A short synthetic route to the natural products cis-3-phenyl-acenaphthene- 1,2-diol and 4-phenyl-benzo[de]isochromene-1,3-dione from acenaphthylene- chromium tricarbonyl

Article abstract of DOI:10.1055/s-2005-869964

Racemic cis-3-phenyl-acenaphthene-1,2-diol (1), a phytoanticipin, and the related phytoalexin, 4-phenyl-benzo[de]isochromene-1,3-dione (2) were prepared via a short sequence of reactions from a common intermediate. Dione 2 was also used to prepare the imi

Full text of DOI:10.1055/s-2005-869964

1926
SHORT PAPER
A Short Synthetic Route to the Natural Products cis-3-Phenyl-acenaphthene-
1,2-diol and 4-Phenyl-benzo[de]isochromene-1,3-dione from Acenaphthylene-
chromium Tricarbonyl
Synthesis of
Ac
a
enaphthyle
u
ne and
N
aph
r
thylene
D
a
erivatives R. Izquierdo, Marcos Kenneth, Teresa A. Grillo,* Javier G. Luis
Instituto Universitario de Bio-Orgánica ‘Antonio González’, Universidad de La Laguna, Carretera de la Esperanza 2,
38206 La Laguna, Tenerife, Canary Islands, Spain
Fax +34(922)318571; E-mail: tereabad@ull.es
Received 24 October 2004; revised 15 March 2005
HO
OH
O
O
O
Abstract: Racemic cis-3-phenyl-acenaphthene-1,2-diol (1), a phy-
toanticipin, and the related phytoalexin, 4-phenyl-benzo[de]iso-
chromene-1,3-dione (2) were prepared via a short sequence of
reactions from a common intermediate. Dione 2 was also used to
prepare the imides 6–8 which are structurally related to a set of re-
cently identified compounds possessing anti-tumor activities.
1
2
R
N
O
O
Key words: total synthesis, phytoanticipins, phytoalexins,
acenaphthylene-chromium tricarbonyl
6 R = CH2CH2CH3
7 R = CH2(CH2)6CH3
8 R = CH2CH2N(CH3)2
Plants combat bacterial infections by producing antimi-
crobials. These antimicrobials can be classified into two
forms. One class of these includes the phytoanticipins,
which are compounds that are generated throughout the
life cycle of healthy plants to ward off infection. The sec-
ond class are the phytoalexins which are produced ‘de no-
vo’ by some plants cells when provoked by biotic,
physical or chemical agents and accumulate in response to
infection.1 The phytoalexins are a group of natural prod-
ucts defined by their physiological rather than their struc-
tural features. Depending on the plant species examined
the group of compounds identified as phytoalexins in-
clude diterpenes, sesquiterpenes, furanocumarins, isofla-
vonoids, poliacetylenes and many more. Both classes of
compounds are of potential importance as new sources of
antimicrobial agents for both plants and humans.
Figure 1
Mori et al.,6 have previously reported the successful intro-
duction of a substituted phenyl group at the desired 2-po-
sition of an acenaphthylene system utilizing Suzuki–
Miyaura palladium chemistry while Treichel and co-
workers utilized the regioselective nucleophilic displace-
ment of acenaphthylene-chromium tricarbonyl complexes
with a small range of alkylcarbanions to generate 2-alkyl
acenaphthylenes.7 We were intrigued to attempt to broad-
en the scope of the latter reaction by investigating the di-
rect displacement of the activated chromium complex by
The acenaphthylene derivative cis-3-phenyl-acenaph-
thene-1,2-diol (1) (the absolute configuration was not de-
termined) was isolated and identified as a phytoanticipin
from healthy rizomas of Musa acuminata2,3 while the car-
boxylic anhydride 4-phenyl-benzo[de]isochromene-1,3-
dione (2) was reported as being a phytoalexin from the
same species (Figure 1).4
Cr(CO)6, DME
51% (ref.6)
3
Cr(CO)3
4
1. PhLi, TMEDA, THF, –78 °C to 0 °C, 1.5 h
2. CF3CO2H, –78 °C, 30 min
3. I2, THF, –78 °C to r.t., overnight
32%
Since the extraction and isolation of 1 and 2 are very time-
consuming and generally lead to only small amounts of
material (micrograms) we decided to investigate their
synthesis. The corresponding imide derivatives 6–8 were
also synthesized in order to investigate their potential anti-
tumor activities (Figure 1).5
5
OsO4, NMO, t-BuOH
H2O–acetone (1:8)
1. H2, Pd/C, EtOAc, 4 h, r.t.
2. K2Cr2O7, AcOH, reflux, 3 h
94%
99%
HO
OH
O
O
O
SYNTHESIS 2005, No. 12, pp 1926–1928
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.06.2005
1
2
DOI: 10.1055/s-2005-869964; Art ID: T12604SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

SHORT PAPER
Synthesis of Acenaphthylene and Naphthylene Derivatives
1927
(10 mL), water (10 mL), sat. aq NaHCO3 (10 mL) and brine (10
mL). The organic layer was dried (Na2SO4) and the solvent was re-
moved to afford the crude product, which was purified by column
chromatography on silica gel (eluent: hexane) to afford 5 as a yel-
low solid.
R
N
O
O
O
O
O
RNH2, NMP
reflux, 6 h
Yield: 102 mg (32%); mp 153–155 °C.
IR (film): 3418, 2360, 2341, 1427, 831 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.91 (d, J = 8.1 Hz, 1 H), 7.85 (d,
J = 8.1 Hz, 1 H), 7.73–7.67 (m, 4 H), 7.61–7.51 (m, 3 H), 7.46–7.42
(m, 1 H), 7.25 (d, J = 5.3 Hz, 1 H), 7.15 (d, J = 5.3 Hz, 1 H).
2
6 R = CH2CH2CH3 (89%)
7 R = CH2(CH2)6CH3 (46%)
8 R = CH2CH2N(CH3)2 (95%)
Scheme 2
13C NMR (75 MHz, CDCl3): d = 140.0, 139.6, 138.2, 136.4, 129.7,
a phenyl moiety. Herein we describe a new synthesis of
both natural products 1 and 2 (Scheme 1) from the same
common intermediate rac-4.8
129.4, 128.8, 128.7, 127.9, 127.5, 126.9, 124.4.
EIMS: m/z = 228 (100.0) [M]+.
HRMS: m/z calcd for C18H12: 228.093900; found: 228.093212.
The acenaphthylene-chromium tricarbonyl complex rac-
4 was reproducibly prepared from commercial acenaphth-
ylene 3, in multigram quantities. Although the yield for
this step was only moderate it was comparable to those
previously reported.7,9 Treatment of rac-4 with phenyl-
lithium followed by subsequent addition of trifluoroacetic
acid, to reduce the formation of polycyclic by-products,
and iodine to aid oxidative elimination of the resulting
complex, afforded 5. The yield obtained for the isolated
product though only modest was comparable to those re-
ported for the alkyl cases and to the best of our knowledge
this is the first example of the reaction between 4 and an
aryl carbanion. Oxidation of 5 with N-methylmorpholine-
N-oxide–OsO4 afforded compound 1 in high yield, while
catalytic hydrogenation of 5 followed by selective oxida-
tion of the benzylic positions with potassium dichromate
gave the desired anhydride 2 in high purity and yield. An-
alytical data for the synthesized compounds 1 and 2 were
identical to those reported for the corresponding isolated
materials.3,4
cis-3-Phenyl-acenaphthene-1,2-diol (1)
To a solution of 5 (35.0 mg, 0.15 mmol) in a mixture of water–ace-
tone (1:8, 0.1 M, 1.5 mL) at r.t. were added N-methylmorpholine N-
oxide (35.0 mg, 0.30 mmol) and a solution of OsO4 (2.0 mg) in t-
BuOH (0.1 mL). The mixture was stirred overnight and quenched
with sat. aq NaHSO3 (5 mL). After stirring for 30 min the reaction
mixture was extracted with EtOAc (2 × 5 mL), washed with brine
(5 mL), and dried (Na2SO4). The organic layer was evaporated un-
der reduced pressure to afford the crude product, which was chro-
matographed on a silica gel column (eluent: CH2Cl2–acetone, 95:5)
to afforded 1 as a white solid.
Yield: 37 mg (94%).
IR (film): 3364, 2359, 1597, 1095 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.87 (d, J = 8.4 Hz, 1 H), 7.79–
7.76 (m, 3 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.62–7.56 (m, 2 H), 7.53–
7.49 (m, 2 H), 7.43–7.40 (m, 1 H), 5.62 (m, 1 H), 5.53 (m, 1 H), 3.05
(d, J = 8.1 Hz, 1 H, OH), 2.58 (d, J = 2.6 Hz, 1 H, OH).
13C NMR (100 MHz, CDCl3): d = 142.8, 139.7, 138.4, 136.4, 135.8,
130.3, 130.0, 128.9, 128.7, 128.3, 127.5, 126.1, 124.7, 121.4, 74.3,
72.6.
EIMS: m/z = 262 (37.0) [M]+, 244 (90.5), 215 (100.0), 213 (20.1).
The interesting imide derivatives 6–8 were prepared by
heating a solution of 2 in N-methylpyrrolidinone in the
presence of the appropriate amines (Scheme 2).10
HRMS: m/z calcd for C18H14O2: 262.099380; found: 262.104179.
4-Phenylbenzo[de]isochromene-1,3-dione (2)
A mixture of 5 (100 mg, 0.44 mmol) and 5% Pd/C (8 mg), in EtOAc
(5 mL) was stirred under 1 atm of H2 for 4 h. Filtration of the mix-
ture through Celite® and removal of the solvent under reduced pres-
sure gave the crude intermediate. AcOH (1.6 mL) was added
followed by potassium dichromate (0.52 g, 1.76 mmol). The reac-
tion mixture was stirred at r.t. for 15 min and then heated at reflux
for 3 h. Hot water (6.7 mL, 60 °C) was added and the mixture was
stirred for 30 min. The precipitate was collected by filtration and the
solid was further purified by crystallization (THF) to afford 2 as yel-
low needles.
1H and 13C NMR spectra were recorded on Bruker AMX400,
AMX300 and WP200SY spectrometers. IR spectra were taken on a
Perkin-Elmer 1600 (FTIR) spectrophotometer. High resolution
mass spectra were run on a VG-Micromass ZAB-2F at 70 eV. Or-
ganic solvents used were dried by standard methods. Commercially
obtained reagents were used without further purification. All reac-
tions were monitored by TLC with Merck 60 F254 silica gel coated
plates. Flash column chromatography was carried out using 230–
240 mesh silica gel at increased pressure.
Yield: 115 mg (99%); mp 191–193 °C.
IR (film): 1765, 1725, 1275, 1005 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.7 (dd, J = 1.2, 7.3 Hz, 1 H), 8.33
(dd, J = 1.0, 8.7 Hz, 1 H), 8.28 (d, J = 8.5 Hz, 1 H), 7.84 (t, J = 7.3
Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.53–7.40 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 160.9, 158.7, 150.2, 140.3, 135.4,
134.2, 133.7, 131.8, 131.2 (2 ×), 128.3 (2 ×), 127.1, 119.2, 115.6,
115.5.
3-Phenyl-acenaphthylene (5)
To a stirred solution of C6H5Li (5.2 mmol, 2.6 mL) and TMEDA
(4.17 mmol, 0.63 mL) in THF (15 mL) under Ar at –78 °C was add-
ed a THF solution of rac-4 (400 mg, 1.38 mmol, 0.14 M) dropwise.
The mixture reaction was allowed to warm to 0 °C and was main-
tained at this temperature for 1.5 h. The solution was chilled to –78
°C and trifluoroacetic acid (19.4 mmol, 1.5 mL) was added. After
30 min, a solution of I2 in THF (7.8 mmol, 0.8 M) was added and
the solution was allowed to warm to r.t. overnight. The solution was
filtered through Celite® and the solvent was evaporated. The residue
was extracted with Et2O (2 × 10 mL). The combined organics were
washed sequentially with 10% aq NaHSO3 (2 × 10 mL), 2 M HCl
EIMS: m/z = 202 (100.0), 230 (52.5), 274 (64.8) [M]+.
HRMS: m/z calcd for C18H10O3: 274.062994; found: 274.058517.
Synthesis 2005, No. 12, 1926–1928 © Thieme Stuttgart · New York

1928
L. R. Izquierdo et al.
SHORT PAPER
2-Propyl-4-phenylbenzo[de]isoquinoline-1,3-dione (6)
Yield: 20.3 mg (95%).
Propylamine (0.06 mL, 0.75 mmol) was added to a solution of 2
(20.5 mg, 0.075 mmol) in N-methylpyrrolidinone (0.75 mL). The
reaction mixture was heated at reflux under Ar for 6 h. The solvent
was removed under reduced pressure and the residue was poured
into water and extracted with CHCl3 (2 × 5 mL). The organics were
collected and washed with water (2 × 2 mL), brine (2 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography on silica gel (eluent:
hexane–EtOAc, 85:15) to afford 6 as a white solid.
IR (film): 2875, 1690, 1650, 1365 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.67 (d, J = 5.3 Hz, 1 H), 8.18 (dd,
J = 6.0, 15.8 Hz, 2 H), 7.76 (t, J = 5.7 Hz, 1 H), 7.55 (d, J = 6.3 Hz,
1 H), 7.49–7.42 (m, 5 H), 4.28 (t, J = 4.7 Hz, 2 H), 2.74 (m, 2 H),
2.41 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 164.1, 163.4, 148.1, 142.2, 134.1,
132.8, 131.7, 131.1, 129.0, 128.1, 127.5, 126.7, 122.8, 119.1, 56.4,
45.1, 37.3.
EIMS: m/z = 274 (100.0), 344 (2.3) [M]+.
Yield: 20.3 mg (89%); mp 101–104 °C.
IR (film): 2929, 1700, 1662, 1325, 1229, 763 cm–1.
HRMS: m/z calcd for C22H20N2O2: 344.152478; found: 344.153824.
1H NMR (300 MHz, CDCl3): d = 8.67 (d, J = 7.2 Hz, 1 H), 8.18 (dd,
J = 8.1, 16.3 Hz, 2 H), 7.76 (t, J = 7.6 Hz, 1 H), 7.56 (d, J = 8.4 Hz,
1 H), 7.51–7.35 (m, 5 H), 4.0 (t, J = 7.6 Hz, 2 H), 1.66 (m, 2 H), 0.93
(t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.0, 163.3, 148.0, 142.4, 133.8,
132.6, 131.6, 131.5, 131.1, 128.9, 128.1, 127.8, 127.5, 126.6, 123.0,
119.2, 109.0, 100.6, 41.9, 21.2, 11.4.
Acknowledgment
This work has been supported by Grant PI998/006 from the Canary
Island Government. We thank the European Community for finan-
cial assistance through the FEDER Program to L.R. Izquierdo.
EIMS: m/z = 315 [M]+, 272 (100.0).
References
HRMS: m/z calcd for C21H17NO2: 315.125929; found: 315.125092.
(1) Snowdon, A. L. In A Colour Atlas of Post-Harvest Diseases
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2-Octyl-4-phenylbenzo[de]isoquinoline-1,3-dione (7)
Using the procedure described above, compound 7 was obtained
from 2 as a white solid (19.1 mg).
Yield: 11.9 mg (46%); mp 80 °C.
IR (film): 3452, 2961, 1701, 1660, 1570, 1327, 1228, 1068, 762
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.67 (d, J = 7.3 Hz, 1 H), 8.18 (dd,
J = 8.1, 16.1 Hz, 2 H), 7.77 (t, J = 7.9 Hz, 1 H), 7.55 (d, J = 8.4 Hz,
1 H), 7.51–7.35 (m, 5 H), 4.05 (t, J = 7.6 Hz, 2 H), 1.63–1.59 (m, 2
H), 1.25 (m, 10 H), 0.85 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 163.9, 163.3, 148.0, 142.4, 133.8,
132.6, 131.6, 131.5, 131.1, 128.9, 128.1, 127.9, 127.5, 126.6, 123.1,
119.3, 40.5, 31.8, 29.7, 29.3, 29.2, 28.1, 27.1, 22.6, 14.0.
(5) Braña, M. F.; Ramos, A. Curr. Med. Chem.: Anti-Cancer
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(7) Rein, U.; Treichel, P. M.; Haller, K. J. Organometallics
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M. Transition Metal Arene p-Complexes in Organic
Synthesis and Catalysis, Vol. 8; Kündig, E. P., Ed.; Springer:
New York, 2004, 232.
EIMS: m/z = 385 [M]+, 286 (64.0), 272 (100.0).
HRMS: m/z calcd for C26H27NO2: 385.204179; found: 385.203773.
(9) King, R. B.; Stone, F. G. A. J. Am. Chem. Soc. 1960, 82,
2-(2-Dimethylaminoethyl)-4-phenylbenzo[de]isoquinoline-1,3-
dione (8)
Using the procedure described above, compound 8 was obtained
from 2 as a yellow oil (17.0 mg).
4557.
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Synthesis 2005, No. 12, 1926–1928 © Thieme Stuttgart · New York