01-title 4/27/99 1:17 AM
Leading References:
Melikyan, G. G. Synthesis, 1993, 833.
Iqbal, J. Bhatia, B. Nayyar, N. K. Chem. Rev. 1994, 94, 519.
Snider, B. B. Chem. Rev. 1996, 96, 339
Melikyan, G. G. In Organic Reactions; Paquette, L. A. Ed;
John Wiley: New York, NY, 1997; Vol. 49, 427.
Melikyan, G. G. Aldrichimica Acta 1998, 31, 50
I. Mn(OAc)3 Intermolecular Additions
II. Mechanism
III. Hexenyl Radical Cyclizations
IV. Heptenyl Radical Cyclizations
V. Mn(pic)3
April 27, 1999
by Victor Cee
An Evans group afternoon seminar
Mn(III) Promoted Radical Reactions
-
2+
+
Mn+
Substitution
02-Mnintro 4/26/99 12:02 PM
+
Mn+
1.92
1.61
1.51
0.77
0.16
E˚ (V)
Electron Transfer
Co +1e → Co
Ce4+ +1e- → Ce3+
Mn3+ +1e- → Mn2+
Fe3+ +1e- → Fe2+
Cu2+ +1e- → Cu1+
3+
Reaction
One Electron Oxidants
RH
RH
-H
-M
+
n-1+
R Mn+
RH
Mn(III) d4
-M
e-
n-1+
+
t2g
-H
eg
R
R
Mn(II) d5
Electronic Structure (Oh, high spin)
Manganese (III): A One Electron Oxidant
eg
t2g
OMe
Me
Me
03-metalinduced radicals 4/26/99 3:03 PM
Ph
O
+
OMe
Me OTMS
O
mixture of isomers
MeO
TMSO Me
MeO
O
Me
OEt
IP = 7.25 eV
Me
OTES
69%
+
OEt
Me
Me
CO2Me
-eRO
OR
+
O
OEt
85%
only product observed
Ph
O
Chan Tetrahedron 1983, 39, 847
Chung J. Org. Chem. 1983, 48, 1125
RO
OR
Fukuzumi J. Org. Chem. 1996, 61, 2951
J. Am. Chem. Soc. 1992, 114, 10271
CH2Cl2, -78 ˚C
cat. SnCl4
cis:trans 1:99
MeO2C
OTES
CO2Me
cis:trans 1:1
MeO2C
IP = 7.74 eV
CH2Cl2, 20 ˚C
2 equiv TiCl4
99%
2 equiv LDA
2 equiv CuBr2
THF, -78 ˚C
Metal-Induced Carboxymethyl Radicals
OH
O
OH
04-Mn induced radicals 4/26/99 3:13 PM
IP ~ 8.8 eV
Me
O
O
IP = 10.65 eV
O
OEt
+
+
+
75 %
AcOH, ∆
Mn(OAc)3·2 H2O
O
HO
Me
Ph
O
O
-e-
Me
Me
Ph
O
Ph
O
Me
CO2Et
Heiba J. Org. Chem. 1974, 34, 3456
57%
AcOH, 45 ˚C
Mn(OAc)3·2 H2O
Heiba J. Am. Chem. Soc. 1968, 90, 5905
79 %
KOAc, AcOH, ∆
Mn(OAc)3·2 H2O
O
Bush and Finkbeiner J. Am. Chem. Soc. 1968, 90, 5903
Me
Mn(III) Induced Carboxymethyl Radicals
HO
O
Distance (Å)
1.848
1.858
2.108
Mn2
Mn3
05-Mn(OAc)3 xtal 4/26/99 3:17 PM
Hessel C. Rec. Trav. Chim. 1969, 88, 545.
Bond
Mn1-O16
Mn3-O16
Mn2-O16
O16
Mn1
Solid-State Structure of Anhydrous Mn(OAc)3
[Mn3O(OAc)6·AcOH·OAc]n
O
n
O
OH
O
O
Mn
Mn
Mn2
Mn1 Mn3
O
Mn
OH
+ AcO-
Mn
AcO
HOAc
O
H
Mn
OAc
HOAc
=
+ AcO-
O
O
CH3
Mn(OAc)3·nAcOH
Dimeric and monomeric species may also be present
.
O
A trimeric solution structure has been proposed
.
Solution Structure (AcOH)
„ Anhydrous Mn(OAc)3 and the dihydrate are indistinguishable in solution, and undergo
metathesis with other acids readily. The commercially available dihydrate is the most popular.
Mn(OAc)3•2H2O and Anhydrous "Mn(OAc)3"
06-Biochem 4/26/99 3:33 PM
L
L Mn
H+, H2O2
L
L
III III
Mn
Mn
L
L
O
OH
OH
H 2O
III
O
O2
Mn
III
=
L
L
O
O
CH3
OH2
Mn
II
L
L
L Mn
L H2O H+
L
II
L Mn
OH2
II
OH
O+
II
Mn
L
L
H 2O
L
L
OH2
Mn
II
OH
II
H3O+
L
L Mn
O
H2O2
Proposed Mechanism
2 H2O2 → O2 + 2 H2O
Catalyzes the disproportionation of H2O2:
T. thermophilus Catalase
1.78
1.51
0.68
E˚ (V)
Dismukes, G. C. Chem. Rev. 1996, 96, 2909.
Net Result: Redox chemistry at the
diffusion-controlled rate
Close proximity of two manganese centers
is established by bridging acetates
H2O2 + 2 H3O+ + 2e- → 4 H2O
Mn3+ + 1e- → Mn2+
O2 + 2 H3O+ + 2e- → H2O2 + 2 H2O
Reaction
Standard Reduction Potentials
Importance of Bridged Mn Centers: Catalases
Cu(II)
Ti(IV), Sn(IV),
O
OR
Ti(IV), Cu(II)
RO
+
CH3
07-Uniqueness Mn 4/26/99 10:11 PM
CO2
pic = pyridinecarboxylate
Ce(IV), Mn(pic)3
M = Ag(II), Pb(IV),
„ Decarboxylation is not a dominant pathway
RO
O
„ Dimerization is not a dominant pathway
RO
OSiR3
„ Ability to oxidize free acids
RO
O
M
O
O
O
CH3
HO
O
HO
M = Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Unique Features of Mn(III) Attributed to the
Trimeric Nature of Mn(OAc)3
O
III
O
M
O
CH3
Mn
Mn
III
O
O
O
OH
Mn
III
O
CH3
CH3
AcOK
R
OH
OH
OH
08-Mechanism Mn_2 4/26/99 10:19 PM
R'
O
-20
K = 4x10
Guthrie, Can. J. Chem. 1995, 73, 1395
O
R'
Mn(III)
Fristad J. Org. Chem. 1985, 50, 10
CO2H
„ Enol Content - Small
R
O
„ Enolization Proposed as the Rate-Determining Step
IP = 10.2 eV
H
O
„ Ionization Potentials: Carbonyl vs. Enol Ether
Mechanism of Mn(III) Oxidative
Lactonization: Enolization
H
Cl
SO2Ph
CO2Me
CN
R
IP = 9.0 eV
H
OMe
III
O
Mn
III
O
O
CH3
Mn
O
Mn
III
O
pKa = 0.1
pKa = 2.2
Li Inorg. Chem. 1996, 35, 4694
[Mn(OH2)6]+3
1
1.1 x 101
3.8 x 103
1.1 x 104
4.0 x 105
relative rate
III
Mn
III
[Fe(OH2)6]+3
„ Activation by Mn
25
22
14
13
9
pKa α-H (ester)
Mn
Mn
III
O
Mechanism of Mn(III) Oxidative
Lactonization: Enolization
Lactone
Solvent Enolization
09-Mechanism Mn_2 4/26/99 9:24 PM
Fristad Tetrahedron 1986, 42, 3429
Conclusion: Once enolization occurs, rapid electron
transfer and reaction ensue. Enolization is irreversible
Olefin
time (min)
Comparison of Enolization and Reaction Rates
mmol
Mn
O
O
CH3
HOAc, reflux
Mn(III), KOAc
Mn
III
O
O
III
Mn
O
O
Mn
III
O
C8H17
Mn
III
O
KOAc, reflux
Mn(III)
CHnD3-nCO2H(D)
1e-
H
OAc
III
O
Mn
II
O
Mn
G. I. Nishikin J. Org. Chem. USSR 1978, 14, 1894
O
Mn
Alternative Conclusion: Enolization and electron
transfer occur in a concerted step
Presence of Mn(III) has no effect on D incorporation!
CH3CO2H + CD3CO2D
Rate of enolization ~ rate of deuterium incorporation:
C8H17
The reaction:
III
Mn
III
II
10-Mechanism Mn 4/26/99 10:36 PM
R1
R2
9.65
8.20
8.14
8.00
1-hexene
4-methylstyrene
indene
trans-stilbene
HOAc
IP (eV)
OH
Mn(III)
Alkene
+ R3
O
Mechanism of Mn(III) Oxidative
Lactonization: Radical Addition
O
Mn
II
O
+
CH2
R1
R2
Ligand Electron
Transfer
O
O
O
OAc
6
54
96
0
0
0
0
0
R2
Mn
II
O
Alkene Electron
Transfer
R1
OAc
O
Mn
III
Mn
III
R
O
R
Fristad Tetrahedron, 1986, 42, 3429
Alkene Electron Transfer (%)
R3 = H
R3 = CO2Me
R3
Mn
III
Mn
III
Mn
III
O
Mn
O
Mn
III
Mn
III
11-Mechanism Mn 4/27/99 1:19 AM
Fristad: No evidence
for carbocation
Fristad: Radical
Cyclization
Heiba: Oxidation to
a carbocation
III
Mn
II
O
Mn
II
O
O
O
KOAc, HOAc, ∆
Mn(OAc)3
R
R
Mechanism of Mn(III) Oxidative
Lactonization: Oxidation and
Cyclization
63%
O
O
R
R
R
III
O
O
O
Mn
II
O
Mn
II
O
1%
+
O
-
O
O
O
Mn
II
O
Mn
II
O
Mn
II
O
CO2H
OAc
R
R
Heiba J. Am. Chem. Soc. 1971, 93, 524
Fristad J. Org. Chem. 1985, 50, 10
OAc
CO2H
O
Mn
II
Mn
III
Mn
III
Mn
II
Mn
O
Mn
II
O
O
Mn
O
III
Mn
III
Mn
III
Mn
II
Mn
III
II
Mn
O
Mn
III
12-Cu_2 4/26/99 11:01 PM
Copper (II) Oxidation
Mechanism
Heiba: Application to
Mn(III) reactions
Kochi: Cu(II) as a radical
oxidant
O
O
R
O
O
R
Elimination is usually
the dominant pathway
O
Cu(OAc)2
III
Cu(OAc)2
R
1
12
350
C9H19
+
Ce(IV)
Cu(II)
O
Relative kox
2
AcOH
Cu(OAc)2
M Oxidant
AcOH, KOAc, 85 ˚C
1-octene, Mn(OAc)3, M
O
O
O
CO2
Introduction of Copper (II)
97%
+
3%
O
OAc
C6H13
Nu
R
O
+
R
+
Cu(OAc)
Heiba J. Am. Chem. Soc. 1971, 93, 524
C5H11
+
Kochi J. Am. Chem. Soc. 1965, 87, 4855
+
O
O
MeO
MeO
OEt
O
OMe
+
O
OMe
OMe
CO2Et
CO2Et
13-Intermolec. cyclizn 4/27/99 12:04 AM
O
O
O
OMe
CO2Et
O
O
56%
MeO
AcOH, 30 min
2.2 Mn(OAc)3
OMe
O
O
O
OMe
CO2Et
CO2Et
EtO2C
O
OMe
OH
O
OMe
O
rt, 70 h
81%
5 equiv SnCl4
Podophyllotoxin
MeO
OMe
OMe
Fristad Tetrahedron Lett. 1987, 28, 1493
O
O
OMe
CO2Et
Intermolecular Cyclizations: Studies Toward
Podophyllotoxin
14-Intramolec cycl intro 4/13/99 9:26 AM
Higher cyclizations
Monocyclizations
X
X
O
O
O
O
OR
OR
X
RO
O
O
O
O
OR
OR
Intramolecular Cyclizations
R
X
O
O
R
O
O
X
OR
k-endo
k-exo
kterm
15-Hexenyl Cyclizn Intro 4/27/99 12:07 AM
„ Representative rates:
kexo = 2 x 105 s-1
kendo = 4 x 103 s-1
kterm = 3 x 106 M-1 s-1 (Bu3SnH)
„ Equilibration: extent of ring opening depends on relative magnitude of kterm
„ Kinetics: kexo/kendo depends on substitution pattern
CH3
kterm
kendo
kexo
Hexenyl Radical Cyclization Is Equilibration Possible?
48 h
∆, C6H12
(PhCO2)2
14
CO2Et
CN
9
-1 -1
CO2Me
CO2Me
10 min
hν, benzene
(Me3Sn)2
90
-1 -1
55 ˚C, 43 h
Cu(OAc)2
Mn(OAc)3
16-Hexenyl Cyclizn Intro 2 4/27/99 12:13 AM
koxidn ~ 1x10 M s
6
CO2Me
CO2Me
„ Rate of oxidation > rate of ring opening
kI ~ 2x10 M s
I
I
O
93
CO2Me
O
CO2Me
CO2Me
„ Rate of iodine abstraction > rate of ring opening
kopen ~ 1x104 s-1
CO2Et
CN
CH3
„ Rate of H abstraction < rate of ring opening
I
+
+
+
10
86
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CN
t-BuO3C
CN
CO2Et
7
CO2Me
CO2Me
Curran J. Org. Chem. 1989, 54, 3140
Snider J. Am. Chem. Soc. 1991, 113, 6609
+
CN
CO2Et
M. Julia Acc. Chem. Res. 1971, 4, 386
t-BuO3C
The same ratio is observed when the
following radical precursors are used:
Reversible vs. Irreversible Radical Cyclization
H
H
H
H
Me
Ph
Me
H
H
R3
R2
5-exo
5%
-
21%
70%
disfavored relative to
6-(enolendo)-exo-trig
5-(enolendo)-exo-trig
2 Mn(OAc)3
Cu(OAc)2
Ph
OAc
-
-
R
R
CO2Me
R2
reference
6-endo
R3
CO2Me
PetersonTetrahedron Lett. 1987, 6109
Snider J. Org. Chem. 1985, 50, 3661
Snider J. Org. Chem. 1989, 54, 38
PetersonTetrahedron Lett. 1987, 6109
R1
OH
X
O
„ Endocyclic ketone and the substitution pattern of the alkene
control the mode of cyclization
„ Similar selectivity seen for α-substituted β-ketoesters
„ Similar selectivity seen for α-radicals generated by atom transfer
91%
-
4 Mn(OAc)3
Cu(OAc)2
2 Mn(OAc)3
Cu(OAc)2
94%
-
4 Mn(OAc)3
Cu(OAc)2
products
R1
6-endo
AcOH
conditions
O
5-exo
conditions
R2
R3
CO2Me
17-Hexenyl MonoCyclizn 4/13/99 10:11 AM
MeOC
O
Me
Me
Me
H
H
O
R2
R1
substrate
R1
O
Hexenyl Radical Cyclization
O
OR
O
CO2Et
Ph
CO2Me
HO
H
CO2H
H
74%
AcOH
2 equiv Mn(OAc)3
Gibberelic Acid
Me
OC
O
R=H
R=CH3
R=OPO(OEt)2
Cu(OAc)2
AcOH
2 equiv Mn(OAc)3
18-HexenylbiCyclizn 4/13/99 10:31 AM
R
O
O
OH
48%
86%
77%
R
O
H
CH3
CO2Et
CO2Me
MeO2C
O
O
18%
-
R
X
O
OR
Snider J. Org. Chem. 1987, 52, 5487
J. Org. Chem. 1991, 55, 5544
Snider Tetrahedron Lett. 1987, 28, 845
OPO(OEt)2
O
O
Hexenyl Radical Bicyclization
O
O
O
O
H
O
H
bilobalide
O
OH
OH
t-Bu
O
CO2Me
O
H
CO2H
18a-Hexenyl Bilobalide O 4/13/99 10:18 AM
H
O
O
H
O
lactone
annulation
65%, two steps
THF/H2O
Al/Hg
H
O
O
O
O
O
H
AcOH, rt, 1h
52%, one isomer
Mn(OAc)3
O
OH
CO2Me
H
O
OH
OH
t-Bu
H
O
O
H
O
H
Mn(III)
79%
HO
H
O
O
O
O
O
H
O
H
O
OH
OH
t-Bu
O
H
methyl bromoacetate
NaH
X
O
O
OR
Corey J. Am. Chem. Soc. 1984, 106, 5384
2) LiOH; H+
1) MsCl, TEA
H
H
Hexenyl Radical Cyclization:
Studies Toward the Ginkgolides
20 - 30%
CuCl, Cu(OBz)2, ∆
Acetonitrile
(PhCO2)2
OH
BzO
H 3C
H3C
HO
H
CH3
H 3C
H
CH3
H 3C
H
OAc
Breslow Tetrahedron Lett. 1968, 1837
Breslow Tetrahedron Lett. 1962, 1207
CH3
van Tamelen, J. Am. Chem. Soc. 1966, 88, 4752
lanosterol
CH3
H 3C
CH3
CH3
18b-Hexenyl polyCyclizn bio 4/13/99 10:37 AM
However, in 1966 the importance of squalene oxide was established: Corey J. Am. Chem. Soc. 1966, 88, 4750;
OAc
squalene
Experiment:
Proposal:
Biosynthetic Radical Cyclization Hypothesis
Me
H
CO2Et
Me
CO2Et
OMe
AcOH, rt, 1h
50%, one isomer
2 equiv Mn(OAc)3
18c-Hexenyl polyCyclizn Podo 4/27/99 12:37 AM
Me
O
OMe
Me
H
CO2H
Me
OMe
H
CO2Et
Me
OMe
Me
O
60%
Zn, HCl
CO2Et
X
O
OR
OMe
Snider J. Org. Chem. 1985, 50, 3659
Ester hydrolysis: Welch J. Org. Chem. 1977, 42, 2879
(±) Podocarpic Acid
Me
O
Hexenyl Radical Bicyclization:
Podocarpic Acid
O
H
Me
O
33%
2) excess n-BuLi
1) H2NNHTs
18d-Hexenyl polyCyclizn beyerol 4/13/99 10:42 AM
HO
H
Me
CO2Et
Me
Me
HO
O
Cu(OAc)2
MeOH, rt, 3h
Mn(OAc)3
H
H
Me
CO2Et
52 %
2) O3, DMS
1) LAH
X
O
OR
Snider J. Org. Chem. 1998, 63, 7945
Me
O
+ 4% 6-8 bicycle
35%, one isomer
Beyer-15-ene-3,19-diol
H
Me
H
CO2Et
HO
Me
Me
HO
O
Me
Me
Hexenyl Radical Tetracyclization:
Beyer-15-ene-3,19-diol
O
O
O
O
Me
CO2Me
CO2Me
CO2Me
Me
Me
O
O
O
CO2Me
19-Hexenyl MonoCyclizn O 4/13/99 10:53 AM
α-substituted
α-unsubstituted
O
O
54%
Cu(OAc)2
AcOH, ∆
2 equiv Mn(OAc)3
21%
Cu(OAc)2
KOAc, AcOH, ∆
2 equiv Mn(OAc)3
73%
Cu(OAc)2
KOAc, AcOH, ∆
2 equiv Mn(OAc)3
43%
Cu(OAc)2
KOAc, AcOH, ∆
2 equiv Mn(OAc)3
O
O
O
O
O
O
O
2
CO2Me
Me
Me
O
Me O
H
O
2:1
:
CO2Me
Me O
O
1
O
Hexenyl Radical Cyclization:
O-Substituted Malonates
OR
X=O
O
O
Snider Tetrahedron 1993, 49, 9447
Me
CO2Me
Bertrand Tetrahedron Lett. 1989, 30, 331
X
O
Me
O
O
O
-
2
1
2
-
product
Cu(OAc)2
AcOH
2 Mn(OAc)3
1
Me
+
O
R
45
90
44
28
-
-
86
100
92
-
yield (%) selectivity (%de)
R
O
Snider J. Org. Chem. 1991, 56, 328; J. Org. Chem. 1993, 58, 7640
O
Ph
O
O
N
N
S
Et2N
Me
Ph
Me
O
O
R
Me
19a-Asymmetric Cyclization 4/13/99 11:00 AM
R
O
Mn(III) Cyclizations: Chiral Auxiliaries
2
Me
Ph
S
O
S O Me
19b-Asymmetric Cyclization 4/13/99 11:01 AM
sulfoxide pseudo-axial
O
O
Ph
Me
O
Me
CO2Et
Me
Me
OMe
sulfoxide pseudo-equatorial
Ph
S
OO
PhOS
O
Snider J. Org. Chem. 1991, 56, 328
Proposed cyclization geometry in podocarpic acid synthesis
O
SOPh
Mn(III) Cyclizations: β-Ketosulfoxide
PhOS
O
Me
92% de
O
O
R
Me
86% de
O
Ph
O
O
19c-Asymmetric Cyclization 4/27/99 12:46 AM
17:1
X
H
N
Me
A1,3 strain minimized
R
O
Me
O
Me
N
Me
Me
Porter J. Am. Chem. Soc. 1991, 113, 7002
Giese Tetrahedron Lett. 1993, 33, 2637
t-Bu
4:1
H
„ The origin of diastereoselectivity is difficult to rationalize when the
radical center is tertiary and the conformation is controlled by A1,3 strain.
O
N
Me
Mn(III) Cyclizations: β-Ketoamide, β-Ketoester
CO2R
O
S
N
O
N
SO2
H
O
O
O
O
R = (-)-phenmenthyl
Me
19d-Asymmetric Cyclization 4/13/99 11:04 AM
O
OMe
A similar
example:
H
O
O
N
O S
O
RO2C
O
O
H
Me
27:1
H
O
O
N
O S
Zoretic Tetrahedron Lett. 1992, 33, 2637
Xc
H
Me
Snider J. Org. Chem. 1993, 58, 7640
Me
Curran; Porter; Geise In Stereochemistry of Radical Reactions,
VCH: Weinheim, 1996, 198.
49%, 50% de
Cu(OAc)2
HOAc, 4h, rt
2 Mn(OAc)3
AcOH, 15 ˚C, 1h, 50%, 75% de
MeOH, 0 ˚C, 8h, 56%, 82% de
2 Mn(OAc)3
OMe
Mn(III) Cyclizations: Chiral Auxiliaries
H
CO2Me
H
Me
20-Heptenyl BiCyclizn 4/13/99 11:16 AM
Me
O
CO2Me
O
25 ˚C, 13 h
R1=H, R2=Me; R'=Me
H
25 ˚C
R1=Me, R2=H; R'=Me
6-exo
R1
R2
CO2R'
H
O
CO2Me
67%
-
12%
6-exo
-
68%
32%
7-endo
products (%yield)
H
Me
Cu(OAc)2
AcOH
2 equiv Mn(OAc)3
conditions
CO2R'
25 ˚C
O
R1=R2=H; R'=Et
substrate
R2
R1
O
Me
R1
R2
CO2R'
reference
7-endo
O
X
O
O
H
H
CO2Me
O
Me
H
H
Snider J. Org. Chem. 1987, 52, 5487
Snider Tetrahedron 1991, 47, 8663
O
OR
CO2Me
Snider Tetrahedron Lett. 1988, 29, 5209
+
Heptenyl Radical Bicyclization
H
Me
H
Me
H
H
Me
Me
OH
OH
CO2Me
O
O
62%
HgSO4
2N H2SO4
H
3
Me
Me
Me
H
H
O
Me
H
Me
2,3-dihydropallescensin D
2
Me
Me
64%, one isomer
2) (i-Pr)2NMgBr;
TMSCl, Et3N
3) mCPBA
1) LiCl, DMSO, ∆
2) LDA, MeO2CCN
52%
1) Li, NH3, t-BuOH
21-Heptenyl Dihydropallescensin 4/13/99 11:20 AM
Me
Me
Me
Me
O
O
OH
Heptenyl Radical Cyclization:
Dihydropallescensin D
Me
controls
facial selectivity
of "O" addition
O
controls facial
selectivity of Nu
addition
O
OR
J. D. White Tetrahedron Lett. 1990, 31, 59
Me
81%
2) K2CO3, MeOH
Li
61%, one isomer
Cu(OAc)2
AcOH, rt, 3h
2 equiv Mn(OAc)3
1) TMS
CO2Me
X
O
O
∆
1:1
Me
Me
OEt
O
O
OMOM
CO2H
Cu(OAc)2
HOAc, 25 ˚C, 2h
85%, mixture of four
diastereomers
O
Me
Me
MeO2C
2) HCl, THF/H2O
57%, 6:1
Me
7 steps
OMOM
CO2H
2 equiv Mn(OAc)3
Me
CHO
Me
Me
MeO2C
1) LDA, iodohexene
22-Heptenyl epiupial 4/27/99 1:02 AM
Me
Me
Snider: Upial Formal Synthesis
Me
Me
Paquette: 14-epiUpial
Heptenyl Radical Cyclization:
Upial and 14-epiUpial
O
O
CHO
CO2Me
CO2Me
Me
H
O
Me
OMOM
O
Me
Me
Upial
O
Paquette Tetrahedron 1987, 43, 5567
Me
MOMO
Me
H
O
14
Snider Tetrahedron 1995, 51, 12983
Taschner J. Am. Chem. Soc. 1985, 107, 5570
O
Me
O
9%
"
68%
HOAc, 70 ˚C
Mn(OAc)3
Me
Upial
Me
Me
O
O
Me
R
TMS
62%, ~1:1
9:1 EtOH/HOAc
90 ˚C, 22 h
15 Mn(OAc)3
30%, 6:1
2) NaH, MeI
Me
Me
O
O
TMS
Me
Me
Me Me
R=H
R=TMS
9:1 EtOH/HOAc
90 ˚C, 20 h
15 equiv Mn(OAc)3
1) LiHMDS,
1-iodo-2-butyne
O
23-Heptenyl gymnomitrol 4/13/99 11:25 AM
Me
Me Me
Synthesis:
Precedent:
Me
+
70%
2) NaBH4
1) HOAc, 100 ˚C
O
4%
58%
R
Me
41%
0%
R
Me
HO
(±) gymnomitrol
Me
H
Snider J. Org. Chem. 1997, 62, 1970
Me
Me
65 %
2) LDA, TMSCl
1) KNH H2N
O
Heptenyl Radical Cyclization: Gymnomitrol
HO
Me
Ph
O
OH
+
+
Ph
OTBS
Ph
OTBS
89%
DMF, 0 ˚C, 2h
2.5 Mn(pic)3
68%
DMF, rt, 2h
2.5 Mn(pic)3
Ph
Ph
O
O
Me
O
Ph
O
Ph
Me
Me
24-Mn picolinate 4/13/99 11:27 AM
MeO2C
O
Cu(OAc)2
AcOH, rt
15%
2 Mn(pic)3
MeO2C
O
Me
Cu(OAc)2
AcOH, rt
86%
2 Mn(OAc)3
N
O
3
Mn
MeO2C
O
Me
Narasaka Chem Lett. 1991, 1193
Narasaka Chem Lett. 1989, 2169
Mn(pic)3
O
„ Mn(pic)3 and Mn(OAc)3 behave differently in acetic acid: Snider J. Org. Chem. 1993, 58, 6217
Ph
O
„ Introduction in synthetic chemistry: Narasaka Chem Lett. 1989, 2169
„ Synthesis: Ray Aust. J. Chem. 1966, 19, 1737
Formerly a water-redox model for photosystem II.
Manganese Tris(2-pyridinecarboxylate)
H
O
H
+
+
Ph
OTBS
H
"chair"
H
Ph
OTBS
25-Mn picolinate ring xpansion 4/27/99 2:02 AM
"boat"
H
( )n
HO
HO
H
O
>9:1
n=1 81%
n=2 63%
DMF, 0 ˚C
2.4 Mn(pic)3
DMF, 0 ˚C
2.4 Mn(pic)3
H
H
H
O
H
( )n
O
77%
O
O
Ph
5%
O
Ph
„ Cyclization selectivity is consistent
with the Beckwith-Houk model
Ph
+
O
Narasaka Bull Chem. Soc. Jpn. 1999, 72, 85
H
O
Mn(pic)3: Oxidative Ring Expansion
2)
76%, >9:1
DMF, 0 ˚C
Mn(pic)3, n-Bu3SnH
83%
MgBr
CuBr•SMe2,
TMSCl
1) DHP, PPTS
26-Mn picolinate Guaianolide 4/27/99 2:01 AM
OTHP
OH
OH
O
THPO
O
OTHP
OTMS
H
Me
H
Me
Narasaka Bull Chem. Soc. Jpn. 1999, 72, 85
10-Isothiocyanatoguaia-6-ene
Me
SCN
81%, 10:1
2) K2CO3, MeOH
1) Et2Zn, CH2I2
Oxidative Ring Expansion:
Synthesis of
10-Isothiocyanatoguaia-6-ene
H
N
CH3
t-Bu
MeO2C
H 2C
H
CH3
MgBr
(-)-methyl cantabradienate
27-Mn picolinate Snider 4/24/99 7:10 PM
45%
3) CH2N2
2) PdCl2(PPh3)2
DIPEA, CO, MeOH
H 3C
55%
2) PDC
1)
1:1, 79%
EDTA•Li
CO2t-Bu
1) KHMDS, PhN(Tf)2
O
H3C
H3C
H
CH3
CH3
46%
58%
OH
H 2C
H 3C
O
H
79%
DMAP, DIPEA,
toluene, ∆
oxalyl chloride
O
CH3
CH2
Snider J. Org. Chem. 1994, 59, 5419
Mn(OAc)3
Mn(pic)3
Mn(III)
CO2H
„ 7 steps, 9% overall yield
HO
H 3C
20:1
H3C
Oxidative Ring Expansion: Synthesis of
(-)-Methyl Cantabradienate
28-conclusion 4/27/99 1:13 AM
„ Mn(pic)3 offers interesting routes to natural products by oxidative cyclopropane fragmentation
„ Liability: polymerization and other side-reactions often lead to modest yields
„ Important in the synthesis of fused- and bridged- polycyclic natural products, often exhibiting
excellent regioselectivity in cyclizations
„ Mn(OAc)3 is a unique one-electron oxidant for acidic C-H bonds
Reflections on Mn(III)