Post on 20-Jan-2016
transcript
- 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
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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.
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
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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
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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.
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
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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
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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
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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
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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
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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