quinone lit talk · - fremy's salt oxidizes most phenols to p-quinones when there is no para...
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Quinones in Organic Chemistry:Synthesis of and Applications Towards Natural Products
Literature PresentationRyan Zeidan
Stoltz Group Meeting 2/16/04
N
O
OH
H3C
O
OH
CH3
CH3H
H3C
H
O
H
O
CH3HO
Tetrapetalone A (revised structure)TL, 2003, 44, 7417
I. Introduction to Quinones A. Nomenclature B. Biochemistry C. Biosynthesis
II. Synthesis of Quinones via Oxidation A. Fremy's Salt B. CAN C. LTA D. DDQ E. Air
III. Other Syntheses of Quinones/Uses A. Boronic Esters B. Indoles C. DMP oxidation of anilides D. Cyclobutenediones E. Benzoin reaction
IV. Applications to Natural Products A. Aflatoxin B B. Elisabethin A C. Lemonomycin
Outline of Quinones
1
Quinone Background - Nomenclature
OH OH
OH O
O O
O
Phenol Hydroquinone p-Quinone o-Quinone
O ON
R
o-Quinone methide p-Quinone methide o-Quinone methide imine
O
OHR
Quinol
Redox Process
Quinone + 2 H+-2e-
2e-
Hydroquinone
O
O
O
O H
O H
O H
H
H-
H
H-
hydroquinone semiquinone quinone
OH
OH
O
O
Jones
SnCl2 orNaBH4
OH
OH O
OAgO2
SnCl2
2
Quinones in Nature
- Ubiquinones mediate electron transfer processes involved in energy production through their redox reactions:
NADH + H+ +
O
O
MeO
MeO
Me
R
OH
OH
MeO
MeO
Me
R
+ NAD+
Reducedform
Oxidized form
OH
OH
MeO
MeO
Me
R
+ 1/2 O2
O
O
MeO
MeO
Me
R
+ H2O
Net Change: NADH + 1/2 O2 + H+ NAD+ + H2O
Biosynthesis of Quinones: Pentaketides
CoAS
O
OO
O
OHO
O OH OH
OH
O
O
O
O
SCoA
O
O
O
O
OH
OH
HO
SCoA
O
O
O
O
OO
O
O
OMe
OH
MeO
3
Biosynthesis Continued
O
OO
O
SCoA
O O O
O
OH
OH
OMe
O
O
HO
O
O
O
OMe
O
O
HO
Heptaketides:
Octaketides:
O
OO
O O
SCoAO O O
O
O
O
O
OH Me
O
O
O
OH
O
OH Me
OH
NADH NAD+
O
HO
OH
O
OH Me
O
O
HO
O
O
OH Me
O
A Representative Difficulty in Direct Oxidation of Arenes
Br
Br
Br
Br
Br
Br
Br
Br
HNO3H2SO4
1. H2NNH2, Pd/C
2. NaNO2, H2SO4
H3O+
Fremy's salt
NO2 OH
O
O
- Direct oxidation of the unactivated arene was not achievable- A round about sequence of nitration, reduction, diazotization, displacement by hydroxide and finally oxidation of the phenol was necessary to form the quinone- Unactivated arenes present a difficulty in quinone synthesis
4
Fremy's Salt
A Typical Example:
O
N
COMe
CO2Me
OH
(KSO3)2NO
O
N
COMe
CO2Me
O
O
MeO
SPh
O
N
COMe
CO2Me
O
O
MeO
SPh
KHCO3
O
N
COMe
CO2Me
O
O
MeO
(Fremy's salt)
(KSO3)2NO
(Fremy's salt) O
N
COMe
CO2Me
O
O
MeO
N
O
KO3S SO3K
Fremy's salt =- Fremy's salt oxidizes most phenols to p-quinones when there is no para substituent on the phenol- Salt is a stable free radical that oxidizes via a free radical mechanism- Oxygen incorporation occurs exclusively from the oxygen of Fremy's salt
JOC, 1981, 46, 2426.
Fremy's Salt (cont'd)
N CO2Me
CO2MeNH
MeO2C
HO
Fremy's salt
93%
N CO2Me
CO2MeNH
MeO2C
O
O
Gives o-quinones when para position is substituted:
O
N
O
Ph
OH
Fremy's salt
90%
O
O
A more oganic soluble form of Fremy's catalyst =
MacKenzie, A. R. Tetrahedron, 1986, 42, 3259
5
Fremy's Salt Mechanism
O
N
O
KO3S SO3K
HO O
H
N
O
KO3S SO3K
O
H O
N(SO3K)2
O
O
N(SO3K)2
O
OR
+
-O18 isotope experiments showed that oxygen incorporation was exclusively from Fremy's salt oxygen
CAN Oxidations
MeO
OMe
O
HO2C
CAN
89%O
O
O
HO2C
MnO2
32%O
O
O
O
O
OH
OMe
Me
MeO
CAN
O
O
Me
OMe
Na2S2O4
OH
OMe
Me
HO
pleurotin
JACS, 1988, 11, 1634
JACS, 2003, 125, 4680
- CAN is the reagent of choice for oxidative demethylation of methoxyarenes- CAN/Na2S2O4 sequence provides an overall net demethylation of methoxyarenes- CAN is (NH4)2Ce(NO3)6
6
LTA Oxidations
OH
OH
O
O
H
HOMe
LTA
73%
O
O
OH
OH OMe
OH OH
J. Chem. Soc., P.T. 1, 1985, 525
H2N
N
O
Bn O
LTA, DCM
0oC
40%
AcN
N
O
Bn O
O
1. H+
2. H2, Pd/C
93%
HO
N
O
H O
OH
- LTA can cause an oxidative isomerization
JOC, 1988, 53, 5355
- Oxidation of the aniline to the o-quinoneimide occurs in modest yield
DDQ Oxidations
OH OH
OHOMe
OMe
MeO
DDQ
95%
OH O
OOMe
OMe
MeO
JOC, 1999, 64, 1720
- DDQ is a competant oxidant for quinone formation, although CAN is more robust and typically higher yielding
NH
R
O
O
Cl
Cl
NH
R
Cl
HO
OH
Cl
DDQ
NH
R
Cl
O
O
Cl
Org. Lett., 2001, 3, 365
7
HN
O
R
OHO
O
HO
OH
HO
OH
MeO Air Oxidation
HN
O
R
OHO
O
HO
OH
O
OH
MeO
air, THF, H2O
24 hours, RT
74%
Kita, Y. JACS, 2001, 123, 3214
N
N
O
O
MeO
HH
H
OH
HO
OH
OMe
NH
OO
N
N
O
O
MeO
HH
H
OH
HO
OH
OMe
NH
OO
NaHCO3
air69%
Saframycin G:
Chem. Pharm. Bull., 1995, 43, 777.
Quinone Boronic Esters
Cr(CO)5
MeO
R' R
+ R2 B
O
O
OH
OMe
R2
B
R
R'
O
O
CAN
O
O
R2
B
R
R'
O
O
PdCl2(dppf), R3Br
O
O
R2R
R' R3
- Allows for regioselective hydroquione formation- Cerium oxidation of crude reaction mixture afforded quinones in good yields- Quinone boronic esters were reactive in Suzuki couplings to give unsymmetrical quinone products as single regioisomers
Harrity, J. P. A., et. al. J. Org. Chem., 2001, 66, 3525
8
Synthesis of Indoles from Quinones
OMeMeO
NBz
+
NHBz
OMe
Diels-AlderR2
R3
R1R1
R2
R3
1. OsO4
2. NaIO4H+
NHBz
OMe
R1
OR2
R4R4
R4
OR3
N
Bz R2
R1
OMe
R4
R3 O
TsOHIndoles made in 32-70% overall yields with wide range ofsubstitution tolerated
Kerr, M. A., et. al. Org. Lett, 2001, 3, 3325.
HN
O
DMP, H2O
O
O
HN
O43%
DMP Oxidations
Mechanism:
N O
R
IO
OAcO
O
O
MeOAc
H
N
RO
IO
O
AcO
AcO
-AcOH
IO
OO
AcO
-AcOH
OI
O
OAc
-
DMP + H2O
N R
O
OH
I OOAcO
B
OI
O
OAc
-
Nicolau, K.C. JACS, 2002, 124, 2212.
9
DMP Oxidation (cont'd)
N
O
O R
IO
OO
AcO
IO
OO
AcO
HN
O R
O
H
B
OI
O
OAc
-
O
OHN
O R
HN
O
DMP, H2O
40%
N
O
O
H
H
H
Nicolau, K.C. JACS, 2002, 124, 2212.
Liebeskind, L. S., et. al. J. Org. Chem., 1992, 57, 4345
Regiospecific Synthesis of Quinones from Cyclobutenediones
O
O
R1
R2
OR1
R2 OH
R3
OR1
R2 OH
Heat
Heat
R1
R2
OH
O
R3 R1
R2
O
O
R3Heat
OH
OH
R1
R2
O
O
R1
R2
CAN
- For synthesis of cyclobutenediones see JOC, 1988, 53, 2477.
10
Benzoin Reaction Approach to Quinones
O N
O
O
OMOM
5 mol% cat
10 mol% DBU
tBuOH, 40oC
0.5 hr, 95%
OMOMNO
OOH
S
N
EtMe
HO
Br-cat =
OMOMNO
OOH
1. Pd/C, H2, rt
2. air, 110oC
75%
OMOMNHOH
O
aq. H2SO4
MeOH, dioxanert, 86%
OMOMOOH
O
- Crossed aldehyde-ketone benzoin reaction worked well for a variety of substrates- Substitution allows access to functionalized anthraquinones
Suzuki, K. JACS,, 2003, 125, 8432
Quinone Approach to Aflatoxin B2
Br
MOMO
MeO OMOM
1, BuLi
2. auxiliary
S
MOMO
MeO OMOM
O p-tol
CAN
S
O
MeO O
O p-tol
O
TiCl4(5 eq)Ti(OiPr)4 (5 eq)
65%O
O
SO p-tol
HO
MeO
H
H
+
O
O
SO p-tol
HO
MeO
H
H
3.31
Noland, W. E. Org. Lett., 2000, 2, 2109
Raney Ni, EtOH
100%
O
OHO
MeO
H
HO
O
MeO
H
H
O
OO
aflatoxin B2
11
Mechanism of Furan Addition
S
O
MeO O
O p-tol
O
HHO
MeO
SO p-tol
OO
Conjugate
Addition
Re-aromatize
MeO
HO
O
O
SO p-tol
MeO
HO
SO p-tol
O
O
Cyclization
Chem. Lett., 1987, 2169
Total Synthesis of Elisabethin A: IMDA Using a Quinone
OTBS
OMe
Me
TBSO
Me
TBAF OH
OMe
Me
HO
Me
FeCl3 (aq)
O
O OMe
Me
Me
O
O
Me
H
OMe
Me
HMe
91%
1. Pd/H22. NaOH
3. BBr3
O
O
Me
H
OH
Me
HMe
elisabethin A
Mulzer, J. JACS, 2003, 125, 4680.
12
IMDA Transition State
O
Me OMe
H
O
HMe
MeH
Minimizing allylic strain controls facial selectivityin the DA transition state, taken into accountwith an endo approach gives rise to the observed selectivity
Stoltz Lab Quinone Work: Lemonomycin
N
N
H
HO
OH
H
OH
MeO
O
O
OH
N
OH
OMe
CAN(aq)
0oC
51%
N
N
H
HO
OH
H
OH
MeO
O
O
OH
N
O
O
Ashley, E.R.; Cruz, E. G.; Stoltz, B.M. JACS, 2003, 125, 15000.
13