Manganese Triacetate-Promoted
Cyclizations & Annulations
Mn1
Mn2
O16
Mn3
Leading References:
Melikyan, G. G. Aldrichimica Acta 1998, 31, 50
Snider, B. B. Chem. Rev. 1996, 96, 339
Melikyan, G. G. Synthesis, 1993, 833.
Daniel Beaudoin
Literature Meeting – September 25, 2006
Under the supervision of Prof. André B. Charette
Oxidative Radical Reactions
Transition Metal Oxidants
Oxidative vs Reductive Radical Reactions
Reductive
Generation
X
Reductive
Termination
H
H
Oxidative
Generation
X
Oxidative
Termination
Transition Metal One Electron Oxidants1
Carboxylic acids oxidation
Malonate ester oxidation
Enolate coupling
Phenol coupling
Fe3+ + e-
0.77 V
Fe2+
Mn3+ + e-
1.51 V
Acyl radicals from aldehydes
Malonate ester oxidation
Mn2+
Co3+ + e-
1.98 V
Co2+
E0 (V)
0.50
0.00
Cu2+ + e-
0.16 V
Cu+
Enol silyl ether coupling
Enolate coupling
1.00
V5+ + e-
1.00 V
V4+
Ring opening oxigenation
Phenol coupling
1
1.50
Ce4+ + e-
1.61 V
2.00
Ce3+
Malonate ester oxidation
Benzyl ether oxidation
Review on transition metal-promoted radical reactions: Iqbal, J. et al. Chem. Rev. 1994, 94, 519.
Mn(OAc)3
Mn(OAc)3.2H2O
An Underappreciated Oxidant
311$/100g (Aldrich)
Preparation1
AcOH
Mn(OAc)2 + KMnO4
Mn(NO3)2
82%
Ac2O
90-98%
Mn(OAc)3.2H2O
Mn(OAc)3
Electronic and Redox Properties
Distorted Octahedron (High Spin)
eg
eg
+1 et2g
t2g
Mn(III) d4
Mn(II) d5
Outer-Sphere Electron Transfer
Inner-Sphere Electron Transfer
L MnIII
L
+
MnII
R
+
MnIII
R
R H
+
MnIII
R H
1
+
MnII
+
MnII
Heiba, E. I. et al. J. Am. Chem. Soc. 1969, 91, 138.
Mn(OAc)3
O
Solid State Structure
O
Mn(OAc)3.2H2O : [Mn2O(OAc)4].2AcOH.3H2O1
Mn O Mn O Mn O Mn O
n
“Anhydrous Mn(OAc)3” : [Mn3O(OAc)7].AcOH2
O
O
Mn
O
Mn1
Mn
Mn2
O16
Mn
HOAc
n
Bond
Distance (A)
Mn1O16
1.848
Mn2O16
1.858
Mn3O16
2.108
Bond
Distance (A)
Mn-O1
1.898
Mn-O2
2.176
Mn-O3
1.936
Mn3
1
Hessel, C. et al. Recl. Trav. Chim. Pays-Bas 1969, 88, 545.
2 Christou, G. et al. Polyhedron 2003, 22, 133.
Mn(OAc)3
O
Solution Structure (AcOH)
O
• Polynuclear solution structure proposed
O
O
Mn
O
• [Mn3O(OAc)7] and Mn(OAc)3.2H2O are indistinguishable in solution
Mn
• [Mn3O(OAc)7] is slightly more reactive than Mn(OAc)3.2H2O (~1.7x)
Mn
• Metathesis with other acids occurs readily
HOAc
n
AcO
AcO
Mn
O
Mn
Mn
HOAc
AcO
OAc
Mn
Mn
AcOH
HOAc
O
Mn O Mn O Mn O Mn O
H
n
Mn(OAc)3
H
Initiation
EWG
MnIII
R
R R'
EWG
R'
Most Common Substrates
Classical Carbonyls Compounds (High T° Required)
H
EWG
EWG = Acid, Ketone, Anhydridre, Nitro, (Aldehyde)
R R'
Activated Methylenes (Low T° Required)
EWG
EWG
EWG = Acid, Ester, Amide, Nitrile, Ketone, Nitro, Sulfone, Sulfoxide
R H
Enolization Precedes Inner-Sphere Electron Transfer
MnIII
AcO
H
O
Me
I.P. (eV) =
10.65
1 eV = 23.1 kCal/mol
Me
10.2
O
MnII
- HOAc
O
OH
O
O
MnIII
O
OEt
H
H
9.0
OEt
O
Me
Me
OEt
8.8
H
Me
8.0
OTES
OEt
7.74
OTES
Me
OEt
Me
7.25
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.
Mn(OAc)3
H
Initiation
MnIII
EWG
R R'
R
EWG
R'
Oxidation of Alkenes
H
R
R
R'
R
Mn(OAc)3
Alkene
Electron Transfer
EWG
R R'
R
Ligand
Electron Transfer
EWG
R'
Alkene Electron Transfer (%)
I.P. (eV)
Acetic acid
(IP = 10.65 eV)
Acetic anhydride
(IP = 10.00 eV)
Dimethyl Malonate
(IP ~ 9.2)
1-Hexene
9.65
0
-
0
Cyclohexene
8.95
0
-
0
p-Methylstyrene
8.20
6
-
0
b-Methystyrene
8.17
22
-
0
Indene
8.14
54
22
0
trans-Stillbene
8.00
96
75
0
Anethole
7.68
100
-
0
Alkene
1,2-Diacetate Formation
Me
MeO
OAc
Mn(OAc)3.2H2O
AcOH, reflux
70%
Me
MeO
OAc
Fristad, W. E. et al. Tetrahedron 1986, 42, 3429.
Mn(OAc)3
Seminal Works
First Reported Reactions
Annulation to g-Lactone1,2
O
Mn(OAc)3.2H2O
O
+
O
OH
AcOH, reflux
Annulation to 2,3-dihydrofuran3
O
EWG
Mn(OAc)3.2H2O
R
EWG
+
O
AcOH, 45°C
H H
R
Proposed Mechanism1,3
O
Mn(OAc)3
X
O
Mn(OAc)2
X
-HOAc
O
-Mn(OAc)2
X
R
R
O
O
X = OH
R
O
X
X = OH
O
R
O
Mn(OAc)3
X
R
-Mn(OAc)2
1
2
X
Bush, J. B. et al. J. Am. Chem. Soc. 1968, 90, 5903.
Heiba, E. I. et al. J. Am. Chem. Soc. 1968, 90, 5905.
3 Heiba, E. I. et al. J. Org. Chem. 1974, 39, 3456.
O
Lactone Annulation
Mn(OAc)3
O
R
Rate-Determining Step
AcOH
R
Enolization Proposed as the Rate-Determining Step
O
.
R' , Mn(OAc)3 2H2O
O
R
R
O
AcOH, 
OH
R'
R
pKA (ester)
Relative Rate
H
25
1.0
Cl
22
1.1 x 101
SO2Ph
14
3.8 x 103
CO2Me
13
1.1 x 104
CO2H
13
1.4 x 104
CN
9
4.0 x 105
Added Base Accelerates Lactone Formation
O
Mn(OAc)3.2H2O, KOAc
C6H12
AcOH, reflux
O
C6H12
[KOAc]
MnIII (equiv)
Reaction Time
Yield
0.005
2.5
23 h
67%
0.010
2.5
>12 h
78%
0.500
2.0
7.5 h
85%
3.050
2.0
1.3 h
81%
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.
O
Lactone Annulation
Mn(OAc)3
O
R
Rate-Determining Step
AcOH
R
Enolization of Carboxylic Acids
Acetic acid enol content negligible1
O
Mn(II) and Mn(III) have no effect on deuterium incorporation2
Mn(OAc)3
or
Mn(OAc)2
OH
OH
K = 4 x 10-20
OH
CH3CO2H + CD3CO2D
KOAc, 
CHnD3-nCO2H(D)
Enolization of a Complexed Acetate
O
Mn(OAc)3.2H2O
C8H17
O
AcOH, 
C8H17
Conclusion:
Enolization must occur irreversibly at a complexed acetate2
O
III
Mn
O
O
MnIII
OAc
slow
III
1
O
Mn
O
O
MnIII
fast
O
Mn
III
O
O
MnII
Guthrie, J. P. et al. Can. J. Chem. 1995, 73, 1395.
2 Fristad, W. E. et al. Tetrahedron 1986, 42, 3429.
O
Lactone Annulation
Mn(OAc)3
O
R
Rate-Determining Step
AcOH
R
Rate-Determining Step is Substrate-Dependant
O
O
RO
Mn(OAc)3.2H2O
OH
Products
RO
AcOH
2
R
R
R2
IP
Me
H
~ 9.2
Et
Me
~ 8.8
O
O
R2
H
AcOD
OH
RO
O
O
R2
D
OH(D)
R
R2
pKA
Deuterium Incorporation
56 h, 6-8 h (excess alkene)
Me
H
10.7
100 % after 2 h @ 25°C
6-8 h, 6-8h (excess alkene)
Et
Me
12.5
50 % after 10 h @ 40°C
Oxidation Time
Concerted Oxidation-Addition Proposed
MnII
Donor
Mn
Mn O O
Mn
O
O
Acceptor
Mn(OAc)3.2H2O
O
HO
MnIII
R'
2 days
O
O
HO
OR
RDS
H
Mixture of overoxidized
products
O
HO
OR
H
R'
Mn(OAc)3.2H2O
O
O
>14 days
OH
O
Snider, B. B. et al. J. Org. Chem. 1988, 53, 2137.
O
Lactone Annulation
Mn(OAc)3
O
R
Termination
AcOH
R
Secondary Carbocation Not a Predominant Intermediate1,2
Mn(OAc)3
O
CO2H
+
O
AcOH
OAc
63%
1%
O
H2SO4 (50%)
CO2H
O
+
O
60 min
A
Fristad: Radical
Snider:
O
Mn
MnIV
O
Radical
Cyclization
O
MnII
O
III
Mn
O
O
MnII
Oxidation
R
II
Mn
O
O
O
O
O
R
MnII
Intermediate3
O
R
Oxidation
O
III
Mn
B
Cyclization1
R
III
A/B = 1.2
O
O
O
MnII
IV
II
Reductive
Elimination
O
Mn
Mn O
II
R
Mn
O
MnII
1
Carbocations are generated from tertiary, alylic and benzylic radicals.
2
R
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.
Davies, D. I. et al. J. Chem. Soc. Perkin Trans. 1 1978, 227.
3 Snider, B. B. Chem. Rev. 1996, 96, 339.
O
Lactone Annulation
Mn(OAc)3
O
R
Scope and Selectivity
AcOH
R
g-Lactone Annulation Isn’t Stereospecific
O
Mn(OAc)3.2H2O
Pr
Mn(OAc)3.2H2O
Pr
O
Pr
AcOH
60%
Pr
Pr
AcOH
69%
Pr
dr 3.3 : 1
Reaction Scope
O
O
O
O
O
O
Me
Ph
C8H17
O
Me
Et
O
O
Et
Me
Ph
O
O
MeO2C
Ph
O
Me
CO2Bu
79%
rr 40 : 1
80%
rr 160 : 1
43%
rr only
68%
rr 38 : 1
82%
rr 41 : 1
57%
rr 3.8 : 1
dr
dr
dr
dr 67 : 1
dr 26 : 1
dr
-
-
-
1
2
only
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 3143.
O
Lactone Annulation
Mn(OAc)3
O
R
Scope and Selectivity
AcOH
R
g-Lactone Annulation Isn’t Stereospecific
O
Mn(OAc)3.2H2O
Pr
Pr
O
Pr
AcOH
60%
Pr
Pr
AcOH
69%
Pr
dr 3.3 : 1
Reaction Scope
O
O
O
Me
Ph
C8H17
O
O
O
O
Me
Et
O
O
Et
Me
O
O
Ph
MeO2C
O
Ph
Me
CO2Bu
79%
rr 40 : 1
80%
rr 160 : 1
43%
rr only
68%
rr 38 : 1
82%
rr 41 : 1
57%
rr 3.8 : 1
dr
dr
dr
dr 67 : 1
dr 26 : 1
dr
O
O
-
-
O
C8H17
52%
dr 1.25 : 1
Cl
-
O
O
O
Cl
Mn(OAc)3.2H2O
O
C8H17
50%
dr 1.5 : 1
NC
O
O
C8H17
69%
dr 3.3 : 1
Cl
Pr
O
Pr
Cl
O
Pr
Pr
Cl
Pr
only
O
O
Pr
Cl
Pr
O
Pr
33%
dr 7.3 : 6.3 : 2 : 1
1
2
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 3143.
O
Lactone Annulation
Mn(OAc)3
O
R
Radical Addition Selectivity
AcOH
R
Relative Rate of Addition (Competition Study)1
Me
Me
Ph
4-Me Ph
Ph
Relative rate : 27
Ph
Ph
19
15
C5H11
12
Me
Ph
2.4
2.1
Ph
Ph
1.3
C6H13
1.0
Relevant Examples2,3
Me
NC
BzO
Mn3O(OAc)7
H
OTIPS
KOAc, MeCN
rt, 15h, 48%
Me
Me
CO2H
OTIPS
O
NC
O
1. Mn(OAc)3.2H2O
AcOH, reflux
2. HCO2H
O
O
Me
HO
OH
(±)-Paeoniflorigenin
OTIPS
Major impurity
(yield not specified)
O
O
43%
1
(±)-Norbisabolide
2
Heiba, E. I. et al. J. Am. Chem. Soc. 1968, 90, 5905.
Corey, E. J. et al. J. Am. Chem. Soc. 1993, 115, 8871.
3 Garda, C. Synth. Coomm. 1984, 14, 1191.
2,3-Dihydrofuran Annulation
Reaction Scope
O
EWG
Mn(OAc)3.2H2O
EWG
+
R
O
AcOH, 45°C
H H
R
O
COMe
COMe
Ph
O
Me
Pr
Me
100%1
O
COMe
Me
Pr
Me
31%1
Ph
74%1
CO2Et
CO2Et
Me
Me
O
H13C6
O
MeO
57%1
O
86%3
Ar
Ar
Me
O
10%1
H
O
H
O
Me
O
Me
50-77%2
CO2Et
CO2Et
O
O
O
53%4
Me
47%5
1
Reaction yield depends mostly on
the ease of carbocation formation
COMe
Heiba, E. I. et al. J. Org. Chem. 1974, 39, 3456.
2 Shi, M. et al. J. Org. Chem. 2005, 70, 3859.
3 Corey, E. J. et al. Chem. Lett. 1987, 223.
4 Mellor, J. M. et al. Tetrahedron 1993, 49, 7557.
5 Mellor, J. M. et al. Tetrahedron Lett. 1991, 7107.
2,3-Dihydrofuran Annulation
OH
O
Synthetic Studies: Podophyllotoxin
O
O
O
MeO
CO2Et
OMe
O
Podophyllotoxin
CO2Et
O
OMe
+
O
MeO
OMe
OMe
Mn(OAc)3.2H2O
56%
AcOH, 30 min
O
EtO2C
O
CO2Et
SnCl4, rt, 70 h
81%
OMe
O
CO2Et
O
CO2Et
O
O
O
OMe
OMe
O
CO2Et
O
CO2Et
via:
MeO
OMe
OMe
Ar
Fristad, W. E. et al. Tetrahedron Lett. 1987, 28, 1493.
2,3-Dihydrofuran Annulation
Chiral Auxiliaries
Oxazolidinone Auxiliaries
MnIII
O
O
Ar
N
MnIII
O
O
R
O
Ar
N
O
O
OMe
R=
CO2R
Me
X
O
Aux*
O
R
X
O
Ar
X = i-Pr
t-Bu
Bn
or
O
O
dr = 2.7 : 1
5.3 : 1
9.0 : 1
Oi-Pr
Scope & Cleavage
O
Ar
OR
O
O
N
O
Mn(OAc)3.2H2O
O
AcOH, 70°C, 3 h
Bn
Ar = 4-MeOPh
R = Me 80%
R = i-Pr 75%
O
O
*Aux
Ar
O
CO2R
LiBr, DBU
Me
THF:MeOH
80-85%
MeO
Ar
CO2R
O
Me
dr 9 : 1
Brun, F. et al. Tetrahedron Lett. 2000, 41, 9803.
Termination
General Scheme
O
R
X
O
O
R
X
Oxidation
CuIII
Addition
to CuII
O
R
X
R
X
O
Addition
to CO
O
Hydrogen
Abstraction
O
Cyclization
R
X
H
or
R
Addition
to ArH
Addition
to Alkenes
R
O
R
X
N
O
X
R
R
O
R
Addition
to R-CN
O
X
X
X
R
Termination
Hydrogen Abstraction
Hydrogen Abstraction
R H
O
O
R'
R
R'
R
H
R
Hydrogen abstraction predominates when primary or secondary radicals are involved
Mn(OAc)3.2H2O
n
EtO2C
CO2Et
55°C, 28 h
EtO2C CO2Et
Acetic Acid: 16%
Ethanol:
40%
Solvent
HAA Rate
Acetic Acid
2 x 102 s-1M-1
Acetonitrile
3 x 102 s-1M-1
Ethanol
5.9 x 102 s-1M-1
EtO2C CO2Et
EtO2C CO2Et
4%
75%
O
O
CO2Me
R
Mn(OAc)3.2H2O
AcOH, rt, 24h
Me
Me
CO2Me
24% R = H
60% R = D
Me
Snider, B. B. et al. J. Org. Chem. 1991, 56, 5544.
Snider, B. B. et al. J. Org. Chem. 1993, 58, 6217.
Termination
R + CuII
Cupric Salts
R CuIII
Radical Oxidation by Cupric Salts1
O
Ligand
Transfer
R'
R
X
O
O
R'
R
R
O
CuX2
R'
Oxidative
Elimination
R'
R
CuX2
O
R'
R
Nu
Oxidative
Substitution
O
R
R'
Oxidation
Rate of Oxidation of Secondary Radicals2
O
Me
O
n
M
C6H13
C6H13
Me
n+1
M
Rate of reaction between CuII and secondary radicals ~ 106 s-1M-1
1
Mn
Relative Rate
MnIII
1
CeIV
12
CuII
350
Kochi, J. K. et al. J. Am. Chem. Soc. 1968, 90, 4616.
2 Heiba, E. I. et al. J. Am. Chem. Soc. 1971, 93, 524.
Termination
R + CuII
Cupric Salts
R CuIII
Oxidative Substitution
SN1-Like Substitution1
H
CuX2
H
CuX
H
CuX
H
Nu
-X
Nu
Applications in Lactone Annulation2
CO2Et
EtO2C
O
EtO2C CO2Et
72%
OH
O
O
EtO2C CO2Et
71%
O
Mn(OAc)3 , 80°C
O
O
AcOH : 50%
Cu(OTf)2, MeCN : 100%
Cu(BF4)2, MeCN : 100%
O
CO
Et
2
EtO2C
O
O
EtO2C CO2Et
O
CO
Et
2
EtO2C
82%
dr 1 : 1
94%
1
O
O
CO
Et
2
EtO2C
O
86%
Kochi, J. K. et al. J. Am. Chem. Soc. 1968, 90, 4616.
2 Burton, J. W. et al. Chem. Comm. 2005, 4687.
Termination
R + CuII
Cupric Salts
R CuIII
Oxidative Elimination
Concerted Elimination1
H
Cu(OAc)2
O
H
O
CuOAc
Cu(OAc)
Follows Hofmann Rule, Stereoselective for trans-Alkene2
O
Mn(OAc)3
O
O
Cu(OAc)2
+
O
MeO2C
CO2Me
MeO2C
MeO2C
70%
O
Me
CO2Et
O
Mn(OAc)3
Me
CO2Et
O
Cu(OAc)2
5%
O
Me
CO2Et
Me
CO2Et
+
39%
1
13%
Kochi, J. K. et al. J. Am. Chem. Soc. 1968, 90, 4616.
2 Snider, B. B. et al. J. Org. Chem. 1990, 55, 1965.
Termination
Nitriles & Carbon Monoxide
Nitriles1
O
O
O
R' CN
X
R
X
R
N
Hydrogen
Abstraction
R'
R
X
HN
R'
O
Me
O
CO2Et
Mn(OAc)3
O
CO2Et
Me
CO2Et
Me
N
O
CO2Et
Me
then w.-up.
21%
N
N
Hydrogen
Abstraction
O
Carbon Monoxide2
O
O
X
O
CO
R
R
X
O
MeO2C
MeO2C
R
X
MnIII
Mn(OAc)3.2H2O
CO (600 psi)
O
MnII
MeO2C CO2Me
CO2H
AcOH, 70°C, 10h
50%
1
2
Snider, B. B. et al. J. Org. Chem. 1992, 57, 322.
Alper H. et al. J. Am. Chem. Soc. 1993,115, 1543.
Cyclization
Radical Aromatic Substitution
Mechanism
Mn(OAc)3
EWG EWG
Mn(OAc)3
-Mn(OAc)2
-HOAc
EWG EWG
EWG EWG
-Mn(OAc)2
-HOAc
EWG EWG
Monocyclization Scope
H
MeO
EtO2C CO2Et
85%
O2N
EtO2C CO2Et
80%
AcHN
EtO2C CO2Et
EtO2C CO2Et
88%
85%
O
EtO2C CO2Et
39%
N
EtO2C CO2Et
90%
CO2Et
CO2Et
EtO2C CO2Et
93%
100%
Citterio, A. et al. J. Org. Chem. 1989, 54, 2713.
Radical Aromatic Substitution
NH
O
Model Studies: Tronocarpine
Me
N
O
HO
Synthesis of Tetrahydroindolizines
Tronocarpine
CO2Me
Mn(OAc)3
MeOH, reflux, 16-24h
CO2Me
CO2Me
N
X = H2
X=O
CO2Me
X
N
56%
70%
Synthesis of the Tronocarpine Skeleton
CN
CN
NaH
N
H
33%
Cl
CO2Me
O
CO2Me
CO2Me
N
CO2Me
O
72%
N
CO2Me
CO2Me
O
NH
H2, Ra-Ni
EtOH:THF, 48 h
87%
CN
Mn(OAc)3.2H2O
MeOH, reflux, 18 h
N
O
O
CO2Me
Kerr, M. A. et al. Org. Lett. 2006, ASAP.
Cyclization
Exo vs Endo Cyclization Mode
Diastereoselectivity (Beckwith-Houk Model)
5-exo & 6-exo Cyclizations
Boat-Like
Chair-Like
Reversibility of Cyclization
kexo
kterm
n
n
kopen
kexo
n
kopen
kterm
n
Representative rates
k5-exo : 2 x 105 s-1
k6-endo : 4 x 103 s-1
k6-exo : 5 x 103 s-1
k7-endo : 7 x 102 s-1
kopen : 1 x 104 s-1
kterm : 3 x 106 s-1M-1 (Bu3SnH)
n
Cyclization
Exo vs Endo Cyclization Mode
Reversible Cyclization
Rate of Iodine Abstraction > Rate of Ring Opening1
NC
EtO2C
I
NC CO2Et
NC CO2Et
(Me3Sn)2, hv
I
I
kI = 2 x
109
90
s-1M-1
10
Rate of Hydrogen Abstraction < Rate of Ring Opening2
NC
H
EtO2C
Bz2O2
kopen = 1 x 104 s-1
NC CO2Et
NC CO2Et
14
86
Rate of Oxidation > Rate of Ring Opening3
MeO2C
H
MeO2C
Mn(OAc)3
Cu(OAc)2
MeO2C CO2Et
kOx = 1 x 106 s-1M-1
93
NC CO2Et
7
1
Halpern, J. Acc. Chem. Res. 1971, 4, 386.
Curran, D. P. et al. J. Org. Chem. 1989, 54, 3140.
3 Snider, B. B. J. Am. Chem. Soc. 1991, 113, 6609.
2
Hexenyl Radical Cyclization
5-exo vs 6-endo Cyclization Mode
O
1
R
OH
O
CO2Me
Mn(OAc)3
R3
1
R1
AcOH
R
X
R2
6-endo
5-exo
Substrate
Conditions
R1
R2
R3
H
H
H
Me
Me
H
H
CO2Me
R3
2
R2
R
CO2Me
Products
Ref
5-exo
6-endo
X
4 Mn(OAc)3
Cu(OAc)2
-
94
-
Peterson, J. R. et al. Tetrahedron Lett. 1987, 6109.
H
4 Mn(OAc)3
Cu(OAc)2
-
91
-
Snider, B. B. et al. J. Org. Chem. 1989, 54, 38.
Me
2 Mn(OAc)3
Cu(OAc)2
21
5
Snider, B. B. et al. J. Org. Chem. 1985, 50, 3661.
OAc
H
H
Ph
Baldwin Rules
for sp2-sp2
cyclization
2 Mn(OAc)3
70
X
MO
R
Y
-
Ph
X
HO
R
Favored 6-7-(enolendo)-exo-trig
Disfavored 3-5-(enolendo)-exo-trig
YM
Peterson, J. R. et al. Tetrahedron Lett. 1987, 6109.
X
MO
R
Y
X
O
R
Favored 3-7-(enolexo)-exo-trig
YM
Hexenyl Radical Cyclization
5-exo vs 6-endo Cyclization Mode
Presence of heteroatoms favors 5-exo cyclization mode
O
O
Me
CO2Me
Mn(OAc)3.2H2O
Cu(OAc)2
AcOH, NaOAc, reflux
73%
O
O
Me
CO2Me
Mn(OAc)3.2H2O
Cu(OAc)2
AcOH, NaOAc, reflux
21%
O
O
Me
CO2Me
Mn(OAc)3.2H2O
Cu(OAc)2
O
O
O Me O
Me
CO2Me O
O
H
1:2
O Me O
O
O
Me
O
O
Me
CO2Me
AcOH, NaOAc, reflux
71%, dr 2 : 1
O
O
Me
CO2Me
AcO
3:1
Snider, B. B. et al. Tetrahedron 1993, 49, 9447.
Hexenyl Radical Cyclization
O
Formal Synthesis: Gibberelic Acid
HO
H
Me
CO2H
Gibberelic Acid
OH
O
OH
O
H
OMEM
O
HO
H
Me
O
CO2H
O
CO2Me
Mn(OAc)3.2H2O
Cu(OAc)2
O
CO2Me
O
O
O
AcOH, rt, 24h
H
R
R
R=H
R = CH3
R = OPO(OEt)2
R = OMEM
O
48%
18%
66%
77%
52% (EtOH, Hydrolysis in AcOH)
O
R
R
CO2Me
R
CO2Me
R
MeO2C
O
MeO2C
O
Snider, B. B. et al. J. Org. Chem. 1987, 52, 5487.
Snider, B. B. et al. J. Org. Chem. 1991, 55, 5544.
Me
Hexenyl Radical Cyclization
Model Studies: Nemorosone
HO
Me
O
Ph
Me
Me
O
O
O
CO2Me
Nemorosone
Me
Me
1. NaH, AllylBr
2. Mn(OAc)3, Cu(OAc)2
AcOH, 80°C, 16 h
Me
Me
MeO2C
56%
O
H
CO2Me
O
Me
Me
1. NBS (3.3 equiv)
2. AcOH:H2O
90%
O
Br
H
CO2Me
O
Me
Me
ONa
1.
2. 140-170°C
HO
45-54% overall
H
O
CO2Me
O
Me
Me
Kraus, G. A. et al. Tetrahedron Lett. 2003, 44, 659.
Kraus, G. A. et al. Tetrahedron 2003, 59, 8975.
Hexenyl Radical Cyclization
O
OH
OH
t-Bu
O
Model Studies: Bilobalide
H
O
H
O
O
O
Bilobalide
O
Mn(OAc)3
O
CO2H
H
H
H
Br
OMe
O
AcOH, rt, 1h
52%
Al/Hg
THF:H2O
65% (2 steps)
O
H
H
O
O
O
O
H
OH
CO2Me
1. MsCl, Et3N
2. LiOH
79%
H
O
NaH
H
H
H
O
CO2Me
H
H
H
O
H
O
O
O
Corey, E. J. et al. J. Am. Chem. Soc. 1984, 106, 5384.
Hexenyl Radical Cyclization
OMe
Synthesis : Podocarpic Acid
Me
H
Me CO H
2
Podocarpic Acid
OMe
OMe
Mn(OAc)3
O
Zn, HCl
60%
Me
AcOH, rt, 1h
50%
O
H
Me CO Et
2
Me CO2Et
O
Me
OMe
Me
H
Me CO Et
2
OMe
EtO2C
Snider, B. B. et al. J. Org. Chem. 1985, 50, 3659.
Today’s Question
(Beer Break)
Predict Diastereoselectivity of this Cyclization (32 possible diastereoisomers!)
Mn(OAc)3
Cu(OAc)2
O
Me CO2Et
MeOH, rt, 3h
35% one isomer
Me
H
O
H
Me CO2Et
Hexenyl Radical Cyclization
Synthesis : Isosteviol
Mn(OAc)3
Cu(OAc)2
O
Me CO2Et
MeOH, rt, 3h
35%
1. NaBH4 (99%)
2. OsO4, NaIO4 (93%)
Me
Me
H
O
H
HO
H
Me CO2Et
1. DEAD, PPh3
2. H2, Pd/C
Me
H
79%
H
Me CO2Et
O
O
1. LAH (95%)
2. Jones (72%)
H
Me CO2Et
Me
O
H
H
Me CO2H
Isosteviol
O
Me
EtO2C
Snider, B. B. et al. J. Org. Chem. 1998, 63, 7945.
Hexenyl Radical Cyclization
Chiral Auxiliaries
O
Mn(OAc)3
Cu(OAc)2
R
Me
O R
O
R
Me
A
Substrate
O
O
Me
AcOH
B
Products
Yield
dr
-
-
-
B
28
96 : 4
A
44
100 : 0
B
90
93 : 7
A+B
45
-
O
N
i-Pr
Me
O
N
Me
Ph
Me
Me
O
S
Ph
O
O
Me
O
Et2N
Snider, B. B. et al. J. Org. Chem. 1991, 56, 328; J. Org. Chem. 1993, 58, 7640
Hexenyl Radical Cyclization
Chiral Auxiliaries
β-Ketosulfoxide Auxiliary
Ph
O O
S
Mn(OAc)3
Cu(OAc)2
Me
SOPh
Ph S O Me
O
Ph S O
O
PhOS
AcOH, rt, 14 h
44%, one isomer
PhOS
Ph S O
PhOS
Me
Me
O
S
Me
Ph
O
O
O
Me
O
Me
Me
O
Me
O
Snider, B. B. et al. J. Org. Chem. 1991, 56, 328.
Hexenyl Radical Cyclization
Chiral Auxiliaries
Phenylmethyl and Pyrrolidine Auxiliaries
Me
Me
Me
Me
Me
O
Ph
R
N
O
O
Me
Me
O
O
O
Me
O
Ph
O
N
O
O
Addition from bottom face
Addition from top face
Selectivity difficult to rationalize with tertiary radicals.
X
H
Me
17:1
O
R
N
H
Me
Me
4:1
O
t-Bu
N
Me
Me
Minimzed A(1,3) strain
Porter, N, A, et al. J. Am. Chem. Soc. 1991, 113, 7002.
Hexenyl Radical Cyclization
Chiral Auxiliaries
Phenylmenthyl and Sultam-Based Auxiliaries
OMe
OMe
Mn(OAc)2
O
RO2C Me
R = Phenylmenthyl
O
N
S
O2 O
AcOH, 15°C, 1h
dr 88 : 12
Me
O
RO2C MeH
MeOH, 0°C, 8h
dr 91 : 9
Mn(OAc)3
Cu(OAc)2
AcOH, rt, 4h
49%, dr 75 :25
O
N
H
S
O2 O
Me
H
Similar example
O
N
S O H
O
O
O
O
N
S O H
O
27 : 1
H
N
S O
O
Snider, B. B. et al. J. Org. Chem. 1993, 58, 7640.
Zoretic, P. A. et al. Tetrahedron Lett. 1992, 33, 2637.
Curran; Porter; Geise In Stereochemistry of Radical Reactions,VCH: Weinheim, 1996, 198.
Heptenyl Radical Cyclization
6-exo vs 7-Endo Cyclization Mode
R1
O
O
Mn(OAc)3, Cu(OAc)2
CO2R
R2
O
CO2R
CO2R
R2
AcOH
R1 R2
R1
6-exo
Substrate
H
Products
Ref
R
R1
R2
6-exo
7-endo
Et
H
H
12%
32%
Snider Tetrahedron Lett. 1988, 29, 5209.
Me
H
Me
-
68%
Snider Tetrahedron 1991, 47, 8663.
Me
Me
Me
67%
-
Snider J. Org. Chem. 1987, 52, 5487.
H
O
O
H
Me
7-endo
CO2Me
H
O
Me
Me
CO2Me
H
O
Me
H
CO2Me
H
O
Me
H
CO2Me
H
CO2Me
Heptenyl Radical Cyclization
Me
Synthesis: Upial & epi-Upial
Me
H
CHO
O
O
Upial
Snider: Formal Synthesis1,2
Me
Me
O
1. LiHMDS,
1-iodo-3-hexene
2. HCl, THF
Mn(OAc)3.2H2O
Cu(OAc)2
Me
Me
O
(57%, dr 6:1)
OEt
O
AcOH, rt, 2h
(85%)
O
Me
Me
Upial
O
Paquette: 14-epi-Upial3
OMOM
Me
MeO2C
CO2H
Me
Me
OMOM
H
Mn(OAc)3
Me
AcOH,70°C
68%
Me
Me
OMOM
MeO2C
O
O
Me
Mn(OAc)3
OMOM
Me
H
AcOH,70°C
9%
MeOMOM
HO2C
CO2Me
MeO2C
CO2H
Me
Me
CO2Me
CO2Me
Me
O
CO2H
OMOM
O
Snider, B. B. et al. Tetrahedron 1995, 51, 12983.
Taschner, M. J. et al. J. Am. Chem. Soc. 1985, 107, 5570.
Paquette, L. A. et al. Tetrahedron 1987, 43, 5567.
Heptenyl Radical Cyclization
Synthesis: Dihydropallescensin D
O
Me Me
Me
1. Li, NH3, t-BuOH
2. LDA, NCCO2Me
CO2Me
52%
64%
Mn(OAc)3,
Cu(OAc)2
Me H
Me
AcOH, rt, 3h
61%
Me
Me
1. LiCl, DMSO, D
2. (i-Pr)2NMgBr,
TMSCl, Et3N
3. mCPBA
O
Me Me
Me H
Me
O
H CO2Me
Li
1. TMS
2. K2CO3, MeOH
Me H
Me
81%
2N H2SO4
62%
OH
H OH
H OH
HgSO4
O
El
Me H
Me
Me
Me
H
O
O
Dihydropallescencin D
Nu
White, J. D. et al. Tetrahedron Lett. 1990, 31, 59.
Heptenyl Radical Cyclization
KAPA =
KNH
Synthesis: Gymnomitrol
NH2
Application to the acetylene zipper reaction:
Brown, C. A. et al. J. Am. Chem. Soc. 1975, 97, 891.
Me
1. LiHMDS,
1-iodo-2-butyne
2. NaH, MeI
Me
O
Me
Me
Me
O
(56%, 2 steps)
Me
1. KAPA (71%)
2. LDA, TMSCl (92%)
Me
TMS
O
Me
Me
O
Mn(OAc)3.2H2O
9:1 EtOH/HOAc
90°C, 22 h
(62%, dr 1.4:1)
Me
Me
Me
1. HOAc (80%)
2. NaBH4 (88%)
HO
H
Me
Me
Me
TMS
Gymnomitrol
Snider, B. B. et al. J. Org. Chem. 1997, 62, 1970.
Oxidative Ring Opening
pic =
Synthesis: Silphiperfolene
N
CO2H
Me
Me
1. BrMg
(65%)
N
CO2t-Bu
Me
Me
Me
H
(COCl)2, DMAP
2. PDC, DMF (84%)
CO2H
t-Bu
i-Pr2NEt, PhMe
(79%)
Me
O
20 : 1
Me
Mn(OAc)3.2H2O,
EtOH (46%)
H
Li.EDA
(79%)
Me
HO
Me
Me
Me
Mn(pic)3,
DMF (58%)
O
Me
H
MeLi
H
H
Na, NH3, EtOH
(93%)
Me
Me OH
(69%)
Me
Me
Me
Silphiperfolene
Snider, B. B. et al. J. Org. Chem. 1994, 59, 5419.
Summary
 Mn(OAc)3 is a unique one electron oxidant.
 There are no reliable equivalent to the one-step Mn(OAc)3mediated lactone and dihydrofuran annulations.
 Cyclizations often exhibits very high selectivity.
 Selectivity observed with chiral auxiliaries aren’t well understood.
 Low yields and large amounts of by-products are common.