manganese triacetate-promoted cyclizations & annulations
DESCRIPTION
Manganese Triacetate-Promoted Cyclizations & Annulations. 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 - PowerPoint PPT PresentationTRANSCRIPT
Mn1 Mn2
Mn3
O16
Manganese Triacetate-Promoted Manganese Triacetate-Promoted Cyclizations & AnnulationsCyclizations & Annulations
Daniel BeaudoinDaniel BeaudoinLiterature Meeting – September 25, 2006
Under the supervision of Prof. André B. Charette
Leading References:
Melikyan, G. G. Aldrichimica Acta 1998, 31, 50Snider, B. B. Chem. Rev. 1996, 96, 339Melikyan, G. G. Synthesis, 1993, 833.
Oxidative Radical ReactionsOxidative Radical ReactionsTransition Metal OxidantsTransition Metal Oxidants
Oxidative vs Reductive Radical Reactions
Transition Metal One Electron Oxidants1
E0 (V)
0.00 1.000.50 1.50
Fe3+ + e- Fe2+0.77 V
Ce4+ + e- Ce3+1.61 V
Mn3+ + e- Mn2+1.51 V
Cu2+ + e- Cu+0.16 V
Enolate couplingPhenol coupling
Enol silyl ether couplingEnolate coupling
Malonate ester oxidationBenzyl ether oxidation
2.00
Co3+ + e- Co2+1.98 V
V5+ + e- V4+1.00 V
Ring opening oxigenationPhenol coupling
Acyl radicals from aldehydesMalonate ester oxidation
Carboxylic acids oxidationMalonate ester oxidation
1 Review on transition metal-promoted radical reactions: Iqbal, J. et al. Chem. Rev. 1994, 94, 519.
ReductiveTermination
OxidativeTermination
X
H
X
H
ReductiveGeneration
OxidativeGeneration
1 Heiba, E. I. et al. J. Am. Chem. Soc. 1969, 91, 138.
Mn(OAc)2 + KMnO4 Mn(OAc)3.2H2O
AcOH
Ac2OMn(NO3)2 Mn(OAc)3
82%
90-98%
Distorted Octahedron (High Spin)
t2g
eg
Mn(III) d4
t2g
eg
Mn(II) d5
+1 e-
Mn(OAc)Mn(OAc)33
An Underappreciated OxidantAn Underappreciated Oxidant
Preparation1
Electronic and Redox Properties
Inner-Sphere Electron Transfer Outer-Sphere Electron Transfer
L MnIII L MnII+ MnIIIR + MnIIR +
MnIIIR + MnIIR +H H
Mn(OAc)3.2H2O
311$/100g (Aldrich)
1 Hessel, C. et al. Recl. Trav. Chim. Pays-Bas 1969, 88, 545.2 Christou, G. et al. Polyhedron 2003, 22, 133.
Mn(OAc)Mn(OAc)33
Solid State StructureSolid State Structure
Mn(OAc)3.2H2O : [Mn2O(OAc)4].2AcOH.3H2O1
“Anhydrous Mn(OAc)3” : [Mn3O(OAc)7].AcOH2
Mn MnMnMn OO
OO
n
Mn
Mn
MnO
O
HOAc
O
n
Mn1 Mn2
Mn3
O16
Bond Distance (A)
Mn1-O16 1.848
Mn2-O16 1.858
Mn3-O16 2.108
Bond Distance (A)
Mn-O1 1.898
Mn-O2 2.176
Mn-O3 1.936
O O
• Polynuclear solution structure proposed
• [Mn3O(OAc)7] and Mn(OAc)3.2H2O are indistinguishable in solution
• [Mn3O(OAc)7] is slightly more reactive than Mn(OAc)3.2H2O (~1.7x)
• Metathesis with other acids occurs readily
Mn(OAc)Mn(OAc)33
Solution Structure (AcOH)Solution Structure (AcOH)
Mn
Mn
MnO
HOAc
AcO
Mn MnMnMn OO
OO
n
Mn
Mn
MnO
O
HOAc
O
n
Mn
H
MnO
AcO
HOAc
OAcAcO
AcOH
O O
Mn(OAc)Mn(OAc)33
InitiationInitiation
Classical Carbonyls Compounds (High T° Required)
Activated Methylenes (Low T° Required)
Enolization Precedes Inner-Sphere Electron Transfer
H
O
- HOAc
AcOMnIII
OMnIII
OMnII
1 eV = 23.1 kCal/mol
I.P. (eV) = 10.65 10.2 9.0 8.8 8.0 7.74 7.25
Me
O
OEt
OO
HMe H
OEt
OEt
OTESMe
Me
OEt
OTES
Me OH
OMe
OEt
Me
H
Most Common Substrates
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.
EWGH
R R'
MnIII EWGR
R'
EWGH
R R'EWG = Acid, Ketone, Anhydridre, Nitro, (Aldehyde)
EWGEWG
R HEWG = Acid, Ester, Amide, Nitrile, Ketone, Nitro, Sulfone, Sulfoxide
Mn(OAc)Mn(OAc)33
InitiationInitiation
Oxidation of Alkenes
Alkene I.P. (eV)
Alkene Electron Transfer (%)
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
-Methystyrene 8.17 22 - 0
Indene 8.14 54 22 0
trans-Stillbene 8.00 96 75 0
Anethole 7.68 100 - 0
Fristad, W. E. et al. Tetrahedron 1986, 42, 3429.
Alkene Electron Transfer
RR'
EWG
R'
RMn(OAc)3Ligand
Electron Transfer
EWG
R'
H
RR
R
EWGH
R R'
MnIII EWGR
R'
Me
MeO
Me
MeO
OAc
OAc
Mn(OAc)3.2H2O
AcOH, reflux
70%
1,2-Diacetate Formation
Mn(OAc)Mn(OAc)33
Seminal WorksSeminal Works
First Reported Reactions
1 Bush, J. B. et al. J. Am. Chem. Soc. 1968, 90, 5903.2 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
OMn(OAc)3
.2H2O
AcOH, reflux
O
OH+
Proposed Mechanism1,3
Annulation to -Lactone1,2
Annulation to 2,3-dihydrofuran3
O
Mn(OAc)3.2H2O
AcOH, 45°C
EWG
R
+R
O
EWG
H H
X
O
X
O
X
O
R
Mn(OAc)3
-HOAc
X = OH
X = OH
X
OMn(OAc)2
-Mn(OAc)2
RX
O
R
OR O
OR X
Mn(OAc)3
-Mn(OAc)2
[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.
Lactone AnnulationLactone AnnulationRate-Determining StepRate-Determining Step
Enolization Proposed as the Rate-Determining Step
Added Base Accelerates Lactone Formation
O
O
R'
R' , Mn(OAc)3.2H2O
AcOH, R
OH
O 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
C6H12O
O
C6H12
Mn(OAc)3.2H2O, KOAc
AcOH, reflux
R O
O
R
Mn(OAc)3
AcOH
Enolization must occur irreversibly at a complexed acetate2
Mn(OAc)3
orMn(OAc)2
CH3CO2H + CD3CO2D CHnD3-nCO2H(D)KOAc,
OH
O
OH
OH
K = 4 x 10-20
1 Guthrie, J. P. et al. Can. J. Chem. 1995, 73, 1395.2 Fristad, W. E. et al. Tetrahedron 1986, 42, 3429.
Lactone AnnulationLactone AnnulationRate-Determining StepRate-Determining Step
Enolization of Carboxylic Acids
Enolization of a Complexed Acetate
Conclusion:
Acetic acid enol content negligible1 Mn(II) and Mn(III) have no effect on deuterium incorporation2
O
O
C8H17
C8H17AcOH,
Mn(OAc)3.2H2O
OIIIMn
OMnIIOO
IIIMnO
MnIIIOO
IIIMnO
MnIIIO
slow fast
OAc
R O
O
R
Mn(OAc)3
AcOH
R R2 pKA Deuterium Incorporation
Me H 10.7 100 % after 2 h @ 25°C
Et Me 12.5 50 % after 10 h @ 40°C
Lactone AnnulationLactone AnnulationRate-Determining StepRate-Determining Step
Concerted Oxidation-Addition Proposed
RO
O
OH
O
R2 HRO
O
OH(D)
O
R2 D
AcOD
Rate-Determining Step is Substrate-Dependant
R R2 IP Oxidation Time
Me H ~ 9.2 56 h, 6-8 h (excess alkene)
Et Me ~ 8.8 6-8 h, 6-8h (excess alkene)
Snider, B. B. et al. J. Org. Chem. 1988, 53, 2137.
R O
O
R
Mn(OAc)3
AcOH
O
OH
O
O
OHO
Mn(OAc)3.2H2O Mixture of overoxidized
productsMn(OAc)3
.2H2O
2 days >14 days
RDSHO
O
OR
O
MnIIIR'
HO
O
OR
O
MnII
R'
H
HO
OMnOMn
Mn
Donor
Acceptor
ProductsRO
O
OH
O
R2
Mn(OAc)3.2H2O
AcOH
1 Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.2 Davies, D. I. et al. J. Chem. Soc. Perkin Trans. 1 1978, 227.
3 Snider, B. B. Chem. Rev. 1996, 96, 339.
Lactone AnnulationLactone AnnulationTerminationTermination
Secondary Carbocation Not a Predominant Intermediate1,2
Fristad: Radical Cyclization1
Snider: MnIV Intermediate3
OO
Mn(OAc)3
AcOH
CO2H
OAc+
63% 1%
CO2H
H2SO4 (50%)
60 min OO + A/B = 1.2
A B
O
O
O OR
OxidationReductiveElimination
OIIIMn
OMnIIO
R
OIVMn
O
OIIMnR O
MnIIIIMn
Carbocations are generated from tertiary, alylic and benzylic radicals.
O OR
RadicalCyclization Oxidation
OIIIMn
OMnIIO
R
OIIIMn
OMnIIO
R
OMnIIIIMn
R O
O
R
Mn(OAc)3
AcOH
Lactone Annulation Lactone Annulation Scope and SelectivityScope and Selectivity
Pr PrPr
PrO
O
Pr Pr
Mn(OAc)3.2H2O
AcOH
Mn(OAc)3.2H2O
AcOH
dr 3.3 : 1
60% 69%
-Lactone Annulation Isn’t Stereospecific
O
PhMe
O
O
PhMeO2C
O
68% 82%
rr
dr
41 : 1
26 : 1
rr
dr
38 : 1
67 : 1
O
O
MePh
80%
rr
dr
160 : 1
-
O
O
EtEtMe
43%
rr
dr
only
-
O
CO2BuMe
O
57%
rr
dr
3.8 : 1
only
79%
rr
dr
40 : 1
-
O
O
C8H17
1 Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.2 Fristad, W. E. et al. J. Org. Chem. 1985, 50, 3143.
R O
O
R
Mn(OAc)3
AcOH
Reaction Scope
Lactone Annulation Lactone Annulation Scope and SelectivityScope and Selectivity
Pr PrPr
PrO
O
Pr Pr
Mn(OAc)3.2H2O
AcOH
Mn(OAc)3.2H2O
AcOH
dr 3.3 : 1
60% 69%
-Lactone Annulation Isn’t Stereospecific
O
PhMe
O
O
PhMeO2C
O
68% 82%
rr
dr
41 : 1
26 : 1
rr
dr
38 : 1
67 : 1
O
O
MePh
80%
rr
dr
160 : 1
-
O
O
EtEtMe
43%
rr
dr
only
-
O
CO2BuMe
O
57%
rr
dr
3.8 : 1
only
79%
rr
dr
40 : 1
-
O
O
C8H17
1 Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.2 Fristad, W. E. et al. J. Org. Chem. 1985, 50, 3143.
O
O
50%
dr 1.5 : 1
O
O
69%
dr 3.3 : 1
52%
dr 1.25 : 1
O
O
C8H17
Cl
C8H17 C8H17
NCCl O
PrPr
O
33%
dr 7.3 : 6.3 : 2 : 1
O
PrPr
O
Cl Cl O
PrPr
O
O
PrPr
O
Cl Cl
R O
O
R
Mn(OAc)3
AcOH
Reaction Scope
Lactone AnnulationLactone AnnulationRadical Addition SelectivityRadical Addition Selectivity
Relative Rate of Addition (Competition Study)1
OO
OH
Me
BzO
HO
OTIPS
MeMe
O
O
OTIPSH
NC
CO2HNC
Mn3O(OAc)7
KOAc, MeCNrt, 15h, 48%
(±)-Paeoniflorigenin
Ph
Me
Ph
PhPh
C5H11
Me
PhMe
PhPh C6H13
Relative rate : 27 19 15 12 2.4 2.1 1.3 1.0
Ph4-Me
R O
O
R
Mn(OAc)3
AcOH
Relevant Examples2,3
1 Heiba, E. I. et al. J. Am. Chem. Soc. 1968, 90, 5905.2 Corey, E. J. et al. J. Am. Chem. Soc. 1993, 115, 8871.
3 Garda, C. Synth. Coomm. 1984, 14, 1191.
1. Mn(OAc)3.2H2O
AcOH, reflux 2. HCO2H
43%
O
O
(±)-Norbisabolide
OTIPS
Me
Major impurity(yield not specified)
2,3-Dihydrofuran Annulation2,3-Dihydrofuran AnnulationReaction ScopeReaction Scope
O
Mn(OAc)3.2H2O
AcOH, 45°C
EWG
R
+R
O
EWG
H H
O
COMe
MePh
100%1
O
COMe
MeMe
Pr O
O
MePr
74%131%1
O
COMe
MeH13C6
10%1
O
COMe
Me
50-77%2
ArAr
O
CO2Et
MePh
57%1
OMeO
86%3
CO2Et
Me O
53%4
CO2Et
MeO
H
H O
47%5
CO2Et
MeOO
1 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.
Reaction yield depends mostly on the ease of carbocation formation
2,3-Dihydrofuran Annulation2,3-Dihydrofuran AnnulationSynthetic Studies: PodophyllotoxinSynthetic Studies: Podophyllotoxin
O
OO
OH
MeO
OMe
OMe
O
Podophyllotoxin
Fristad, W. E. et al. Tetrahedron Lett. 1987, 28, 1493.
Mn(OAc)3.2H2O
AcOH, 30 min
O
EtO2C
O
O
CO2Et
OMe
OMe
OMe
56%
O
O
O
MeO
OMe
OMe
CO2Et
CO2Et
CO2Et
O
O
O MeO
OMe
OMe
CO2Et
+
O
O
O
Ar
CO2Et
CO2Et
via:
SnCl4, rt, 70 h81%
2,3-Dihydrofuran Annulation2,3-Dihydrofuran AnnulationChiral AuxiliariesChiral Auxiliaries
Oxazolidinone Auxiliaries
ON
O O
Bn
Ar
O
CO2R
MeAr
O*Aux
Ar = 4-MeOPh
O
OR
O
Mn(OAc)3.2H2O
AcOH, 70°C, 3 hO
CO2R
MeAr
OMeOLiBr, DBU
THF:MeOH
R = MeR = i-Pr
80%75%
80-85%
dr 9 : 1Brun, F. et al. Tetrahedron Lett. 2000, 41, 9803.
Scope & Cleavage
ON
O O
X
Ar
MnIII
O
CO2RMe
Ar O
Aux*R
ON
O O
X
MnIII
Ar
R
R =
O
OMe
O
X = i-Pr t-Bu Bn
dr = 2.7 : 1 5.3 : 1 9.0 : 1
or
O
Oi-Pr
O
TerminationTerminationGeneral SchemeGeneral Scheme
X
O
RX
O
R
X
O
X
O
R
R
H
O
X
R
X
O
R
X
O
R
O
N R
X
O
R
X
O
R
CuIII
X
O
R
or
HydrogenAbstraction
Additionto CO
Cyclization
Additionto R-CN
Addition
to CuII
Additionto ArH
Additionto Alkenes
Oxidation
R
TerminationTerminationHydrogen AbstractionHydrogen Abstraction
Hydrogen Abstraction
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
R
O
R'R
O
R'
H
R H
R
Hydrogen abstraction predominates when primary or secondary radicals are involved
EtO2C CO2Et EtO2C CO2Et
Mn(OAc)3.2H2O
55°C, 28 h EtO2C CO2Et EtO2C CO2Etn
16% 4% 75%40%
Acetic Acid:Ethanol:
Snider, B. B. et al. J. Org. Chem. 1991, 56, 5544.Snider, B. B. et al. J. Org. Chem. 1993, 58, 6217.
O
Me
CO2Me
O
Me
CO2Me
Me24% R = H60% R = D
Mn(OAc)3.2H2O
AcOH, rt, 24hR
Mn Relative Rate
MnIII 1
CeIV 12
CuII 350
TerminationTerminationCupric SaltsCupric Salts
Radical Oxidation by Cupric Salts1
Rate of Oxidation of Secondary Radicals2
Rate of reaction between CuII and secondary radicals ~ 106 s-1M-1
R + CuII R CuIII
Me
O
C6H13
Mn
Me
O
C6H13
Mn+1
R
O
R' R
O
R'
CuX2
R
O
R'
R
O
R'
Nu
CuX2
R
O
R'
X
R
O
R' Oxidation
OxidativeSubstitution
OxidativeElimination
LigandTransfer
1 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.
TerminationTerminationCupric SaltsCupric Salts
Oxidative SubstitutionSN1-Like Substitution1
R + CuII R CuIII
Applications in Lactone Annulation2
OEtO2C CO2Et
O OEtO2C CO2Et
OO O
EtO2C CO2EtO O
EtO2C CO2Et
94%82%71%72%dr 1 : 1
O OEtO2C CO2Et
86%
OH
O
EtO2C
CO2Et O O
EtO2C CO2Et
Mn(OAc)3 , 80°C
AcOH : 50%Cu(OTf)2, MeCN : 100%Cu(BF4)2, MeCN : 100%
1 Kochi, J. K. et al. J. Am. Chem. Soc. 1968, 90, 4616.2 Burton, J. W. et al. Chem. Comm. 2005, 4687.
H CuX2 H CuX
-X
H NuH
CuX
Nu
TerminationTerminationCupric SaltsCupric Salts
Oxidative EliminationConcerted Elimination1
Follows Hofmann Rule, Stereoselective for trans-Alkene2
R + CuII R CuIII
O
CO2Me
O
MeO2C
O
MeO2C
O
MeO2C
70% 5%
Cu(OAc)2+
Mn(OAc)3
O
CO2EtMe
O
CO2EtMe
O
CO2EtMe
O
CO2EtMe
39% 13%
Cu(OAc)2+
Mn(OAc)3
1 Kochi, J. K. et al. J. Am. Chem. Soc. 1968, 90, 4616.2 Snider, B. B. et al. J. Org. Chem. 1990, 55, 1965.
Cu(OAc)
H Cu(OAc)2
CuOAcOO
H
X
O
R X
O
R
O
X
O
R
OMnIII MnII
CO
MeO2C
MeO2CCO2H
MeO2C CO2MeMn(OAc)3
.2H2OCO (600 psi)
AcOH, 70°C, 10h50%
TerminationTerminationNitriles & Carbon MonoxideNitriles & Carbon Monoxide
Nitriles1
Carbon Monoxide2
X
O
R X
O
R
N
X
O
R
HN
R' CN
R'Hydrogen
Abstraction R'
1 Snider, B. B. et al. J. Org. Chem. 1992, 57, 322. 2 Alper H. et al. J. Am. Chem. Soc. 1993,115, 1543.
CO2EtMe
O
CO2EtMe
O
N
CO2EtMe
O
N
N
Mn(OAc)3CO2Et
Me
O
O
Hydrogen Abstraction
then w.-up.21%
CyclizationCyclizationRadical Aromatic SubstitutionRadical Aromatic Substitution
Mechanism
EWG EWG EWG EWG EWG EWG
Mn(OAc)3
EWG EWG
-Mn(OAc)2
-HOAc
Mn(OAc)3
-Mn(OAc)2
-HOAc
Monocyclization Scope
Citterio, A. et al. J. Org. Chem. 1989, 54, 2713.
N
EtO2C CO2EtMeO
EtO2C CO2EtO2N
EtO2C CO2EtAcHN
EtO2C CO2EtH
EtO2C CO2Et
EtO2C CO2Et
O
EtO2C CO2Et
90% 93%
CO2EtCO2Et
100%39%
85% 80% 88% 85%
Radical Aromatic SubstitutionRadical Aromatic SubstitutionModel Studies: TronocarpineModel Studies: Tronocarpine
Synthesis of Tetrahydroindolizines
N
NH
O
HO
Tronocarpine
O
Me
Kerr, M. A. et al. Org. Lett. 2006, ASAP.
N
O
CO2Me
CO2Me
CN
N
O
CO2Me
CO2Me
CN
N
NH
OCO2Me
O
NH
CN
Cl
O
CO2Me
CO2Me
NaHMn(OAc)3
.2H2OMeOH, reflux, 18 h
72%
H2, Ra-NiEtOH:THF, 48 h
87%
33%
N
X
CO2Me
CO2MeN
CO2MeCO2Me
X = H2 56%X = O 70%
Mn(OAc)3
MeOH, reflux, 16-24h
Synthesis of the Tronocarpine Skeleton
CyclizationCyclizationExo Exo vsvs Endo Cyclization Mode Endo Cyclization Mode
Diastereoselectivity (Beckwith-Houk Model)
Representative rates
Reversibility of Cyclization
5-exo & 6-exo Cyclizations
Boat-Like Chair-Like
n nn
kexo
kopenn n
kterm ktermkexo
kopen
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)
CyclizationCyclizationExo Exo vsvs Endo Cyclization Mode Endo Cyclization Mode
Reversible Cyclization
Rate of Hydrogen Abstraction < Rate of Ring Opening2
Rate of Iodine Abstraction > Rate of Ring Opening1
Rate of Oxidation > Rate of Ring Opening3
kopen = 1 x 104 s-1
kI = 2 x 109 s-1M-1
kOx = 1 x 106 s-1M-1
1 Halpern, J. Acc. Chem. Res. 1971, 4, 386.2 Curran, D. P. et al. J. Org. Chem. 1989, 54, 3140.3 Snider, B. B. J. Am. Chem. Soc. 1991, 113, 6609.
IEtO2CNC CO2EtNC CO2EtNC
90 10
II
(Me3Sn)2, hv
Bz2O2HEtO2CNC CO2EtNC CO2EtNC
14 86
HMeO2CMeO2C CO2EtMeO2C CO2EtNCMn(OAc)3
Cu(OAc)2
93 7
Baldwin Rulesfor sp2-sp2
cyclization
Hexenyl Radical CyclizationHexenyl Radical Cyclization5-exo 5-exo vsvs 6-endo Cyclization Mode 6-endo Cyclization Mode
O
CO2Me
R3
R2
R1
X
CO2Me
O
R1
R2R2
R3
R1OH
CO2MeMn(OAc)3
AcOH
5-exo 6-endo
Substrate Conditions Products Ref
R1 R2 R3 5-exo 6-endo X
H H H4 Mn(OAc)3
Cu(OAc)2
- 94 - Peterson, J. R. et al. Tetrahedron Lett. 1987, 6109.
Me Me H4 Mn(OAc)3
Cu(OAc)2
- 91 - Snider, B. B. et al. J. Org. Chem. 1989, 54, 38.
H H Me2 Mn(OAc)3
Cu(OAc)2
21 5 Snider, B. B. et al. J. Org. Chem. 1985, 50, 3661.
H H Ph 2 Mn(OAc)3 70 - Peterson, J. R. et al. Tetrahedron Lett. 1987, 6109.Ph
OAc
YX
MOR
YMX
OR
Favored 3-7-(enolexo)-exo-trig
R
MO YX
R
HOYM
X
Favored 6-7-(enolendo)-exo-trigDisfavored 3-5-(enolendo)-exo-trig
Hexenyl Radical CyclizationHexenyl Radical Cyclization5-exo 5-exo vsvs 6-endo Cyclization Mode 6-endo Cyclization Mode
Presence of heteroatoms favors 5-exo cyclization mode
O
O
CO2MeMe
OO
Me
H
O O
O
O
CO2MeMe
O
O
CO2MeMe
O
O
CO2MeMe
1 : 2
Mn(OAc)3.2H2O
Cu(OAc)2
AcOH, NaOAc, reflux73%
OO
Me
Me
O O
O
O
CO2MeMe
Mn(OAc)3.2H2O
Cu(OAc)2
AcOH, NaOAc, reflux21%
Mn(OAc)3.2H2O
Cu(OAc)2
AcOH, NaOAc, reflux71%, dr 2 : 1
O
O
CO2MeMe
AcO3 : 1
Snider, B. B. et al. Tetrahedron 1993, 49, 9447.
Hexenyl Radical CyclizationHexenyl Radical CyclizationFormal Synthesis: Gibberelic AcidFormal Synthesis: Gibberelic Acid
OH
CO2HHMe
HO
O
O
Gibberelic Acid
R
O
CO2Me R
O
CO2Me O
R
MeO2C O
R
MeO2C
Snider, B. B. et al. J. Org. Chem. 1987, 52, 5487.Snider, B. B. et al. J. Org. Chem. 1991, 55, 5544.
O
R
CO2Me
O
R
CO2MeMn(OAc)3.2H2O
Cu(OAc)2
AcOH, rt, 24h
R = HR = CH3
R = OPO(OEt)2
R = OMEM
O
H
OO
48%66%77%52% (EtOH, Hydrolysis in AcOH)
18%
OH
CO2HHMe
HO
O
O
OMEM
O
H
Hexenyl Radical Cyclization Hexenyl Radical Cyclization Model Studies: NemorosoneModel Studies: Nemorosone
O
HO O
Ph
O
Me
Me
MeMe
Nemorosone
Kraus, G. A. et al. Tetrahedron Lett. 2003, 44, 659.Kraus, G. A. et al. Tetrahedron 2003, 59, 8975.
O
MeMe
H CO2Me
HO O
O
MeMe
H CO2Me
O Br
O
MeMe
H CO2Me
O
CO2Me
MeMe
1. NaH, AllylBr2. Mn(OAc)3, Cu(OAc)2
AcOH, 80°C, 16 h
56% MeO2C
O
MeMe
1. NBS (3.3 equiv)2. AcOH:H2O
90%
ONa1.2. 140-170°C
45-54% overall
Hexenyl Radical Cyclization Hexenyl Radical Cyclization Model Studies: BilobalideModel Studies: Bilobalide
O
O
O
O
O
O
H
H
OHOH
t-Bu
Bilobalide
CO2H
OO
O
HH H
H
O
O
HH H
CO2MeOO
O
O
HH H
CO2MeOH
O
O
HH H
O
O
H
Mn(OAc)3
AcOH, rt, 1h52%
NaH
BrOMe
O
Al/Hg
THF:H2O65% (2 steps)
1. MsCl, Et3N2. LiOH
79%
Corey, E. J. et al. J. Am. Chem. Soc. 1984, 106, 5384.
Hexenyl Radical Cyclization Hexenyl Radical Cyclization Synthesis : Podocarpic AcidSynthesis : Podocarpic Acid
OMe
CO2HMe
Me
H
Podocarpic Acid
OMe
OCO2EtMe
OMe
OCO2EtMe
Me
H
Zn, HCl60%Mn(OAc)3
AcOH, rt, 1h50%
OMe
CO2EtMe
Me
H
Snider, B. B. et al. J. Org. Chem. 1985, 50, 3659.
O
Me
EtO2C
OMe
Today’s QuestionToday’s Question(Beer Break)(Beer Break)
OMe CO2Et
OMe CO2Et
Me
H
H
Mn(OAc)3
Cu(OAc)2
MeOH, rt, 3h35% one isomer
Predict Diastereoselectivity of this Cyclization (32 possible diastereoisomers!)
Hexenyl Radical Cyclization Hexenyl Radical Cyclization Synthesis : IsosteviolSynthesis : Isosteviol
OMe CO2Et
OMe CO2Et
Me
H
H
HOMe CO2Et
Me O
H
H
Me CO2Et
Me O
H
HMe CO2H
Me O
H
H
Isosteviol
Mn(OAc)3
Cu(OAc)2
MeOH, rt, 3h35%
1. NaBH4 (99%)2. OsO4, NaIO4 (93%)
1. DEAD, PPh3
2. H2, Pd/C
79%
1. LAH (95%)2. Jones (72%)
Snider, B. B. et al. J. Org. Chem. 1998, 63, 7945.
O
Me
EtO2C
Hexenyl Radical Cyclization Hexenyl Radical Cyclization Chiral AuxiliariesChiral Auxiliaries
Substrate Products Yield dr
- - -
B 28 96 : 4
A 44 100 : 0
B 90 93 : 7
A + B 45 -
PhS
O
O N
O
i-Pr
N
O
Me
Me
O
O
O
Me
PhMeMe
Et2N
O
Snider, B. B. et al. J. Org. Chem. 1991, 56, 328; J. Org. Chem. 1993, 58, 7640
R
O
Me
O
R Me
O
Me
RMn(OAc)3
Cu(OAc)2
AcOH
A B
Hexenyl Radical CyclizationHexenyl Radical CyclizationChiral AuxiliariesChiral Auxiliaries
β-Ketosulfoxide Auxiliary
Snider, B. B. et al. J. Org. Chem. 1991, 56, 328.
S
O
Me
O
PhOS Me
Mn(OAc)3
Cu(OAc)2
AcOH, rt, 14 h44%, one isomer
Ph
O
MeS
O
Ph O
O
S OPhMe
O
Me O
PhOSMe
O
PhOS Me
SOPh
O
SMe
O
PhO
S OPhMe
Hexenyl Radical CyclizationHexenyl Radical CyclizationChiral AuxiliariesChiral Auxiliaries
Phenylmethyl and Pyrrolidine Auxiliaries
N
O
Me
O
ON
Me
MeMe
O
OO
Me
Ph
MeMe
O
Me
R
O
OPh
O
Addition from top faceAddition from bottom face
Selectivity difficult to rationalize with tertiary radicals.
N
Me
Me
O
Met-BuN
Me
Me
O
HR
HX
17:1 4:1
Minimzed A(1,3) strain
Porter, N, A, et al. J. Am. Chem. Soc. 1991, 113, 7002.
Hexenyl Radical CyclizationHexenyl Radical CyclizationChiral AuxiliariesChiral Auxiliaries
Phenylmenthyl and Sultam-Based Auxiliaries
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.
NSO2
O
O
NSO2
O
O
Me
HH
Mn(OAc)3
Cu(OAc)2
AcOH, rt, 4h49%, dr 75 :25
NS O
O
O
H
O
NS O
O
O
H
NS O
O
OH
27 : 1
Similar example
OMe
OMeRO2C
OMe
O
MeRO2C
Me
H
Mn(OAc)2
AcOH, 15°C, 1h dr 88 : 12
R = PhenylmenthylMeOH, 0°C, 8h
dr 91 : 9
Heptenyl Radical CyclizationHeptenyl Radical Cyclization 6-exo 6-exo vsvs 7-Endo Cyclization Mode 7-Endo Cyclization Mode
O
CO2R
R1
R2
Mn(OAc)3, Cu(OAc)2
AcOH
6-exo 7-endo
O
R2R1
CO2R CO2R
R1
R2
O
Substrate ProductsRef
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
Me
O
CO2Me
H
H
O
CO2MeMe
H
Me
O
CO2MeH
CO2Me
H O
Me
HCO2Me
H O
Me
H
Heptenyl Radical CyclizationHeptenyl Radical Cyclization Synthesis: Upial & Synthesis: Upial & epiepi-Upial-Upial
Me
Me O
OEt
Me O
O
MeO
O
Me Me
1. LiHMDS, 1-iodo-3-hexene2. HCl, THF
(57%, dr 6:1)
Mn(OAc)3.2H2O
Cu(OAc)2
AcOH, rt, 2h(85%)
Upial
Snider: Formal Synthesis1,2
Paquette: 14-epi-Upial3
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.
OO
CO2Me
OMOM
Me
H Me
Me OMOMMe
CO2HMeO2C
Me
MeOMOMHO2C
MeO2C
Me
OMOMMe
CO2Me
CO2H
OO
CO2Me
OMOM
H
Me Me
Me OMOMMe
CO2HMeO2C
Mn(OAc)3
AcOH,70°C68%
Mn(OAc)3
AcOH,70°C9%
OO
H
Me Me
CHO
Upial
Heptenyl Radical CyclizationHeptenyl Radical Cyclization Synthesis: Dihydropallescensin DSynthesis: Dihydropallescensin D
White, J. D. et al. Tetrahedron Lett. 1990, 31, 59.
Me
Me
OMeMe
Me
OMeMeCO2Me
OH
OHH
HMeMe
OHH
HMeMe O
H
HMeMe O
CO2Me
H
HMeMe
OMe
MeO
El
Nu
1. Li, NH3, t-BuOH2. LDA, NCCO2Me
52%
Mn(OAc)3, Cu(OAc)2
AcOH, rt, 3h61%
1. LiCl, DMSO, D2. (i-Pr)2NMgBr, TMSCl, Et3N3. mCPBA
64%
1. 2. K2CO3, MeOH
81%
LiTMS
HgSO4
2N H2SO4
62%
Dihydropallescencin D
Heptenyl Radical CyclizationHeptenyl Radical CyclizationSynthesis:Synthesis: GymnomitrolGymnomitrol
KNH NH2
KAPA =
Application to the acetylene zipper reaction:
Snider, B. B. et al. J. Org. Chem. 1997, 62, 1970.
Brown, C. A. et al. J. Am. Chem. Soc. 1975, 97, 891.
O
Me
Me
1. LiHMDS, 1-iodo-2-butyne2. NaH, MeI
1. KAPA (71%)
2. LDA, TMSCl (92%)O
Me
Me
Me
Me
O
Me
Me
MeTMS
O
MeMe
Me
TMS
MeMe
MeHO H
(56%, 2 steps)
Mn(OAc)3.2H2O
9:1 EtOH/HOAc90°C, 22 h
(62%, dr 1.4:1)
1. HOAc (80%)2. NaBH4 (88%)
Gymnomitrol
Oxidative Ring OpeningOxidative Ring OpeningSynthesis: SilphiperfoleneSynthesis: Silphiperfolene
Snider, B. B. et al. J. Org. Chem. 1994, 59, 5419.
N
t-Bu
CO2t-Bu
Me
CO2H
Me Me
Me
HMe
HO
Me
HMe
O
Me
HMe
Me
Me
HMe
O
BrMg1.
2. PDC, DMF (84%)
(65%)
20 : 1
(COCl)2, DMAP
i-Pr2NEt, PhMe(79%)
Li.EDA
(79%)
Mn(OAc)3.2H2O,
EtOH (46%)
Mn(pic)3, DMF (58%)
Na, NH3, EtOH
(69%)
Me
(93%) Me
HMe
MeLi
Me OHMe
Silphiperfolene
pic =N CO2H
SummarySummary
Mn(OAc)3 is a unique one electron oxidant.
There are no reliable equivalent to the one-step Mn(OAc)3- mediated 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.