- 1 -

Anodic Oxidative Cyclizations:

Tools for the Synthetic Organic Chemist

Mélina Girardin

October 19th 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

O

AcO

OROH

R=Ac heptemerone B R=H 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-

R RR+ e - 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 (LiClO4, R4N+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 (i0):

- Often used

- Simple setup

- Potential increases

Controlled potential (E0):

- High selectivity

- Need a potensiostat

- Current decreases

- Used when needed

- 7 -

RH2

is an

electrophile

What is the Reactivity of a Radical Cation?

RH2·+

radicalcation

is an

acid

is an

oxidizer

RH2Nu·

RH·

- 8 -

Kolbe Oxidation of Carboxylic Acids (1849)

is an

electrophile

RH2·+

radicalcation

is an

acid

is an

oxidizer

RH2Nu·

RH·

is a

radicaldimerization; chain reaction

RH2

- 9 -

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.

MeO

O

O

O

MeOH, NaOMe

Pt anode2 x

MeO

O

OMe

O

8

sebacicacid

hydrolysis

1 2

- e

MeO

O

O

O

2 xMeO

O

2 x- 2 CO2

3 4

- 10 -

Anodic Functionalization of Amino Acids

is an

electrophile

RH2·+

radicalcation

is an

acid

is an

oxidizer

RH2Nu·

RH·

is a

radical

- e-

dimerization; chain reaction

RH+

is an

acidR

is an

electrophile

RHNu

RH2

- 11 -

Anodic Functionalization of Amino Acids

Shono, T.; Matsumura, Y.; Tsubata, K. Org. Syntheses 1990, Coll. Vol. 7, 307-310

N

CO2Me

CO2MeEt4NOTs, MeOH

graphite anode2.5 F/mol

N

CO2Me

CO2MeMeO

87%5 6

N

CO2Me

CO2Me

- e

- H

N

CO2Me

CO2MeH

HH

- e

N

CO2Me

CO2MeH

MeOH

- H

7 8 9

- 12 -

TEMPO-Mediated Oxidative Resolution

is an

electrophile

RH2·+

radicalcation

is an

acid

is an

oxidizer

RH2Nu·

RH·

is a

radical

- e-

dimerization; chain reaction

RH+

is an

acidR

is an

electrophile

RHNu

mediated electrochemical reaction

- 13 -

TEMPO-Mediated Oxidative Resolution

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

O

HN N O- e

N O

Ph

OH

Ph

ON OH

- e

- H B*

(S)-10

11

TEMPO-modified anode(–)-sparteine

NaClO4, MeCNdiv. cell, controlled E

OH O OH

+

52.9% 46.2%(99.6% ee)

(rac)-10 11 (R)-10

- 14 -

Intramolecular Trapping of Radical Cations

is an

acid

is an

electrophile

RH2·+

radicalcation

is an

acid

is an

oxidizer

RH2Nu·

RH·

is a

radical

- e-

dimerization; chain reaction

RH+

is an

acidR

is an

electrophile

RHNu

is a

radical

- e-

RH2Nu+

…

is an

electrophileRH2Nu2

mediated electrochemical reaction

- 15 -

General Mechanism for Anodic Cyclizations

Umpolung reactivity results in coupling of bis-nucleophiles:

NuH

X

n

- e

NuH

X

n

- H

Nu

X

n

NuH

X

n

- e

Nu

X

n

Nu

X

n

ROROH

- H

X = electron-donating group

- 16 -

Oxygen Nucleophiles: Furans/Pyrans Synthesis

Sutterer, A.; Moeller, K.D. J. Am. Chem. Soc. 2000, 122, 5636-5637.

HOOMe

Me RVC anode,30% MeOH/THF

Et4NOTs, 2,6-lutidine2 F/mol

OOMe

Me

OMe

13 (5:1)

HO

Me

Me

OMe

HOOMe

Me

Me O OMe

Me

OMe

15 (3:1)

Me

O

Me

Me

OMe

OMe

17 (1:1)

same conditions

same conditions

95%

74%

56%

12

14

16

- 17 -

Improving Stereoselectivity

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

OOMe

S SO

MeOMe

S SO

MeOMe

S SO

OMe

S S

83% 70%83%(3:1)

50%(10:1)

Me

MeMe

Me

Me

Me

19a 19b 19c 19d

HO

R2 RVC anode,30% MeOH/THF

Et4NOTs, 2,6-lutidine2.2 F/mol

O

R2

MeS

S MeOMe

S S

n nR1

R1

18 19

- 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):

O

Me

Me

OMe

OMe

17 (1:1)

HOOMe

Me

MeHO

Me

Me

OMe

O OMe

Me

OMe

15 (3:1)

Me

(E)-14 (Z)-14

anodic

oxidation

anodic

oxidation

O

MeMe

HH

O

Me

Me

HH

OMe

vsOMe

Me

H OMe

Me

O

H

MeO

Me

O

HH

Me

- 19 -

A Little More on the Reaction Conditions…

RVC anode,30% MeOH/THF

Et4NOTs, 2,6-lutidine2 F/mol

-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

O SO

O

OH

OMe

N

OHOMe

Me

+

+

+

+

+

+

+

+

+

IHP OHPGrahame, D.C. Chem. Rev. 1947, 41, 441-501.

-

- 20 -

A Challenge in Chemoselectivity?

Duan, S.; Moeller, K.D. J. Am. Chem. Soc. 2002, 124, 9368-9369.

S S

HOMeO OBn

Curtin-

Hammet

S S

HOMeO OBn - e

- HS S

OMeO

OBn

MeOH - H

methanolysis

S S

HOMeO OBn

E1/2 = +1.16 VE1/2 = +1.40 V

20

RVC anode,30% MeOH/THF

Et4NOTs, 2,6-lutidine45oC, 2.5 F/mol

70%

S S

O

OMe OBn

MeO

10% methanolysis

21

- 21 -

Expanding the Methodology to Lactones

Brandt, J.D.; Moeller, K.D. Org. Lett. 2005, 7, 3553-3556.

OEt2N

Me S

S

OHO

Me S

S

23

24

OEtO

Me S

S

23

O

RVC anode,10% H2O/MeOH,

Et4NOTs O Me

SS

OMe

25

X cyclized product

83%

? Kolbe-type oxidation

- 22 -

OEt2N

Me S

S

OEt2N

Me S

S

- e

- H

- e

OEt2N Me

SS

OEt2N Me

SS

MeOH

OEt2N Me

SS

OMe

- NH2Et2

H2O

OO Me

SS

OMe

24

25

Possible Mechanism Explaining Solvent Effects

Brandt, J.D.; Moeller, K.D. Org. Lett. 2005, 7, 3553-3556.

- H

OEt2N Me

SS

OMe

over-oxidation

...

27

- 23 -

Early C-C Bond Formation: Bis Enol Ethers

Moeller, K.D.; Tinao, L.V. J. Am. Chem. Soc. 1992, 114, 1033-1041.

Pt anode,10% MeOH/MeCN

LiOCl4, 2,6-lutidine

OMe

OMen

MeO

MeOOMe

OMe

n

26 27

MeO

MeOOMe

OMeMeO

MeOOMe

OMeMeO

MeOOMe

OMe

70% 65% 50%27a 27b 27c

- 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.

OMeMeOOMe

RVC anode,50% MeOH/THF,

LiOCl4, 2,6-lutidine,2.2 F/mol

75%28 29 (19:1)

S

SS

S

OMe

RVC anode,50% MeOH/THF,

LiOCl4, 2,6-lutidine,2.2 F/mol

OMe

MeOOMe

TBDMSO SiMe3 TBDMSO

83%30 31 (1:1)

- 25 -

Electron-Rich Phenyls and Over-Oxidation

New, D.G.; Tesfai, Z.; Moeller, K.D. J. Org. Chem. 1996, 61, 1578-1598.

E1/2 = 1.40 V

E1/2 = 0.9-1.0V

OMe

SMe

35 X=S 36 X=S (72%) (---)

OMe

MeO

XMeOMe

MeO

RVC anode,20% MeOH/DCM

LiOCl4, 2,6-lutidine2.0 F/mol

32 X=O (28% recovered) 33 X=O (31%)

OMe

MeO

+

OMe

34 (33%)

MeOXMe

OMe

MeO

- e

MeOH

- OMe

MeO

- e

OMeMeO

HMeOOMe

- 26 -

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.

RVC anode,20% MeOH/DCM,

LiOCl4, 2,6-lutidine,2.0 F/mol

O

OMe

O

MeOOMe

O

MeO

MeO

acidic

work-up

n n n

R

MeO

R R

37 38 39

O R

OMe OMe

O

n

R

OMe

O

n

R

- e

MeO

- H

MeOH

- e , MeOH, -H

- 27 -

Wright’s Furan Annulation Strategy

Whitehead, C.R.; Sessions, H.; Ghiviriga, I.; Wright, D.L. Org. Lett. 2002, 4, 3763-3765.

OMgBr

, CuI, TMSCl, TMEDA, Et3N, THF

TMSO OO

n

O OOi-Pr

acidic

work-up

O

n

O

anodic oxidation

n

n

40 41

4243

m

m

mm

- 28 -

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.

O OMgBr

, CuI, TMSCl, TMEDA, Et3N, THF

TMSO O O O

conditions

44 45 46

- 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.

O O O OMe O O

Me48a 70% 48b 78%48c 64%

O O

48d 68%

OH

48e 58% (4:1 = trans/cis)

O O O

48f 61%

O

n

O

n

OR1

R2

R1

R2

OMgBr

1) , CuI, TMSCl, TMEDA, Et3N, THF

2) carbon anode, i-PrOH, MeCN, 2,6-lutidine, LiOCl4

47 48

- 30 -

7-Membered Rings: the gem-Dialkyl Effect

Sperry, J.B.; Wright, D.L. J. Am. Chem. Soc. 2005, 127, 8034-8035.

O O

R

O

1) , CuI, TMSCl, TMEDA, Et3N, THF

2) carbon anode, i-PrOH, MeCN, 2,6-lutidine, LiOCl4

MgBr

R

O

n n

49 50

O O O

R

O

Me

O

50a 0% (dec)50b R=Me50c R=i-Pr50d R=Ph50e R=vinyl

50f 61%

O

61%63%62%63%

- 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.

TMSO O O O

TMSO O O O

N

TMSO O

N

O O

EtO2C

CO2Me

61%

76%

65%

anodic

oxidation

anodic

oxidation

anodic

oxidation

EtO2C

CO2Me

51

53

55

52

54

56

- 32 -

Replacing the Furan for a Thiophene

Sperry, J.B.; Wright, D.L. Tetrahedron 2006, 62, 6551-6557.

O O XXMgBr

, CuI,

TMSCl, TMEDA, Et3N, THF

TMSO Xcarbon anode,

i-PrOH, MeCN2,6-lutidine, LiOCl4

59 X = O 64%60 X = S 81%

57 58

Competition study: furan vs thiophene

OOMgBr

, CuI,

TMSCl, TMEDA, Et3N, THF

TMSO O

S S61 62

O Ocarbon anode,

i-PrOH, MeCN2,6-lutidine, LiOCl4

76% overallS 63

- 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.

TMSO O

O OOR

enol ether isoxidized first

furan isoxidized first

41

42

TMSO O- e

TMSO O

+ ROH, - H

TMSO OOR

- e

- TMSOR

TMSO O- e

- TMSOR

O O

- e

O O+ ROH

- H

- 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.

OTMS

E1/2 = 0.87V

TMSO

E1/2 = 0.83V

O

E1/2 = 1.31V

TBSO

O

- 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.

TMSO O

TMSO O

A radical or cation at C- promotes cyclopropane ring-opening:

At C-, it does not promote cyclopropane ring-opening:

65

64

anodic

oxidation

TMSO O

anodic

oxidation

TMSO O

O O

60%

O

~25%

O

Oi-Pr

67

66

- 36 -

Mechanism: Refined Proposition

Sperry, J.B.; Wright, D.L. Tetrahedron 2006, 62, 6551-6557.

TMSO O

TMSO O

- e

- TMSORO O

fast

41

O OOi-Pr

O O

O O

O O

- e

- e

+ i-PrOH - H

O O

acidic

work-up

43 42

- 37 -

The Guanacastepene and Hepteromone Families

neodolastane(guanacastane)

A BC

1 35

81112

15

161718

GuanacastepenesIsolation 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

HepteromonesIsolation from Coprinus heptemerus ("inkcap" mushroom)Sterner, O. et. al. Tetrahedron 2005, 61, 9527-9532.No published total synthesis.

O

AcO

OHCOH

guanacastepene A

O

AcO

OH

guanacastepene E

O

AcO

OAc

heptemerone B

OOH H

- 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

O

AcO

OHOH

ent-guanacastepene E

R3SiO

PO

OP'OO

PO

i-Pr

OP'O

+

HOO

OHI

IO

+

PO

i-Pr

O

PhO

OO

i-Pr

+

A BC

- 39 -

Synthesis of the A-Ring FragmentO

AcO

OHOH

A BC

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

O

BnO BnO

O

PhO

O

O

, SnCl4,

DCM,- 78oC

64%Ph

O

O

OH

68 69(anti/syn=10:1)

1) NaH, BnBr, (n-Bu)4NI, THF 100%

2) DIBAL, DCM, -78oC 85%

BnO

O

1) , CeCl3, THF, -78oC 82%

2) Dess-Martin per. DCM 86%

MgBrGrubbs 2nd generation catalyst,

toluene,

86%

70

7172

- 40 -

Synthesis of the C-Ring Fragment

Hughes, C.C.; Miller, A.K.; Trauner, D. Org. Lett. 2005, 7, 3425-3428.

O

AcO

OHOH

A BC

O

I

I

Oi) n-BuLi,

Et2O, -78oC62%

O

I

Li

1) Dess-Martin per., DCM 88%

2) (+)-DIP-Cl, THF, -20oC 75%

O

I

OH

(+)-75 (94% ee)

Pd(OAc)2, Et3N, (n-Bu)4NBr,

MeCN, H2O, 75oC

75%

OHO

76 (5.1:1)

ii)O

I

OH

(rac)-7573

74

)2BCl

(+)-DIP-Cl

- 41 -

Diastereoselectivity of the Coupling

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

O

AcO

OHOH

A BC

OH

H

O

Pd

OH

H

Pd

O

vs

OHOOH

H

O

O

I

OH

(+)-75

Pd(OAc)2, Et3N, (n-Bu)4NBr,

MeCN, H2O, 75oC

Eclipsed insertion topography with hydroxyle coordination

in 6-exo cyclization

76

- 42 -

Assembly of Fragments A and CO

AcO

OHOH

A BC

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

TBDPSCl,imid., DMAP,

DCM, 0oC

ODPSO

I2,PPh3,imid.,THF

90%

81%

OHO

76

ODPSO

HO

O

Me

BnOiii) BF3 Et2O, -40oC

O

BnO

ODPSO

54%

i) 9-BBN, THF,

ii) EtOH, NaOH, H2O2

98%

ODPSO

I

i) t-BuLi, Et2O, -78oCii) (2-thienyl)Cu(CN)Li, THF

ODPSO

Cu(CN)Li2S

80 (single diastereomer)

77 78

79

72

- 43 -

B-Ring by Anodic Oxidation O

AcO

OHOH

A BC

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

TBSO

BnO

ODPSO

BnO

ODPSOO

KHMDS, TBSOTf, 18-crown-6, THF, -78oC 94%

80

81

O

BnO

ODPSO

OMe

HRVC anode,

2,6-lutidine, LiClO4,

20% MeOH/DCM,rt, 16.5h, 2.61 F/mol

81% 82

HO

BnO

ODPSOH

DIBAL,toluene,

-78oC rt 61%

83

- 44 -

Completion of the Total SynthesesO

AcO

OHOH

A BC

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

HO

BnO

ODPSOH 1) MOMCl, DIPEA,

NaI, THF, 95%

2) TBAF, THF 100% 3) Na, NH3(l), THF 94%

MOMO

HO

OHOH

1) Ac2O, DMAP, p-xylene, 93%2) BF3 OEt2, DMS, DCM, -20oC 3) Dess-Martin per., DCM 69%

O

AcO

OAcOH

ent-heptemerone B

K2CO3, MeOH

28% (39% brsm)

O

AcO

OHOH

ent-guanacastepene E

83 84

- 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:

HOOMe

OOMe

OMeanodic oxidation

Nucleophiles

R3SiO O O O

anodic oxidation

- 46 -

Anodic Oxidations in Total Synthesis

OMe

MeOOMe

Me

MeHO

linalool oxideMoeller 2001

O CO2H

Me

MeMe

CO2H

(+)-nemorensic acidMoeller 2002

N

NH2

HAcO

slaframineShono 1990

O

OMe

OH

O

O

OAc

OAc

acourtia isocedreneYamamura 1999

O

O

OH

O

(–)-alliacol AMoeller 2003/2004

O

AcO

OROH

R=Ac ent-heptemerone B19 steps (3.4%)

R=H ent-guanacastepene ETrauner 2006

- 47 -

Aknowledgments

Prof. Louis BarriaultPatrick AngSteve ArnsÉric BeaulieuMarie-Christine BrochuRachel BeingessnerChristiane GriséNathalie Goulet Véronique LabergeRoch LavigneDr. Louis MorencyMaxime RiouEffiette SauerGuillaume Tessier

Prof. Dirk Trauner