Catalytic asymmetric synthesis of halenaquinone and halenaquinol

Article abstract of DOI:10.1055/s-1998-5939

A catalytic asymmetric synthesis of halenaquinone (1) and halenaquinol (2) has been achieved using an asymmetric Heck reaction or a cascade Suzuki cross-coupling and an asymmetric Heck reaction as a key step. This synthesis also features the one-pot construction of a unique pentacyclic ring system from a tricyclic system using palladium chemistry. Moreover, the use of Ph₃As as an achiral ligand has been found to enhance both the cascade Suzuki cross-coupling and also the Heck reaction to a synthetically useful extent.

Full text of DOI:10.1055/s-1998-5939

SYNTHESIS
April 1998
581
Catalytic Asymmetric Synthesis of Halenaquinone and Halenaquinol
Akihiko Kojima, Toshiyasu Takemoto, Mikiko Sodeoka, Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113, Japan
Fax +81(3)56845206; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Received 30 September 1997
Abstract: A catalytic asymmetric synthesis of halenaquinone (1)
and halenaquinol (2) has been achieved using an asymmetric
Heck reaction or a cascade Suzuki cross-coupling and an asym-
metric Heck reaction as a key step. This synthesis also features the
one-pot construction of a unique pentacyclic ring system from a
tricyclic system using palladium chemistry. Moreover, the use of
Ph3As as an achiral ligand has been found to enhance both the
cascade Suzuki cross-coupling and also the Heck reaction to a
synthetically useful extent.
Key words: asymmetric Heck reaction, Suzuki cross-coupling,
cascade reaction, triphenylarsine
Halenaquinone (1) and halenaquinol (2), which have a
benzylic quaternary carbon center as well as a unique pen-
Scheme 1
tacyclic skeleton, have been isolated from a variety of sea
sponges (Figure 1).1 These marine natural products have
been shown to possess antibiotic, cardiotonic and protein
tyrosine kinase inhibitory activity.2 To date, only Harada
and co-workers have succeeded in the total synthesis of 1
and 2 starting from optically pure Wieland–Miescher ke-
tone.3 We report here a full account of a catalytic asym-
metric synthesis of 1 and 2 starting from commercially
available 6,7-dimethoxy-1-tetralone (3).4,5,6 This synthe-
sis features the use of an asymmetric Heck reaction or the
first use of a cascade Suzuki cross-coupling and an asym-
metric Heck reaction as well as the one-pot construction
of a unique pentacyclic ring system from a tricyclic ring
system using palladium chemistry. Moreover, a cascade
Suzuki cross-coupling and a Heck reaction using Ph3As as
an achiral ligand, leading to an efficient synthesis of (±)-
1 and (±)-2, are also described.
able 6,7-dimethoxy-1-tetralone (3) was efficiently con-
verted to the catechol derivative 7 in a five-step sequence
of reactions in 58% overall yield. This synthetic route to 7
is applicable to a large scale synthesis because of the easy
purification of 4 and 6 by recrystallization. The catechol
derivative 7 was transformed into 8 by monosilylation fol-
lowed by trifluoromethanesulfonylation in 85% yield.
Then, cross-coupling using allylmagnesium bromide8
gave 9 in quantitative yield. Treatment of 9 with 9-BBN
followed by Suzuki cross-coupling9 using the alkenyl io-
dide 12 afforded 10 in 90% yield. Alternatively, 10 was
prepared in a single step (69%) using the alkylborane 13
with a trisubstituted alkenic double bond. The resulting si-
lyl ether 10 was converted to the triflate 11 by convention-
al means.
With the substrate 11 for an asymmetric Heck reaction
available in large quantities, we then focused our attention
on the crucial catalytic asymmetric cyclization. First of
all, using the model compound 14, the feasibility of an in-
tramolecular Heck reaction was examined, and it turned
out that treatment of 14 with Pd(OAc)2 (10 mol %), 1,3-
bis(diphenylphosphino)propane (dppp) (20 mol %) and
K2CO3 (3 equiv) in THF at 50°C for 120 h gave (±)-15 in
42% yield. Moreover, based on the previous information
obtained in the catalytic asymmetric synthesis of eptazo-
cine with a benzylic quaternary carbon center,7 14
was treated with Pd(OAc)2 (10 mol %), (R)-BINAP10
(20 mol %), and K2CO3 (3 equiv) in THF at 50°C for 32
h, giving rise to 15 in 92% ee and in 68% yield. The enan-
tiomeric excess of 15 was determined by HPLC analysis
using DAICEL CHIRALCEL OD (hexane–propan-2-ol,
9:1) of the 4-nitrobenzoate of 16, and the absolute config-
uration of 15 was unequivocally determined by X-ray
analysis of 18 derived from 15. Having developed an ef-
fective catalytic asymmetric synthesis of the model com-
pound 15, we next attempted a catalytic asymmetric
synthesis of 19, and we were pleased to find that treatment
of 11 with Pd(OAc)2 (10 mol %), (S)-BINAP (20 mol %),
Figure 1
A retrosynthetic analysis for the catalytic asymmetric syn-
thesis of 1 and 2 was made as shown in Scheme 1. The
reason behind the adoption of the (Z)-configuration for the
trisubstituted alkene substrate for the asymmetric Heck
reaction stems from experience gained during a catalytic
asymmetric synthesis of eptazocine, in which a benzylic
quaternary carbon atom was introduced by similar
means.7 In that case we obtained a much higher enantio-
meric excess when using the (Z)-trisubstituted alkene than
when using the (E)-configuration.
In order to determine the feasibility of the above-de-
scribed analysis, the substrate 11 was first of all prepared
by two different routes (Scheme 2). Commercially avail-

SYNTHESIS
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582
Reaction conditions: (a) (1) BBr3 (2.1 equiv), CH2Cl2, –78 ºC to r.t.,
(2) BnBr (2.0 equiv), K2CO3, Bu4NI, DMF, 60 ºC (two steps, 92%);
(b) CrO3 (5 equiv), HOAc–H2O, 0 ºC to r.t.; (c) KHMDS (3 equiv),
THF, –78 ºC, then MeI (6 equiv), –78 ºC to r.t. (63% from 4); (d) H2
(1 atm), Pd–C, EtOAc, r.t. (quant.); (e) (1) TBSCl (1.1 equiv), Et3N,
CH2Cl2, 0 ºC, (2) Tf2O (1.3 equiv), Et3N, CH2Cl2, –78 ºC to r.t. (two
steps, 85%); (f) CH2=CHCH2MgBr (5 equiv), PdCl2(dppf)•CH2Cl2 (9
mol %), Et2O, –78ºC to r.t. (quant.); (g) (1) 9-BBN (2.1 equiv), THF,
0 ºC to r.t., (2) 12 (1.5 equiv), PdCl2(dppf)•CH2Cl2 (5 mol %),
K3PO4•nH2O, THF, 50 ºC (90% from 9); (h) 13 (1.3 equiv), PdCl2(dp-
pf)•CH2Cl2 (10 mol %), K2CO3, THF, 50 ºC (69 %); (i) (1) Bu4NF
(1.0 equiv), THF, 0 ºC, (2) Tf2O (1.3 equiv), Et3N, CH2Cl2, –78 ºC to
r.t. (two steps, 69 %).
Scheme 3
Scheme 2
and K2CO3 (3 equiv) in THF at 60°C for 22 h gave 19
with 87% ee in 78% yield. Expected S configuration of 19
was confirmed by the fact that 19 was successfully con-
verted to natural 1 and 2.
Heck reaction would be generated in the reaction medium,
leading to 19 with high enantiomeric excess. In order to ex-
amine the feasibility of the above-mentioned cascade reac-
tion, first of all 7 was converted to 20 in 99% yield. Then,
the cascade reaction was investigated in detail under a vari-
ety of reaction conditions, and it turned out that, against our
expectations, the cascade reaction didn’t proceed effective-
ly, instead giving rise to 21 and 22 as major products. The
desired product 19, however, was securely obtained in 20%
yield under the conditions described in Scheme 4 and, as
expected, the enantiomeric excess of resulting 19 was
found to be 85%. Improvement of the cascade reaction to a
synthetically useful extent is still under investigation.
Is it possible to develop another shorter synthetic route to
optically active 19? We noticed that the catechol deriva-
tive 7 could be converted to the ditriflate 20, which was
expected to be transformable into 19 by way of a cascade
Suzuki cross-coupling and an asymmetric Heck reaction
in a single step. Since the reaction rate of an asymmetric
Heck reaction is generally lower than that of a Suzuki
cross-coupling, a similar substrate 11 for an asymmetric

SYNTHESIS
April 1998
583
(1 atm) in the presence of KO-t-Bu in tert-butyl alcohol
gave the enol 28 in 79% yield. Treatment of 28 with NaI
and CuSO4•5H2O in aqueous methanol afforded the req-
uisite alkenyl iodide 29 quite efficiently (97%),14 and ex-
posure of 29 to p-toluenesulfonic acid in aqueous acetone
furnished 30 in 98% yield. Moreover, 32 was also synthe-
sized from 24 in a five-step sequence of reactions (59%
–
overall yield, i. LDA/31, –78°C, then H+, then OH; ii.
HO(CH2)3OH, TsOH•H2O; iii. DDQ; iv. O2, KO-t-Bu; v.
NaI, CuSO4•5H2O).
Reaction conditions: (a) Tf2O (3 equiv), pyridine, CH2Cl2, –78°C to
r.t. (99%); (b) 13 (1.1 equiv), Pd(OAc)2 (20 mol %), (S)-BINAP
(40 mol %), K2CO3 (6 equiv), THF, 60°C.
Scheme 4
We felt that the cascade Suzuki cross-coupling and Heck
reaction process had an intrinsic interest even if lacking
the asymmetric aspect, and so we decided to experiment
with a range of achiral ligands for the conversion of 20 to
19. We were pleased to find that the use of Ph3As as an
achiral ligand gave racemic 19 in a much better yield
(46%), and the results are summarized in Table 1.11–13
Table 1. Cascade Suzuki Cross-Coupling and Heck Reaction
Using Achiral Ligands
Reaction conditions: (a) (1) Bu4NF (2 equiv), HOAc (3 equiv), THF,
0 ºC to r.t., (2) NaBH4 (5 equiv), MeOH, 0 ºC to r.t. (two steps, 93%);
(b) Tf2O (1.2 equiv), pyridine, CH2Cl2, –78 ºC to r.t.; (c) LDA/31 (1.5
equiv), THF, –78 ºC, then H+, then –OH, then Bu4NF, HOAc (82%
from 23); (d) (1) HO(CH2)3OH (10 equiv), TsOH•H2O, benzene, re-
flux (98%), (2) BuLi (2 equiv), THF, –78 to –50ºC, then TIPSCl
(2 equiv), –78ºC to r.t. (98%); (e) DDQ (3 equiv), CH2Cl2, H2O, r.t.
(96%); (f) O2 (1 atm), KO-t-Bu (5 equiv), t-BuOH, 35 ºC (79%); (g)
NaI (10 equiv), CuSO4•5H2O (10 equiv), MeOH, H2O, r.t. (97%); (h)
TsOH•H2O, acetone, H2O, 60 ºC (98%).
With large quantities of optically active 19 in 87% ee and
(±)-19 in hand, we then pursued a catalytic asymmetric
synthesis of 1 and 2. In accordance with the retrosynthetic
analysis shown in Scheme 1, optically active 19 was first
converted to the aldehyde, followed by reduction with
NaBH4 to give the alcohol 23 (93%). The alcohol 23 un-
derwent trifluoromethanesulfonylation to afford the tri-
Scheme 5
flate 24, which was then treated with the acyl anion Having synthesized 29, 30, and 32 as substrates for the
equivalent derived from 31. The resulting product was crucial construction of the unique pentacyclic skeleton,
further converted to the ketone 25 in 82 % overall yield we examined the cascade reaction in detail. First of all,
from 23. After protection of the carbonyl functionality as compound 32 was treated with Pd2(dba)3•CHCl3 (0.5 mo-
an acetal (98%), and of the ethynyl functionality with a lar equiv) and K2CO3 (5 equiv) in MeCN at room temper-
triisopropylsilyl group (98%), 26 underwent benzylic ox- ature for 24 h, and we were pleased to find that the
idation to give 27 in 96% yield. Exposure of 27 to O2 expected product 33 was obtained albeit in a modest 36%

SYNTHESIS
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584
yield. In order to improve the yield, solvent and base ef- achiral ligand have been developed, demonstrating the
fects as well as effects of additives such as Ag2CO3 and versatility of modern palladium chemistry. The new
Bu4NCl were investigated. Unfortunately, however, the chemistry described herein should be quite useful for the
chemical yield of 33 was not improved. Furthermore, in synthesis of a variety of biologically significant com-
an attempt to improve the construction of the unique pen- pounds. Further studies along these lines are currently un-
tacyclic skeleton, the reaction of 29 was next examined der investigation.
under several reaction conditions, but no 34 was obtained,
with 28 being obtained as the major product. Finally we
Melting points were determined on a Yanagimoto Micro Melting
were very pleased to find that treatment of 30 with
Pd2(dba)3•CHCl3 (0.28 molar equiv) and K2CO3 (5 equiv)
in DMF at room temperature for 8 h gave the desired pen-
tacycle 35 in a single step (72%). At the same time Larock
and co-workers also reported a method for the synthesis of
a variety of furan skeletons using a similar strategy.15 The
pentacyclic intermediate 35 was subjected to desilylation,
which gave 36 in 83% yield: [α]D23 +123.7 (c = 0.335,
CH2Cl2, 87% ee). The compound 36 was then converted
to halenaquinone (1) in 99% yield, and 1 was further con-
verted to halenaquinol (2) using Harada’s procedure (al-
most quantitative yield).3
Point Apparatus and are uncorrected. Infrared (IR) spectra were re-
corded on a JASCO A-300 diffraction grating infrared spectrometer.
NMR spectra were measured on a JEOL JMN-EX 270 spectrometer,
1
operating at 270 MHz for H and 68 MHz for 13C NMR. Chemical
shifts are expressed in ppm (δ) with TMS as an internal standard.
Mass spectra (MS) were measured on a JEOL JMS-DX303 or JEOL
JMN-SX-102A instrument. Optical rotation was measured on a JAS-
CO DIP-140 polarimeter. Column chromatography was carried out
with silica gel, Merck Type 60 (230–400 mesh ASTM). In general, re-
actions were carried out in anhyd solvents, unless otherwise men-
tioned. THF and Et2O were distilled from sodium benzophenone
ketyl. CH2Cl2 was distilled from CaH2.
6,7-Dibenzyloxy-3,4-dihydronaphthalen-1(2H)-one (4):
To a solution of 6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one
(25.0 g, 121 mmol) in CH2Cl2 (500 mL), was added a solution of BBr3
(24.5 mL, 255 mmol) in CH2Cl2 (230 mL) at –78°C. After stirring for
1 h at r.t., the mixture was poured into an ice-water mixture, extracted
with EtOAc (3000 mL) and the extract was washed with brine
(1000 mL), dried (Na2SO4), and concentrated. To a solution of the
deep red colored residue (21.5 g) in DMF (368 mL) was added K2CO3
(66.9 g, 484 mmol), BnBr (28.8 mL, 24.2 mmol), and Bu4NI (8.94 g,
24.2 mmol). After stirring for 9 h at 60°C, the mixture was poured
into H2O, extracted with EtOAc (2000 mL) and the extract was
washed with brine (1000 mL), dried (Na2SO4), and concentrated. The
residue was purified by recrystallization from MeOH, and the residue
from the mother liquor was purified by silica gel column chromatog-
raphy (hexane–EtOAc, 4:1) to give 33.6 g and 6.30 g of 4 respectively
(2 steps, 92%) as a white powder; mp 96°C.
IR (Nujol): ν =1652, 1594, 1152, 1022 cm–1.
1H NMR (CDCl3): δ = 2.01–2.12 (m, 2H), 2.55 (t, J = 6.8 Hz, 2H),
2.82 (t, J = 6.2 Hz, 2H), 5.16 (s, 2H), 5.20 (s, 2H), 6.72 (s, 1H), 7.24–
7.49 (m, 10H), 7.62 (s, 1H).
MS m/z = 358 (M+).
Anal. Calcd for C24H22O3: C, 80.42; H, 6.19; Found: C, 80.28; H,
6.25.
6,7-Dibenzyloxy-1,4-dimethoxynaphthalene (6):
To a mixture of 4 (1.05 g, 2.93 mmol), HOAc (8.0 mL), and H2O
(2.0 mL) was added CrO3 (1.46 g, 14.6 mmol) under ice bath cooling.
After stirring for 36 h at r.t., the mixture was poured into an ice-water
mixture, extracted with CH2Cl2 (100 mL) and the extract was washed
with sat. NaHCO3 (30 mL) and brine (30 mL) successively, dried
(Na2SO4), and concentrated to give 1.08 g of crude 5. A solution of
crude 5 (1.08 g) in anhyd THF (42 mL) was added to potassium
bis(trimethylsilyl)amide (0.5 M in toluene, 17.6 mL, 8.79 mmol) at –
78°C. After stirring for 30 min, MeI (1.1 mL, 17.7 mmol) was added
to the mixture. After stirring for an additional 1.5 h at r.t., the mixture
was poured into sat. NH4Cl, extracted with EtOAc (100 mL) and the
extract was washed with brine (50 mL), dried (Na2SO4), and concen-
trated. The residue was purified by silica gel column chromatography
(CH2Cl2–EtOAc, 1:1) to give 6 (0.75 g, 2 steps, 63%) as a white pow-
der; mp 124°C. In larger scale experiments, the residue was also pu-
rified by recrystallization from cyclohexane.
Reaction conditions: (a) Bu4NF (16 equiv), HOAc (24 equiv), CH3CN,
THF, 60 ºC (83%); (b) CAN (6.7 equiv), CH3CN, H2O, r.t. (99%); (c)
Na2S2O4, acetone, H2O, 0 ºC (quant.).
Scheme 6
In conclusion, we have achieved an efficient catalytic
asymmetric synthesis of halenaquinone (1) and halena-
quinol (2), in which an asymmetric Heck reaction, and a
cascade Suzuki cross-coupling and an asymmetric Heck
reaction as well as a single step construction of a unique
pentacyclic skeleton using palladium chemistry are in-
volved. Moreover, a synthetically useful cascade Suzuki
cross-coupling and a Heck reaction which use Ph3As as an
IR (Nujol): ν = 1598, 1377, 1269 cm–1.
1H NMR (CDCl3): δ = 3.93 (s, 6H), 5.27 (s, 4H), 6.60 (s, 2H), 7.26–
7.57 (m, 10H), 7.63 (s, 2H).
13C NMR (CDCl3): δ = 55.7, 70.6, 102.1, 103.8, 121.9, 127.3, 127.7,
128.4, 137.2, 148.7, 149.1.
MS m/z = 400 (M+).

SYNTHESIS
April 1998
585
Anal. Calcd for C26H24O4: C, 77.98; H, 6.04; Found: C, 77.79: H,
5.97.
1H NMR (CDCl3): δ = 0.25 (s, 6H), 0.98 (s, 9H), 1.03 (s, 9H), 1.57–
1.68 (m, 2H), 1.69 (s, 3H), 1.95 (t, J = 7.1 Hz, 2H), 2.60 (t, J = 7.8 Hz,
2H), 3.92 (s, 6H), 4.21 (d, J = 6.3 Hz, 2H), 5.39 (t, J = 6.3 Hz, 1H),
6.52 (d, J = 7.7 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 7.30–7.44 (m, 6H),
7.45 (s, 1H), 7.62–7.74 (m, 4H), 7.87 (s, 1H).
6-tert-Butyldimethylsilyloxy-1,4-dimethoxy-7-trifluoromethane-
sulfonyloxynaphthalene (8):
A mixture of 6 (1.63 g, 4.07 mmol), EtOAc (70 mL), and 10% Pd–C
(0.71 g) was stirred under H2 atmosphere (1 atm) at r.t. for 5 h. The
insoluble material was filtered off, and the filtrate was concentrated
in vacuo, and the residue was triturated with hexane to give 6,7-dihy-
droxy-1,4-dimethoxynaphthalene (7) (0.95 g, 100%). To a mixture of
7 (896 mg, 4.07 mmol), Et3N (1.13 mL, 8.14 mmol), and CH2Cl2
(20 mL) was added a solution of TBSCl (673 mg, 8.95 mmol) in
CH2Cl2 (8.1 mL) under ice bath cooling. After stirring for 3 h, the
mixture was poured into sat. NH4Cl, extracted with CH2Cl2 (50 mL)
and the extract was washed with brine (50 mL), dried (MgSO4), and
concentrated. The residue was purified by silica gel column chromatog-
raphy (hexane–CH2Cl2, 1:1) to give 6-tert-butyldimethylsilyloxy-7-hy-
droxy-1,4-dimethoxynaphthalene (1.26 g, 93%). To a mixture of 6-
tert-butyldimethylsilyloxy-7-hydroxy-1,4-dimethoxynaphthalene
(11.7 g, 35.0 mmol), Et3N (12.7 mL, 90.9 mmol), and CH2Cl2 (100 mL)
was added Tf2O (7.65 mL, 45.5 mmol) at –78°C. After stirring for 30
min at r.t., the mixture was poured into sat. NaHCO3, extracted with
CH2Cl2 (500 mL) and the extract was washed with 1M HCl (200 mL)
and brine (300 mL) successively, dried (MgSO4), and concentrated.
The residue was purified by silica gel column chromatography (hex-
ane–CH2Cl2, 7:3) to give 8 (14.9 g, 91%) as a white solid; mp 79–80°C.
IR (neat): ν = 2933, 1605 cm–1.
MS m/z = 668 (M+, 16), 611 (M+-t-Bu, 5), 596 (M+-t-BuMe, 30), 199
(100).
Anal. Calcd for C41H56O4Si: C, 73.60; H, 8.44; Found: C, 73.44; H,
8.59.
(Z)-6-(9-Borabicyclo[3.3.1]nonan-9-yl)-1-tert-butyldiphenylsilyl-
oxy-3-methylhex-2-ene (13):
To a solution of 1216 (2.00 g, 4.58 mmol) in anhyd Et2O (40 mL) were
added PdCl2(dppf•CH2Cl2 (374 mg, 0.458 mmol), and allylmagne-
sium bromide (1.27 M in Et2O, 18 mL, 22.9 mmol) under Ar at –78°C.
After stirring for 10 h at r.t., the mixture was poured into sat. NH4Cl
(100 mL), extracted with CH2Cl2 (300 mL) and the extract was
washed with brine (100 mL), dried (MgSO4), and concentrated. The
residue was purified by silica gel column chromatography (hexane–
CH2Cl2, 5:1) to give (Z)-6-tert-butyldiphenylsilyloxy-4-methylhexa-
1,4-diene (1.22 g, 76%).
(Z)-6-tert-Butyldiphenylsilyloxy-4-methylhexa-1,4-diene: colorless
syrup; bp 180°C (bath temp)/0.005 mmHg.
IR (neat): ν = 1598, 1377, 1269 cm–1.
1H NMR (CDCl3): δ = 1.13 (s, 9H), 1.75 (t, J = 1.0 Hz, 3H), 2.68 (d,
J = 6.6 Hz, 2H), 4.29 (d, J = 6.3 Hz, 2H), 4.94–5.06 (m, 2H), 5.55 (t,
J = 6.3 Hz, 1H), 5.58–5.79 (m, 1H), 7.38–7.53 (m, 6H), 7.73–7.81 (m,
1H).
1H NMR (CDCl3): δ = 0.34 (s, 6H), 1.05 (s, 9H), 3.93 (s, 6H), 6.61 (d,
J = 8.3 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 8.03 (s, 1H).
MS m/z = 466 (M+).
13C NMR (CDCl3): δ = 19.2, 23.3, 26.9, 36.6, 60.7, 115.4, 125.6,
127.6, 129.5, 134.0, 135.3, 135.6.
6-Allyl-7-tert-butyldimethylsilyloxy-1,4-dimethoxynaphthalene (9):
To a solution of 8 (10.55 g, 22.6 mmol) in anhyd Et2O (200 mL) were
added PdCl2(dppf)•CH2Cl2 (1.65 g, 2.02 mmol), and allylmagnesium
bromide (1.27 M in Et2O, 89 mL, 113 mmol) under Ar at –78°C. Af-
ter stirring for 42 h at r.t., the mixture was poured into sat. NH4Cl, ex-
tracted with EtOAc (500 mL) and the extract was washed with brine
(200 mL), dried (MgSO4), and concentrated. The residue was purified
by silica gel column chromatography (hexane–CH2Cl2, 4:1) to give 9
(8.10 g, 100%) as a colorless syrup.
MS m/z = 350 (M+).
Anal. Calcd for C23H30OSi: C, 78.80; H, 8.63; Found: C, 78.52; H,
8.39.
To a solution of freshly distilled (Z)-6-tert-butyldiphenylsilyloxy-4-
methylhexa-1,4-diene (1.0 mmol) in anhyd THF (2.0 mL) was added
a freshly prepared 9-BBN solution in THF (from 9-BBN dimer and
anhyd THF, then titrated) (ca. 0.5 M, 1.0 mmol) under Ar at 0°C. Af-
ter stirring for 6 h at r.t., the mixture was used for the next reaction.
IR (neat): ν = 1601, 1406, 1332, 1260 cm–1.
6-[(Z)-6-tert-Butyldiphenylsilyloxy-4-methylhex-4-enyl]-1,4-
dimethoxy-7-trifluoromethanesulfonyloxynaphthalene (11):
To a solution of 10 (6.53 g, 9.76 mmol) in THF (60 mL) was added
Bu4NF (1.0 M in THF, 9.76 mL, 9.76 mmol) under ice bath cooling.
After stirring for 10 min, the mixture was poured into sat. NH4Cl
(100 mL), extracted with Et2O (300 mL) and the extract was washed
with brine (100 mL), dried (MgSO4), and concentrated. The residue
was purified by silica gel column chromatography (CH2Cl2) to give
the 7-naphthol derivative (4.48 g) as a pale-yellow syrup. To a mix-
ture of the naphthol (4.48 g, 8.07 mmol), Et3N (3.54 mL, 25.4 mmol),
and CH2Cl2 (65 mL) was added Tf2O (2.13 mL, 12.7 mmol) at –
78°C. After stirring for 30 min at r.t., the mixture was poured into sat.
NaHCO3 (100 mL), extracted with CH2Cl2 (300 mL) and the extract
was washed with brine (100 mL), dried (MgSO4), and concentrated.
The residue was purified by silica gel column chromatography (hex-
ane–CH2Cl2, 3:1) to give 11 (4.70 g, 2 steps, 69%) as a white solid;
mp 57–59°C.
1H NMR (CDCl3): δ = 0.31 (s, 6H), 1.04 (s, 9H), 3.53 (d, J = 6.2 Hz,
2H), 3.93 (s, 6H), 5.02–5.13 (m, 2H), 6.00–6.16 (m, 1H), 6.52 (d, J =
8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.98 (s, 1H).
MS m/z = 358 (M+, 100), 301 (M+-t-Bu, 86), 286 (M+-t-BuMe, 23).
Anal. Calcd for C21H30O3Si: C, 70.35; H, 8.43; Found: C, 70.44; H,
8.60.
6-tert-Butyldimethylsilyloxy-7-[(Z)-6-tert-butyldiphenylsilyloxy-
4-methylhex-4-enyl]-1,4-dimethoxynaphthalene (10):
To a solution of 9 (4.30 g, 12.0 mmol) in anhyd THF (28 mL), was
added 9-BBN (0.5 M in THF, 50.4 mL, 25.2 mmol) under Ar at 0°C.
After stirring for 6 h at r.t., to the mixture were added K3PO4·nH2O
(13.8 g), a solution of 12 (7.85 g, 18.0 mmol) in THF (5 mL), and
PdCl2(dppf)•CH2Cl2 (490 mg, 0.60 mmol). After stirring for 4 h at
50°C, the mixture was poured into sat. NaCl, extracted with EtOAc
(200 mL) and the extract was washed with brine (300 mL), dried
(MgSO4), and concentrated. The residue was purified by silica gel
column chromatography (hexane–CH2Cl2, 4:1, then hexane–EtOAc,
19:1) to give 10 (7.22 g, 90%).
IR (neat): ν = 2934, 1419 cm–1.
1H NMR (CDCl3): δ = 1.04 (s, 9H), 1.64–1.73 (m, 2H), 1.72 (s, 3H),
1.96 (t, J = 8.4 Hz, 2H), 2.70 (t, J = 8.1 Hz, 2H), 3.93 (s, 3H), 3.94 (s,
3H), 4.19 (d, J = 6.6 Hz, 2H), 5.43 (t, J = 6.6 Hz, 1H), 6.71 (s, 2H),
7.31–7.43 (m, 6H), 7.63–7.71 (m, 4H), 8.035 (s, 1H), 8.041 (s, 1H).
MS m/z = 686 (M+).
To a solution of 8 (50.0 mg, 0.107 mmol) in THF (0.1 mL) were add-
ed K2CO3 (73.9 mg, 0.535 mmol), a THF solution of 13
(0.139 mmol), and PdCl2(dppf)•CH2Cl2 (16.8 mg, 0.0205 mmol). Af-
ter stirring for 13 h at 50°C, the mixture was poured into brine
(20 mL), extracted with EtOAc (50 mL) and the exract was washed
with brine (20 mL), dried (MgSO4), and concentrated. The residue
was purified by silica gel column chromatography (hexane–CH2Cl2,
4:1) to give 10 (49.5 mg, 69%) as a colorless syrup.
Anal. Calcd for C36H41F3O6SSi: C, 62.95; H, 6.07; Found: C, 62.65;
H, 6.20.
(1S)-1-[(E)-2-tert-Butyldiphenylsilyloxyethenyl]-5,8-dimethoxy-
1-methyl-1,2,3,4-tetrahydroanthracene (19):
After degassing (freeze-pump-thaw cycle (F.P.T. method)) a mixture
of 11 (68.7 mg, 0.10 mmol), K2CO3 (41.5 mg, 0.30 mmol), (S)-
IR (neat): ν = 1602, 1460, 1332, 1259 cm–1.

SYNTHESIS
1,4-Dimethoxy-6,7-bis(trifluoromethanesulfonyloxy)naphtha-
Papers
586
BINAP (12.5 mg, 0.020 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol), and
anhyd THF (2.0 mL) was stirred for 22 h at 60°C, diluted with EtOAc
(30 mL), washed with water (10 mL) and brine (10 mL), and the or-
ganic layer was dried (MgSO4), and concentrated. The residue was
purified by silica gel column chromatography (hexane–EtOAc, 9:1)
to give 19 (41.8 mg, 78%) as a colorless syrup.
lene (20):
To a mixture of 7 (300 mg, 1.36 mmol), pyridine (0.661 mL,
8.17 mmol), and CH2Cl2 (4 mL) was added Tf2O ( 0.688 mL, 4.09
mmol) at –78°C. After stirring for 3 h at r.t., the mixture was poured
into sat. NaHCO3 (10 mL), extracted with CH2Cl2 (30 mL) and the
extract was washed with 1M HCl (10 mL) and brine (10 mL) succes-
sively, dried (Na2SO4), and concentrated. The residue was purified by
silica gel column chromatography (hexane–CH2Cl2, 4:1) to give 20
(655 mg, 99%) as a white solid; mp 83–85°C.
IR (neat): ν = 2929, 1653 cm–1.
1H NMR (CDCl3): δ = 1.05 (s, 9H), 1.37 (s, 3H), 1.59–1.83 (m, 4H),
2.85–2.96 (m, 2H), 3.91 (s, 3H), 3.93 (s, 3H), 5.31 (d, J = 13.1 Hz,
1H), 6.01 (d, J = 13.1 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 6.59 (d, J =
9.2 Hz, 1H), 7.26–7.43 (m, 6H), 7.57–7.72 (m, 4H), 7.81 (s, 1H), 8.07
(s, 1H).
IR (KBr): ν = 2951, 2847, 2361, 1603 cm–1.
1H NMR (CDCl3): δ = 3.97 (s, 6H), 6.84 (s, 2H), 8.27 (s, 2H).
MS m/z = 484 (M+), 351 (M+-SO2CF3), 190 (bp).
MS m/z = 536 (M+).
[α]D24 –31.5 (c = 0.60, CHCl3) (87% ee).
Anal. Calcd for C14H10O8F6S2: C, 34.72; H, 2.08; Found: C, 34.84; H,
1.95.
Enantiomeric Excess Determination of Compound 19:
To a solution of 19 (1.00 g, 1.86 mmol) in THF (18.6 mL) were added
HOAc (0.32 mL, 5.59 mmol), and Bu4NF (1.0 M in THF, 3.73 mL,
3.73 mmol) under ice bath cooling. After stirring for 3 h at r.t., the
mixture was poured into sat. NH4Cl (20 mL), extracted with EtOAc
(50 mL) and the extract was washed with brine (20 mL), dried
(Na2SO4), and concentrated. To a solution of the residue in MeOH
(8.4 mL) was added NaBH4 (352 mg, 9.31 mmol) under ice bath cool-
ing. After stirring for 1 h at r.t., the solvent was removed in vacuo. To
the residue was carefully added 1M HCl (10 mL), the resulting mix-
ture was extracted with CH2Cl2 (20 mL) and the extract was washed
with brine (10 mL), dried (MgSO4), and concentrated. The residue
was purified by silica gel column chromatography (CH2Cl2–EtOAc,
9:1) to give 23 (523 mg, 2 steps, 93%).
Cascade Suzuki Cross-Coupling–Asymmetric Heck Reaction:
To a mixture of 20 (24.2 mg, 0.050 mmol), K2CO3 (41.5 mg,
0.30 mmol), (S)-BINAP (12.5 mg, 0.020 mmol), Pd(OAc)2 (2.2 mg,
0.010 mmol), and anhyd THF (0.50 mL) was added a solution of 13
(0.054 mmol) in THF. After degassing (F.P.T. method), the mixture
was stirred for 42 h at 60°C, diluted with EtOAc (10 mL), and the or-
ganic extract was washed with H2O (10 mL) and brine (10 mL), dried
(MgSO4), and concentrated. The residue was purified by silica gel
column chromatography (hexane–EtOAc, 9:1, then hexane–CH2Cl2,
3:1) to give 19 (5.30 mg, 20%, 85% ee). (Ee of 19 was determined by
HPLC analysis as described above.)
Cascade Suzuki Cross-Coupling–Heck Reaction; General Proce-
dure:
(1S)-1-(2-Hydroxyethyl)-5,8-dimethoxy-1-methyl-1,2,3,4-tetrahy-
droanthracene (23):
To a mixture of 20 (41.4 mg, 0.10 mmol), K2CO3 (83.0 mg, 0.60
mmol), ligand (see Table 1), Pd-source (see Table 1), and anhyd THF
(1.0 mL), was added a solution of 13 (0.13 mmol) in THF. After degas-
sing (F.P.T. method), the mixture was stirred for 24 h at 60°C, diluted
with EtOAc (20 mL), and the organic extract was washed with H2O
(10 mL) and brine (10 mL), dried (MgSO4), and concentrated. The res-
idue was purified by silica gel column chromatography (CH2Cl2 and
then hexane–EtOAc, 9:1 to 4:1) to give (±)-19, 21, and 22.
White solid; mp 74–75°C.
IR (neat): ν = 3380, 2930, 1597 cm–1.
1H NMR (CDCl3): δ = 1.42 (s, 3H), 1.62–2.03 (m, 5H), 2.14–2.30 (m,
1H), 2.92–3.03 (m, 2H), 3.54–3.76 (m, 2H), 3.93 (s, 3H), 3.94 (s, 3H),
6.56 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 8.13
(s, 1H).
13C NMR (CDCl3): δ = 19.9, 31.1, 31.5, 36.2, 36.4, 46.2, 55.4, 55.6,
59.9, 101.7, 102.2, 119.2, 121.0, 124.6, 125.1, 135.5, 143.1, 148.9,
149.1.
4-Trimethylsilyl-2-trimethylsilyloxybut-3-ynenitrile (31):
To a mixture of 3-trimethylsilylpropynal17 (1.00 g, 7.92 mmol), and
trimethylsilyl cyanide (1.16 mL, 8.71 mmol) was added ZnI2
(25.3 mg, 0.079 mmol) under Ar at r.t. After stirring for 30 min at r.t.,
the mixture was purified by distillation to give 31 (1.68 g, 91%) as a
light-yellow oil; bp 90°C (bath temp)/1 mmHg.
MS m/z = 300 (M+).
HRMS Calcd for C19H24O3: 300.1725, Found: 300.1737.
[α]D24 –31.3 (c = 0.70, CHCl3) (87% ee).
To a mixture of 23 (11.1 mg, 0.037 mmol), Et3N (0.013 mL,
0.0813 mmol), DMAP (1.3 mg, 0.0111 mmol), and CH2Cl2 (0.8 mL)
was added 4-nitrobenzoyl chloride (7.5 mg, 0.0406 mmol) under ice
bath cooling. After stirring for 30 min, the mixture was poured into
sat. NH4Cl (5 mL), extracted with CH2Cl2 (10 mL) and the extract
was washed with brine (5 mL), dried (MgSO4), and concentrated. The
residue was purified by silica gel column chromatography (hexane–
CH2Cl2, 1:2) to give (1S)-5,8-dimethoxy-1-methyl-1-[2-(4-nitroben-
zoyloxy)ethyl]-1,2,3,4-tetrahydroanthracene (16.0 mg, 96%).
IR (neat): ν = 3422, 2963, 1688, 1414, 1254 cm–1.
1H NMR (CDCl3): δ = 0.20 (s, 9H), 0.26 (m, 9H), 5.23 (s, 1H).
13C NMR (CDCl3): δ = -0.72, 0.11, 51.8, 95.9, 96.7, 116.2.
MS m/z = 225 (M+).
HRMS Calcd for C10H19NOSi: 225.1005, Found: 225.1001.
(1S)-5,8-Dimethoxy-1-methyl-1-(3-oxopent-4-ynyl)-1,2,3,4-tet-
rahydroanthracene (25):
To a solution of 23 (825.0 mg, 2.75 mmol) in CH2Cl2 (9.0 mL) were
added pyridine (0.289 mL, 3.57 mmol) and then Tf2O (0.554 mL,
3.30 mmol) at –78°C. After stirring for 20 min at r.t., the mixture was
washed with H2O (10 mL), and the organic layer was dried (MgSO4),
and concentrated in vacuo (below at 25°C) to give crude triflate 24.
To a solution of LDA (8.24 mmol) in anhyd THF (8.0 mL) was added
a solution of 31 (930 mg, 4.12 mmol) in anhyd THF (8.0 mL) at
–78°C. After stirring for 30 min at –78°C, a solution of crude 24 in
anhyd THF (8.0 mL) was added to the mixture at –78°C. After stir-
ring for 30 min at –50°C, the mixture was quenched with sat. NH4Cl
(50 mL), extracted with EtOAc (50 mL) and the extract was washed
with brine, dried (Na2SO4), and concentrated. To the residue was add-
ed THF (10 mL), and 1M HCl (2 mL), and the mixture was stirred for
30 min at r.t., diluted with EtOAc (50 mL). The organic layer was sep-
arated, shaken with 2% aq. NaOH for 10 min, and washed with 2%
NaOH (20 mL), and brine (30 mL) successively, dried (MgSO4), and
concentrated. To a solution of the residue in THF (20 mL) were added
HOAc (1.5 mL, 5.59 mmol), and Bu4NCl (1.0 M in THF, 3.5 mL,
(1S)-5,8-Dimethoxy-1-methyl-1-[2-(4-nitrobenzoyloxy)ethyl]-
1,2,3,4-tetrahydroanthracene: yellow syrup.
IR (neat): ν = 1724, 1600, 1528, 1274 cm–1.
1H NMR (CDCl3): δ = 1.46 (s, 3H), 1.66–2.16 (m, 5H), 2.49–2.63 (m,
1H), 2.97 (t, J = 5.9 Hz, 2H), 3.91 (s, 6H), 4.44 (t, J = 5.9 Hz, 2H),
6.50 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 7.4 Hz, 1H), 7.78 (d, J = 8.9 Hz,
2H), 7.80 (s, 1H), 8.02 (d, J = 8.9 Hz, 2H), 8.10 (s, 1H).
MS m/z = 449 (M+, 90), 255 (100).
HRMS Calcd for C26H27NO6: 449.1832, Found: 449.1831.
[α]D24 –48.4 (c = 0.52, CHCl3) (87% ee).
HPLC conditions for ee determination of (1S)-5,8-dimethoxy-1-me-
thyl-1-[2-(4-nitrobenzoyloxy)ethyl]-1,2,3,4-tetrahyroanthracene:
column: DAICEL CHIRALCEL OD; solvent : hexane – propan-2-ol,
9 : 1; flow rate: 0.5 mL/min; detector: UV detector (254 nm); reten-
tion time: 23.1 min (for (S)), 31.7 min (for (R)); retention volume: V0
= 5.0 mL, 23°C.

SYNTHESIS
April 1998
587
3.5 mmol) under ice bath cooling. After stirring for 10 min at r.t., the
mixture was poured into sat. NH4Cl (20 mL), extracted with EtOAc
(70 mL) and the extract was washed with aq sat. NaHCO3 (30 mL)
and brine (30 mL) successively, dried (Na2SO4), and concentrated.
The residue was purified by silica gel column chromatography (hex-
ane–EtOAc, 9:1) to give 25 (750 mg, 82%) as a colorless syrup.
IR (neat): ν = 3264, 2936, 2093, 1683, 1593 cm–1.
for 10 h at r.t., the mixture was diluted with CH2Cl2 (30 mL), and the
organic layer was washed with sat. NaHCO3 (10 mL) and brine
(10 mL) successively, dried (MgSO4), and concentrated. The residue
was purified by silica gel column chromatography (hexane–EtOAc,
4:1) to give 27 (30.5 mg, 96%) as a greenish yellow syrup.
IR (neat): ν = 2941, 2360, 1685 cm–1.
1H NMR (CDCl3): δ = 1.00–1.14 (m, 1H), 1.05 (s, 21H), 1.23–1.38
(m, 1H), 1.50 (s, 3H), 1.66–2.18 (m, 6H), 2.71 (ddd, J = 5.3, 5.3, 18.1
Hz, 1H), 2.87 (ddd, J = 6.3, 10.9, 18.1 Hz, 1H), 3.78–3.92 (m, 2H),
3.94 (s, 6H), 4.25 (ddd, J = 2.3, 10.9, 10.9 Hz, 2H), 6.63 (d, J = 8.3
Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 8.13 (s, 1H), 8.96 (s, 1H).
13C NMR (CDCl3): δ = 11.1, 18.6, 25.3, 26.9, 34.2, 34.9, 36.3, 37.1,
55.6, 62.3, 88.8, 96.6, 102.4, 102.9, 105.8, 118.9, 123.6, 124.5, 128.7,
129.3, 132.7, 146.8, 148.9, 150.9, 198.5.
1H NMR (CDCl3): δ = 1.40 (s, 3H), 1.60–1.73 (m, 1H), 1.74–1.94 (m,
3H), 1.95–2.08 (m, 1H), 2.24–2.42 (m, 1H), 2.42–2.64 (m, 2H), 2.87–
3.05 (m, 2H), 3.15 (s, 1H), 3.94 (s, 6H), 6.57 (d, J = 8.3 Hz, 1H), 6.61
(d, J = 8.3 Hz, 1H), 7.89 (s, 1H), 8.07 (s, 1H).
13C NMR (CDCl3): δ = 19.7, 31.1, 31.4, 35.7, 36.7, 37.1, 41.6, 55.5,
55.7, 78.3, 81.5, 101.9, 102.4, 119.3, 121.2, 124.7, 125.2, 135.7,
142.3, 148.9, 149.2, 187.5.
MS m/z = 336 (M+), 255 (M+-CH2CH2COCCH, 100).
MS m/z = 564 (M+).
HRMS Calcd for C22H24O3: 336.1725, Found: 336.1747.
HRMS Calcd for C34H48O5Si: 564.3271, Found: 564.3239.
[α]D27 –68.8 (c = 0.20, CHCl3) (87% ee).
[α]D28 –11.0 (c = 0.74, CHCl3) (87% ee).
(1S)-1-[3-(1,3-Dioxan-2-yl)pent-4-ynyl]-5,8-dimethoxy-1-methyl-
1,2,3,4-tetrahydroanthracene:
(4R)-4-[3-(1,3-Dioxan-2-yl)-5-triisopropylsilylpent-4-ynyl]-2-hy-
droxy-5,8-dimethoxy-4-methyl-1-oxo-1,4-dihydroanthracene (28):
A mixture of 27 (58.0 mg, 0.103 mmol), t-BuOK (58.0 mg,
0.517 mg), and t-BuOH (5.8 mL) was stirred under an O2 atmosphere
(1 atm) for 7 h at 35°C. The mixture was poured into sat. NH4Cl
(10 mL), extracted with CH2Cl2 (50 mL), and the extract was washed
with brine (20 mL), dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography (hexane–EtOAc,
4:1) to give 28 (47.0 mg, 79%) as a yellow amorphous solid.
IR (neat): ν = 3395, 2941, 2360, 1652, 1626 cm–1.
A mixture of 25 (18.0 mg, 0.0535 mmol), propane-1,3-diol (0.039
mL, 0.535 mmol), TsOH•H2O (1.0 mg, 0.0054 mmol), and benzene
(10 mL) was refluxed for 6 h with azeotropic removal of water using
a Dean–Stark trap. The mixture was poured into sat. NaHCO3
(10 mL), extracted with EtOAc (20 mL) and the extract was washed
with brine (10 mL), dried (MgSO4), and concentrated. The residue
was purified by silica gel column chromatography (hexane–EtOAc,
9:1) to give the title compound (20.6 mg, 98%) as a white powder; mp
132–134°C.
1H NMR (CDCl3): δ = 1.05 (s, 21H), 1.15–1.40 (m, 1H), 1.50–1.59
(m, 1H), 1.62 (s, 3H), 1.82–2.07 (m, 1H), 2.14 (ddd, J = 2.3, 13.2,
13.2 Hz, 1H), 2.41 (ddd, J = 5.3, 13.2, 13.2 Hz, 1H), 3.70–3.88 (m,
2H), 3.95 (s, 3H), 3.98 (s, 3H), 4.12–4.33 (m, 2H), 6.14 (s, 1H), 6.51
(s, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H),
9.13 (s, 1H).
IR (neat): ν = 3245, 2961, 2870, 2099, 1597 cm–1.
1H NMR (CDCl3): δ = 1.25–1.38 (m, 1H), 1.40 (s, 3H), 1.57–2.22 (m,
9H), 2.63 (s, 1H), 2.97 (t, J = 6.6 Hz, 2H), 3.80–4.00 (m, 2H), 3.93
(s, 6H), 4.22 (ddd, J = 2.6, 12.5, 12.5 Hz, 2H), 6.55 (d, J = 8.3 Hz,
1H), 6.59 (d, J = 8.3 Hz, 1H), 7.86 (s, 1H), 8.14 (s, 1H).
13C NMR (CDCl3): δ = 19.6, 25.2, 30.8, 31.2, 35.5, 36.4, 36.9, 37.1,
55.6, 55.7, 62.26, 62.30, 75.2, 79.5, 96.5, 101.7, 102.1, 119.5, 120.8,
124.6, 125.3, 135.8, 143.7, 148.9, 149.3.
13C NMR (CDCl3): δ = 11.1, 18.6, 25.2, 30.9, 37.1, 38.3, 40.2, 55.6,
55.7, 62.2, 88.8, 96.2, 102.3, 103.1, 105.8, 119.6, 123.2, 124.9, 125.2,
127.4, 128.5, 144.2, 146.5, 148.8, 150.7, 181.7.
MS m/z = 394 (M+), 255 (M+-CH2CH2C(OCH2CH2CH2O)CCH,
100).
MS m/z = 578 (M+).
HRMS Calcd for C34H46O6Si: 578.3064, Found: 578.3085.
Anal. Calcd for C25H30O4: C, 76.11; H, 7.67; Found: C, 76.10; H, 7.61.
[α]D28 –58.5 (c = 1.03, CHCl3) (87% ee).
[α]D24 –52.1 (c = 1.04, CHCl3) (87% ee).
(1S)-1-[3-(1,3-Dioxan-2-yl)-5-triisopropylsilylpent-4-ynyl]-3-hy-
droxy-2-iodo-5,8-dimethoxy-1-methyl-4-oxo-1,4-dihydroan-
thracene (29):
(1S)-1-[3-(1,3-Dioxan-2-yl)-5-triisopropylsilylpent-4-ynyl]-5,8-
dimethoxy-1-methyl-1,2,3,4-tetrahydroanthracene (26):
To
a
solution of (1S)-1-[3-(1,3-dioxan-2-yl)pent-4-ynyl]-5,8-
To a solution of 28 (47.5 mg, 0.0821 mmol) in MeOH (6 mL) were
added a solution of CuSO4•5H2O (205 mg, 0.821 mmol) in H2O
(2 mL), and then NaI (12 mg, 0.821 mmol). After stirring for 21 h at
r.t., the mixture was quenched with 5% Na2S2O3(20 mL), extracted
with CH2Cl2 (50 mL) and the extract was washed with brine (20 mL),
dried (MgSO4), and concentrated. The residue was purified by silica
gel column chromatography (hexane–EtOAc, 4:1) to give 29 (56.1
mg, 97%) as a yellow amorphous solid.
dimethoxy-1-methyl-1,2,3,4-tetrahydroanthracene (95 mg, 0.241
mmol) in anhyd THF (1 mL) was added BuLi (1.5 M in hexane, 0.321
mL, 0.482 mmol) at –78°C. After stirring for 30 min at –50°C, TIP-
SCl (0.103 mL, 0.482 mmol) was added to the mixture at –78°C. Af-
ter stirring for 30 min at r.t., the mixture was quenched with sat.
NH4Cl (10 mL), extracted with EtOAc (100 mL) and the extract was
washed with brine (30 mL), dried (MgSO4), and concentrated. The
residue was purified by silica gel column chromatography (hexane–
Et2O, 9:1) to give 26 (130 mg, 98%) as a colorless syrup.
IR (neat): ν = 2940, 2865, 2833, 1598, 1433 cm–1.
IR (neat): ν = 3853, 2940, 2360, 1653, 1623 cm–1.
1H NMR (CDCl3): δ = 1.10 (s, 21H), 1.18–1.32 (m, 1H), 1.42 (ddd, J
= 4.3, 12.9, 12.9 Hz, 1H), 1.75 (s, 3H), 1.80–2.02 (m, 1H), 2.30–2.60
(m, 2H), 3.65–3.87 (m, 2H), 3.96 (s, 3H), 3.98 (s, 3H), 4.10–4.30 (m,
2H), 6.69 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H),
8.47 (s, 1H), 9.16 (s, 1H).
1H NMR (CDCl3): δ = 1.10 (m, 21H), 1.15–1.39 (m, 1H), 1.39 (s,
3H), 1.61–1.75 (m, 1H), 1.75–2.08 (m, 8H), 2.96 (t, J = 6.3 Hz, 2H),
3.86 (dd, J = 4.0, 11.6 Hz, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 4.21–4.34
(m, 2H), 6.53 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 7.84 (s,
1H), 8.11 (s, 1H).
13C NMR (CDCl3): δ = 11.1, 18.7, 25.1, 33.8, 36.4, 39.4, 46.0, 55.66,
55.69, 62.0, 88.9, 95.6, 101.9, 103.3, 106.2, 111.3, 121.5, 123.8,
125.0, 126.2, 128.5, 142.5, 148.7, 150.2, 150.5, 176.6.
MS m/z = 704 (M+).
13C NMR (CDCl3): δ = 11.1, 18.6, 19.6, 25.3, 30.0, 31.1, 35.6, 36.6,
37.0, 55.4, 55.6, 62.3, 88.5, 96.9, 101.4, 102.1, 102.6, 119.4, 120.7,
124.6, 125.2, 135.5, 144.2, 148.9, 149.4.
HRMS Calcd for C34H45IO6Si: 704.2030, Found: 704.2058.
MS m/z = 550 (M+).
[α]D24 –44.6 (c = 1.00, CHCl3) (87% ee).
Anal. Calcd for C34H50O4Si: C, 74.13; H, 9.15; Found: C, 74.20; H, 9.36.
[α]D28 –32.8 (c = 0.825, CHCl3) (87% ee).
(1S)-3-Hydroxy-2-iodo-5,8-dimethoxy-1-methyl-4-oxo-1-(3-oxo-
5-triisopropylsilylpent-4-ynyl)-1,4-dihydroanthracene (30):
A mixture of 29 (7.10 mg, 0.010 mmol), TsOH•H2O (0.5 mg,
0.0026 mmol), and acetone (1.0 mL) was stirred for 12 h at 60°C. The
mixture was poured into sat. NaHCO3 (5 mL), extracted with EtOAc
(20 mL) and the extract was washed with brine (10 mL), dried
(1S)-1-[3-(1,3-Dioxan-2-yl)-5-triisopropylsilylpent-4-ynyl]-5,8-
dimethoxy-1-methyl-4-oxo-1,2,3,4-tetrahydroanthracene (27):
To a solution of 26 (31.0 mg, 0.0563 mmol) in CH2Cl2 (3.6 mL) were
added H2O (0.3 mL), and DDQ (38.3 mg, 0.169 mmol). After stirring

SYNTHESIS
Papers
588
(MgSO4), and concentrated. The residue was purified by silica gel
column chromatography (hexane–EtOAc, 4:1) to give 30 (6.37 mg,
98%) as a yellow amorphous solid.
145.71, 146.99, 148.25, 148.66, 150.80, 172.72, 192.16.
MS m/z = 362 (M+,100), 347 (M+-CH3, 98).
HRMS Calcd for C22H18O5: 362.1154, Found: 362.1154.
IR (neat): ν = 3356, 2943, 2866, 1655, 1624 cm–1.
1H NMR (CDCl3): δ = 1.03 (s, 21H), 1.57–1.72 (m, 1H), 1.75 (s, 3H),
2.12–2.38 (m, 1H), 2.48–2.69 (m, 2H), 3.98 (s, 3H), 4.00 (s, 3H), 6.73
(d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 8.46 (s, 1H),
9.21 (s, 1H).
[α]D23 +123.7 (c = 0.335, CH2Cl2) (87% ee).
(12bS)-12b-Methyl-1H-benzo[6,7]phenanthro[10,1-bc]furan-
3,6,8,11(2H,12bH)-tetrone (Halenaquinone) (1):
To a solution of 36 (56.0 mg, 0.115 mmol) in MeCN (15 mL) was
added a solution of cerium(IV) ammonium nitrate (CAN, 424 mg,
0.773 mmol) in H2O (1.5 mL) at r.t. After stirring for 10 min, the mix-
ture was poured into brine (15 mL), extracted with EtOAc (50 mL),
and the extract was washed with brine (20 mL), dried (MgSO4), and
concentrated. The residue was purified by silica gel column chroma-
tography (hexane–EtOAc, 2:1) to give 1 (51.0 mg, 99%) as a yellow
solid.
13C NMR (CDCl3): δ = 10.9, 18.5, 33.9, 39.2, 40.6, 45.7, 55.68,
55.73, 96.0, 103.7, 103.8, 106.6, 109.9, 121.5, 124.2, 125.1, 126.0,
128.5, 141.5, 148.6, 150.4, 150.5, 176.4, 186.1.
MS m/z = 646 (M+).
HRMS Calcd for C31H39IO5Si: 646.1612, Found: 646.1602.
[α]D24 –128.4 (c = 1.03, CHCl3) (87% ee).
(12bS)-8,11-Dimethoxy-12b-methyl-3,3-trimethylenedioxy-2,3-
dihydro-1H-benzo[6,7]phenanthro[10,1-bc]furan-6(12bH)-one
(33):
To a mixture of 32 (3.00 mg, 0.00547 mmol), K2CO3 (0.0274 mmol),
and MeCN (0.5 mL) was added Pd2(dba)3•CHCl3 (0.00274 mmol).
After stirring for 24 h at r.t., the mixture was quenched with sat.
NH4Cl (5 mL), extracted with EtOAc (10 mL) and the extract was
washed with brine (5 mL), dried (MgSO4), and concentrated. The res-
idue was purified by silica gel column chromatography (hexane–
EtOAc, 5:1) to give 33 (0.83 mg, 36%) as a yellow amorphous solid.
1H NMR (DMSO-d6): δ = 1.66 (s, 3H), 2.21 (ddd, J = 4.4, 13.2, 13.2
Hz, 1H), 2.68 (ddd, J = 3.9, 4.4, 18.6 Hz, 1H), 2.94 (ddd, J = 4.4, 5.4,
13.2 Hz, 1H), 3.11 (ddd, J = 5.4, 13.2, 18.6 Hz, 1H), 7.19 (s, 2H), 8.32
(s, 1H), 8.69 (s, 1H), 8.89 (s, 1H).
13C NMR (DMSO-d6): δ = 29.9, 32.3, 36.4, 36.8, 122.5, 123.9, 125.1,
130.4, 133.7, 136.5, 139.2, 139.3, 144.1, 148.7, 151.1, 154.7, 170.1,
184.0, 184.4, 191.7.
MS m/z = 332 (M+,48), 317 (M+-CH3, 100), 304 (14), 248 (22).
HRMS Calcd for C20H12O5: 332.0685, Found: 332.0659.
1H NMR (CDCl3): δ = 1.57 (s, 3H), 1.70–1.83 (m, 1H), 1.95–2.09 (m,
1H), 2.12–2.26 (m, 1H), 2.37–2.52 (m, 1H), 2.57–2.68 (m, 2H), 3.91–
4.02 (m, 2H), 3.98 (s, 6H), 4.07–4.15 (m, 2H), 6.71 (d, J = 8.3 Hz,
1H), 6.82 (d, J = 8.3 Hz, 1H), 8.03 (s, 1H), 8.25 (s, 1H), 9.26 (s, 1H).
MS m/z = 420 (M+).
(12bS)-8,11-Dihydroxy-12b-methyl-1H-benzo[6,7]phenan-
thro[10,1-bc]furan-3,6(2H,12bH)-dione (Halenaquinol) (2):
To a solution of 1 (1.02 mg, 0.0031 mmol) in acetone (1 mL) was add-
ed aqueous Na2S2O4 (0.57 M, 0.11 mL, 0.063 mmol) at 0°C in the ab-
sence of light. After stirring for 30 min, the mixture was diluted with
CH2Cl2, and the organic layer was separated, dried (Na2SO4), and
carefully evaporated in vacuo giving 2 in an almost quantitative yield
as a yellow solid.
(12bS)-8,11-Dimethoxy-12b-methyl-4-triisopropylsilyl-1H-ben-
zo[6,7]phenanthro[10,1-bc]furan-3,6(2H,12bH)-dione (35):
To a mixture of 30 (4.00 mg, 0.00619 mmol), K2CO3 (4.30 mg,
0.0309 mmol), and DMF (2.0 mL) was added Pd2(dba)3•CHCl3
(1.80 mg, 0.00174 mmol). After stirring for 8 h at r.t., the mixture was
quenched with sat. NH4Cl (10 mL), extracted with EtOAc (20 mL)
and the extract was washed with brine (10 mL), dried (MgSO4), and
concentrated. The residue was purified by silica gel column chroma-
tography (hexane–EtOAc, 5:1) to give 35 (2.30 mg, 72%) as a yellow
amorphous solid.
1H NMR (DMSO-d6): δ = 1.63 (s, 3H), 2.0–2.4 (m, 1H), 2.6–3.3 (m,
3H), 6.76 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 8.26 (s, 1H),
8.82 (s, 1H), 9.00 (s, 1H), 9.63 (s, 1H), 9.82 (s, 1H).
Other spectral data have not been measured, because this compound
is very sensitive to light, heat, and air as previously reported.3
(1) Roll, D. M.; Scheuer, P. J.; Matsumoto, G. K.; Clardy, J. J. Am.
Chem. Soc. 1983, 105, 6177.
IR (neat): ν = 2943, 2359, 1672, 1629, 1614 cm–1.
1H NMR (CDCl3): δ = 1.11 (d, J = 7.6 Hz, 9H), 1.14 (d, J = 7.6 Hz,
9H), 1.66 (s, 3H), 1.70–1.81 (m, 3H), 2.32 (ddd, J = 5.0, 13.2, 13.2
Hz, 1H), 2.72–3.10 (m, 3H), 3.99 (s, 3H), 4.00 (s, 3H), 6.73 (d, J = 8.3
Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 8.32 (s, 1H), 9.30 (s, 1H).
13C NMR (CDCl3): δ = 11.3, 18.6, 18.7, 32.1, 34.0, 36.0, 37.1, 55.7,
103.6, 106.2, 118.3, 124.5, 124.8, 127.6, 130.9, 131.5, 144.8, 147.5,
148.7, 150.8, 172.2, 172.5, 192.8.
Kobayashi, M.; Shimizu, N.; Kyogoku, Y.; Kitagawa, I. Chem.
Pharm. Bull. 1985, 33, 1305.
Kobayashi, M.; Shimizu, N.; Kitagawa, I.; Kyogoku, Y.; Hara-
da, N.; Uda, H. Tetrahedron Lett. 1985, 26, 3833.
Nakamura, H.; Kobayashi, J.; Kobayashi, M.; Ohizumi, Y.; Hir-
ata, Y.; Chem.Lett. 1985, 713.
Schmitz, F. J.; Bloor, S. J. Org. Chem. 1988, 53, 3922.
(2) Ikegami, S.; Kitagawa, I.; Takayama, S.; Makihara, R.; Koba-
yashi, M.; Miyashiro, S. JP 03173881, 1991.
MS m/z = 518 (M+), 475 (M+-CH(CH3)2, 100).
HRMS Calcd for C31H38O5Si: 518.2489, Found: 518.2501.
[α]D25 +38.3 (c = 0.68, CHCl3) (87% ee).
Lee, R. H.; Slate, D. L.; Moretti, R.; Alvi, K. A.; Crews, P.
Biochem. Biophys. Res. Comm. 1992, 184, 765.
Alvi, K. A.; Diaz, M. C.; Crews, P.; Slate, D. L.; Lee, R. H.; Mo-
retti, R. J. Org. Chem. 1992, 57, 6604.
(3) Harada, N.; Sugioka, T.; Ando, Y.; Uda, H.; Kuriki, T. J. Am.
Chem. Soc. 1988, 110, 8483.
(12bS)-8,11-Dimethoxy-12b-methyl-1H-benzo[6,7]phenan-
thro[10,1-bc]furan-3,6(2H,12bH)-dione (Halenaquinol Dimethyl
Ether) (36):
To a solution of 35 (8.13 mg, 0.0157 mmol) in MeCN (3.0 mL) were
added HOAc (0.0215 mL, 0.376 mmol), and Bu4NCl (1.0 M in THF,
0.250 mL, 0.250 mmol) under ice bath cooling. After stirring for 2.5 h
at 60°C, the mixture was poured into sat. NH4Cl (10 mL), extracted
with EtOAc (20 mL) and the extract was washed with brine (10 mL),
dried (MgSO4), and concentrated. The residue was purified by silica
gel column chromatography (hexane–EtOAc, 1:1, and then CHCl3) to
give 36 (4.71 mg, 83%) as a yellow solid; mp 220–225°C.
IR (neat): ν = 1697, 1673, 1628, 1464, 1339 cm–1.
(4) For a preliminary communication, see: Kojima, A.; Takemoto,
T.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1996, 61, 4876.
(5) For a synthetic approach to 1 and 2, see: Cristofoli, W. A.;
Keay, B. A. Synlett 1994, 625.
(6) For a total synthesis of (+)-xestoquinone, see: Harada, N.; Su-
gioka, T.; Uda, H.; Kuriki, T. J. Org. Chem. 1990, 55, 3158.
Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.; Keay, B.
A. J. Am. Chem. Soc. 1996, 118, 10766.
For a total synthesis of (±)-xestoquinone, see: Kanematsu, K.;
Soejima, S.; Wang, G. Tetrahedron Lett. 1991, 32, 4761.
Carlini, R.; Higgs, K.; Older, C.; Randhawa, S.; Rodrigo, R.
J. Org. Chem. 1997, 62, 2330.
1H NMR (CDCl3): δ = 1.677 (s, 3H), 2.334 (ddd, J = 4.6, 12.9, 12.9
Hz, 2H), 2.75–3.12 (m, 3H), 3.989 (s, 3H), 3.992 (s, 3H), 6.734 (d, J
= 8.6 Hz, 1H), 6.848 (d, J = 8.6 Hz, 1H), 8.220 (s, 1H), 8.310 (s, 1H),
9.301 (s, 1H).
(7) Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am.
Chem. Soc. 1993, 115, 8477.
13C NMR (CDCl3): δ = 31.74, 34.20, 35.76, 36.80, 55.73, 103.76,
106.52, 118.47, 122.53, 124.73, 124.80, 127.58, 130.44, 144.42,

SYNTHESIS
April 1998
For a recent review of an asymmetric Heck reaction, see: Shiba-
589
respect of the Suzuki cross-coupling and asymmetric Heck re-
action sequence. See: Kojima, A.; Boden, C. D. J.; Shibasaki,
M. Tetrahedron Lett. 1997, 38, 3459.
saki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53,
7371.
(8) For a general review, see: Tamao, K. Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Pattenden, G., Eds; Perga-
mon: New York, 1991; Vol. 3, p 435.
(9) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(10) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(11) Farina, V. Pure Appl. Chem. 1996, 68, 73.
(12) Kojima, A.; Honzawa, S.; Boden, C. D. J.; Shibasaki, M. Tetra-
hedron Lett. 1997, 38, 3455.
(13) In the light of these successful results, we prepared the chiral ar-
sine ligand BINAs. This, however, turned out not to be useful in
(14) Starostin, E. K.; Mazurchik, A. A.; Ignatenko, A. V.; Nikishin,
G. I. Synthesis 1992, 917.
(15) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org.
Chem. 1995, 60, 3270.
(16) Compound 12 was prepared from the corresponding known al-
cohol by conventional means. See, Cochrane, J. S.; Hanson, J.
R. J. Chem. Soc., Perkin Trans. 1 1972, 3, 361.
(17) Kruithof, K. J. H.; Schmits, R. F.; Klumpp, G. W. Tetrahedron
1983, 39, 3073.