Anodic Oxidative Cyclizations: Tools for the Synthetic Organic Chemist

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Anodic Oxidative Cyclizations Tools for the
Synthetic Organic Chemist

• Mélina Girardin
• October 19th 2006

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Presentation overview

• Introduction to organic electrochemistry
• - Electrosynthesis cell
• - Electrode potential
• - Radical cation reactivity
• Cyclizations with oxygen nucleophiles
• Cyclizations with formation of C-C bond
• Total synthesis of heptemerone B and
  guanacastepene E

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What is Anodic Oxidation?
Electron transfer initiated at an electrode

• Non-thermal activation of molecules

It is an heterogeneous reaction

• Reactivity is influenced by the electrode material

Electrode potential is the energy for the
electron transfer

• Selectivity between electrophores

Current is a flow of electrons
1 Faraday (F) 1 mole of e-
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What is an Electrosynthesis Cell?

• The basic setup
• Beaker, vial, round-bottom flask
• Power supply domestic or specialized
• Ammeter and voltmeter
• Working electrode the anode for oxidation
• Auxiliary electrode the cathode
• Solvent (ROH, MeCN, DCM, THF, etc.)
• Soluble supporting electrolyte (LiClO4, R4NX-)
• Agitation

d.
e.
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Can we Improve the Setup?
j.

• The options
• Divided cell with porous disk
• Potensiostat
• Reference electrode
• Inert atmosphere
• Thermoregulation

k.
i.
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The Importance of the Potential
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What is the Reactivity of a Radical Cation?
is an acid
RH
RH2 radical cation
is an electrophile
RH2Nu
is an oxidizer
RH2
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Kolbe Oxidation of Carboxylic Acids (1849)
is a radical
dimerization chain reaction
is an acid
RH
RH2 radical cation
is an electrophile
RH2Nu
is an oxidizer
RH2
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Kolbe Oxidation of Carboxylic Acids (1849)
Asahi (Japan) 100 tons sebacic acid annually
Organic Electrochemistry, 4th Ed. Lund, H.,
Hammerich, O., Ed. Marcel Dekker, Inc., New
York, 2001, 1391 p.
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Anodic Functionalization of Amino Acids
is a radical
dimerization chain reaction
is an acid
is an acid
R
RH
- e-
RH
is an electrophile
RHNu
RH2 radical cation
is an electrophile
RH2Nu
is an oxidizer
RH2
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Anodic Functionalization of Amino Acids
Shono, T. Matsumura, Y. Tsubata, K. Org.
Syntheses 1990, Coll. Vol. 7, 307-310
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TEMPO-Mediated Oxidative Resolution
is a radical
dimerization chain reaction
is an acid
is an acid
R
RH
- e-
RH
is an electrophile
RHNu
RH2 radical cation
is an electrophile
RH2Nu
is an oxidizer
mediated electrochemical reaction
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TEMPO-Mediated Oxidative Resolution
Kashiwagi, Y. Yanagisawa, Y. Kurashima, F.
Anzai, J. Osa, T. Bobbitt, J.M. Chem. Commun.
1996, 24, 2745-2746.
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Intramolecular Trapping of Radical Cations
is a radical
dimerization chain reaction
is an acid
is an acid
R
RH
- e-
RH
is an electrophile
RHNu
is an acid
- e-
RH2 radical cation
RH2Nu
is an electrophile
is an electrophile
RH2Nu
RH2Nu2
is a radical

is an oxidizer
mediated electrochemical reaction
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General Mechanism for Anodic Cyclizations
Umpolung reactivity results in coupling of
bis-nucleophiles
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Oxygen Nucleophiles Furans/Pyrans Synthesis
Sutterer, A. Moeller, K.D. J. Am. Chem. Soc.
2000, 122, 5636-5637.
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Improving Stereoselectivity
Liu, B. Duan, S. Sutterer, A. Moeller, K.D. J.
Am. Chem. Soc. 2002, 124, 10101-10111.
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Accounting for the Stereoselectivity?
17 ratio suggests a kinetically controlled
cyclization Proof of the independance on enol
ether geometry
Sterics and stereoelectronic effects
(Bürgi-Dunitz angle)
Liu, B. Duan, S. Sutterer, A. Moeller, K.D. J.
Am. Chem. Soc. 2002, 124, 10101-10111.
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A Little More on the Reaction Conditions

• Reticulated Vitreous Carbon anode chemically
  inert
• Supporting electrolyte (Et4NOTs) 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.
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A Challenge in Chemoselectivity?
Duan, S. Moeller, K.D. J. Am. Chem. Soc. 2002,
124, 9368-9369.
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Expanding the Methodology to Lactones
Brandt, J.D. Moeller, K.D. Org. Lett. 2005, 7,
3553-3556.
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Possible Mechanism Explaining Solvent Effects
Brandt, J.D. Moeller, K.D. Org. Lett. 2005, 7,
3553-3556.
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Early C-C Bond Formation Bis Enol Ethers
Moeller, K.D. Tinao, L.V. J. Am. Chem. Soc.
1992, 114, 1033-1041.
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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.
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Electron-Rich Phenyls and Over-Oxidation
New, D.G. Tesfai, Z. Moeller, K.D. J. Org.
Chem. 1996, 61, 1578-1598.
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Preliminary Results on Furan Cyclization
Entry R n Yield ()
1 H 1 75
2 Me 1 54
3 H 2 62
New, D.G. Tesfai, Z. Moeller, K.D. J. Org.
Chem. 1996, 61, 1578-1598.
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Wrights Furan Annulation Strategy
Whitehead, C.R. Sessions, H. Ghiviriga, I.
Wright, D.L. Org. Lett. 2002, 4, 3763-3765.
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Chemical and Electrochemical Oxidations
Entry Conditions Observation Yield ()
1 CAN, MeCN hydrolysis ---
2 Mn(OAc)3, Et2O hydrolysis ---
3 VO(OCH2CF3)Cl2 decomposition ---
4 Ar3NSbCl6 cyclization 68
5 carbon anode, i-PrOH, MeCN, 2,6-lutidine, LiOCl4 cyclization 76
Sperry, J.B. Whitehead, C.R. Ghiviriga, I.
Walczak, R.M. Wright, D.L. J. Org. Chem. 2004,
69, 3726-3734.
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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.
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7-Membered Rings the gem-Dialkyl Effect
Sperry, J.B. Wright, D.L. J. Am. Chem. Soc.
2005, 127, 8034-8035.
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Functional Group Tolerance
Sperry, J.B. Whitehead, C.R. Ghiviriga, I.
Walczak, R.M. Wright, D.L. J. Org. Chem. 2004,
69, 3726-3734.
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Replacing the Furan for a Thiophene
Sperry, J.B. Wright, D.L. Tetrahedron 2006, 62,
6551-6557.
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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.
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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.
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Mechanistic Probe Molecules
Sperry, J.B. Whitehead, C.R. Ghiviriga, I.
Walczak, R.M. Wright, D.L. J. Org. Chem. 2004,
69, 3726-3734.
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Mechanism Refined Proposition
Sperry, J.B. Wright, D.L. Tetrahedron 2006, 62,
6551-6557.
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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 (A2002), Mehta (C2005),
Sorensen (E2006), Overman (N2006) Formal
syntheses Snider (A2003), Hanna (A2004),
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.
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Trauners 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
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Synthesis of the A-Ring Fragment
Miller, A.K. Chambers, C.H. Kennedy-Smith,
J.J. Gradl, S.N. Trauner, D. Submitted
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Synthesis of the C-Ring Fragment
Hughes, C.C. Miller, A.K. Trauner, D. Org.
Lett. 2005, 7, 3425-3428.
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Diastereoselectivity of the Coupling
Iimura, S. Overman, L.E. Paulini, R. Zakarian,
A. J. Am. Chem. Soc. 2006, 128, 13095-13101.
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Assembly of Fragments A and C
Miller, A.K. Chambers, C.H. Kennedy-Smith,
J.J. Gradl, S.N. Trauner, D. Submitted
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B-Ring by Anodic Oxidation
Miller, A.K. Chambers, C.H. Kennedy-Smith,
J.J. Gradl, S.N. Trauner, D. Submitted
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Completion of the Total Syntheses
Miller, A.K. Chambers, C.H. Kennedy-Smith,
J.J. Gradl, S.N. Trauner, D. Submitted
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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

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Anodic Oxidations in Total Synthesis
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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