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

- 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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.

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

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

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

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

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

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

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

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

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, Sterics and stereoelectronic effects ( Bürgi -Dunitz angle):

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,

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

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

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

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

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

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

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

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

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,

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

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

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

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

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,

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

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

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

The Guanacastepene and Hepteromone Families Guanacastepenes Isolation from an unidentified fungus (Costa Rica) Clardy, J. et. al. J. Am. Chem. Soc. 2000, 122, Clardy, J. et. al. J. Am. Chem. Soc. 2001, 123, 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, No published total synthesis.

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

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

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

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

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

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

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

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:

Anodic Oxidations in Total Synthesis

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