Baran lab GM
11/6/2010
Methods for Dearomatization
Dearomatization under enzymatic conditions
Any hydrocarbon or heterocycle with 4n+2 electrons in a fully conjugated cyclic π
system is considered aromatic.
General characteristics of aromatic compounds:
- chemical behavior (electrophilic substitution vs addition, resistance to oxidation)
- structural characteristics (bond length equalization)
- energetic profile (resonance energy)
- magnetic properties (ring current effects-downfield shifts of peripheral protons)
Pure&Appl. Chem. 1996, 68, 209
P450
R
R
Available methods for "controlled" dearomatization:
- Enzymatic
- Photochemical / Thermal (concerted)
- Radical
- Transition-metal mediated
- Nucleophilic
------------------------------------------------------------------------------------------- Oxydative (polyvalent iodine mediated)
- Reductive (Birch reduction/reductive alkylation; cat hydrogenation)
NIH
shift
R
O
H
O
H
H se
GS fera
s
an
-tr
H
R
Oepoxide
hydrase
S
Why are aromatic compounds desirable building blocks?
- ubiquitous
- very stable (many are crystalline)
- easy to functionalize
- aromaticity can be view as masked functionality
Florina Voica
OH
OH
R
R
OH
R
SR'
glutathione
conjugate
OH
on heme oxygenases Chem. Rev., 1996, 96, 2841
on arene oxides Science, 1974, 185, 573
The carcenogenicity of polyaromatic compounds might be due to reactive intermediates generated upon
dearomatization. For polyaromatic hydrocarbons, oxidation occurs primarily in the K-region.
Among the oxidized products, epoxide-diols are particularly prone to nucleophilic ring-opening by DNA.
OH
OH
O
O
HO
O
OH
Acc. Chem. Res., 1981, 14, 218
CHO
O
TFDO
-20 °C, 8 min
TFDO, freon
0 °C, 6 h
96%
35%
CHO
TFDO
-20 °C, 30 min
O
muconic
aldehyde
90%
O
Other reagents for direct epoxidation of polycyclic aromatics:
DMDO
J. Am. Chem. Soc., 1984, 106, 2462
mCPBA
Angew. Chem. Int. Ed., 1977, 16, 171
Mn(TDCPP)Cl, H2O2 Chem. Commun., 2004, 608
NaOCl, Na2HPO4 J. Am. Chem. Soc. 1984, 106, 2463
Tet. Lett., 1990, 31, 6097
Methods for Dearomatization
Baran lab GM
11/6/2010
CO2tBu
O
HN
+
O
CO2tBu
Triton-B
DMSO
SS
O
N SS
66%
N
R Me
OH
O
OH
N SS
N Me
R
OH
O
Br
Br
O
Cl
Florina Voica
Pseudomonas putida
(Aldrich, $53/g)
N Me
R
OH
99% ee
O
+ 22% epimer
R = C6H4OMe-p
PhLi, THF
45%
BnO
O
N
OH
S
S N Me
N S N
S
Me
OH
O
Cl
O
R
O
OH
OBn
gliotoxin
J. Am. Chem. Soc., 1976, 98, 6723
For a biosynthetic proposal involving a benzene oxide: J. Org. Chem., 1980, 45, 3149
OBz
OBz
O2 ,
hematoporphyrin
O
60%
O
O
OBz
O
P(OEt)3
benzene
O
O
88%
(5 steps from
benzoic acid)
10% AcOH
THF
OBz
O
OAc
OBz
Ac2O
O
OH
+
OAc
senepoxide
HO
HO
OH
OH
32%
OBz
OBz
OH
O
OH
+
HO
21%
J. Am. Chem. Soc., 1978, 100, 6483
For an extensive review on cyclohexane epoxide natural products Chem. Rev., 2004, 104, 2857
Also, see Baran Lab GM Shikimic Acid, Ambhaikar, 2005.
21%
For an extensive list of substrates and applications in total
synthesis (conduritols, inositols, carbohydrates, prostaglandins, some alkaloids) see
Aldrichimica Acta, 1999, 32, 35; Synlett, 2009, 685
For more on biocatalysis, see Baran Lab GM Biocatalysis, Gulder, 2009
Methods for Dearomatization
Baran lab GM
11/6/2010
CO2H
A. eutrophus
mCPBA
CO2H
Org. Lett., 2001, 3, 2923
OH
O
79%
OH
CO2H
1.TMSCHN2
2. TBSOTf, Et3N
70%
OH
> 95% ee
Florina Voica
O
TBSO
N
CO2Me
OH
O
OTBS
73%
Li
Et
N
OBn
THF
1.
Me
D
OH
H
H
OH
6
5
C
B
O
OH
CO2Ph
OBoc
LDA, TMEDA,
N
H
OH
A
OH
NH2
H
N
H
N
N
N
HO
O
71% (3 steps)
(-) deoxycycline
OBn
O
OTBS
OH
TBSO
O
O
62%
N
TBSO
OBn
O
N
1. LiOTf (5 mol%),
PhCH3, 60 °C
2. TFA, DCM
O
O
2. HF, ACN
3. H2, Pd/C
O
O
BnO2CO
OBn
OTBS O
Science, 2005, 308, 395
Cl
1. P. putida
2. p-MBDMA
Ar
NaH, THF
reflux
MgBr
CN
PhH, reflux
quant
O
Me
CN
Cl
O
70%
OBn
O
O
Me
Me
Ar
Me
OBn
Me
O
OH
Ar = C6H4OMe-p
H
OBn
HO
H
H
O
Ti(OiPr)4
DCM, reflux
82%
OBn
OH
97%
Me
Me
Me
cat SnCl2
CHCl3
mCPBA
OH
O
OBn
H
OBn
O
H
OBn
aq NH4Cl
O-
90%
Me
Me
Synlett, 1998, 897
1. OsO4(1.3 mol%), hv
Ba(ClO4)2
AcO
2. Ac2O, Et3N
OAc
OAc
+
36%
AcO
Angew. Chem. Int. Ed., 1995, 34, 2031
OH
OAc
OAc
OH
OH
+
OAc
OAc
OAc
[FeII(TPA)(NCMe)2](OTf)2
H2O2
6.2
:
1
OAc
Chem. Commun., 2009, 50
4
:
1
"These experiments certainly demonstrate that the chemical equivalent of dihydroxylation of aromatics is feasible, although at this time it does not compete with the biological process in terms of
selectivity and efficiency. We hope that present and future generations of organic chemists are stimulated by the magnitude of this challenge and eventually succeed in the development of catalytic
process that would rival the enzymatic transformation and allow for this reaction to be removed from the list of unsolved problems in organic chemistry"
Tomas Hudlicky, Synlett 2009, 685
Methods for Dearomatization
Baran lab GM
11/6/2010
Florina Voica
Photochemical methods
" The aromatic nucleus, known for its rigidity in the ground state, becomes an extremely flexible and extrovert acrobat when being doped with a light quantum"
Egbert Havinga, Helv. Chem. Acta, 1967, 50, 2550
[2+2] cycloadditions
[4+2]
OMe
CN
+
Cl
OMe CN
hν
74%
90%
O
O
O
O
J. Chem. Soc. Perkin Trans 1 1992, 1145
MeO2C
O
H+
OMe
tBu
MeOH/H+
E
+
E
O
O
OH
64%
51%
16%
nBu
OMe
O
O
OH
O
O
hν
hν
85%
O
O
O
+
H
nBu
35%
O
O
Tetrahedron, 2002, 58, 7933
For more examples of [2+2] with arenes:
J. Org. Chem. 1981, 46, 2405
Tetrahedron 1985, 41, 2405
J. Chem. Soc. Perkin Trans. 1 1980, 2425
1. NaOH
2. Pb(OAc)4,
O2, pyr
H
H
cat Rh(I)
H
15%
Chem. Commun. 1979, 1038
H
+
85%
50%
O
O
H
32%
O
80%
O
O
OMe
OMe
hν
H+
J. Am. Chem. Soc. 102,
3641
O
[4+4]
+
nBu
tBu
E
OMe
Synthesis, 2001, 1236
O
Co(TPP) (5 mol%)
acetone, -10 °C
OMe
O
J. Org. Chem. 1976, 41, 899; 900
O
O
38%
O
O
O
H+
PhCOMe
O
hν, O2, Rose Bengal
acetone, -78 °C
hν
O
O
NC
hν
O
O
O
Tet. Lett. 1974, 787
NC
CN
hν
O
Cl
Me
CN
O
+
Tet. Lett., 1977, 18, 3629
Cl
Cl
Methods for Dearomatization
Baran lab GM
11/6/2010
"The problems originally posed by many synthetic targets have now been solved at a practical level.
However, for the majority of synthetic problems, solutions either do not exist or are far from being
practical. In general, few solutions approach the ideal, wherein a target is prepared from readilyavailable starting materials in one step that proceeds in 100% yield and is operationally safe, simple
and ecologically acceptable. Obviously, this is a rather demanding but no unrealistic objective.
While it is unlikely to be commonly achieved, efforts to reach this standard of sophistication are of
great importance as they are likely to lead to the fundamentally new science that will clearly have a
profound impact on the ways in which total synthesis will be done in the future."
HH
OMe
O
O
H
hν
(254 nm)
Florina Voica
H
H
O
O
O
H
O
O
8%
MeO
R
R
R1
hν
*
R1
R
R1
R
DG
R
=E
TMSO
R1
R
R
R1
=E
R1
R
R
Me
hν (254 nm)
cyclohexane
89%
TMSO
Me
+
O
O Me
R1
1. mCPBA, DCM
2. pTsOH, MeOH
TMSO Me
TMSO Me
R
H
H
Chem. Rev. 1993, 93, 615
O
H
1 : 1.2
69%
(3 steps)
R1
R1
Me
H
H
O
R1
R1
TMSO
R1
W
G
Generalities:
- the nature of the reactive intermediates
is not yet decided (biradical vs zwiterrion)
- depending on the electronic nature of the arene
substituents, the reaction is regioselective
- RDS - bonding between the arene and the
alkene
- reaction proceeds via a concerted mechanism
(alkene stereochemistry preserved)
- reaction can be performed neat or in an
inert solvent
- it is temperature independent
- for intermolecular reaction, an excess of the arene
is required
J. Am. Chem. Soc. 2009, 130, 404
R1
R1
Me
H
H
Paul Wender, Pure&Appl. Chem. 1990, 62, 1597
[2+3] meta-photocycloaddition
H
O
O
+
OH
O
HO
O
Li
Me
hν
Me
OMe
OMe
HO OMe
+
Me
H
H
O
Me
Me
O
Li, NH3
H
H
Me
For a review of applications in total synthesis see
Pure&Appl. Chem. 1990, 62, 1597
For a recent application in an asymmetric synthesis
see J. Am. Chem. Soc. 2009, 131, 452
CO2H
H
Me
HO
H
silphinene
Tet. Lett. 1985, 2625
HO
Lancidifolactone F
Org. Lett. 2008, 10, 1223
Methods for Dearomatization
Baran lab GM
11/6/2010
Radical methods for dearomatization
Thermal cycloaddition
CN
NC
CN
CN
O
I
O
CO2H
Δ
14%
J. Am. Chem. Soc. 1968, 90, 215
Cl
Cl
Cl
Cl
O
30%
1,4 : 1,3 = 10:1
I2, NaHCO3
71%
O
O
pancratistatin
tBu
O
O
Cl
Cl
Cl
+
21%
Me
Me
SiMe2Ph
Cl
SiMe2Ph
N
•
Ni, AcOH
reflux
O
N
Cl
CCl3
O
tBu
N
Synthesis 1975, 707
Me
46%
Cl
Tet. Lett. 1997, 38, 5985
Chem. Ber. 1986, 119, 1953
CO2Me
tBuOK, 180 °C
CO2Me
CO2Me
OH
Me
Br
OH
OH
tBu
N
Me
Δ
O
O
CO2H
J. Am. Chem. Soc. 1989, 111, 4829
benzobarrelene
N
H I
86%
Cl
O
O
Tetrahedron 2006, 62, 6830
Cl
60%
OH
H
Bu3SnH, AIBN
(PhSe)2, PhH,
reflux
Na, tBuOH
THF
Cl
PhH, -10°C
Cl
Florina Voica
SmI2 (3.5 eq)
THF
75%
50%
Tet. Lett. 1976, 4559
OMe
SmI2 (5 eq), HMPA (18 eq)
iPrOH (2 eq), THF, 0 °C
OMe
H
HO
Me
O
Chem. Commun. 2002, 316
α:β=1:8
O
OH
O
+
OH
O
O
neat, 250 °C
H
Me
O
O
O
O
J. Chem. Soc. Perkin Trans. 1 1987, 1147
N
O
H
SmI2, HMPA,
tBuOH, THF, rt
56%
N
H
Me
OH
Chem. Eur. J. 2007, 13, 6047
Methods for Dearomatization
Baran lab GM
11/6/2010
Pd-catalyzed dearomatization reactions
Transition-metal mediated dearomatization methods
Pd2(dba)3•CHCl3 (5 mol%)
PPh3 (40 mol%), acetone, rt
Cr(CO)6 Inorg. Synth. 1990, 28, 136
SnBu3
Cl
Cr(CO)3
82%
Me
Pd2(dba)3 (5 mol%)
PPh3 (20 mol%), DCM, rt
SnBu3
unreactive
Br
Br
Angew. Chem. Int. Ed. 2008, 47, 4366
Pd2(dba)3 (5 mol%)
PPh3 (20 mol%), DCM, rt
SnBu3
Me
(naphtalene)Cr(CO)3
J. Organomet. Chem. 1985, 286, 183
LiCH(CO2R)2
LiCH2COR
MeMgBr
tBuMgBr
Me2CuLi
metalation
successful
LiCH2CO2R
LiCH2CN
KCH2COtBu
LiCH(CN)(OR)
LiCH2SPh
LiCH=CH2
LiPh
LiC≡CR
LiCH2CH=CH2
tBuLi
nBuLi
LiMe
sBuLi
Me
J. Am. Chem. Soc. 1979, 101, 3535
Cl
71%
Cl
- yellow to red (often) crystalline compounds
- air stable in solid state
- somewhat light sensitive
- reactive towards strong nucleophiles
(Cr(CO)3 enhances reactivity similar to a nitro group...)
Cr(CO)3L3 (L = ACN, Py, NH3)
J. Org. Chem. 1992, 57, 6487
Reactivity of nucleophiles toward (PhH)Cr(CO)3 in THF
89%
Cl
+
Me
J. Am. Chem. Soc. 2001, 123, 759
Cl
Florina Voica
R
Tetrahedron 2010, 66, 6013
R
Cr(CO)3
R'Li
Cr(CO)3
R'
Ph
Br
N
H
Pd2(dba)3 (3 mol%), ligand (4.5 mol%)
Li(OtBu) (1.2 eq), THF, reflux
93%, 93% ee
ligand =
Ph
Regioselectivity of nucleophilic addition
N
Pcy2
NMe2
J. Am. Chem . Soc. 2009, 131, 6676
R
OMe
NMe2
Me, Et
Cl
Hydrazone
Imine
Oxazoline
SiMe3
tBu
CF3
Product
meta
meta
meta/ortho
ortho/meta
ortho
ortho
ortho
para
para
para
Chem. Rev. 2000, 100, 2917
Methods for Dearomatization
Baran lab GM
11/6/2010
O
MeLi then
MeI, CO, HMPA
THF
NCy
Florina Voica
NHCy
NaH
Br
Me
58% (2 steps)
Cr(CO)3
Me
J. Org. Chem. 1994, 59, 4773
Synlett 1990, 565
Mn(CO)3ClO4
Mn(CO)3(acetone)+
O
O
Me
+
Mn+(CO)3
Me
Mn(CO)3+
(in situ from Mn(CO)3Br and AgBF4)
- stable, yellow compounds
- often crystalline
- increased electrophilicity compared to
Cr-arene complexes
- most common reactivity pattern:
sequential nucleophilic attack
J. Organomet. Chem. 1981, 204, C25
Mn(CO)3Br, AlBr3
(for arenes with sensitive functionality)
J. Am. Chem. Soc. 1957, 79, 5826
NR*
N
OMe
N
PhLi, THF, -90 °C
then
N
Br
Ph
TMS
H
TMS
Pure Appl. Chem. 1997, 69, 543
OMe
1. Li
OEt
N
Mn+(CO)3
Mn(CO)3
CN
CN
88%
Organometallics 1993, 12, 224
O
Me
H
2. MeI, CO, HMPA
3. NaOEt, MeI
O
OEt
Me
53%, >95% ee
Me
2. O2
OAc
CHO
Cr(CO)3
1.
LAH
73%, >98% ee
Cr(CO)3
H
O
Me
O
(-) acetoxytubifuran
Bu3P (1 eq), NaH (2 eq)
DME, rt, 12h
N
Me
NMe
47%
RuCp
Ru+Cp
J. Am. Chem. Soc. 2002, 125, 5642
O
(OC)5Cr
OR*
OR*
Me
1. sBuLi, THF
2. MeOTf
Cr(CO)5
HO
1. C5H5
2. LAH
3. H+
N+O-
Ph
R* = (-) menthyl
[CpRu(CO)2]Br
Me
+
Ph
Me
HO
Me
68%
Ph
CuBr2
THF/H2O,
CO
HO
sBu
+
NMe
55%
Angew. Chem Int. Ed. 2007, 46, 2887
Tetrahedron 2008, 64, 10123
Ph
sBu
3 : 1
For a review on organo-iron complexes see Tetrahedron 1983, 39, 4027
J. Am. Chem. Soc. 1996, 118, 13099
Methods for Dearomatization
Baran lab GM
11/6/2010
OR
Os2+(NH3)5
+
[Os(NH3)5(OTf)](OTf)2
(1.5 - 20 eq) !!!
E1+
H2, Pd/C
OMe
Nu1
E1
Nu2
Nu2
[Os]2+
E2
Nu1
TMSO
[Os]2+
E1
[Os]2+ and/or
OMe
E2
E2+
Nu2-
E2
Nu1
Nu3
Nu2 OR
E2
-
[Os]2+
Nu1
Nu3
E1
MeO
OMe
[Os]2+
E1
Nu3 Nu2
CH2(OMe)2
TfOH
OR
Nu1
[Os]2+
89%
Nu1-
[Os]2+
- η2-Os complexes are e-rich and prone to electrophilic substitution
- thermally stable complexes
- stable under inert atmosphere in solution
- decomplexation with Mg or Zg/Hg in DME or MeOH
[Os]2+
OR
OR
[Os]2+
Florina Voica
E2
H+
[Os]2+
-ROH
Nu1
E1
E1
E1
E = H+ (TfOH), acetals, ketals, Michael acceptors, (RCO)2O, pyrroles, furans
Tetrahedron, 2001, 57, 8203
AgOTf
82%
(3 steps)
[Os]2+
[Os]2+
MeO2C
Me
O
H2O, rt
[Os]2+
MeO2C
[Os]2+
MVK, TfOH
ACN, -40 °C
96%
Me
H
N
O
CO2Me
[Os]2+
Me
Me
+
Me
R = H, Ph
J. Am. Chem. Soc. 1998, 120, 2218
TfO-
H
N
CO2Me
DMA, rt
95%
CO2Me
[Os]2+
CO2Me
1. TBSOTf, ACN
2. H2O/MeOH
98%
dr 1:1
N+ H
[Os]2+
[Os]2+
H
Me
Me
J. Am. Chem. Soc. 1998, 120, 6205
HO
Me
Me
dr 7:1
H
1. TBAB,
ACN/MeOH
2. TfOH, MeOH
HO
supindine
N
N
H
HO
labournine
H
MeO2C
O
CO2Me
H
MeO2C
O+Me
N
O
R
N
O
96% DMAc
O
O
[Os]2+
H
[Os]2+
Me
H
H
71%
O+Me
OMe
Other viable dienophiles:
OMe
O
OMe
1. Cu(OTf)2
2. Me3N, aq Na2CO3
65%
dr 1:1
Tetrahedron, 2001, 57, 8203
[Os]2+
H TfON+ H
H
MeO2C
CO2Me
Methods for Dearomatization
Baran lab GM
11/6/2010
Nucleophilic methods for dearomatization
NCy
R*
R*
Florina Voica
R'M
CHO
Me
1. nBuLi, HMPA
2. MeI
3. H+
R'
OH
Me
nBu
nBu
NaBH4
60%
M = Li, Mg
Tet. Lett. 1987, 28, 5279
O
R* =
O
R
OR
R
NH2
O
R
O
O
O
X
OMe
NR
N
C
R
O
N
gBr
O
iPr
CPh3
1.
CO2tBu
Ber. Dtsch. Chem. Ges. 1910, 43, 1145
CPh3
CO2Me
CHO
J. Org. Chem. 2000, 65, 3018
Ph
Ph
iPr
3
OMe
KCN, MeOH
quant
CO2Me
OH
Chem. Rev. 2007, 107, 1580
PhM
OMe
65%
etc.
N
OH
1. iPrMgCl
2. ClCO2Me
3. H+
PhM
NLi
Me
, HMPA
2. MeI
N
CO2tBu
N
+
O
gBr
64%
CPh3
O
32%
J. Org. Chem. 1995, 60, 7445
Ph
J. Am. Chem. Soc. 1953, 75, 4604
O Me
1,4-addition to aromatic ketones is favored in the case of hindered ketones
or when a bulky LA is employed
Mes
O
Mes
O
MgBr
2. NH4Cl
1. tBuLi (2 eq), HMPA
2. NH4Cl
Ph 3. 1M HCl
N
94%
Ph
MeO
1.
Me
MeO
H
O
O
Me
Me
N
H
H
Me
Ph
Ph
H
CO2Me
NBoc
O
50%
OH
J. Org. Chem. 1961, 26, 756
OMe
O
Me
1. ATPH, Tol/THF
2. tBuLi
3. MeOTf
68%
Me
Me
Ph
O
tBu
Me
CO2H
CO2Me
Me
H
O
ATPH =
Ph
J. Am. Chem. Soc. 1995, 117, 9091
3
Al
CO2H
N
H
kainic acid
O
1. mCPBA
2. NaOH
3. TMSCHN2
H
N
Boc
CO2Me
Chem. Commun. 2000, 317
For the synthesis of isodomoic acid C by a similar strategy see J. Am. Chem. Soc. 2005, 127, 2412
Methods for Dearomatization
Baran lab GM
11/6/2010
O
O
OLi
tBu LDA, THF
N
1. hν, 500 nm
2. NH4Cl
NtBu
MeO
Ph
MeO
H
73%
N
NHtBu
Ph
H
Ph
Me
N
N
Me
1. BuLi
2. Boc2O
N
N
75%
Me
BnN
BnN
O
Boc
N
69%
Bn
N
1. BuLi
2. Boc2O
N
N
H
MeO
J. Am. Chem. Soc. 2003, 125, 9278
O
Florina Voica
NBoc
N
Me
1. Tf2O, 2,6-lutidine
2. Ph3COH
O
O
CPh3
67%
N
+
O
O
CPh3
dr 30:1
Angew. Chem. Int. Ed. 2002, 41, 484
Tetrahedron 2006, 62, 10854
N
Tf
N
Tf
Chem. Commun. 2009, 1964
For an example of nucleophilic dearomatization of aryl phosphinamidines see
J. Org. Chem. 2007, 72, 9704
Miscellaneous dearomatization methods
1. THMPLi
2. MeSO3H
O
O
O
64%, 96% ee
O
tBu
tBu
O
Ph
Si
CO2Me
89%
dr 10:1
N
tBu
1. DMDO
2. LHMDS
3. NH4Cl
N
H
iPr Ph
O
95%
Me
OH
O
O
O
O
4A MS
ZnCl2
98%
97% ee
O
OH 1. ClSiMe2CH2Br
2. HSnBu3, AIBN
3. KF, KHCO3, H2O2
68%, 97% ee
O
OH
N
O
CO2Me
MeO
OMe
OMe
(-) Epipodophyllotoxin
N
H
1. Tf2O, 2-ClPyr
2. nPrMgBr
MeO
nPr
N
iPr
N
MeO
OMe
iPr
O
O
CO2Me
MeO
tBu
N
J. Org. Chem. 2008, 73, 8113
OMe
OH
tBu
Si
iPr
Me
OMe
MeO
O
MeO
OMe
H
OMe
OMe
N
nPr
77% (4 steps)
Angew. Chem. Int. Ed. 2003, 42, 2487
Org. Lett. 2009, 11, 3398
O