Addition of 2-tert-butyldimethylsilyloxythiophene to activated quinones: An approach to thia analogues of kalafungin

Article abstract of DOI:10.1016/j.tet.2006.01.040

The uncatalyzed reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-quinones bearing either an electron withdrawing acetyl or a carbomethoxy group at C-2, was investigated. No reaction was observed using 1,4-quinones 8 and 9 bearing an ester grou

Full text of DOI:10.1016/j.tet.2006.01.040

Tetrahedron 62 (2006) 3021–3027
Addition of 2-tert-butyldimethylsilyloxythiophene to activated
quinones: an approach to thia analogues of kalafungin
*
Margaret A. Brimble, Olivia Laita and James E. Robinson
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Received 1 November 2005; revised 21 December 2005; accepted 12 January 2006
Available online 2 February 2006
Abstract—The uncatalyzed reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-quinones bearing either an electron withdrawing
acetyl or a carbomethoxy group at C-2, was investigated. No reaction was observed using 1,4-quinones 8 and 9 bearing an ester group at C-2
whereas use of 1,4-quinones 10 and 11 bearing an acetyl group at C-2 only provided low yields of the silyloxythiophenes 15 and 16 resulting
from electrophilic substitution of the silyloxythiophene by the 1,4-quinone. Use of the Lewis acids InCl3, Cu(OTf)2 and BF3$Et2O were
investigated in an effort to improve the yield of the desired annulation reaction. BF3$Et2O proved to be the optimum catalyst for the synthesis
of thiolactone naphthofuran adducts 14 and 18 from 1,4-naphthoquinones 9 and 11, respectively. Reaction of 2-tert-butyldimethylsilyloxy-
thiophene 2 with 1,4-benzoquinones 8 and 10 bearing a carbomethoxy or an acetyl group at C-2, respectively, afforded thiolactone
benzofuran adducts 13 and 17, respectively, catalyzed by either InCl3 or Cu(OTf)2. Addition of 2-tert-butyldimethylsilyloxythiophene 2 to
3-acetyl-5-methoxy-1,4-naphthoquinone 12 afforded adduct 19 that underwent oxidative rearrangement to thiolactone pyranonaphthoqui-
none 20 using ceric ammonium nitrate in acetonitrile, thus providing a novel approach for the synthesis of a thia analogue of the
pyranonaphthoquinone antibiotic kalafungin.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
We have studied the reaction of the silyl enolate d4 synthons,
TMSOF 1 and TBSOP 3 with 1,4-benzoquinones and 1,4-
naphthoquinones bearing electron withdrawing groups at C-2
in which initial conjugate addition to the quinone is followed
by intramolecular cyclization to afford either a furobenzo-
furan or pyrrolobenzofuran or a furonaphthofuran or
pyrrolonaphthofuran, respectively (Scheme 2). This annula-
tion step formed a key step in our synthesis of the
pyranonaphthoquinone antibiotic kalafungin11 and the syn-
thesis of aza analogues12 thereof, by effecting a facile
oxidative cyclization of the initial annulation product.
The silyl enolate d4 synthons 2-trimethylsilyloxyfuran
(TMSOF) 1, 2-(tert-butyldimethylsilyloxy)thiophene
(TBSOT) 2 and N-(tert-butoxycarbonyl)-2-tert-butyldi-
methylsilyloxypyrrole (TBSOP) 3 readily undergo vinylo-
gous aldol-like reactions1 with aldehydes, vinylogous
imino-aldol reactions2 (Mannich type addition) with imines
and vinylogous addition to heteroatom-stablized carbenium
ions (Scheme 1).3 The resultant aldol-like products provide
ready access to many bioactive molecules including the
Annonaceous acetogenins,4,5 carbasugars,6 densely
hydroxylated indolizidine alkaloids,7 hydroxylated pro-
lines,8 aminosugars9 and peptidyl C-glycosides.10
As an extension to this work, we now herein report the
results of our studies on the hitherto unreported addition of
+
Y
Z
Z
or
+
YH
or
RO
O
X
X
O
X
n = 1,2
Y = O, NH; Z = O, N
n = 1,2
1: X = O; R = SiMe3
2: X = S; R= SitBuMe2
3: X = NCO2 Bu; R= SitBuMe2
t
Scheme 1.
Keywords: Silyloxythiophene; Quinones; Pyranonaphthoquinone antibiotics; Annulation.
*
Corresponding author. Fax: C64 9 3737422; e-mail: m.brimble@auckland.ac.nz
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.040

3022
M. A. Brimble et al. / Tetrahedron 62 (2006) 3021–3027
OMe
O
O
OMe OH
O
O
OMe
O
O
O
HO Me
O
OH
Me H
Me
Me
O
CAN
H
H
O
H
+
X
H
H
O
H
O
X
O
O
O
RO
X
kalafungin
1: X = O; R = SiMe3
X = O
X = NCO2 Bu
X = O
X = NCO2 Bu
3: X = NCO2 Bu; R= SitBuMe2
t
t
t
Scheme 2.
2-(tert-butyldimethylsilyloxy)thiophene (TBSOT) 2 to a
series of benzoquinones and naphthoquinones bearing either
an acetyl group or a carbomethoxy group at C-2. The
resultant annulation products would provide access to thia
analogues of the kalafungin skeleton that were of interest
due to their potential bioactivity as bioreductive alkylating
agents.13
reported an alternative procedure for the preparation of
thiolactone 6 employing tert-butyl ether 7. Accordingly, the
Grignard generated from 2-bromothiophene 4 was treated
with tert-butyl peroxybenzoate and the resultant tert-butyl
ether 7 hydrolyzed with p-toluenesulfonic acid at 160 8C.
Gratifyingly, thiolactone 6 was isolated in 61% yield.
Silyl enol ether formation14 using tert-butyldimethylsilyl
trifluoromethane sulfonate and 2,6-lutidine proceeded
smoothly to furnish TBSOT 2 in 84% yield.
2. Results and discussion
With TBSOT 2 in hand, the conjugate addition reactions to
several readily accessible quinones 8, 9, 10, 11, similar in
structure to the quinone precursor 12 required to prepare a
thia analogue of kalafungin (Scheme 4), were next
investigated (Table 1). Our previous paper describing the
addition of silyloxypyrrole 3 to activated quinones reports
the syntheses of the quinone starting materials.12
It was proposed that addition of 2-(tert-butyldimethylsilyl-
oxy)thiophene (TBSOT) 2 to 1,4-quinones bearing an
electron withdrawing group at C-2 would follow a similar
pathway to the addition of TMSOF 1 and TBSOP 3
affording thia analogues of the corresponding furo[3,2-b]-
benzofuran and furo[3,2-b]naphthofuran adducts. Initial
synthesis of TBSOT 2 was therefore required.
It was anticipated that the uncatalyzed addition of TBSOT 2
to 2-carbomethoxyquinones 8 and 9 would provide
thiolactone adducts 13 and 14, respectively. However,
after stirring the quinones 8 and 9 with TBSOT 2 at room
temperature in acetonitrile for 16 h, no reaction was
observed (Table 1). Treatment of the more electron
withdrawing 2-acetylquinones 10 and 11 with TBSOT 2
was more encouraging, providing substituted silyloxythio-
phenes 15 and 16, arising from direct eletrophilic aromatic
It was envisaged that TBSOT 2 could be prepared from
thiolactone 6 using the procedure reported by Casiraghi
et al.14 (Scheme 3). The thiolactone precursor 6 was
originally prepared by Hawkins15 from 2-bromothiophene 4
via the boronate ester 5. Following the procedure
of Hawkins15 2-bromothiophene 4 was treated with
n-butyllithium followed by trimethylborate. Oxidative
work-up of the resultant boronate 5, however, furnished
thiolactone 6 in only 26% yield. Frisell and Lawesson16
S
i
ii
B(OMe)3–n
n
5
OSitBuMe2
S
S
S
v
Br
O
2
4
6
S
iii
iv
Ot-Bu
7
Scheme 3. Reagents and conditions: (i) n-BuLi, THF, reflux 1 h then B(OMe)3, 60 8C, 2 h; (ii) H2O2, 0 8C to rt, 26% over two steps; (iii) Mg, Et2O, rt, 3 h,
reflux, 0.5 h then PhCO2OtBu, 0 8C, 12 h; (iv) p-TsOH, 160 8C, 10 min, 61% over two steps; (v) tBuMe2SiOTf, 2,6-lutidine, CH2Cl2, 0 8C to rt, 1 h, 84%.
Me
H
OH
O
OMe O
OMeOH
O
OMe O
O
Me
S
Me
i
ii
H
H
OSitBuMe2
S
O
S
O
O
O
12
H
2
19
20
O
Scheme 4. Reagents and conditions: (i) BF3$OEt2, CH2Cl2, K78 8C, 1 h, 45%; (ii) CAN (2.0 equiv), MeCN–H2O (1:1), 21%.

M. A. Brimble et al. / Tetrahedron 62 (2006) 3021–3027
Table 1. Addition of TBSOT 2 to 1,4-quinones 8, 9, 10 and 11
3023
Uncatalyzeda
InCl3
Cu(OTf)2
BF3$OEt2
b
c
d
Quinone
OH
O
O
O
O
OMe
OMe
O
H
No reaction
13 13%
—
S
O
O
8
H
13 11%
O
OH O
OMe
OMe
H
No reaction
S
14 30%
17 22%
18 33%
14 31%
O
O
H
9
O
14 27%
O
O
O
OH O
OH
O
Me
S
Me
O
Me
H
S
OSitBuMe2
—
OH
O
O
10
H
15 35%
17 35%
O
O
OH O
Me
Me
H
S
18 48%
O
H
O
11
18 9%
a Reactions carried out using 2 (1.1 equiv) in acetonitrile at rt for 16 h.
b Reactions carried out using 2 (1.0 equiv) InCl3 (5%) in acetonitrile at rt, 0 8C then rt, 16 h.
c Reactions carried out using 2 (1.0 equiv), Cu(OTf)2 (1.0 equiv) in dichloromethane, K78 8C then rt, 2 h.
d Reactions carried out using 2 (1.0 equiv), BF3$Et2O (1.1 equiv) in dichloromethane, K78 8C then rt, 1 h.
substitution of the thiophene ring, in 35 and 11% yield,
respectively.
(1.0 equiv) in dichloromethane at K78 8C and the resultant
mixture then treated with TBSOT 2. Although the reactions
proceeded cleanly to completion, as monitored by thin-layer
chromatography, it was nevertheless disappointing to
observe no significant improvement in the isolated yields
of the desired adducts 13, 14, 17 and 18.
Whilst the uncatalyzed addition of TBSOT 2 to the
aforementioned quinones 8, 9, 10 and 11 failed to furnish
the desired thiolactone adducts 13, 14, 17 and 18, it was
hoped that use of a Lewis acid to promote the desired
annulation reaction would be more fruitful. Yadav
et al.17,18,19,20 and Loh and Wei21,22 have reported the
catalysis of conjugate addition reactions using indium(III)
chloride, however, neither group had investigated the use
of 2-silyloxythiophenes as nucleophiles or quinones as
Michael acceptors. Accordingly, quinones 8, 9, 10 and 11
were treated with TBSOT 2 in the presence of indium(III)
chloride (5 mol%) in acetonitile at 0 8C. After allowing the
reaction mixture to warm to room temperature and stirring
for 16 h gratifyingly, the desired corresponding thiolactone
adducts 13, 14, 17 and 18 were isolated in modest yield after
purification by flash chromatography.
The desired adducts were highly susceptible to degradation
upon flash chromatography presumably accounting for the
low yields of the isolated products. Efforts to try to improve
the stability of the adducts via protection of the free phenol
as either an acetate or a tert-butyldimethylsilyl ether were
unsuccessful, and led only to the formation of a complex
mixture of products in both instances. Use of reverse phase
HPLC and alumina or florisil as solid supports for
chromatography also did not offer any improvement.
Catalysis of the conjugate addition reaction using boron
trifluoride etherate was next investigated. Accordingly, a
solution of each of the quinones 8, 9, 10 and 11 and TBSOT
2 in dichloromethane at K78 8C was treated with boron
trifluoride etherate (1.1 equiv). The reaction of benzo-
quinones 8 and 10 led to the formation of a complex mixture
of products, whilst naphthoquinones 9 and 11 afforded
thiolactone naphthofurans 14 and 18 in 31 and 48% yield,
respectively; possibly reflecting the lower reactivity of the
naphthoquinones 9 and 11 compared to the corresponding
benzoquinones 8 and 10.
In an effort to improve the yields of the desired adducts 13,
14, 17 and 18, the use of an alternative Lewis acid was next
investigated. Brimble et al.23 have employed copper(II)
trifluoromethanesulfonate as a Lewis acid in the Michael
addition of TMSOF 1 to various chiral naphthoquinones.
Following this precedent, a solution of each of the quinones
8, 9, 10 and 11 in dichloromethane was added to a
suspension of copper(II) trifluoromethanesulfonate

3024
M. A. Brimble et al. / Tetrahedron 62 (2006) 3021–3027
Having successfully prepared thiolactone naphthofuran 18 in
a modest 48% yield using boron trifluoride etherate as a
Lewis acid, the synthesis of a thia analogue of kalafungin was
next undertaken (Scheme 4). Following the procedure
established for the preparation of 18, a solution of
naphthoquinone 12 and TBSOT 2 in dichloromethane at
K78 8C was treated with boron trifluoride etherate
(1.1 equiv) affording thiolactone naphthofuran 19 in 45%
yield. Facile oxidative cyclization of 19 to the desired
thiolactone pyranonaphthoquinone 20 using ceric ammonium
nitrate proceeded in 21% yield. Use of alternative oxidants
was unsuccessful affording none of the desired oxidative
cyclization product. Disappointingly, the thia analogue 20 of
kalafungin thus prepared was unstable rapidly degrading to a
complex mixture of products.
(cmK1). 1H and 13C NMR spectra were obtained using either a
BrukerDRX-400spectrophotometer operatingateither400 or
100 MHz or a Bruker Avance 300 spectrometer operating at
300 or 75 MHz, respectively. Data are expressed in parts per
million downfield shift from tetramethylsilane as an internal
standard or relative to CDCl3. All J values are given in Hertz.
Assignments are made with the aid of DEPT 135, COSY and
HSQC experiments. High-resolution mass spectra were
recorded using a VG70-SE spectrometer operating at a
nominal accelerating voltage of 70 eV. Fast atom bombard-
ment (FAB) mass spectra were obtained using 3-nitrobenzyl
alcohol as the matrix. Quinones 8, 9, 10 and 11 were prepared
as described in our previous paper.12
4.2. Preparation of 2-(tert-butyldimethylsilyloxy)
thiophene 2
3. Conclusions
4.2.1. 3-Thiolen-2-one 6. Procedure A. In an adaptation of
the procedure used by Hawkins,15 2-bromothiophene 4
(2.00 mL, 20.7 mmol) was dissolved in dry tetrahydrofuran
(25 mL) at room temperature under an atmosphere of
nitrogen. To this stirred solution was added n-butyllithium
(15.2 mL, 22.7 mmol, 1.50 M) dropwise slowly over
20 min. The resultant solution was heated at reflux for 1 h,
cooled to 45 8C then trimethylborate (1.6 mL, 13.8 mmol)
added via syringe. After heating for 2 h at 60 8C the reaction
was cooled to 0 8C. Water (5 mL) was added followed by
hydrogen peroxide (4.9 mL, 161.1 mmol) dropwise and the
solution allowed to warm to room temperature. After 2 h
the mixture was acidified and extracted with diethyl ether
(3!50 mL). The combined organic extracts were dried over
magnesium sulphate, filtered and the solvent removed at
reduced pressure. Purification by flash column chromato-
graphy using hexane–ethyl acetate (8/2) as eluent provided
the title compound 6 (538 mg, 26%) as a yellow oil; dH
(300 MHz, CDCl3) 4.15 (2H, dd, JZ2.7, 2.0 Hz, H5), 6.43
(1H, dt, JZ5.9, 2.0 Hz, H3) and 7.58 (1H, dt, JZ5.9,
2.7 Hz, H4). This data was in agreement with that reported
in the literature.24
In summary, a study of the addition of TBSOT 2 to several
electron deficient quinones is reported. Uncatalyzed
addition of TBSOP 2 to 1,4-quinones 8 and 9 bearing
carbomethoxy substituents at C-2 was unsuccessful whilst
use of the 2-acetylquinones 10 and 11 afforded the
electrophilic substitution products 15 and 16, respectively.
Use of the Lewis acids InCl3, Cu(OTf)2 and BF3$Et2O to
promote the annulation reaction afforded the desired
thiolactone adducts 13, 14, 17 and 18. BF3$Et2O proved
to be the optimum catalyst for the reaction of TBSOT 2 with
the naphthoquinones 9 and 11 to provide adducts 14 and 18,
respectively, whilst InCl3 and Cu(OTf)2 were more effective
for the reaction of TBSOT 2 with the benzoquinones 9 and
11 to provide adducts 13 and 17, respectively. These
thiolactone benzofuran and naphthofuran adducts provide
novel heterocyclic ring systems that can be further
elaborated to provide thia analogues of natural products as
demonstrated by the conversion of adduct 19 to a thia
analogue 20 of the bioreductive alkylating agent kalafungin.
4. Experimental
Procedure B. In an adaptation of the procedure used by
Frisell and Lawesson,16 a two-necked flask was charged
with magnesium turnings (527 mg, 21.7 mmol) and a single
crystal of iodine then covered with dry diethyl ether
(40 mL). To this stirred mixture was added 10% of a
solution of 2-bromothiophene 4 (2.0 mL, 20.7 mmol) in
diethyl ether (70 mL). After gently heating the mixture to
initiate a reaction the remainder of the 2-bromothiophene
solution was then added dropwise. The mixture was stirred
for 3 h at room temperature then 0.5 h under reflux before
cooling to 0 8C in an ice-bath. tert-Butylperoxy benzoate
(3.3 cm3, 17.6 mmol) was added dropwise and the mixture
allowed to warm to room temperature. After 12 h the
mixture was poured into ice-water (30 mL) and acidified
with concentrated hydrochloric acid. The aqueous layer was
extracted with diethyl ether (3!100 mL) and the combined
extracts dried over magnesium sulphate. Filtration and
removal of the solvent afforded a crude oil that was purified
by flash column chromatography using hexane as eluent.
The resultant 2-tert-butoxythiophene 7 was treated with
p-toluenesulfonic acid (10 mg) and heated at 160 8C for
10 min. Purification by flash column chromatography using
hexane–ethyl acetate (8/2) as eluent gave the title compound
4.1. General details
All reactions were carried out in oven-dried or flame-dried
glassware under a nitrogen atmosphere using standard
syringe and septum techniques unless otherwise stated.
Diethyl ether and tetrahydrofuran were freshly distilled
from sodium/benzophenone. Hexane, pentane, dichloro-
methane, triethylamine and diethylamine were distilled
from calcium hydride. Thin-layer chromatography was
performed on precoated 0.2 mm Merck Kieselgel 60 F254
silica plates and compounds were visualized under 365 nm
ultraviolet irradiation followed by staining with either
alkaline permanganate or ethanolic vanillin solution. Flash
column chromatography was performed using Reidel-de
¨
Haen Kieselgel or Merck Kieselgel 60 F (both 230–400
mesh) with the indicated solvents. Melting points were
determined on an electrothermal melting point apparatus
and are uncorrected. Infrared spectra were recorded with a
Perkin-Elmer Spectrum One Fourier Transform IR
spectrophotometer as thin films between sodium chloride
plates. Absorption maxima are expressed in wavenumbers

M. A. Brimble et al. / Tetrahedron 62 (2006) 3021–3027
3025
6 (1.26 g, 61%) as a yellow oil. The spectroscopic data was
identical to that reported above and was in agreement with
that reported in the literature.24
was added a solution of 2-(tert-butyldimethylsilyloxy)thio-
phene 2 (214 mg, 1.00 mmol) in dichloromethane (5 mL).
Boron trifluoride etherate (0.14 mL, 1.10 mmol) was added
dropwise and the mixture stirred for 1 h. The reaction was
quenched by the addition of water (3 cm3) and allowed to
warm to room temperature. The aqueous layer was extracted
with dichloromethane (3!15 mL) and the combined
organic extracts dried over magnesium sulphate. Filtration
and removal of the solvent at reduced pressure gave a
residue that was purified by flash column chromatography to
afford the title compound.
4.2.2. 2-(tert-Butyldimethylsilyloxy)thiophene 2.
Following the procedure reported by Casiraghi et al.14
3-thiolen-2-one 6 (1.25 g, 12.5 mmol) was dissolved in
dichloromethane (25 mL) under an atmosphere of nitrogen
and the solution cooled to 0 8C. To this stirred solution
was added 2,6-lutidine (4.4 mL, 37.4 mmol) followed by
tert-butyldimethylsilyl trifluoromethanesulfonate (4.30 mL,
18.7 mmol). The mixture was allowed to warm to room
temperature, stirred for 1 h then the solvent was removed
under reduced pressure. Purification of the resultant residue
by flash column chromatography using hexane as eluent
provided the title compound 2 (2.24 g, 84%) as a colourless
oil; dH (300 MHz, CDCl3) 0.22 (6H, s, tBuMe2Si), 0.98 (9H,
4.3.2. cis-8-Carbomethoxy-7-hydroxy-2-oxo-2,3,3a,8b-
tetrahydro-1H-[1]benzofuro[3,2-b]thiophene13.Flash col-
umn chromatography using hexane–ethyl acetate (8/2) as
the eluent gave the title compound 13 (Procedure B 11%;
Procedure C 13%) as a red solid; mp 160–162 8C;
nmax(film)/cmK1 3426br (OH) and 1644s (CO); dH
(400 MHz, CDCl3), 3.12 (1H, dd, JZ18.2, 6.2 Hz, H3),
3.23 (1H, d, JZ18.2 Hz, H3), 3.98 (3H, s, Me), 5.31 (1H, t,
JZ6.2 Hz, H3a), 5.76 (1H, d, JZ6.2 Hz, H8b), 6.92 (1H, d,
JZ8.9 Hz, H6), 7.03 (1H, d, JZ8.9 Hz, H5) and 10.44 (1H,
s, OH); dC (75 MHz, CDCl3) 47.8 (CH2, C3), 52.6 (CH3,
Me), 56.2 (CH, C8b), 83.2 (CH, C3a), 108.5 (quat., C8),
118.2 (CH, C6), 119.4 (CH, C5), 127.4 (quat., C8a), 152.3
(quat., C7), 157.1 (quat., C4a), 169.3 (quat., CO) and 204.4
(quat., C2); m/z (EI): 266 (MC, 100), 234 (MKCH3OH,
78), 224 (MKCH2CO), 207 (MKCO2Me, 2), 192
(MKCH2SCO, 16) and 57 (C4H9, 14); HRMS (EI): Found
MC, 266.0239. C12H10O5S requires 266.0249.
t
s, BuMe2Si), 6.14 (1H, dd, JZ3.1, 1.6 Hz, H3), 6.50 (1H,
dd, JZ5.9, 1.6 Hz, H5), 6.65 (1H, dd, JZ5.9, 3.1 Hz, H4).
This data was in agreement with that reported in the
literature.14
4.3. Addition of 2-(tert-butyldimethylsilyloxy)thiophene
2 to quinones
4.3.1. Representative experimental procedures. A. Unca-
talyzed conjugate addition. To a stirred solution of quinone
(0.10 mmol) in acetonitrile (15 mL) at 0 8C under an
atmosphere of nitrogen was added a solution of 2-(tert-
butyldimethylsilyloxy)thiophene 2 (24 mg, 0.11 mmol) in
acetonitrile (6 mL). The mixture was allowed to warm to
room temperature and stirred for 16 h. The solvent was
removed at reduced pressure and the resultant residue
purified by flash column chromatography to afford the title
compound.
4.3.3. cis-10-Carbomethoxy-9-hydroxy-2-oxo-2,3,3a,
10b-tetrahydro-1H-[1]naphthofuro[3,2-b]thiophene 14.
Flash column chromatography using hexane–ethyl acetate
(7/3) as the eluent gave the title compound 14 (Procedure B
27%; Procedure C 30%; Procedure D 31%) as pale yellow
needles; mp 221–223 8C; nmax(film)/cmK1 3376br (OH),
1697s (CO), 1665s (CO) and 1233s; dH (400 MHz, CHCl3)
3.22 (1H, dd, JZ18.4, 6.3 Hz, H3), 3.37 (1H, d, JZ18.4 Hz,
H3), 4.00 (3H, s, OMe), 5.46 (1H, t, JZ6.3 Hz, H3a), 5.91
(1H, d, JZ6.3 Hz, H10b), 7.58 (1H, t, JZ7.7 Hz, H7), 7.66
(1H, t, JZ7.7 Hz, H6), 7.90 (1H, d, JZ7.7 Hz, H5), 8.40
(1H, d, JZ7.7 Hz, H8) and 11.83 (1H, s, OH); dC (75 MHz,
CDCl3) 48.0 (CH2, C3), 52.5 (CH3, OMe), 57.8 (CH, C10b),
83.2 (CH, C3a), 101.5 (quat., C10), 117.3 (quat., C10a),
121.7 (CH, C5), 124.2 (quat., C8a), 125.6 (quat., C4b),
127.0 (CH, C7), 129.9 (CH, C6), 148.3 (quat., C9), 157.3
(quat., C4a), 170.5 (quat., CO2Me) and 204.9 (quat., C2); m/
z (FAB): 316 (MC, 42%) and 89 (100); HRMS (FAB):
Found MC, 316.04008. C16H12O3S requires 316.04055.
B. Indium(III) chloride catalyzed conjugate addition. To a
suspension of indium(III) chloride (11 mg, 0.05 mmol) in
acetonitrile (2 cm3) at 0 8C under an atmosphere of nitrogen
was added a solution of quinone (1.00 mmol) in acetonitrile
(3 mL) followed by a solution of 2-(tert-butyldimethyl-
silyloxy)thiophene 2 (236 mg, 1.10 mmol) in acetonitrile
(3 mL). The mixture was allowed to warm to room
temperature and stirred for 16 h. The solvent was removed
at reduced pressure and the resultant residue purified by
flash column chromatography to afford the title compound.
C. Copper(II) trifluoromethane sulfonate catalyzed con-
jugate addition. To a stirred suspension of copper(II)
trifluoromethanesulfonate (362 mg, 1.00 mmol) in dichloro-
methane (2 mL) at K78 8C under an atmosphere of nitrogen
was added a solution of quinone (1.00 mmol) in dichloro-
methane (3 mL) followed by a solution of 2-(tert-
butyldimethylsilyloxy)thiophene 2 (214 mg, 1.00 mmol) in
dichloromethane (3 mL). After stirring for 2 h, the mixture
was allowed to warm to room temperature then filtered
through a pad of Celitew. The solvent was removed at
reduced pressure and the resultant residue purified by flash
column chromatography to afford the title compound.
4.3.4. 2-(2-Acetyl-1,4-dihydroxy-3-phenyl)-5-(tert-butyl-
dimethylsilyloxy)-1H-thiophene 15. Flash column chro-
matography using hexaneKethyl acetate (7/3) as the eluent
gave the title compound 15 (Procedure A 35%) as a pale
yellow oil; nmax(film)/cmK1 3384br (OH) and 1635s (CO);
t
dH (400 MHz, CDCl3) 0.09 (6H, s, BuMe2Si), 1.00 (9H, s,
tBuMe2Si), 2.12 (3H, s, Me), 5.28 (1H, s, OH), 6.26 (1H, d,
JZ3.7 Hz, H4), 6.69 (1H, d, JZ3.7 Hz, H3), 06.98 (1H, d,
JZ9.0 Hz, H60), 7.13 (1H, d, JZ9.0 Hz, H5 ) and 11.36
(1H, s, OH); dC (100 MHz, CDCl3) K5.0 (CH3, tBuMe2Si),
18.2 (quat., tBuMe2Si), 20.9 (CH3, tBuMe2Si), 60.3
(CH3, Me), 110.3 (CH, C4), 119.8 (quat., C20), 119.8
D. Boron trifluoride etherate catalyzed conjugate addition.
To a stirred solution of quinone (1.00 mmol) in dichloro-
methane (5 mL) at K78 8C under an atmosphere of nitrogen

3026
M. A. Brimble et al. / Tetrahedron 62 (2006) 3021–3027
(CH, C60), 122.2 (quat., C30), 122.2 (quat., C2), 122.7 (CH,
C50), 127.8 (CH, C3), 147.2 (quat., C40), 155.1 (quat., C10),
171.1 (quat., C5) and 205.8 (quat., CO); m/z (EI): 364 (MC,
66%), 349 (MKMe, 2), 307 (MKC4H9, 6), 233 (12), 115
(6) and 43 (18); HRMS (EI): Found MC, 364.11671.
C18H24O4SSi requires 364.11646.
133.4 (quat., C9), 160.3 (quat., C4a), 202.1 (quat., CO) and
202.8 (quat., C2); m/z (EI): 300 (MC, 100), 257 (MK
COMe, 2), 256 (4), 57 (7) and 43 (37); HRMS (EI): Found
MC, 300.04557. C16H12O4S requires 300.04563.
4.3.8. cis-10-Acetyl-9-hydroxy-8-methoxy-2-oxo-2,3,3a,
10b-tetrahydro-1H-[1]naphthofuro[3,2-b]thiophene 19.
Flash column chromatography using hexane–ethyl acetate
(7/3) as the eluent gave the title compound 19 (Procedure D
45%) as a brown solid; mp 230–233 8C (degradation);
nmax(film)/cmK1 3439br (OH), 1694s (CO), 1649, 1631,
1450, 1399, 1244, and 1229; dH (300 MHz, CHCl3) 2.75
(3H, s, Me), 3.20 (1H, dd, JZ18.2, 5.9 Hz, H3), 3.31 (1H, d,
JZ18.2 Hz, H3), 4.13 (3H, s, OMe), 5.39 (1H, t, JZ5.9 Hz,
H3a), 5.92 (1H, d, JZ5.9 Hz, H10b), 6.92 (1H, d, JZ
8.0 Hz, H7), 7.49 (1H, t, JZ8.0 Hz, H6), 7.55 (1H, dd, JZ
8.0, 1.0 Hz, H5) and 10.38 (1H, s, OH); dC (75 MHz,
CDCl3) 33.2 (CH3, Me), 48.1 (CH2, C3), 56.6 (CH3, OMe),
57.1 (CH, C10b), 83.4 (CH, C3a), 106.5 (CH, C7), 115.5
(quat., C8), 115.7 (quat., C10a), 116.0 (CH, C5), 121.7
(quat., C10), 124.9 (quat., C4b), 129.1 (CH, C6), 148.2
(quat., C4a), 153.6 (quat., C9), 157.4 (quat., C8), 199.5
(quat., CO) and 205.8 (quat., C1); m/z (FAB): 331 (MHC,
23%), 330 (M, 18), 120 (59) and 89 (100); HRMS (FAB):
Found MC, 330.05675. C17H14O5S requires 330.05620.
4.3.5. 2-(2-Acetyl-1,4-dihydroxy-3-naphthyl)-5-(tert-
butyldimethylsilyloxy)-1H-thiophene 16. Flash column
chromatography using hexane–ethyl acetate (8/2) as the
eluent gave the title compound 16 (Procedure A 11%) as a
yellow oil; nmax(film)/cmK1 3434br (OH) and 1675s (CO);
t
dH (400 MHz, CDCl3) 0.29 (6H, s, BuMe2Si), 1.00 (9H, s,
tBuMe2Si), 2.19 (3H, s, Me), 5.85 (1H, s, OH), 6.29 (1H, d,
JZ3.6 Hz, H4), 6.78 (1H, d, JZ3.6 Hz, H3), 7.60 (1H, ddd,
JZ7.6, 7.6, 1.2 Hz, H70), 7.69 (1H, ddd, JZ7.6, 7.6, 1.2 Hz,
H600), 8.20 (1H, d, JZ7.6 Hz, H50), 8.47 (1H, d, JZ7.6 Hz,
H8 ) and 13.82 (1H, s, OH); dC (100 MHz, CDCl3) K4.9
(CH3, tBuMe2Si), 18.3 (quat., tBuMe2Si), 25.5 (CH3,
tBuMe2Si), 30.1 (CH3, Me), 109.0 (quat., C20), 109.5 (CH,
C4), 114.7 (quat., C30), 122.6 (CH0, C50), 123.5 (quat., C2),
124.6 (CH, C80), 126.2 (quat.0, C4a ), 127.2 (CH, C3), 127.6
(CH, C70), 130.1 (CH, C6 0), 130.9 (quat., C8a0), 143.3
(quat., C40), 156.9 (quat., C1 ), 163.7 (quat., C5) and 205.3
(quat., CO); m/z (EI): 414 (MC, 78), 399 (MKMe, 3), 371
(MKCOMe, 7), 282 (12), 115 (9) and 43 (17); HRMS (EI):
Found MC, 414.13198. C22H26O4SSi requires 414.13211.
4.3.9. cis-(3a,5,9b)-3,3a,5,11b-Tetrahydro-5-hydroxy-7-
methoxy-5-methyl-1H-[1]naptho[2,3-c]pyran-2,6,11-
trione thiophene 20. To a stirred solution of thienyl-
naphthofuran 11 (40 mg, 0.12 mmol) in acetonitrile (2 cm3)
and water (2 cm3) at 0 8C was added ceric ammonium
nitrate (133 mg, 0.24 mmol). After stirring for 20 min,
water (2 cm3) was added and the aqueous layer extracted
with dichloromethane (3!10 cm3). The combined extracts
were dried over magnesium sulphate, filtered and the
solvent removed under reduced pressure. Purification of the
resultant residue by flash column chromatography using
hexane–ethyl acetate (8/2) as eluent gave the title compound
20 (9 mg, 21%) as an unstable red-brown oil that rapidly
degraded to a complex mixture of products; dH (300 MHz,
CHCl3) 1.78 (3H, s, Me), 2.88 (1H, d, JZ17.1 Hz, H3), 2.99
(1H, dd, JZ17.1, 3.8 Hz, H3), 4.04 (3H, s, OMe), 4.87 (1H,
t, JZ3.8 Hz, 3a), 4.92 (1H, d, JZ3.8 Hz, 11b), 7.34–7.38
(1H, m, H8), 7.70–7.78 (2H, m, H9 and H10).
4.3.6. cis-8-Acetyl-7-hydroxy-2-oxo-2,3,3a,8b-tetra-
hydro-1H-[1]benzofuro[3,2-b]thiophene 17. Flash col-
umn chromatography using hexane–ethyl acetate (7/3) as
the eluent gave the title compound 17 (Procedure B 35%;
Procedure C 22%) as a pale-yellow solid; mp 125–127 8C
(degradation); nmax(film)/cmK1 3376br (OH), 1716s (CO),
1637s (CO), 1472 and 1210; dH (400 MHz, CHCl3) 2.68
(3H, s, Me), 3.13 (1H, dd, JZ18.2, 5.6 Hz, H3), 3.30 (1H, d,
JZ18.2 Hz, H3), 5.31 (1H, t, JZ5.6 Hz, H3a), 5.70 (1H, d,
JZ5.6 Hz, H8b), 6.94 (1H, d, JZ9.0 Hz, H6), 7.07 (1H, d,
JZ9.0 Hz, H5) and 12.25 (1H, s, OH); dC (75 MHz, CDCl3)
31.2 (CH3, Me), 47.3 (CH2, C3), 56.6 (CH, C8b), 83.2 (CH,
C3a), 116.1 (quat., C8), 119.4 (CH, C5), 120.8 (CH, C6),
126.2 (quat., C8a), 152.5 (quat., C7), 158.7 (quat., C4a)
202.4 (quat., CO2Me or C2) and 202.5 (quat., CO2Me or
C2); m/z (EI): 250 (MC, 100%), 208 (37), 189 (44), 175
(27), 152 (18), 147 (18), 137 (28) and 43 (49); HRMS (EI):
Found MC, 250.03021. C12H10O4S requires 250.02998.
Acknowledgements
4.3.7. cis-10-Acetyl-9-hydroxy-2-oxo-2,3,3a,10b-tetra-
hydro-1H-[1]naphthofuro[3,2-b]thiophene 18. Flash col-
umn chromatography using hexane–ethyl acetate (1/1) as
the eluent gave the title compound 18 (Procedure B 9%;
Procedure C 33%; Procedure D 48%) as orange needles; mp
210–212 8C; nmax(film)/cmK1 3345br (OH), 1677s (CO) and
1593s (CO); dH (400 MHz, CDCl3) 2.74 (3H, s, Me), 3.26
(1H, dd, JZ18.3, 5.7 Hz, H3), 3.43 (1H, d, JZ18.3 Hz,
H3), 5.48 (1H, dd, JZ5.7, 6.4 Hz, H3a), 5.87 (1H, d, JZ
6.4 Hz, H10b), 7.58 (1H, ddd, JZ7.6, 7.6, 1.1 Hz, H7), 7.70
(1H, ddd, JZ7.6, 7.6, 1.1 Hz, H6), 7.92 (1H, d, JZ7.6 Hz,
H5), 8.48 (1H, d, JZ7.6 Hz, H8) and 14.56 (1H, s, OH); dC
(75 MHz, CDCl3) 30.7 (CH3, Me), 47.5 (CH2, C3), 58.2
(CH, C10b), 83.1 (CH, C3a), 109.5 (quat., C10a), 116.3
(quat., C10), 121.6 (CH, C5), 124.3 (quat., C8a), 124.8 (CH,
C8), 125.4 (quat., C4b), 126.4 (CH, C7), 130.7 (CH, C6),
The authors thank the University of Auckland for financial
support of this work.
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