.B.; Whitehead, C.R.; Ghiviriga, I.; Walczak, R.M.; Wright, D.L. J. Org. Chem. 2004, 69, 3726-3734.

30. - 30 - 7-Membered Rings: the gem-Dialkyl Effect Sperry, J.B.; Wright, D.L. J. Am. Chem. Soc. 2005, 127, 8034-8035.

31. - 31 - Functional Group Tolerance Sperry, J.B.; Whitehead, C.R.; Ghiviriga, I.; Walczak, R.M.; Wright, D.L. J. Org. Chem. 2004, 69, 3726-3734.

32. - 32 - Replacing the Furan for a Thiophene Sperry, J.B.; Wright, D.L. Tetrahedron 2006, 62, 6551-6557. Competition study: furan vs thiophene

33. - 33 - Which Functionality Gives the First Electron? Sperry, J.B.; Whitehead, C.R.; Ghiviriga, I.; Walczak, R.M.; Wright, D.L. J. Org. Chem. 2004, 69, 3726-3734.

34. - 34 - Cyclic Voltammetry: an Electrochemical Tool Sperry, J.B.; Whitehead, C.R.; Ghiviriga, I.; Walczak, R.M.; Wright, D.L. J. Org. Chem. 2004, 69, 3726-3734.

35. - 35 - Mechanistic Probe Molecules Sperry, J.B.; Whitehead, C.R.; Ghiviriga, I.; Walczak, R.M.; Wright, D.L. J. Org. Chem. 2004, 69, 3726-3734.

36. - 36 - Mechanism: Refined Proposition Sperry, J.B.; Wright, D.L. Tetrahedron 2006, 62, 6551-6557.

37. - 37 - The Guanacastepene and Hepteromone Families Guanacastepenes Isolation from an unidentified fungus (Costa Rica) Clardy, J. et. al. J. Am. Chem. Soc. 2000, 122, 2116-2117. Clardy, J. et. al. J. Am. Chem. Soc. 2001, 123, 9900-9901. Total syntheses: Danishefsky (A:2002), Mehta (C:2005), Sorensen (E:2006), Overman (N:2006) Formal syntheses: Snider (A:2003), Hanna (A:2004), etc. Synthetic approaches: more than 10 Hepteromones Isolation from Coprinus heptemerus ("inkcap" mushroom) Sterner, O. et. al. Tetrahedron 2005, 61, 9527-9532. No published total synthesis.

38. - 38 - Trauner’s Convergent Retrosynthetic Analysis Hughes, C.C.; Miller, A.K.; Trauner, D. Org. Lett. 2005, 7, 3425-3428. Miller, A.K.; Chambers, C.H.; Kennedy-Smith, J.J.; Gradl, S.N.; Trauner, D. Submitted

39. - 39 - Synthesis of the A-Ring Fragment Miller, A.K.; Chambers, C.H.; Kennedy-Smith, J.J.; Gradl, S.N.; Trauner, D. Submitted

40. - 40 - Synthesis of the C-Ring Fragment Hughes, C.C.; Miller, A.K.; Trauner, D. Org. Lett. 2005, 7, 3425-3428.

41. - 41 - Diastereoselectivity of the Coupling Iimura, S.; Overman, L.E.; Paulini, R.; Zakarian, A. J. Am. Chem. Soc. 2006, 128, 13095-13101.

42. - 42 - Assembly of Fragments A and C Miller, A.K.; Chambers, C.H.; Kennedy-Smith, J.J.; Gradl, S.N.; Trauner, D. Submitted

43. - 43 - B-Ring by Anodic Oxidation Miller, A.K.; Chambers, C.H.; Kennedy-Smith, J.J.; Gradl, S.N.; Trauner, D. Submitted

44. - 44 - Completion of the Total Syntheses Miller, A.K.; Chambers, C.H.; Kennedy-Smith, J.J.; Gradl, S.N.; Trauner, D. Submitted

45. - 45 - Organic Electrochemistry: What to Remember? - The electron is a reagent transfered at the electrode - The electrode potential is the reagent strength - Electrochemistry can probe reaction mechanisms - Electron transfer triggers umpolung reactivity:

46. - 46 - Anodic Oxidations in Total Synthesis

47. - 47 - Aknowledgments Prof. Louis Barriault Patrick Ang Steve Arns Éric Beaulieu Marie-Christine Brochu Rachel Beingessner Christiane Grisé Nathalie Goulet Véronique Laberge Roch Lavigne Dr. Louis Morency Maxime Riou Effiette Sauer Guillaume Tessier Prof. Dirk Trauner