Applications of Mn(III) in Organic Chemistry
Baran lab GM
2/6/2010
Contents:
Oxidative radical cyclization of β-keto acids
Discussion of the reaction mechanism
Oxidative radical cyclization of β-keto esters
Oxidative radical cyclization of 1,3-diketones
Oxidative cyclization of ketones
Oxidative fragmentation-cyclization
Asymmetric radical cyclization
Miscellaneous applications of Mn(III) salts
Mn(OAc)3
This summary will not address the chemistry of Mn(III)salen complexes
and Mn(III)porphyrins.
For a review on the Jacobsen-Katsuki epoxidation see:
Jacobsen, Catal. Asymmetric Synth. (ed. Ojima, I.), 159-202,
(VCH, New York, 1993) and ref therein
For a representative example in the field of Mn(III) porphyrins see
Groves, J. Am. Chem. Soc., 1988, 110, 8628.
Thornton, J. Chem. Soc. Chem. Comm., 1978, 62.
- crystallizes as Mn3O(OAc)7
- anhydrous form does not exist
- sold as Mn(OAc)2• 2H2O
- insoluble in most organic solvents;
soluble in hot AcOH
- can be prepared in situ from
Mn(OAc)2 and KMnO4 in AcOH
First reports...
a)
Ph
Reductive processes
H
•
O
MnIII
AcOslow
MnIII
MnIII
Oxidative processes
fast
O
MnIII O
-MnII
Ph
Ph
O
O
MnIII O
MnIII O
MnII
O
Ph
OMnIII
O
b)
MnIII O
O
MnIII
MnIII
O
MnII
O
Ph
O
Bush J. Am. Chem. Soc. 1968, 90, 5903
Heiba J. Am. Chem. Soc. 1968, 90, 5905
Ph
OR
cyclization
Ph
60%
O
H
Sn
R3
reflux
xs
Br
3 Sn
O
O
O
Excluding the applications in olefin epoxidation (or alkane oxidation), Mn(III) is
most commonly used for oxidative radical cyclizations. This chemistry, largely
developed by Barry Snider (Chem. Rev. 1996, 96, 339) has found broad
applications in the total synthesis of natural products.
R
AcOH
+ 2 MnIII
MnIII
Some common commercially available Mn(III) species:
Mn(OAc)3•2H2O (Aldrich, $6/g)
Mn(acac)3 (Aldrich, $3.1/g)
MnF3 (Aldrich, $3.2/g)
Mn2O3 (Aldrich, $10/g)
Florina Voica
O
Mn(OAc)3•2H2O
AcOH, 45 °C
Ph
O
OR
Heiba J. Org. Chem. 1974, 39, 3456
Applications of Mn(III) in Organic Chemistry
Baran lab GM
2/6/2010
The experts:
Key concepts:
Barry Snider
- single electron oxidant
E. J. Corey
- oxidative radical cyclization
M. P. Bertrand
- radical oxidation
Janine Cossy
- tandem radical cyclization
Phillip Zoretic
- hydrogen abstraction
and others
O
O
O
H
H
O
H
63%
Paquette, Tetrahedron Lett. 1987, 43, 5567
For syntheses of upial see:
Taschner, J. Am. Chem. Soc. 1985, 107, 5570 (key step:
intramolecular aldol); Honda, Angew. Chem. Int. Ed. 2008, 47,
131 (key step: carbonyl ene reaction)
H
H
O
Corey, J. Am. Chem. Soc. 1984, 106, 5384
O
O
H
O
X
OH
Mn(OAc)3
AcOH, 70 °C
X
58%
X = CN (50%), only cis
X = CO2Me (64%) cis:trans 4:1
O
H
Fristad, Tetrahedron Lett. 1985, 26, 3761
MeO2C
CO2Me
CHO
OMOM
1. KOH, MeOH
2. Mn3O(OAc)7 (2 eq)
AcOH, 70 °C
(one pot)
68% yield
the major isomer
after a Luche reduction
O
H
H
Mechanism?
R
O
Mn(OAc)3
AcOH
CO2Me
OMe
O
31%
Reaction mechanism
O
O
O
Wallace, J. Chem. Soc. Perkin Trans. 1, 2001, 206.
OMOM
H
O
MeO2C
HO
Mn(OAc)3
AcOH, 65 °C
CO2Me
O
O
O
O
O
O
Mn(OAc)3
AcOH, 80 °C
CO2Me
O
O
O
O
H
O
H
CHO
(±) - 14-epiupial
Early paper by Corey hinted at the potential of this new methodology to efficiently
assemble complex polycyclic structures.
1.3 eq Mn3O(OAc)7
AcOH, 20 min, rt
Upial could not be obtained
by the same strategy since
the other isomer did not
react in the radical cyclization!
O
Oxidative cyclization of β-keto acids
OH
Florina Voica
CO2Me
H
Mn(OAc)3
R = H Et
R = Me
R
Cu(OAc)2
AcOH
O
R
CO2Me
R = H 71%
R = Me 56%
Applications of Mn(III) in Organic Chemistry
O
The oxidant
Mn(OAc)3
OMe
fast
Mn(OAc)3
- most common oxidant/initiator for these reactions.
Other oxidants/initiators used: Fe(ClO4)3; CAN; Co(OAc)2
- in the termination step, its oxidative ability is limited:
∼ γ-carboxy radicals (2° and 3°) will be oxidized to carbocations
∼ tertiary radicals will be oxidized to carbocations to give
alkene or to form a tertiary acetate
∼ allylic radicals will be oxidized to allylic acetates
∼ isolated 1° and 2° radicals wont be oxidized. If no oxidant is
present they will be quenched by H-abstraction from the solvent or
Cu(OAc)2
- oxidizes 2° radicals 350X faster than Mn(OAc)3
- reacts rapidly with radicals (∼ 106 M/sec) to form alkyl-CuIII species
- 1° and 2° radicals are taken to alkenes via direct oxidative elimination
from the alkyl-Cu intermediate (E-olefins and the less substituted
alkene)
- allylic, 3° radicals are oxidized to carbocations
CuX2 (X = Cl, Br, I, SCN)
- oxidize radicals to carbocations or they undergo ligand transfer
Kochi, Acc. Chem. Res. 1974, 7, 351
Et
Et
no discrete keto-ester radical detected!
OH
O
OMe
Et
solvent
O
O
O
OMe
OMe
Et
O
O
O
MnIIIO
Me
Mn(OAc)3
slow
OMe
O
Me
fast
CO2Me
CO2Me
- MnII
Et
Et
Et
O
Me
Me
CO2Me
CO2Me
H
56% cis
O
O
O
Cu(OAc)2
OMe
Me
Et
O
AcOH is the most common solvent with Mn(OAc)3.
EtOH is a better H-donor than AcOH so it is preferred when vinyl radicals
are involved in the termination step (vinyl radicals cannot be oxidized so
they need to be quenched).
O
OMe
The solvent
DMSO, MeOH, dioxane, CH3CN can also be used but they require
higher temp and the yields are sometimes lower.
O
O
boat TS
OMe slow
- MnII
Ac
)2
O
u(
O
Factors that determine the reaction mechanism/product distribution:
MnIII
O
O
Florina Voica
C
Baran lab GM
2/6/2010
or
OMe
Et
14%
O
Me
O
II
OMe
3% H trans
Cu
O
Me
CO2Me
Et
H
O
Me
CO2Me
Snider, J. Org. Chem. 1988, 53, 2137
Baran lab GM
2/6/2010
Applications of Mn(III) in Organic Chemistry
Radical cyclizations of β-keto esters
Florina Voica
Proposed reaction mechanism:
a. Monocylization
O
R'
Mn(OAc)3 (3 eq)
Cu(OAc)2 (2 eq)
AcOH, 80 °C
O
MeO
OMe
OMe
O
76%
vannusal A
O
Nicolaou, Chem Commun. 2002, 2480
O
Mn(OAc)3 (1eq)
Cu(OAc)2 (1 eq)
AcOH, rt
MeO2C
H
H
O
61%
H
CO2Me
O Me
MeO
O Me
H
O
Me CO2Me
OMe
Me
MeO2C
7%
+
O
OH
O
H
MeO2C
triptolide
O
40%
Trick to improve selectivity... (we shall see more of this later)
MeO
OMe
Me
Mn(OAc)3
AcOH
70%
Me CO2Me
O
H
O
H
Me
O
O
O
O
MeO2C
H
O-methylpodocarpate
MeO
H
Me
O
Me
Me
O Me
HO
CO2Me
60%
H
R
H
O
Me
Snider, J. Org. Chem. 1985, 50, 3659
O
O
Zn, HCl
O
MeO2C
Me
MeO2C
Mn(OAc)2•2H2O
AcOH
O
Me
R'
O
O
H
OMe
Mn(OAc)3
AcOH
50%
H
Me
b. Bicycle formation with termination onto an arene
OMe
O Me
R'
dehydropallescensin D
White, Tetrahedron Lett. 1990, 31, 59
R
R
Mn(OAc)3
Me
MeO2C
Me
MeO2C
O Me
O
Me CO2Me
MeO
CO2Me Me
Mn(OAc)3
OMe
O
MeO2C
Me
H
OMe
Mn(OAc)2•2H2O
AcOH
90%
O
(±)-Triptoquinone B and C
Takaishi, J. Chem. Soc., Chem. Commun. 1993, 793
Cl
CO2Et
Yang, J. Org. Chem. 1998, 63, 6446
Me
OMe
O
EtO2C
Cl
H
triptolide
Applications of Mn(III) in Organic Chemistry
Baran lab GM
2/6/2010
Mn(OAc)3
Cu(OAc)2
O
Ph2t-BuO
O
O
O
+
H
H
Danishefsky, J. Am. Chem. Soc. 1998, 120, 12684
N
O
Me
OMe
Cl
O
60%
Me
N
conocarpan
O
O
Snider, J. Org. Chem. 1997, 6978
N
Oxidative fragmentation-cyclization
Me
N
mersicarpine O
H
Kerr, Org. Lett. 2008, 10, 1437
Oxidative cyclization of ketones
O
Me
Mn(OAc)3 (15eq)
9:1 EtOH/AcOH
90 °C, 22h
O
Me
+
gymnomitrol
NaBH4,
MeOH
88%
Me
Me
Me
H
Me
silphiperfol-6-ene
Snider, J. Org. Chem. 1994, 59, 5419
Me
TMS
Mn(pic)3
Bu3SnH
37%
O
H
Me
Me
Me
H
Me
HO
25% TMS
Me
Me
Me
TMS
Me
HO
Me
Me
O
Me
O
Me
Mn(pic)3
DMF
58%
HO
Me
1. KOtBu (92%)
2. LiPPh2 (84%)
OH
O
O
Mn(OAc)3
AcOH, reflux
O
Cl
tricycloillicinone
O
Mn(OAc)3 (4eq)
benzene, 100 °C
25%
Mechanism?
O
O
AcOH, 50 °C
75%
O
O
OMe
O
O
O
Florina Voica
AcOH
100 °C
80%
Snider, J. Org. Chem. 1997, 62, 1970
O
H
H
Me
Me
DMF, 0 °C
OTHP
THPO H
SCN
Me H
10-isothiocyanatoguaia-6-ene
Narasaka, Chem. Lett. 1994, 1697
Applications of Mn(III) in Organic Chemistry
Baran lab GM
2/6/2010
HH
H
Mn(OAc)3
O
5
13
CO2Me
5
13
O
O
OAc
H
CO2Me
35%
A:B/1:2
Me
Me
HO
O
Me
Me
1.5%
O
EtO2C
2 eq Mn(OAc)3
1 eq Cu(OAc)2
AcOH
38-45%
CN
H
O
35% yield
Me
CO2Et
Me
O
Me
H
3%
OAc
B
H
CO2Me
Zoretic, J. Org. Chem. 1996, 61, 1806
8
H
Me
H
CO2Me
Me
OAc
A
H
CO2Me
Me
isospongiadiol
Me
H
O
O
Me
H
O
Me
Me
CN
H
O
EtO2C Me
H
H
H
H
O
EtO2C
H
Me
H
Me
O
EtO2C
Me
Me
O
Me
Me
Beyer-15-ene-3,19-diol
H
H
Me
O
H
Me
OH
CO2Me
H
d. Tandem polycyclizations
Other observed products:
H
Mn(OAc)3
Cu(OAc)2, AcOH
O
HO
Mn(OAc)3
Cu(OAc)2
MeOH
rt, 3h
Mechanism?
Me
+
H
O
MeO2C
Pattenden, Synlett. 1997, 398
O
EtO2C
EtO2C
isosteviol
Snider, J. Org. Chem. 1998, 63, 7945
40%
CO2Me
H
H
Mn(OAc)3
Cu(OAc)2, AcOH
4
Me
OAc
O
H
HO
H
Mn(OAc)3
Cu(OAc)2, AcOH
8%
CO2Me
OAc
Me
H
confirmed by X-rays
Mn(OAc)3
Cu(OAc)2, AcOH
5
O
H
CO2Me
O
37%
CO2Me
O
EtO2C
O
Me
H
Mn(OAc)3
Cu(OAc)2, AcOH
44%
Mechanism?
O
H
H
CO2Me
O
Me
Me
Me
Me
transanular cyclization
CO2Me
H
H
Florina Voica
H
Zoretic, Tetrahedron Lett. 1996, 7909
Applications of Mn(III) in Organic Chemistry
Baran lab GM
2/6/2010
Me
2 eq Mn(OAc)3
1 eq Cu(OAc)2
AcOH
CN
8
Me
O
Cl
CO2Me
Me
Me
CN
H
O
MeO2C Cl
5% yield
Me
Me
CF2CO2H
O
MeO2C Cl
H
H
61% (mixture of
three isomers)
HO
Zoretic, J. Org. Chem. 1998, 63, 7213
Me
O
O
H
O
HO
Me
Me
H
O
1. TBAF
2. AcCl
70%
OAc
H
H
9-Acetoxyfukinanolide
Me
Me
MeO
Me
SmI2
92%
N
Mn(OAc)3
Cu(OAc)2
OMe
H
N
MeO
O
H
O O
Me
MeO
O
H
O
O
MeO
Me
65%
H
O
(-)-Estafiatin
5-α pregnane
Mn(OAc)3
EtOH, rt
O
O
H
Zn, HCl
87%
CO2Me
Oxidative Radical Cyclization of 1,3-diketones
H
Me
CO2Me
O
H
H
Me
O
Lee, J. Am. Chem. Soc. 1997, 119, 8391
H
H
Cl
H
α-Chloro substitution prevents overoxidation of the product!
O
H
H
Me
CO2Me
H
Me
O
EtOH, reflux
65%
H
H
Me
HO
O
THPO
O
Me
Me
Cl
CN
H
70%
H
H
H
Mn(OAc)2•2H2O
Cu(OAc)2•H2O
THPO
Me
+
H
H
H
H
MeO2C Cl
Oxidative Radical Cyclization of 1,3-diesters
CN
H
O
OAc
Florina Voica
O
OMe
O
AcOH, rt
72%
OMe
O
OMe
H
O
Fredericamycin A
O
OH
H
Greene, J. Am. Chem. Soc. 1996, 118, 9992
Rao, J. Chem. Soc. Perkin Trans. 1, 1993, 3171
Applications of Mn(III) in Organic Chemistry
Baran lab GM
2/6/2010
Mn(OAc)3
Cu(OAc)2
O
Ph2t-BuO
O
O
O
+
H
H
Danishefsky, J. Am. Chem. Soc. 1998, 120, 12684
N
O
Me
OMe
Cl
O
60%
Me
N
conocarpan
O
O
Snider, J. Org. Chem. 1997, 6978
N
Oxidative fragmentation-cyclization
Me
N
mersicarpine O
H
Kerr, Org. Lett. 2008, 10, 1437
Oxidative cyclization of ketones
O
Me
Mn(OAc)3 (15eq)
9:1 EtOH/AcOH
90 °C, 22h
O
Me
+
gymnomitrol
NaBH4,
MeOH
88%
Me
Me
Me
H
Me
silphiperfol-6-ene
Snider, J. Org. Chem. 1994, 59, 5419
Me
TMS
Mn(pic)3
Bu3SnH
37%
O
H
Me
Me
Me
H
Me
HO
25% TMS
Me
Me
Me
TMS
Me
HO
Me
Me
O
Me
O
Me
Mn(pic)3
DMF
58%
HO
Me
1. KOtBu (92%)
2. LiPPh2 (84%)
OH
O
O
Mn(OAc)3
AcOH, reflux
O
Cl
tricycloillicinone
O
Mn(OAc)3 (4eq)
benzene, 100 °C
25%
Mechanism?
O
O
AcOH, 50 °C
75%
O
O
OMe
O
O
O
Florina Voica
AcOH
100 °C
80%
Snider, J. Org. Chem. 1997, 62, 1970
O
H
H
Me
Me
DMF, 0 °C
OTHP
THPO H
SCN
Me H
10-isothiocyanatoguaia-6-ene
Narasaka, Chem. Lett. 1994, 1697
Baran lab GM
2/6/2010
Applications of Mn(III) in Organic Chemistry
Asymmetric radical cyclization
O
O
S
44%
100% de
O
Miscellaneous applications of Mn(III) salts
O
Mn(OAc)3
Ph Cu(OAc)
2
Me
S
Ph
1. oxone
2. Na/Hg
O
O
H
Me
Mn(OAc)3
Cu(OAc)2
Ph
O
O
+
O
MeO
N
O
MeO
O
O
Mn(OAc)3
AcOH
70%
Ph
O
+
O
Ph
(-)-virgatusin
Brun, Eur. J. Org. Chem. 2009, 2306
93%
O
Ph
Ph
O
Ph
O
O
Ph
Ph
O O
1 eq
1.5 eq
B(OH)2
O
MeO
B(OH)2
O
MeO
OMe
OH
O
Ph
Nishino, Eur. J. Org. Chem. 2008, 2404
CO2Me
O
MeO
Mn(OAc)3 (0.1eq)
AcOH, rt
85%
Ph
O
O
O
1 eq
1.5 eq
O
Ph
MeO
O
NBn
O
Mechanism?
77%
Ph
Ph
O
MeO
O
Nishino, Tetrahedron Lett. 2006, 47, 7259
O
O
CO2Me
O
N
Snider, J. Org. Chem. 1993, 58, 7640
O
+
O
O
Ph
Mn(OAc)3 (1eq)
AcOH, rt
Mn(OAc)3 (3eq)
AcOH, reflux
Ph
Ph
Me
N
EtO
Ph
Nishino, Tetrahedron Lett. 1998, 39, 7931
O
O
Mn(OAc)3
Cu(OAc)2
28%
92% de
air
1 eq
tetramic acid
2eq
O
O
Ph
Ph
HO
Me
90%
86% de
O
+
NBn
Snider, J. Org. Chem. 1991, 56, 328
O
O
EtO
O
Ph
O
Florina Voica
Ph
Ph
N
O
40% yield
80% de
B(OH)2
Mn(OAc)3 (3eq)
benzene
reflux
Mn(OAc)3 (3eq)
thiophene
reflux
Mn(OAc)3 (3eq)
furan
reflux
95%
S
73%
O
62%
Demir, J. Org. Chem. 2003, 68, 578
Applications of Mn(III) in Organic Chemistry
Baran lab GM
2/6/2010
Ph
Mn(OAc)3 (5eq) O
benzene, reflux
64%
Ph
O
O
OAc
1. NaBH4/CeCl3 OAc
2. Ac2O/Et3N
O
89%
Ph
OAc
O
OH
N
O
O
Florina Voica
O
Mn(OAc)3 (1eq)
benzene, reflux
88%
O
O
Danishefsky, Tetrahedron Lett. 1985, 26, 3411
O
O
OBz
OMe
Br
O
H
OEt
Mn(OAc)3
benzene
reflux, 24h
67%
Mn(OAc)3 (1eq)
benzene, reflux
OBz
AcO
OMe
Br
91%
N OH
O
H
O
Demir, Tetrahedron Lett. 1997, 38, 7267
OEt
Watt, Synth. Commun. 1989, 19, 1127
CHO
For a review on methods of α'-oxidation of enones see:
Demir, Synthesis 1991, 235
OH
OH
MeO
N
H
Me
CN
NMe
H
OMe N
O
H
MeO
Me
H
H
O
OMe
EtO2C
AcOH
CO2Et
MeO
CO2Et
4 eq
MeO
O
H
H
O
CO2Et
N
t-BuHN
CO2Et
O
O
N
t-BuHN
MeO
MeO
MeO
MeO
59%
(±)-Cyanocycline A
OTBS
O
TBSO
H
OMe
CO2Et
N
H
Proposed reaction mechanism:
NMe
O
Mn(OAc)3 (0.1eq)
TBHP (5eq)
CN
H
N
O
H
+
NH2
N
H
55%
OTBS
O
H
OH
O
Mn(OAc)3 (xs)
0.3% H2SO4-ACN
rt, 2h
Fukuyama, J. Am. Chem. Soc. 1987, 109, 1587
TBSO
NC
O
1. MeOH, rt
2. Mn(OAc)3 (4.5eq)
AcOH
OMe
O
O
t-BuHN
H
72%
H
H
H
O
O
O
N
1,4 aryl transfer
MeO
OMe
Shing, Org. Lett. 2006, 8, 3149
MeO
EtO2C
CO2Et
CO2Et
EtO2C
t-BuHN
O
N
MeO
MeO
EtO2C
CO2Et
Baran lab GM
2/6/2010
O
Applications of Mn(III) in Organic Chemistry
O
O
N
t-BuHN
Mn(III)
AcOH
MeO
MeO
t-BuHN
CO2Et
EtO2C
O
OH
OAc
N
MeO
H2O
O
TMS
CO2Et
OMe CO Et
2
CO2Et
CO2Et
MeO
Mn(III)
O
OMe
CO2Et
Vieu, Org. Lett. 2007, 9, 4171
Mn(OAc)3•2H2O (0.1eq)
AcOH (2 eq), MeOH, 40 °C
MeO
Ph
90%
Mechanism?
1.5 eq
H
N
Me
CO2Me
Narasaka, Org. Lett. 2008, 10, 5019
OH
Ph
O
CO2Me
O
CO2Et
5-exo-trig
indane
O
N
CO2Me
CO2Me
Mikami, Synlett. 2002, 1868
NH
MeO
MeO
OH
MnF3 (1.2eq)
DCM
61%
O
N
H
N3
+
via
O
+
CO2Me
Florina Voica
1.2 eq
(slow addition)
Mn(acac)3 (0.1eq)
MeOH, rt, 1h
Mechanism?
HO
Ph
(1.5 eq)
Ph
N3
Mn(acac)3 (1.7eq) Ph
MeOH, rt, 5 min
then
AcOH (2eq), rt, 1h
N
Ph
84%
Chiba, J. Am. Chem. Soc. 2009, 131, 12570
Conclusions:
- oxidative tandem cyclization provides access to complex carbon
skeletons
- stereo- and regiospecific method for rapid assembly of polycyclic
structures from simple linear precursors
- numerous applications in natural product synthesis
- Mn(OAc)3 selective, mild oxidant
- very little chemistry of Mn(III) salts other than Mn(OAc)3
Underdevelopped aspects of this chemistry:
- efficient asymmetric radical cyclization
- catalytic oxidative radical cyclization
- model studies to understand the tandem cyclizations better
- more creative examples for the termination step