Reactivity of acyclic (pentadienyl)iron(1+) cations: Synthetic studies directed toward the frondosins

Article abstract of DOI:10.1039/c1ob05720k

A short, 4-step route to the scaffold of frondosin A and B is reported. The [1-methoxycarbonyl-5-(2′,5′-dimethoxyphenyl)pentadienyl]Fe(CO) ₃⁺ cation was prepared in two steps from (methyl 6-oxo-2,4-hexadienoate)Fe(CO)₃. Re

Full text of DOI:10.1039/c1ob05720k

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PAPER
Reactivity of acyclic (pentadienyl)iron(1+) cations: Synthetic studies directed
toward the frondosins†
Do W. Lee, Rajesh K. Pandey, Sergey Lindeman and William A. Donaldson*
Received 6th May 2011, Accepted 17th August 2011
DOI: 10.1039/c1ob05720k
A short, 4-step route to the scaffold of frondosin A and B is reported. The [1-methoxycarbonyl-5-(2¢,5¢-
+
dimethoxyphenyl)pentadienyl]Fe(CO)3 cation was prepared in two steps from (methyl 6-oxo-2,4-
hexadienoate)Fe(CO)3. Reaction of this cation with isopropenyl Grignard or cyclohexenyllithium
reagents affords (2-alkenyl-5-aryl-1-methoxycarbonyl-3-pentene-1,5-diyl)Fe(CO)3 along with other
addition products. Oxidative decomplexation of these (pentenediyl)iron complexes, utilizing CuCl2,
affords 6-aryl-3-methoxycarbonyl-1,4-cycloheptadienes via the presumed intermediacy of a
cis-divinylcyclopropane.
Introduction
The (+)-frondosins A–E (1A–E, Fig. 1, Scheme 1) are a family of
sesquiterpenes hydroquinone derivatives isolated from the sponge
Dysidea frondosa in 1997.1 These compounds were found to
inhibit the binding of interleukin-8 (IL-8) to its receptor in the
micromolar range, with 1A and 1B being the most active (IC50
=
3.4 and 9.6 mM, respectively). Since IL-8 is involved in enlisting
neutrophiles to a site of inflammation, inhibitors of IL-8 might
be useful in treating autoimmune disorders as well as tumor
suppression. Additionally, frondosins A and D of the opposite
optical rotation were found in organic extracts of Euryspongia sp
which exhibited HIV inhibitory activity.1b More recently, liphagal
(2), a structurally related compound was isolated from the sponge
Aka coralliphaga.2 Liphagal was found to be a selective inhibitor
of PI3 kinase a at 100 nM level. In addition to their intriguing
biological activity, the structural complexity of 1A–E and 2 has
generated significant synthetic interest.3,4
We have previously reported an iron-mediated route to
cycloheptadienes.5 This route involves the addition of alkenyl
Grignard reagents to (1-methoxycarbonylpentadienyl)iron(1+)
cations 3 to afford the corresponding neutral (2-alkenyl-3-penten-
1,5-diyl)iron complexes 4. Oxidatively induced reductive elimina-
tion of 4 results in the formation of divinylcyclopropanes 5 which
undergo Cope rearrangement to afford 1,4-cycloheptadienes 6. We
have previously utilized this methodology for the preparation of
the 5-7-5 fused ring system of the guianolides.5d We herein report
Scheme 1
on synthetic studies directed toward frondosins A and B which
utilizes this methodology for the formation of the seven-membered
ring (Scheme 2).
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee,
WI, USA. E-mail: william.donaldson@marquette.edu; Fax: +1-414-288-
7066; Tel: +1-414-288-7374
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra of new compounds and ORTEPs for 10, 11, 15 and 16a.
CCDC reference numbers 823811–823815. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1ob05720k
Scheme 2
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be unique from 10. These tentative structural assignments were
eventually corroborated by single crystal diffraction analysis of
each.‡
Results and discussion
The reaction of tricarbonyl(methyl 6-oxo-2,4-hexadienoate)iron 7
with the Grignard formed from 1-bromo-2,5-dimethoxybenzene
gave (dienol)iron complex 8, which upon dehydration with
HPF6/acetic anhydride afforded the acyclic (pentadienyl)iron(1+)
cation 9a (Scheme 3). This cation was assigned a cisoid structure
on the basis of its 1H NMR spectral data. In particular, the signals
for H-2 and H-4 each appear as a doublet of doublets (J = ca.
7 and 11-14 Hz); the larger couplings are consistent with a trans
orientation with H-1 and H-5 respectively. The chemical shifts
and coupling constants for 9a are similar to those reported for the
Oxidative decomplexation of 10 with cerium ammonium nitrate
(CAN) gave the cycloheptadiene ( )-12 in low and variable yield
(conditions A, Scheme 4). This reaction presumably proceeds via
the intermediacy of the cis-divinylcyclopropane 13, which was not
observed. The low yield of this product may be due to further
oxidation of the p-dimethoxybenzene ring with CAN to afford a
p-quinone substituted product. Oxidative decomplexation of 10
with CuCl2 (conditions B, Scheme 4) gave 12 in considerably
improved yield (95%). Attempts to use CuBr2, Ag2O, Pb(OAc)4
or Dess–Martin periodinane for oxidative decomplexation were
unsuccessful, giving only unreacted starting material. The struc-
ture of 12 was assigned on the basis of its NMR spectral data; in
particular signals for the three olefinic protons appear at d 5.65–
5.75 (2H) and 6.04 (1H) ppm, while multiplets at 4.07–4.14 and
4.25–4.31 ppm correspond to H-3 and H-6.
(1-methoxycarbonyl-5-phenylpentadienyl)Fe(CO)3 cation 9b.6
+
With successful model studies completed, attention was turned
to preparing the bicyclo[5.4.0]undecane scaffold of the frondosins.
In our hands, attempts to prepare the Grignard reagent from com-
mercially available 1-bromocyclohexene (14a) were unsuccessful.7
For this reason, it was necessary to prepare 1-cyclohexenyllithium
by lithium-halogen exchange using t-BuLi/pentane. Addition of
a solution of this organolithium reagent, prepared in THF, to
9a in CH2Cl2 (-78 ◦C) gave the 2-substituted (pentenediyl)iron
complex 15 (eqn (1)). This segment of the structure was assigned
by comparison of portions of its NMR spectral data with those for
10; in particular the chemical shifts for H-1, H-2, H-3, H-4, and
H-5 of 15 (d 0.68, ca. 3.7, 4.45, 5.44 and 4.50 ppm) are similar to
those for 10. The exact nature of the substituent at C-2 was initially
unclear, however single crystal diffraction analysis‡ revealed this
to be a dichloromethyl substituent. Presumably 15 arises via
deprotonation of the CH2Cl2 solvent, followed by nucleophilic
addition of the resultant dichloromethyl anion at C-2.
Scheme 3
Reaction of ( )-9a, in methylene chloride, with commercially
available isopropenylmagnesium bromide in THF, gave a separable
mixture of isomeric complexes ( )-10 and ( )-11 (Scheme 4). The
structures of 10 and 11 were tentatively assigned on the basis
of their NMR spectral data; in particular, the three separate
signals at d 200–212, the signal at d 94–100 and the signal at
d 11–15 ppm in the 13C NMR spectra of each 10 and 11 are
characteristic of the three metal carbonyls, the central allyl carbon
and the carbon s-bonded to iron in (3-pentene-1,5-diyl)iron
complexes.6 (Pentenediyl)iron complex 10 was tentatively assigned
as resulting from nucleophilic attack at C-2 of 9 by comparison
of its 1H NMR spectral data with a similar 2-substituted-
(5-aryl-1-methoxycarbonylpent-3-ene-1,5-diyl)iron complex pro-
duced from 9b,6 while 11 was assigned a 4-substituted-(5-aryl-
1-methoxycarbonylpent-2-ene-1,5-diyl)iron structure in order to
(1)
In contrast, addition of the organolithium reagent from 1-
bromocyclohexene by lithium-halogen exchange, prepared in
ether/pentane, to 9a in CH2Cl2 (-78 ◦C) gave a separable mixture
of 16a and 17a (Scheme 5). Complex 16a was assigned a
(pentenediyl)iron structure by comparison of its NMR spectral
data with that for 10. This assignment was corroborated by single
crystal diffraction analysis.‡ The structure of 17a was assigned
on the basis of its NMR spectral data. In particular signals at
d 2.81 (d), 5.24 (dd) and 5.98 (dd, J = 5.3 and 10.5) in the
‡ The cif files for 10, 11, 15, 16a and 16b have been deposited with the
CCDC. 10: CCDC # 823813; 11: CCDC # 823815; 15: CCDC # 823811;
16a: CCDC # 823812; 16b: CCDC # 823814. Crystal structure data for
¯
compound ( )-16b: C26H30O7Fe; M = 510.35; triclinic, P1; a = 10.2155(4),
◦
◦
˚
b = 10.631◦5(4), c = 13.0110(5) A, a = 102.007(3) , b = 106.062(3) , g =
3
˚
110.218(3) ; U = 1199.83(8) A ; T = 100 K; Z = 2; 18938 reflections
Scheme 4 (Ar = 2,5-dimethoxyphenyl).
measured, 5984 unique (Rint = 0.0366). The final wR2 was 0.1155 (all data).
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1H NMR spectrum and signals at d 80.4 and 88.9 ppm in the
13C NMR spectrum and are characteristic of H-2, H-3, H-4, C-
3 and C-4 of (2E,4Z-hexadienoate)Fe(CO)3 complexes.6,8 In a
similar fashion, addition of the organolithium reagent prepared
by lithium-halogen exchange of 6,6-dimethyl-1-iodocyclohexene
(14b)9 in ether/pentane, to 9a in CH2Cl2 (-78 ◦C) gave a separable
mixture of 16b and 17b (Scheme 5). The structures of 16b and
17b were assigned by comparison of their NMR spectral data
with those for 16a and 17a. The structural assignment for 16b was
corroborated by single crystal diffraction analysis (Fig. 1).
Conclusions
A 4-step route from (methyl 6-oxo-2,4-hexadienoate)Fe(CO)3
to the 2-arylbicyclo[5.4.0]undecane scaffold of the frondosins
was developed. This route relies on nucleophilic addition of an
alkenylmetal species to the acyclic (pentadienyl)iron cation 9a.
The low regioselectivity of this nucleophilic addition remains a
challenge in this approach. A modified approach to the requisite
(pentenediyl)iron complex 16b, which addresses this limitation, is
under investigation and results will be reported in due course.
Experimental
General methods
All reactions involving moisture or air sensitive reagents were
carried out under a nitrogen atmosphere in oven-dried glassware
with anhydrous solvents. Purifications by chromatography were
carried out using silica gel 60 (40–63 mm). NMR spectra were
recorded on either a Varian Mercury+ 300 MHz or a Varian
UnityInova 400 MHz instrument. CDCl3 and CD3NO2 were
purchased from Cambridge Isotope Laboratories. 1H NMR
spectra were calibrated to 7.27 ppm for residual CHCl3 or 4.33 ppm
for CD2HNO2. 13C NMR spectra were calibrated from the central
peak at 77.23 ppm for CDCl3 or 60.5 for CD3NO2. Coupling
constants are reported in Hz. Elemental analyses were obtained
from Midwest Microlabs, Ltd., Indianapolis, IN, USA, and high-
resolution mass spectra were obtained from the University of
Nebraska Center for Mass Spectrometry or the COSMIC lab at
Old Dominion University. 1-Bromocyclohexene was purchased
from Combi-Blocks, LLC, San Diego, CA, USA. 6,6-Dimethyl-1-
iodocyclohexene was prepared from 2,2-dimethylcyclohexanone
according to the literature procedure.9
Scheme 5 (Ar = 2,5-dimethoxyphenyl).
Tricarbonyl[1-methoxycarbonyl-5-(2¢,5¢-dimethoxy-
phenyl)pentadienyl]iron(1+) hexafluorophosphate 9a
To a three necked 300 mL round-bottomed flask, equipped with
a dropping funnel, condenser and a stirring bar, were charged Mg
turnings (0.54 g, 22 mmol) and freshly distilled dry THF (30 mL)
under nitrogen. A solution of 1-bromo-2,5-dimethoxybenzene
(4.40 g, 20.3 mmol) in dry THF (10 mL) was added dropwise with
vigorous stirring under nitrogen. After addition was complete,
the reaction mixture was heated at reflux for 30 min. To a
solution of 7 (5.20 g, 18.6 mmol) in dry THF (70 mL), cooled
to -40 ◦C, was added dropwise, over 15 min, the previously
prepared Grignard solution. After addition was complete, the
cooling bath was removed and the reaction mixture was warmed
to room temperature and stirred for 3 h. Water (30 mL) was
cautiously added, and the mixture was extracted several times
with ethyl acetate. The combined extracts were dried (MgSO4) and
concentrated to give a crude compound 8 (6.40 g, 82%). dH (300
MHz, CDCl3) 1.04 (1H, d, J = 7.8, H-2), 1.80 (1H, t, J = 8.1, H-5),
3.01 (1H, d, J = 8.1, OH), 3.65 (3H, s, OMe), 3.78 (3H, s, OMe),
3.85 (3H, s, OMe), 4.64 (1H, t, J = 7.5, H-6), 5.67 (1H, dd, J = 4.8
and 9.0, H-4), 5.82 (1H, dd, J = 4.8 and 9.0, H-3), 6.80–6.90 (3H,
m, ArH); dC (75 MHz, CDCl3) 46.1, 51.8, 55.8, 55.9, 66.6, 73.7,
83.6, 85.7, 111.8, 113.4, 113.6, 132.1, 150.6, 154.0, 172.8 (signal
for Fe–CO not observed). This compound was used in the next
step without further purification. To an ice cold solution of crude
Fig. 1 Molecular structure of ( )-16b (arbitrary atom numbering).
The origin of the differences in the reactivity of 9a with
the alkenylmetal species indicated above is presently unclear.
However, the results reveal that the regioselectivity of this reaction
may depend on such subtle factors as the aggregation of these
organometal species.10
Oxidative decomplexation of 16a or 16b with CuCl2 gave the
bicyclo[5.4.0]undecadiene products ( )-18a or ( )-18b, respec-
tively. The structures of 18a/18b were assigned by comparison
of their NMR spectral data with that for 12.
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8 (3.00 g, 7.18 mmol) and acetic anhydride (2.2 mL) in dry ether
(10 mL) was added dropwise a cold solution of HPF6 (60 wt%
in H2O, 2.46 mL, 10.1 mmol) in acetic anhydride (4.5 mL). An
orange precipitate developed and the reaction mixture was stirred
for 20 min and then added to a large excess of ether. The solid
was collected by filtration through a sintered-glass funnel, and the
solid was washed several times with dry ether. Recrystallization
from CH2Cl2/hexanes gave 9a (3.30 g, 84%) as a bright orange
solid (Found: C, 39.24; H, 3.36. Calcd for C18H17O7FePF6: C,
39.59; H, 3.14.); nmax (KBr)/cm-1 2116, 2081 and 1717; dH (300
MHz, CD3NO2) 3.14 (1H, d, J = 10.8, H-1), 3.81 (3H, s, OMe),
3.92 (3H, s, OMe), 4.01 (3H, s, OMe), 4.78 (1H, d, J = 13.5, H-5),
6.70 (1H, dd, J = 7.2 and 10.5, H-2), 6.96 (1H, dd, J = 7.1 and 13.5,
H-4), 7.12–7.26 (4H, m, H-3 and ArH); dC (75 MHz, CD3NO2)
52.2, 54.3, 54.7, 61.3, 92.5, 95.4, 95.9, 102.6, 111.0, 112.4, 119.6,
120.2, 152.5, 153.3, 168.1 (the signals for the metal carbonyls were
not observed).
Tricarbonyl[2-dichloromethyl-1-methoxycarbonyl-5-(2¢,5¢-dime-
thoxyphenyl)-3-pentene-1,5-diyl)iron ( )-15. To a stirring solu-
tion of 1-bromo-1-cyclohexene (0.10 g, 0.62 mmol) in dry THF
(5 mL) at -78 ◦C, in a 50 mL Schlenk flask, was added dropwise
a solution of t-BuLi (1.7 M in pentane, 0.74 mL, 1.26 mmol).
After addition was complete, the mixture was stirred at -78 ◦C
for 1 h, and then the anion solution was transferred by cannula
into a stirring solution of cation 9a (0.15 g, 0.27 mmol) in dry
CH2Cl2 (20 mL) at -78 ◦C. To ensure complete transfer of the
solution, a further portion of dry THF (1 mL) was transferred by
cannula from the flask used for anion preparation. The reaction
mixture was stirred for 30 min at -78 ◦C, then slowly warmed
to 0 ◦C for 4 h, and finally quenched with water (10 mL). The
resulting mixture was extracted several times with CH2Cl2, and
the combined extracts were dried (MgSO4) and concentrated. The
residue was purified by column chromatography (hexanes-ethyl
acetate = 20 : 1 → 4 : 1 gradient) to afford ( )-15 (30 mg, 23%) as a
pale yellow solid. Single crystals suitable for X-ray diffraction were
obtained from layering in hexanes over a concentrated solution in
CH2Cl2. (Found: C, 47.09; H, 3.99. Calcd for C19H21Cl2O7Fe: C,
46.75; H, 4.34); mp 163–166 ◦C (dec.); nmax (KBr)/cm-1 2066, 1995
and 1688; dH (400 MHz, CDCl3) 0.68 (1H, d, J = 8.8, H-1), 3.73
(3H, s, OMe), 3.75–3.80 (1H, m, H-2), 3.76 (3H, s, OMe), 3.92
(3H, s, OMe), 4.45 (1H, t, J = 7.2, H-3), 4.50 (1H, d, J = 12.9,
H-5), 4.94 (1H, d, J = 10.0, -CHCl2), 5.44 (1H, dd, J = 7.2 and
12.8, H-4), 6.83 (1H, d, J = 2.6, ArH), 6.84 (1H, s, ArH), 6.87
(1H, d, J = 2.4, ArH); dC (100 MHz, CDCl3) 13.0, 50.3, 51.8, 54.9,
55.91, 55.94, 70.8, 75.8, 93.6, 109.3, 111.6, 113.6, 128.0, 151.3,
153.8, 179.5, 203.8, 209.2, 209.4.
Reaction of 9a with isopropenylmagnesium bromide
To a solution of cation 9a (0.55 g, 1.0◦mmol) in dry CH2Cl2
(40 mL) in a 100 mL Schlenk flask -78 C under nitrogen, was
slowly added a solution of isopropenylmagnesium bromide (0.5
M solution in THF, 2.2 mL, 1.1 mmol). The reaction mixture
◦
was stirred at -78 C for 1 h, and then slowly warmed to room
temperature. Saturated NH4Cl solution (10 mL) was added and
the resulting mixture was extracted several times with CH2Cl2. The
combined extracts were dried (MgSO4) and concentrated to give
1
a mixture of 10 and 11 (71 : 29 by H NMR integration; 0.36 g,
81%) as a yellow solid. The mixture was separated by purification
over column chromatography (hexanes-ethyl acetate = 20 : 1 →
4 : 1 gradient). Single crystals of 10 and of 11, suitable for X-ray
diffraction, were obtained by slow evaporation of concentrated
CH2Cl2/hexanes (1 : 9) solutions at room temperature.
Reaction of 9a with cyclohexenyllithium in ether
To a stirring solution of 1-bromo-1-cyclohexene (174 mg,
1.08 mmol) in dry Et2O/dry pentane (2 : 3, 1 mL) at -78 ◦C, was
added dropwise a solution of t-BuLi (1.7 M in pentane, 1.28 mL,
2.2 mmol). After addition was complete, the mixture was stirred
at -78 ◦C for 1 h, and then the solution was transferred by cannula
into a stirring solution of cation 9a (300 mg, 0.549 mmol) in dry
CH2Cl2 (40 mL) at -78 ◦C. To ensure complete transfer of the
solution, a further portion of dry Et2O/dry pentane (1 mL) was
transferred by cannula from the flask used for anion preparation.
The reaction mixture was stirred for 30 min at -78 ◦C, then
slowly warmed to room temperature over a 3 h period, and finally
quenched with water (10 mL). The resulting mixture was extracted
several times with CH2Cl2, and the combined extracts were dried
(MgSO4) and concentrated to give a mixture of 16a and 17a (50 : 50
by 1H NMR integration; 222 mg, 84%) as a sticky yellow solid. The
mixture was separated by column chromatography (hexanes-ethyl
acetate = 20 : 1 → 4 : 1 gradient). Crystals of 16a suitable for X-ray
diffraction were obtained by slow evaporation from a concentrated
CH2Cl2/hexanes (1 : 9) solution at room temperature.
Tricarbonyl[1-methoxycarbonyl-5-(2¢,5¢-dimethoxy-phenyl)-2-
(1-methylethenyl)-3-pentene-1,5-diyl)iron ( )-10. (Found: C,
57.16; H, 5.01. Calcd for C21H22O7Fe: C, 57.03; H, 5.01); mp
136–139 ◦C; dH (400 MHz, CDCl3) 0.78 (1H, d, J = 8.9, H-1),
1.56 (3H, s, C CMe), 3.70–3.83 (1H, m, H-2), 3.72 (3H, s, OMe),
3.76 (3H, s, OMe), 3.89 (3H, s, OMe), 4.37 (1H, t, J = 7.4, H-3),
4.45 (1H, d, J = 12.3, H-5), 4.61 and 4.63 (2H, 2 ¥ s, C CH2),
5.46 (1H, dd, J = 7.1 and 12.5, H-4), 6.75–6.82 (3H, m, ArH); dC
(100 MHz, CDCl3) 11.7, 19.6, 45.4, 51.6, 55.9, 56.0, 57.7, 70.2,
94.1, 109.2, 109.5, 111.7, 113.0, 129.1, 147.4, 151.5, 153.7, 181.1,
204.6, 210.2, 210.7.
Tricarbonyl[1-methoxycarbonyl-5-(2¢,5¢-dimethoxy-phenyl)-4-
(1-methylethenyl)-2-pentene-1,5-diyl)iron ( )-11. (Found: C,
57.15; H, 5.08. Calcd for C21H22O7Fe: C, 57.03; H, 5.01); mp
117–118 ◦C; nmax (KBr)/cm-1 2057, 1986 and 1707; dH (400 MHz,
CDCl3) 1.39 (3H, s, C CMe), 1.77 (1H, d, J = 10.6, H-5), 3.23
(1H, d, J = 10.6, H-1), 3.51 (1H, t, J = 7.5, H-4), 3.75–3.85 (1H,
m, H-3), 3.78 (3H, s, OMe), 3.79 (3H, s, OMe), 3.85 (3H, s, OMe),
4.59 (2H, s, C CH2), 5.44 (1H, dd, J = 7.8 and 10.2, H-2), 6.61
(1H, dd, J = 1.6 and 8.6, ArH), 6.69 (1H, d, J = 8.6, ArH), 6.94
(1H, d, J = 1.6, ArH); dC (100 MHz, CDCl3) 15.0, 20.0, 48.5, 52.1,
55.3, 55.9, 59.9, 62.0, 100.6, 109.2, 109.3, 110.3, 111.1, 139.0,
148.3, 151.3, 153.5, 173.9, 200.6, 210.4, 212.4.
Tricarbonyl[2-(1¢-cyclohexenyl)-1-methoxycarbonyl-5-(2¢,5¢-di-
methoxy-phenyl)-3-pentene-1,5-diyl)iron ( )-16a. (Found: C,
59.53; H, 5.67. Calcd for C24H26O7Fe: C, 59.77; H, 5.43); mp 147–
150 ◦C (dec.); nmax (KBr)/cm-1 2058, 1989 and 1682; dH (400 MHz,
CDCl3) 0.76 (1H, d, J = 9.1, H-1), 1.40–1.64 (4H, m), 1.74–1.81
(2H, m), 1.86–1.95 (2H, m), 3.68 (1H, t, J = 8.3, H-2), 3.71 (3H, s,
OMe), 3.76 (3H, s, OMe), 3.90 (3H, s, OMe), 4.33 (1H, t, J = 7.4,
H-3), 4.44 (1H, d, J = 12.2, H-5), 5.27 (1H, br s, C CH), 5.44
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(1H, dd, J = 7.0 and 12.4, H-4), 6.76–6.91 (3H, m, ArH); dC (100
MHz, CDCl3) 12.4, 22.6, 22.7, 25.1, 25.6, 45.5, 51.5, 55.9, 56.0,
58.4, 70.0, 94.4, 109.5, 111.7, 112.9, 120.0, 129.4, 139.9, 151.5,
153.7, 181.3, 204.6, 210.3, 210.8.
5.5 and 7.2, H-4), 5.92–5.98 (2H, m, H-3 and C CH), 6.68–6.80
(3H, m, ArH); dC (100 MHz, CDCl3) d 19.1, 26.5, 28.1, 28.4, 35.6,
40.0, 42.7, 51.9, 53.5, 56.0, 56.2, 62.7, 80.1, 89.1, 110.4, 111.8,
112.3, 125.8, 130.0, 146.0, 151.1, 153.7, 174.3, 210.8; ESI-HRMS
calcd for C26H30O7FeNa (M+Na+): m/z 533.1239. Found: m/z
533.1219.
Tricarbonyl[methyl 5-(1¢-cyclohexenyl)-5-(2¢,5¢-dimeth-oxyphen-
yl)-2E,4Z-pentadienoate]iron ( )-17a. nmax (KBr)/cm-1 2044,
1973 and 1736; dH (400 MHz, CDCl3) 1.48–1.64 and 1.84–2.02
(8H, m), 2.81 (1H, d, J = 11.5, H-2), 2.97 (1H, dd, J = 8.1 and
11.5, H-5), 3.60 (1H, d, J = 10.4, H-6), 3.75 (3H, s, OMe), 3.79 (3H,
s, OMe), 3.85 (3H, s, OMe), 5.24 (1H, dd, J = 5.5 and 7.7, H-4),
5.54 (1H, br s, C CH), 5.98 (1H, dd, J = 5.3 and 10.5, H-3), 6.68–
6.80 (3H, m, ArH); dC (100 MHz, CDCl3) 22.2, 22.9, 25.4, 26.8,
51.8, 51.9, 54.5, 55.9, 56.0, 57.9, 80.4, 88.9, 110.4, 111.4, 112.2,
124.0, 129.8, 137.9, 151.0, 153.6, 173.2, 210.8; ESI-HRMS calcd
for C24H26O7FeNa (M+Na+): m/z 505.0926, found: m/z 505.0924.
3-Methoxycarbonyl-7-(2¢,5¢-dimethoxyphenyl)-1-methyl-1,4-
cycloheptadiene ( )-12. To a stirring solution of complex 10
(100 mg, 0.226 mmol) in CH3CN (3 mL) at room temperature, was
slowly added a solution of CuCl2 (91 mg, 0.68 mmol) in CH3CN
(10 mL). The solution was stirred at room temperature for 30 min
and then warmed to 50 ◦C with stirring for 1 h. After cooling to
room temperature, the solution was concentrated and the residue
was taken up in CH2Cl2 and charged onto a silica gel column.
Purification by column chromatography (hexanes-ethyl acetate =
20 : 1 → 10 : 1 gradient) gave ( )-12 (65 mg, 95%) as a colorless oil.
dH (300 MHz, CDCl3) 1.41 (3H, t, J = 1.8, Me), 2.37 (1H, dd, J =
7.5 and 14.5, H-7), 2.64 (1H, dd, J = 3.9 and 14.5, H-7¢), 3.76 (3H,
s, OMe), 3.77 (3H, s, OMe), 3.81 (3H, s, OMe), 4.07–4.14 (1H, m),
4.25–4.31 (1H, m), 5.65–5.75 (2H, m), 6.04 (1H, dddd, J = 1.2,
2.1, 3.9 and 11.4), 6.72 (1H, dd, J = 3.3 and 8.7, ArH), 6.79 (1H,
d, J = 8.7, ArH), 6.82 (1H, d, J = 3.3, ArH); dC (75 MHz, CDCl3)
26.1, 35.1, 36.7, 43.5, 52.4, 55.9, 56.2, 111.3, 111.5, 115.8, 122.3,
127.3, 133.6, 134.2, 139.1, 151.0, 153.7, 174.5; FAB-HRMS calcd
for C18H22O4 (M+) 302.1518, found 302.1526.
Reaction of 9a with dimethylcyclohexenyllithium
To a stirring solution of 1-iodo-6,6-dimethylcyclohex-1-ene
(310 mg, 1.31 mmol) in a solution of dry Et2O/dry pentane (2 : 3,
◦
1 mL) at -78 C in a 50 mL Schlenk flask, was added dropwise
a solution of t-BuLi (1.7 M in pentane, 1.55 mL, 2.6 mmol).
After addition was complete, the mixture was stirred at -78 ◦C
for 1 h, and then the solution was transferred by cannula into a
stirring solution of cation 9a (360 mg, 0.659 mmol) in dry CH2Cl2
(40 mL) at -78 ◦C. To ensure complete transfer of the solution, a
further portion of dry Et2O/dry pentane (1 mL) was transferred
by cannula from the flask used for anion preparation. The reaction
mixture was stirred for 30 min at -78 ◦C, then slowly warmed to
room temperature over a 3 h period, and finally quenched with
water (10 mL). The resulting mixture was extracted several times
with CH2Cl2, and the combined extracts were dried (MgSO4) and
concentrated to give a mixture of 16b and 17b (69 : 31 by 1H
NMR integration; 235 mg, 70%) as a sticky yellow solid. The
mixture was separated by column chromatography (hexanes-ethyl
acetate = 20 : 1 → 4 : 1 gradient). Crystals of 16b suitable for X-ray
diffraction were obtained by slow evaporation of a concentrated
CH2Cl2/hexanes (1 : 9) solution at room temperature.
3-Methoxycarbonyl-6-(2¢,5¢-dimethoxyphenyl)-bicyclo[5.4.0]-
undeca-1,4-diene ( )-18a. The decomplexation of 16a (100 mg,
0.207 mmol) with CuCl2 (84 mg, 0.63 mmol) was carried out in
a fashion similar to the decomplexation of 10. Purification of the
residue by column chromatography (SiO2, hexanes-ethyl acetate =
20 : 1 → 10 : 1 gradient) gave ( )-18a (50 mg, 71%) a pale ivory solid
product; dH (400 MHz, CDCl3) 1.10–1.30 (3H, m), 1.58–1.72 (3H,
m), 1.91–2.01 (1H, m), 2.06–2.12 (1H, m), 2.18–2.26 (1H, m), 3.77
(3H, s, OMe), 3.78 (3H, s, OMe), 3.79 (3H, s, OMe), 4.42–4.48 (1H,
m), 4.68–4.72 (1H, m), 5.64 (1H, br s, H-2), 6.05–6.11 (1H, m, H-
3), 6.18 (1H, dd, J = 4.2 and 10.2, H-4), 6.72 (1H, dd, J = 3.0 and
8.9, ArH), 6.80 (1H, d, J = 8.9, ArH), 6.94 (1H, d, J = 3.0, ArH);
dC (100 MHz, CDCl3) 26.2, 28.0, 28.9, 38.2, 39.7, 42.5, 44.6, 52.4,
55.9, 56.1, 110.7, 111.4, 116.2, 116.6, 130.0, 131.7, 132.1, 145.8,
151.4, 153.2, 174.9; ESI-HRMS calcd for C21H26O4Na+ (M+Na+):
m/z 365.1723. Found: m/z 365.1728.
Tricarbonyl[1-methoxycarbonyl-5-(2¢,5¢-dimethoxy-phenyl)-2-
(6¢,6¢-dimethylcyclohex-1¢-enyl)-3-pentene-1,5-diyl)iron ( )-16b.
(Found: C, 61.67; H, 6.19. Calcd for C26H30O7Fe: C, 61.19; H,
5.92.); mp 150–152 ◦C (dec.); nmax (KBr)/cm-1 2056, 2000, and
1691; dH (400 MHz, CDCl3) 0.88 (1H, d, J = 9.2, H-1), 0.96 (3H,
s, Me), 1.10 (3H, s, Me), 1.47–1.51 (2H, m), 1.33–1.37 (2H, m),
1.89–1.93 (2H, m), 3.71 (3H, s, OMe), 3.76 (3H, s, OMe), 3.86
(1H, t, J = 8.6, H-2), 3.90 (3H, s, OMe), 4.36 (1H, t, J = 7.5, H-3),
4.57 (1H, d, J = 12.5, H-5), 5.26 (1H, t, J = 3.5, C CH), 5.37
(1H, dd, J = 7.2 and 12.3, H-4), 6.76–6.90 (2H, m, ArH); dC (100
MHz, CDCl3) 16.3, 19.0, 26.3, 28.4, 29.5, 34.0, 40.8, 41.6, 51.5,
56.0, 56.1, 61.2, 69.4, 93.5, 109.5, 111.7, 112.9, 123.7, 129.6, 148.2,
151.5, 153.8, 180.7, 204.8, 210.5, 210.8. ESI-HRMS calcd for
C26H30O7FeNa (M+Na+): m/z 533.1239. Found: m/z 533.1232.
3-Methoxycarbonyl-6-(2¢,5¢-dimethoxyphenyl)-11,11-dimethyl-
bicyclo[5.4.0]undeca-1,4-diene ( )-18b. The decomplexation 16b
(100 mg, 0.207 mmol) with CuCl2 (79 mg, 0.58 mmol) was carried
out in a fashion similar to the decomplexation of 10. Purification
of the residue by column chromatography (SiO2, hexanes-ethyl
acetate = 20 : 1 → 10 : 1 gradient) gave ( )-18b (42 mg, 58%) as
a pale ivory solid; nmax(neat)/cm-1 1734; dH (400 MHz, CDCl3)
1.06 (3H, s, Me), 1.08 (3H, s, Me), 1.14–1.28 (2H, m), 1.34–1.50
(3H, m), 1.59–1.66 (1H, m), 2.45 (1H, qd, J = 3.2 and 12.8, H-7),
3.792 (3H, s, OMe), 3.796 (3H, s, OMe), 3.80 (3H, s, OMe), 4.49
(1H, q, J = 3.2, H-3), 4.69 (1H, t, J = 4.0, H-6), 5.67 (1H, d, J =
2.0, H-2), 6.18–6.21 (2H, m, H-4 and H-5), 6.74 (1H, dd, J = 2.8
and 8.8, ArH), 6.82 (1H, d, J = 8.8, ArH), 6.98 (1H, d, J = 2.8,
ArH); dC (100 MHz, CDCl3) 22.7, 26.1, 28.5, 30.2, 38.3, 39.2, 40.1,
42.5, 42.9, 52.4, 55.9, 56.1, 110.5, 111.5, 114.0, 116.3, 129.9, 131.5,
Tricarbonyl[methyl 5-(2¢,5¢-dimethoxyphenyl)-5-(6¢,6¢-dimethyl-
cyclohex-1¢-enyl)-2E,4Z-pentadienoate]iron
( )-17b. nmax
(KBr)/cm-1 2042, 1991, 1958 and 1720; dH (400 MHz, CDCl3)
0.87 (3H, s, Me), 0.95 (3H, s, Me), 1.38–1.60 (4H, m), 1.98–2.04
(2H, m), 2.94–3.05 (2H, m), 3.75 (3H, s, OMe), 3.76 (3H, s, OMe),
3.86 (3H, s, OMe), 3.87 (1H, d, J = 10.7, H-6), 5.19 (1H, dd, J =
7746 | Org. Biomol. Chem., 2011, 9, 7742–7747
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132.3, 151.4, 152.1, 153.2, 175.3. ESI-HRMS Calc. for C23H30O4
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(M+Na+): m/z 393.2042. Found: m/z 393.2026.
Acknowledgements
This work was supported by the National Science Founda-
tion (CHE-0848870) and NSF instrumentation grants (CHE-
0521323). High-resolution mass spectra were obtained at the
University of Nebraska-Center for Mass Spectrometry and the
COSMIC lab at Old Dominion University. The authors thank
Anobick Sar for obtaining IR spectra.
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