λ3-Iodane-mediated arenol dearomatization. Synthesis of five-membered ring-containing analogues of the aquayamycin ABC tricyclic unit and novel access to the apoptosis inducer menadione

Article abstract of DOI:10.1016/j.tet.2004.11.072

The λ³-iodane [bis(trifluoroacetoxy)]iodobenzene (BTI)-mediated oxidative dearomatization of 2-alkoxyarenols with soft external carbon-based nucleophiles constitutes a rapid access to highly functionalized naphthoid cyclohexa-2,4-dienones. These synthons can serve as valuable intermediates in the construction of the angularly-oxygenated benz[a]naphthalene ABC ring system of aquayamycin- and SS-228Y-type antibiotic angucyclinones, and analogues thereof. This methodology led to the elaboration of five-membered A ring-containing analogues of this ABC tricyclic unit. In addition, the BTI-mediated oxidative activation of 2-methylnaphthol can be exploited to prepare menadione (i.e. vitamin K₃), known to induce apoptosis and autoschizis, a novel type of cancer cell death.

Full text of DOI:10.1016/j.tet.2004.11.072

Tetrahedron 61 (2005) 1551–1562
l3-Iodane-mediated arenol dearomatization.
Synthesis of five-membered ring-containing analogues of the
aquayamycin ABC tricyclic unit and novel access to the
apoptosis inducer menadione
*
´
Nathalie Lebrasseur, Gao-Jun Fan, Mayalen Oxoby, Matthew A. Looney and Stephane Quideau
´ ´ ´
Institut Europeen de Chimie et Biologie, 2 rue Robert Escarpit, F-33607 Pessac Cedex, Laboratoire de Chimie des Substances Vegetales,
´
´
´
Centre de Recherche en Chimie Moleculaire, Universite Bordeaux 1, 351 cours de la Liberation, F-33405 Talence Cedex, France
Received 15 July 2004; revised 1 November 2004; accepted 25 November 2004
Available online 15 December 2004
Abstract—The l3-iodane [bis(trifluoroacetoxy)]iodobenzene (BTI)-mediated oxidative dearomatization of 2-alkoxyarenols with soft
external carbon-based nucleophiles constitutes a rapid access to highly functionalized naphthoid cyclohexa-2,4-dienones. These synthons
can serve as valuable intermediates in the construction of the angularly-oxygenated benz[a]naphthalene ABC ring system of aquayamycin-
and SS-228Y-type antibiotic angucyclinones, and analogues thereof. This methodology led to the elaboration of five-membered A ring-
containing analogues of this ABC tricyclic unit. In addition, the BTI-mediated oxidative activation of 2-methylnaphthol can be exploited to
prepare menadione (i.e. vitamin K3), known to induce apoptosis and autoschizis, a novel type of cancer cell death.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
angucyclinones bearing two hydroxy groups in a cis-
configuration at the AB ring junction (i.e. positions 4a and
12b), as exemplified by aquayamycin (1)26,27 and SS-228Y
(2)28 remains a challenge for synthetic organic chemists. A
further justification for tackling this challenge is found in
the fact that most angucyclines or angucyclinones of this
subclass display therapeutically-significant activities.29–35
Angucyclines and angucyclinones are structurally charac-
terized by their benz[a]anthraquinone ABCD cyclic
skeleton and constitute an important class of microbial
antibiotics exhibiting a wide variety of biological activities,
including antitumor, antifungal, and antiviral properties.1,2
The high structural diversity that these natural products
feature, especially on their angular ABC ring system, gave
impetus to many studies aimed at their total synthesis. Until
now, most efforts have been directed toward angucyclinones
in which the B ring is aromatic. In most cases, the
strategy followed for constructing the benz[a]anthracene
framework was based on Diels-Alder reactions.3–13 The
repertoire of other approaches that have been examined
encompass Michael-type cyclization,14 phthalide anion-
based annulation,15,16 Friedel–Crafts reactions,17–19
chromium carbenoid-mediated benzannulation,20 benzyne-
furan cycloaddition,21 metal-induced free radical annula-
tion,22 cobalt-catalyzed [2C2C2] triyne cycloaddition23
and biomimetic polyketide condensation reactions.1,24,25
Despite this enormous amount of work, the synthesis of
Only two relevant model studies have been reported,25,36
and two syntheses of angucyclinones of this subclass have
been described; the first total synthesis of (C)-1, in more
than 50 steps,37–39 and the synthesis of the racemic 8-deoxy
analogue of WP 3688-2 (3).40 In both cases, the key A ring
annulation step relied on a biomimetic pinacolic-type
coupling. Our previous investigation on the regioselective
formation of naphthoid cyclohexa-2,4-dienones by oxi-
dative dearomatization of naphthols using the l3-iodane
bis(trifluoroacetoxy)]iodobenzene (BTI) in the presence of
soft carbon-based nucleophiles41,42 led us to examine a
novel approach to the polycyclic core of aquayamycin-type
angucyclinones (Scheme 1). The first key to the success of
this approach resides in the use of either naphthoid or an
anthranoid cyclohexa-2,4-dienone orthoquinol of type 5 that
can be generated from the corresponding arenol 6 by the
aforementioned BTI-mediated oxidative nucleophilic sub-
stitution reaction. In this event, the silyl enol ether 7b
constitutes an ideal second reaction partner, since it adds a
Keywords: Angucyclines; Aquayamycin; Dearomatization; Cyclohexa-2,4-
Dienones; l3-Iodane.
* Corresponding author. Tel.: C33 66 291 6551; fax: 33 54 000 6439;
e-mail: s.quideau@iecb.u-bordeaux.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.072

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N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
good yields (Scheme 2).41,42 The diene 7b has the advantage
of bearing an additional methyl group prefiguring that of the
aquayamycin-type A cycle. It was prepared in one step in
63% as the (E)-isomer from methyl-3-but-2-enal (8).43
A
mixture of 2-methoxynaphthol (6a, ZZH, RZMe,
Scheme 1) and 7b was then treated with BTI (1.8 equiv)
in CH2Cl2 at 0 8C for 2 h to furnish both the orthoquinol 5b
and the naphthol 9b in moderate yields, together with the
paraquinone 1044 (20%) and the iodoaryl compound 11
(2%) (Scheme 2). The desired and major orthoquinol
product 5b was obtained as a 1.3:1 mixture of the E and Z
isomers; their assignment was determined by NOE
spectroscopy that revealed a correlation between the
aldehydic proton and the methyl group only for the E
geometry. We were much intrigued by the formation of 10
in such a significant yield (i.e. 20%), for this type of
paraquinone was not obtained in previous reactions
performed with 2-methoxy- and 2-benzyloxynaphth-1-ols
in the presence of silyl enol ethers or allylsilane.41,42
Scheme 1.
The only case in which we observed such an oxidative
oxygenation was when we used 2-methylnaphth-1-ol (12).
The treatment of this arenol with BTI led to the formation of
menadione (17, i.e. vitamin K3) as a bright yellow solid in
an excellent yield of 80% (Scheme 3). Vitamin K3, which
displays the antihemorrhagic activity of the naturally
occurring vitamin K, has also recently been found to induce
cell death via apoptosis45 and autoschizis, a new type of
cancer cell death.46 Vitamin K3 is produced on industrial
scale by stoichiometric oxidation of 2-methylnaphthalene
with chromium trioxide in sulfuric acid,47 but the environ-
mental concerns linked to the use of chromium and the
interesting pharmacological properties recently unveiled for
this 1,4-naphthoquinone45 encouraged the development of
novel procedures of varying preparative values.48–51
Although 2-methylnaphth-1-ol (12) is a more expensive
starting material than 2-methylnaphthalene and CH2Cl2 is
not the most appropriate solvent from an environmental
point of view, the use of a l3-iodane oxidizing agent such as
BTI, nevertheless, constitutes an alternative preparation of
vitamin K3 (17). Several reports have described the use of
l3-iodanes in aqueous solvent systems to efficiently
generate paraquinones from phenols,52–58 but, to the best
of our knowledge, none were concerned with the
preparation of 17.
four-carbon appendage adequately functionalized for
making the A ring in one step. We wish to report in full
detail the work carried out so far on this orthoquinol route
toward the synthesis of aquayamycin-type angucyclinones
and model compounds thereof.
2. Results and Discussion
The first task to accomplish was to ascertain the possibility
of generating an orthoquinol of type 5 using the silyl enol
ether 7b in our BTI-mediated arenol dearomatization
reaction. We previously used a simpler and commercially
available silyl enol ether (i.e. 7a, 1-trimethylsilyloxybuta-
1,3-diene) to prepare naphthoid orthoquinols, such as 5a, in
Scheme 2.
Scheme 3.

N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
1553
For the desired conversion of 6a into 5b (Scheme 2), we
chose to use BTI to prevent any competing nucleophilic
attack by the trifluoroacetate anion released during the
reaction. This anion has a relatively low nucleophilic power
and its participation in displacing the l3-iodanyl unit of the
initial ligand exchange product 13, either directly or by
quenching an arenoxenium ion intermediate of type 14
(Scheme 3), was not expected to be a favored process in the
presence of other nucleophilic species. Furthermore, special
care was taken to ensure that the reaction was run under
strictly anhydrous conditions to avoid any competitive
substitution reaction with water. Hence, the possibility
that the formation of 10 and 17 might be derived from the
nucleophilic attack of the trifluoroacetate anion at the
4-position of 13 or 14 cannot be disregarded. The resulting
trifluoroacetate esters of type 15 would then be hydrolysed
during the aqueous workup and rapidly air oxidized during
silica gel chromatography to furnish paraquinones 10 or 17
(Scheme 3). The attack of the trifluoroacetate anion onto
2-naphthol derivatives has previously been reported in
special cases.59 However, our experimental observations
and NMR analyses of the crude products, which contain
small amounts of paraquinones 10 or 17, do not allow us to
confirm the formation of trifluoroacetate esters of type 15.
Another possibility would be that the l3-iodanyl conjugate
base of 13 remains intact in significant amounts during the
reaction and that their conversion into paraquinones 10 or
17 occurs via the attack of H2O to give the hydroquinone
intermediate 16 during the aqueous workup and silica gel
chromatography (Scheme 3).
Scheme 4.
cyclization into 21 by treating these phenols with a base (eg.
LDA, LHMDS) failed.42
The solution came from annulating the B ring to a CD
bicyclic unit via a cycloaddition process.62,63 The bromo-
naphthoquinone CD unit 22 was prepared in 97% yield over
two steps from 1,5-dihydroxynaphthalene, as previously
described,64,65 and was used as the dienophile in a Diels-
Alder reaction with diene 23a (Schemes 4 and 5). We
were particularly eager to carry out this reaction, for a
C-glycosylated version of this dienophile bearing the
aquayamycin D-olivose at the appropriate position has
already been synthesized by Sulikowski and his co-
workers.9 The silyl ketene acetal 23a was prepared as a
2:1 mixture of geometric isomers in 74% yield over three
steps from 1-cyano-2-propenylacetate 26, as previously
described (Scheme 5).62,66,67 Of particular note is the fact
that it was crucial to maintain the reaction mixture at low
temperature to avoid isomerization of 28a to 29.
The only explanation we can propose for the minor
formation of the iodoaryl compound 11 in the reaction
between 6a and 7b (Scheme 2) is that iodobenzene released
from BTI underwent an initial one-electron oxidation by
excess BTI to generate a phenyl radical cation species,
which was then quenched by the nucleophile 7b. The
resulting radical intermediate could then be further one-
electron oxidized to furnish 11 after proton loss. Despite the
decrease in chemical yield, chemo- and regioselectivity as
compared to the results obtained using the simpler silyl enol
ether 7a, we were nevertheless satisfied to have developed a
rapid access to the highly functionalized orthoquinol 5b
(Scheme 2) that we could subsequently use to investigate
modes of cyclization onto the aquayamycin ABC ring
system. Only the Z isomer of 5b had a chance to cyclize into
the desired angular polycycle.
The Diels–Ader reaction between 22 and 23a was first
carried out at room temperature in toluene to afford, after
First, we decided to examine the possibility of performing
the same type of oxidative nucleophilic substitution reaction
on an anthranoid derivative in order to build directly an
aquayamycin BCD ring system appended by a four-carbon
precursor of the A ring (Scheme 1). Using 2-alkoxy-1-
hydroxyanthraquinones as starting arenols, the first
approach we tried to build such anthraquinones was that
of Mitchell and Russell,15,60 which, involved a conjugated
addition of the phtalide anion derived from 19 to non-
dimerizing orthoquinol acetates such as 18a/b (Scheme 4).61
Unfortunately, the rapid rearomatizing departure of AcOH
from the Michael-type adduct intermediate prevented the
desired annulation into 21 to occur in situ, and led to the
formation of phenols 20a/b. Several attempts to induce
Scheme 5.

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N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
silica gel flash chromatography, an undefined and unstable
mixture that slowly (ca. 7 days) and completely evolved into
the deacetylated anthraquinone 25b68 (Scheme 4). The
mixture probably contained some anthraquinone 25b
together with the initial cycloadduct 24 still in significant
amounts, as suggested by the observation of a phenolic
acetate group by NMR analysis. Furthermore, TLC analysis
of this mixture did not show evidence of any formation of
25a. The elimination of HBr and concomitant aromatization
of the B ring, possibly induced by a bromine-mediated
cleavage of the acetal O-Si bond, occurred slowly upon
standing, but the bromine anion then also mediated
deacetylation via a nucleophilic addition-elimination at
the carbonyl acetate carbonyl group. Attempts to carry out
the reaction in the presence of a base (e.g. Et3N, DBU) in
order to promote elimination of HBr, while quenching it in
The use of fluorinated solvents such as 2,2,2-trifluoroethanol
(TFE) and hexafluoroisopropanol (HFIP), as first
recommended by Kita and co-workers in place of CH2Cl2
for similar iodane-mediated reactions with phenolic com-
pounds and their simple ethers,69–71 did not help and
resulted only in complex reaction mixtures. Interestingly,
the only product we could extract from these mixtures,
albeit in a very low yield (i.e. 4%), was the anthranoid
orthoquinone monoketal 31 that resulted from attack of TFE
at the 2-position of 25a. Although TFE is recommended
because of its low nucleophilicity, similar solvolyses have
been observed in such a solvent.59,71 We then tried to
augment the electrophilicity of the iodine(III) by adding a
Lewis acid to the medium in the form of complexes of BTI
or iodosylbenzene (PhIO) with BF3 etherate,70,72,73 as well
as PhIO with HBF4,74,75 but no better formation of the
desired C–C bond was observed. Another option was to
reduce 25a into its corresponding dimethyl hydroquinone 32
before performing the BTI-mediated reaction. This was
accomplished by reductive methylation of the benzyl ether
of 25a. The difficulty of performing this preliminary
benzylation, which necessitated the use of silver(I) oxide
with benzyl bromide in refluxing CHCl3 (Scheme 6), is
probably due to the participation of the free phenol function
of 25a in a hydrogen-bond with the adjacent carbonyl
function. This lowering of the nucleophilic power of the
phenolic oxygen, however, had no major effect on its
reactivity towards the iodane reagent used, since the BTI-
mediated hydration of 25a into 30 occurred in high yield
(Scheme 6). Nevertheless, it is conceivable that the
electron-withdrawing effect of the paraquinone motif of
the ligand exchange reaction intermediate (e.g. A,
Scheme 6) sufficiently disfavors any displacement of the
iodanyl unit by soft carbon-based nucleophiles such as 7a
˚
situ, failed. The introduction of 4 A molecular sieves in the
reaction medium brought to reflux after 1 h at room
temperature solved this problem, and the desired anthra-
quinone 25a was thus obtained as an orange powder in 50%
yield (Scheme 4). The role of the molecular sieves remains
unknown, but they must in some way trap the bromine anion
before it cleaves the acetate group. In any event, access to
this novel 5-acetoxy-1-hydroxy-2-methoxyanthraquinone
(25a) allowed us to proceed as planned to mount a four-
carbon tether at its 2-position. Unfortunately, the only
product isolated after performing the BTI-mediated reaction
between 25a and 7a in CH2Cl2 at various temperatures was
the 1,4-dihydroxy compound 30 (Scheme 6). Again, this
hydroxylation must have arisen either from an in situ
attack of the trifluoroacetate anion released from BTI or
from a l3-iodanyl displacement by water during reaction
processing (Scheme 3).
Scheme 6.

N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
1555
(path a), while augmenting its phenyliodonium B character
(path b).
Reduction with sodium dithionite, methylation with
dimethyl sulftate in aqueous potassium hydroxide and a
final hydrogenolytic cleavage of the benzyl ether bond
furnished the tetramethoxylated anthranol 32 (Scheme 6).
Unfortunately, all attempts to promote the attack of the silyl
enol ether 7a onto 32 with BTI failed because of rapid
oxidation of the dimethyl ether hydroquinone unit with
concomitant displacement of a methyl group onto the free
hydroxy group, giving rise to the formation of the
anthraquinone 3376 in 48% yield (Scheme 6).
These recurring problems caused by the extreme sensitivity
of the anthracene unit toward oxidation led us to envisage
another approach to the benz[a]anthraquinone skeleton of
angucyclinones. Since the BTI-mediated C–C bond-form-
ing dearomatization of 2-alkoxynaphthols was successful
(Scheme 2),41,42 we thought of first constructing a
paraquinonic ABC ring system of type 35, on which the D
ring would then be added by a Diels–Alder reaction with a
C-glycosidic diene of type 34 (Scheme 7). With this in
mind, the synthesis of the required naphthoquinone 36 was
carried out also via a Diels–Alder reaction between the
commercially available 1,4-benzoquinone 37 and 23,
according to the method of Brassard and co-workers.62
Both the methoxylated 23a and the more labile methoxy-
methoxylated 23b were used in these reactions. In these
cases, complete B ring aromatization was ensured before
purification by stirring the crude cycloaddition product with
SiO2 in CH2Cl2 for 6 h (Scheme 7).62
Scheme 8.
reagent to enable the reaction to occur at the phenolic
function, the nucleophilicity of which was also lowered by
its participation into an intramolecular hydrogen bond with
the neighboring carbonyl group. Unfortunately, all attempts
to dearomatize 40, as well as the free phenol 36a, with BTI
into the desired orthoquinol in the presence of 7b mainly
gave back the staring material 36a, plus up to 8% of the
iodoaryl compound 11 as the only isolated compounds.
We thus decided to investigate the possibilities of convert-
ing the bicyclic orthoquinol ether 5b into an angucyclinone
ABC ring model system. The first tactic we examined for
annulating its four-carbon enal unit onto the A ring part was
a thiazolium ion-catalyzed benzoin-type coupling,79,80 but
the heating of 5b in absolute ethanol at 80 8C in the presence
of 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium
chloride (41) and triethylamine only gave 42, after enal
isomerization and aromatization of the thermally-induced
Cope rearrangement product (Scheme 9).81–83 The cyano-
hydrin-based cyclisation approach reported by Kraus25 for
making similar ring systems was then tried. The cyano-
hydrin 43 was generated as a 1:1 diastereomeric mixture in a
moderate yield of 37% by treating 5b with trimethylsilyl
Scheme 7.
Before submitting 36a/b to the BTI-mediated dearomatiza-
tion reaction in the presence of 7b, its phenolic group was
silylated in the hope of improving the yield of the desired
C–C bond forming reaction. Indeed, such silylations, in
particular those using a tripropylsilyl group, have been
proven beneficial in similar iodane-mediated transform-
ations reported by Kita77 and McKillop.78 Although
2-methoxynaphthol 6a was quantitatively converted into
the corresponding tripropylsilyl phenyl ether 38 and to the
orthoquinol methyl ether 5b, albeit with no yield improve-
ment, the tripropylsilylation of 36a did not occur at the
phenolic locus, but, surprisingly, at the C-7 center to furnish
39 (Scheme 8). Once again, we had to rely on more drastic
conditions using silver(I) oxide and a smaller silylating
Scheme 9.

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N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
cyanide in the presence of catalytic amounts of KCN and
18-crown-6,84,85 but treatment of 43 with LDA in THF at
K78 8C gave no cyclized product. In fact, the starting
aldehydic orthoquinol ether 5b was quantitatively
recovered, probably via a mechanism involving an initial
deprotonation at a g-allylic position of the reacting tether
(Scheme 9).
The last draw of this study led us to results of value for the
synthesis of angucyclinone analogues. Since the presence of
a double bond on the four-carbon tether allowed other
reactions to compete with the desired cyclization, the
alternative was to transform the enal unit of 5b into a
b-hydroxyaldehyde before cyclization. Furthermore, such a
transformation would convert both the (E)- and (Z)-enal
tethers of the 1.3:1 product mixture 5b into cyclizing motifs.
Reductive opening of an a,b-epoxyaldehyde was the tactic
chosen to elaborate the desired tertiary alcohol function.
In the context of this study, we felt obliged to use the oxido-
l3-iodane reagent 45, recently reported by Ochiai and
co-workers to epoxidize a,b-unsaturated carbonyl com-
pounds.86 Treatment of pure (E)-5b with 45 in THF at room
temperature did not lead to the desired epoxide, but to the
five-membered ring-containing tricycle 46 (32%), together
with the starting 5b (43%), now enriched in the (Z)-isomer
(Scheme 10). The high nucleofugality of the l3-aryl-
iodanyl87 group did not force the enolate intermediate 47
to follow the epoxidation path (route c), usually driven by
reductive elimination at the iodine(III) center, and this
enolate instead evolved through the intramolecular aldol
reaction path (route a) and the isomerizing reversal of the
initial Michael-type addition (route b).
Scheme 11.
The first conditions tried were those proposed by Miyashita
and co-workers90 by using a phenylseleno(triethyl)borate
complex to initiate epoxide opening by a one-electron
reduction of the aldehydic carbonyl. These conditions are
known to preclude dehydration of the resulting b-hydroxy-
carbonyl product.90 Opening of the epoxide was indeed
successful, but the boron enolate intermediate 49 generated
under these conditions, like enolate 47, quickly followed the
intramolecular aldol reaction path before being quenched
during workup. The five-membered ring-containing tricycle
50 was thus obtained in 46% yield, together with the related
epoxide 51 in 35% yield, the formation of which remains
unclear (Scheme 11). Stereochemical assignments of 50
were deduced from the observation of strong NOE signals
between the two hydroxyl hydrogens. Reduction of 48 using
zinc in aqueous EtOH containing ammonium chloride88
gave the dehydrated analogue 46 in 14% yield. Samarium
diiodide reduction in THF in the presence of MeOH as a
proton source89 furnished only traces of 50 and 46 in 14%
yield (Scheme 11). Although these epoxide-opening reac-
tions did not lead to the formation of a six-membered A
ring, the five-membered ring cyclization path they unveiled
constitutes a valuable approach for the synthesis of
aquayamycin-type angucyclinone analogues. In particular,
the use of Miyashita’s selenoborate complex on an
orthoquinol epoxide such as 48 affords two related angularly
oxygenated tricyclic analogues (i.e. 50 and 51) of the
aquayamycin ABC ring system in good yields.
Scheme 10.
In conclusion, the synthesis studies described here in full
details on the orthoquinol route to aquayamycin-type
angucyclinones and related compounds led to a novel and
convenient access to five-membered ring-containing
analogues of their ABC tricylic system. This work has
confirmed the value of l3-iodane-mediated arenol dear-
motization reactions for the direct elaboration of highly
functionalized synthetic intermediates. We are actively
We had to rely on a more classic methodology to prepare the
required epoxide. Treatment of 5b with H2O2/Na2CO3 in
aqueous EtOH afforded the epoxyaldehyde 48 as a
diastereomeric mixture in 60–65% yield (Scheme 11).88
Various reaction conditions known to reduce regio-
selectively a,b-epoxyketones88–90 were then examined for
opening the epoxide moiety of 48.

N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
1557
pursuing our efforts with the aim of fully synthesizing five-
membered ring-containing analogues of aquayamycin,
while investigating other transformations of orthoquinols
of type 48 into benz[a]naphthoquinones en route to
aquayamycin. Furthermore, the use of the l3-iodane BTI
reagent for dearomatizing arenols allowed us to propose a
novel and rapid preparation of the apoptosis inducer
menadione (i.e. vitamine K3).
129.8, 129.6, 128.7, 127.9, 127.2, 82.3, 53.7, 49.6, 19.7. (Z)-
5b: 1H NMR (CDCl3, 300 MHz) d 1.93 (s, 3H, b-CH3), 2.79
(d, JZ13.2 Hz, 1H, g-CH2), 2.91 (d, JZ13.2 Hz, 1H,
g-CH2), 3.09 (s, 3H, OCH3), 5.69 (d, JZ7.9 Hz, 1H, H-a),
6.02 (d, JZ9.8 Hz, 1H, H-3), 6.71 (d, JZ9.8 Hz, 1H, H-4),
7.17 (m, 1H, H-5), 7.30 (m, 1H, H-7), 7.52 (m, 1H, H-6),
7.92 (d, JZ7.5 Hz, 1H, H-8), 9.61 (d, JZ7.9 Hz, 1H, CHO);
13C NMR (CDCl3, 75.5 MHz) d 199.4, 190.7, 156.8, 136.7,
135.3, 134.8, 131.3, 129.7, 129.5, 128.7, 127.9, 127.1, 82.0,
53.7, 41.3, 27.7. LSIMS m/z (rel intensity) 279 (MNaC, 58),
257 (MHC, 41), 256 (MC, 35), 225 (59); HMRS (LSIMS)
calcd for C16H16O3 256.1099, found 256.1091.
3. Experimental
3.1. General
3.1.3. 4-(E-3-Formylprop-2-enyl)-2-methoxynaphthol
(9b). IR (KBr) 3292, 1649 cmK1 1H NMR (CDCl3,
;
Tetrahydrofuran (THF) and diethyl ether (Et2O) were
purified by distillation from sodium/benzophenone under
N2 immediately before use. CH2Cl2 was distilled from
CaH2. Light petroleum refers to the 40–60 8C boiling range.
Moisture and oxygen sensitive reactions were carried out in
flame-dried glassware under N2. Evaporations were con-
ducted under reduced pressure at temperatures less than
45 8C unless otherwise noted. Column chromatography was
carried out under positive pressure using 40–63 mm silica
gel (Merck). Preparative layer chromatography (PLC) was
performed using glass-coated silica gel plates (SILG-100
UV 254, Macherey-Nagel). Melting points are uncorrected.
NMR spectra of samples in the indicated solvent were run at
200, 250 or 300 MHz. Carbon multiplicities were deter-
mined by DEPT135 experiments. Diagnostic bond con-
nectivities and stereochemical assignments were obtained
by two-dimensional HMQC, HMBC and NOESY experi-
ments run on Bruker 200- and 400-DPX spectrometers.
Electron impact mass spectra (EIMS) were obtained at
50–70 eV. Low and high resolution electron impact and
liquid secondary ion mass spectrometry data (EIMS, and
LSIMS, HRMS) were obtained from the mass spectrometry
250 MHz) d 2.20 (s, 3H), 3.88 (s, 2H), 3.94 (s, 3H), 5.75
(br d, JZ8.1 Hz, 1H), 6.20 (s, 1H), 7.07 (s, 1H), 7.41 (m,
2H), 7.73 (d, JZ8.1 Hz, 1H), 8.20 (d, JZ7.9 Hz, 1H), 9.98
(d, JZ8.0 Hz, 1H); 13C NMR (CDCl3, 62.9 MHz) d 191.4,
162.9, 140.6, 139.4, 131.9, 128.3, 127.9, 125.4, 124.8,
124.6, 123.6, 122.0, 115.6, 57.3, 43.7, 17.8; LSIMS m/z (rel
intensity) 279 (MNaC, 18), 256 (MC, 100); HMRS
(LSIMS) calcd for C16H16O3 256.1099, found 256.1098.
3.1.4. 2-Methoxy-1,4-naphthoquinone (10).44 IR (NaCl)
1685, 1651 cmK1; 1H NMR (CDCl3, 250 MHz) d 3.91 (s,
3H), 6.18 (s, 1H), 7.71–7.76 (m, 2H), 8.07–8.15 (m, 2H);
13C NMR (CDCl3, 62.9 MHz) d 184.8, 180.1, 160.4, 133.3,
132.0, 131.0, 126.1, 109.8, 56.4; EIMS m/z (rel intensity)
188 (MC, 100), 174 (40); HMRS (EIMS) calcd for C11H8O3
188.0473, found 188.0471.
3.1.5. 4-(4-Iodophenyl)-3-methyl-but-2-enal (11). IR
1
(NaCl) 1670 cmK1; H NMR (CDCl3, 300 MHz) d 2.10
(s, 3H), 3.42 (s, 2H), 5.84 (d, JZ7.9 Hz, 1H), 6.90 (d, JZ
6.8 Hz, 2H), 7.62 (q, JZ6.8 Hz, 2H), 9.97 (d, JZ7.9 Hz,
1H), 13C NMR (CDCl3, 75.5 MHz) d 191.1, 161.2, 137.7,
136.5, 131.1, 128.6, 92.3, 46.2, 17.3; EIMS m/z (rel
intensity) 286 (MC, 35), 159 (100); HMRS (EIMS) calcd
for C11H11OI 285.9855, found 285.9851.
´
laboratory at the CESAMO, Universite Bordeaux 1.
3.1.1. Bis(trifluoroacetoxy)]iodobenzene-mediated trans-
formation of 2-methoxynaphthol (6a) in the presence of
1-trimethylsilyloxy-3-methylbuta-1,3-diene (7b). To a
stirring ice-cold solution of 6a (1.0 g, 5.7 mmol)42 and 7b
(2.6 g, 16.6 mmol)43 in CH2Cl2 (17 mL) was added BTI
(4.4 g, 10.2 mmol) as a solid, in one portion. The mixture
was stirred at rt for 2 h, after which time it was diluted with
CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3
(2!20 mL), 1M H3PO4 (20 mL), brine (20 mL), dried over
Na2SO4, and evaporated at rt. The resulting brownish oil
was purified by column chromatography, eluting with light
petroleum/Et2O (1:1), to furnish a 1.3:1 mixture E/Z mixture
of 5b (532 mg, 36%) as a red oil, 9b (192 mg, 13%) as a pale
yellow gum, 10 (216 mg, 20%) as a yellow solid and 11
(32.8 mg, 2%) as a brownish oil.
3.1.6. 2-Methyl-1,4-naphthoquinone (17, menadione). To
a stirring ice-cold solution of 2-methylnaphthol 12 (100 mg,
0.63 mmol) in CH2Cl2 (5 mL) was added dropwise a
solution of BTI (408 mg, 0.95 mmol) in CH2Cl2 (5 mL).
The mixture was stirred at rt for 45 min, after which time it
was diluted with CH2Cl2 (20 mL), washed with saturated
aqueous NaHCO3 (2!20 mL), 1M H3PO4 (20 mL), brine
(20 mL), dried over Na2SO4, and evaporated. The residue
was purified by column chromatography, eluting with light
petroleum/Et2O (1:1), to furnish 17 (87 mg, 80%) as a bright
1
yellow solid: mp 103–104 8C; IR (KBr) 1664 cmK1; H
NMR (CDCl3, 200 MHz) d 2.17 (d, JZ1.5 Hz, 3H), 6.82 (q,
JZ1.5 Hz, 1H), 7.7–7.8 (m, 2H), 8.0–8.1 (m, 3H); 13C
NMR (CDCl3, 50.3 MHz) d 185.6, 185.0, 148.2, 135.7,
133.6, 133.6, 132.3, 132.2, 126.5, 126.1, 16.5; EIMS m/z
(rel intensity) 172 (MC, 100).
3.1.2. 1,2-Dihydro-2-(3-formylprop-2-enyl)-2-methoxy-
1-oxonaphthalene (5b). (E)-5b: IR (KBr) 2938, 1670,
1
1596, 1120 cmK1; H NMR (CDCl3, 200 MHz) d 2.20 (s,
3H, b-CH3), 2.57 (s, 2H, g-CH2), 3.16 (s, 3H, OCH3), 5.74
(d, JZ8.0 Hz, 1H, H-a), 6.08 (d, JZ10.1 Hz, 1H, H-3),
6.76 (d, JZ10.1 Hz, 1H, H-4), 7.23 (dd, JZ1.2, 7.6 Hz, 1H,
H-5), 7.37 (m, 1H, H-7), 7.58 (m, 1H, H-6), 7.98 (m, 1H,
H-8), 9.89 (d, JZ8.0 Hz, 1H, CHO); 13C NMR (CDCl3,
62.9 MHz) d 199.5, 190.8, 157.8, 136.9, 135.3, 134.8, 131.3,
3.1.7. 5-Acetoxy-1-hydroxy-2-methoxyanthraquinone
(25a). To a stirring solution of 2-bromo-5-acetoxynaphtho-
quinone 22 (666 mg, 2.26 mmol)64,65 in toluene (7 mL) was
added dropwise a solution of 1,2-dimethoxy-1-trimethyl-
silyloxy-1,3-butadiene 23a (1.14 g, 5.64 mmol)62 in toluene

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N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
˚
(3 mL). The mixture was stirred in the presence of 4 A
molecular sieves at rt for 1 h and then heat to reflux
overnight. The residue was evaporated, dissolved in
CH2Cl2, adsorbed on silica gel and purified by column
chromatography, eluting with EtOAc/hexane [(1:2)/
(1:1)], to afford 25a (354 mg, 50%) as an orange powder,
which was crystallized from EtOAc/hexane: mp 180–
mixture was diluted with CH2Cl2 (20 mL), washed with
saturated aqueous NaHCO3 (10 mL), 1M H3PO4 (10 mL),
brine (10 mL), dried over Na2SO4, filtered, and evaporated
at rt. The residue was purified by column chromatography,
eluting with hexane/EtOAc [(4:1)/(2:1)], to afford 30
(40 mg, 76%) as red needles. The same result was obtained
without allyltrimethylsilane. 30: mp 176–177 8C; IR (KBr)
3442, 1763, 1614, 1587 cmK1; 1H NMR (CDCl3, 250 MHz)
d 2.47 (s, 3H), 4.00 (s, 3H), 6.70 (s, 1H), 7.44 (dd, JZ1.5,
7.9 Hz, 1H), 7.81 (t, JZ7.9 Hz, 1H), 8.34 (dd, JZ1.5,
7.9 Hz, 1H), 13.43 (s, 1H), 13.43 (s, 1H); 13C NMR (CDCl3,
62.9 MHz) d 186.3, 183.8, 169.7, 161.1, 157.4, 150.6, 150.2,
135.1, 134.6, 130.5, 125.6, 125.4, 112.0, 107.4, 106.6, 56.6,
21.2; EIMS m/z (rel intensity) 328 (MHC, 28); HMRS
(LSIMS) calcd for C17H12O7 328.0583, found 328.0572.
1
181 8C; IR (KBr) 3420, 1759, 1661, 1637, 1590 cmK1; H
NMR (CDCl3, 250 MHz) d 2.49 (s, 3H), 4.01 (s, 3H), 7.17
(d, JZ8.5 Hz, 1H), 7.43 (dd, JZ1.2, 7.9 Hz, 1H), 7.79 (t,
JZ7.9 Hz, 1H), 7.79 (d, JZ8.5 Hz, 1H), 8.30 (dd, JZ1.2,
7.9 Hz, 1H), 12.88 (s, 1H); 13C NMR (CDCl3, 50.3 MHz) d
188.2, 180.1, 169.5, 153.6, 152.4, 150.4, 135.1, 134.5,
130.6, 125.8, 125.4, 125.3, 121.0, 116.1, 115.5, 56.3, 21.1;
LSIMS m/z (rel intensity) 335 (MNaC, 3), 313 (MHC, 36),
312 (MC, 5), 271 (100); HMRS (LSIMS) calcd for
C17H13O6 313.0712, found 313.0704.
3.1.11. 5-Acetoxy-1,6-dihydro-6-methoxy-6-(2,2,2-tri-
fluoroethoxy)-1-oxoanthraquinone (31). To a stirring
ice-cold solution of BTI (90 mg, 0.21 mmol) in CF3CH2OH
(3 mL) was added dropwise a solution of 5-acetoxy-1-
3.1.8. 1,5-Dihydroxy-2-methoxyanthraquinone (25b).68
To a stirring solution of 2-bromo-5-acetoxynaphthoquinone
22 (509 mg, 1.73 mmol)64,65 in toluene (6 mL) was added
dropwise a solution of 1,2-dimethoxy-1-trimethylsilyloxy-
1,3-butadiene 23a (700 mg, 3.46 mmol)62 in toluene
(3 mL). The mixture was stirred at rt for 4 days. The
residue was evaporated, dissolved in CH2Cl2, adsorbed on
silica gel and purified by column chromatography, eluting
with Et2O/hexane (1:1), to afford 25b (290 mg, 54%) as
orange needles after crystallization from EtOAc/hexane: mp
hydroxy-2-methoxyanthraquinone
(25a)
(60 mg,
0.19 mmol) in dry CF3CH2OH (2 mL). After 2 min, the
diene 7a (47 mL, 0.27 mmol) was added dropwise. After
30 min, an another portion of diene 7a (47 mL, 0.27 mmol)
was added dropwise. After 1 h at rt, the mixture was diluted
with CH2Cl2 (20 mL), washed with saturated aqueous
NaHCO3 (10 mL), 1M H3PO4 (10 mL), brine (10 mL),
dried over Na2SO4, filtered, and evaporated. The residue
was purified by column chromatography, eluting with
hexane/EtOAc (2:1), to afford 31 (3 mg, 4%): IR (NaCl)
227 8C; IR (KBr) 3464, 1624 cmK1 1H NMR (CDCl3,
;
200 MHz) d 4.03 (s, 3H), 7.16 (d, JZ8.4 Hz, 1H), 7.30 (dd,
JZ1.1, 8.4 Hz, 1H), 7.65 (t, JZ8.4 Hz, 1H), 7.83 (dd, JZ
1.1, 8.4 Hz, 1H), 7.86 (d, JZ8.4 Hz, 1H), 12.84 (s, 1H),
13.07 (s, 1H); 13C NMR (CDCl3, 50.3 MHz) d 188.4, 187.0,
162.7, 154.5, 153.1, 136.2, 133.3, 125.0, 124.8, 121.0,
119.2, 116.3, 115.9, 115.6, 56.4; EIMS m/z (rel intensity)
271 (MHC, 18), 270 (MC, 100); HMRS (EIMS) calcd for
C15H10O5 270.0528, found 270.0518.
1
1759, 1715, 1687 cmK1; H NMR (CDCl3, 250 MHz) d
2.38 (s, 3H), 3.36 (s, 3H), 3.86–4.01 (m, 2H), 6.00 (d, JZ
10.3 Hz, 1H), 6.24 (d, JZ10.3 Hz, 1H), 7.35 (d, JZ7.9 Hz,
1H), 7.68 (d, JZ7.9 Hz, 1H), 7.95 (d, JZ7.9 Hz, 1H);
LSIMS m/z (rel intensity) 433 (MNaC, 85), 411 (MHC, 30).
3.1.12. 2,5,9,10-Tetramethoxyanthracenol (32). A mix-
ture of 25a (173 mg, 0.55 mmol), Ag2O (514 mg,
2.22 mmol) and benzyl bromide (196 mL, 1.65 mmol) in
CHCl3 (8 mL) was heat to reflux for 4 h. The mixture was
cooled down to rt, filtered through Celite and evaporated.
The residue was submitted to column chromatography,
eluting with CH2Cl2/Et2O (50:1), to give 5-acetoxy-1-
benzyloxy-2-methoxy-anthraquinone (150 mg, 68%): mp
3.1.9. Methyl 2-methoxymethyl-3-butenoate (28b). To a
stirred solution of methyl 2-hydroxy-3-butenoate (2 g,
17.2 mmol) in THF (25 mL) was added dropwise at 0 8C
diisopropylethylamine (6.6 mL, 32.8 mmol) and chloro-
methylmethylether (3.9 mL, 51.6 mmol). The mixture was
allowed to warm up to rt and stirred for 6 days, after which
time it was diluted with Et2O (40 mL), washed with 0.1 M
HCl (30 mL), saturated aqueous NaHCO3 (30 mL), brine
(30 mL), dried over Na2SO4, and evaporated to afford a
colorless oil (2.2 g, 80%), which was used without any
146.7–147.4 8C; IR (KBr) 1759, 1675 cmK1 1H NMR
;
(CDCl3, 250 MHz) d 2.48 (s, 3H), 3.92 (s, 3H), 5.11 (s, 2H),
7.21 (d, JZ8.8 Hz, 1H), 7.33–7.45 (m, 4H), 7.66 (dd, JZ
1.5, 7.9 Hz, 2H), 7.73 (t, JZ7.9 Hz, 1H), 8.04 (d, JZ
8.5 Hz, 1H), 8.20 (dd, JZ1.5, 7.9 Hz, 1H); 13C NMR
(CDCl3, 62.9 MHz) d 181.7, 180.9, 169.5, 158.8, 149.5,
147.5, 137.0, 136.8, 134.4, 129.0, 128.6, 128.2, 128.0,
127.7, 126.6, 125.6, 125.2, 124.2, 116.1, 75.0, 56.1, 21.1;
EIMS m/z (rel intensity) 402 (MC, 6), 91 (BnC, 100);
HMRS (EIMS) calcd for C24H18O6 402.1103, found
402.1107.
further purification: IR (NaCl) 2964, 2900, 2830, 1762 cmK1
;
1H NMR (CDCl3, 300 MHz) d 3.4 (s, 3H), 3.75 (s, 3H), 4.64
(d, JZ6.4 Hz, 1H), 4.70 (s, 2H), 5.32 (d, JZ10.6 Hz, 1H),
5.46 (d, JZ17.9 Hz, 1H), 5.82–5.94 (m, 1H); 13C NMR
(CDCl3, 75.5 MHz) d 170.9, 132.3, 119.1, 95.0, 75.7, 55.8,
52.9; EIMS m/z (rel intensity) 160 (MC, 0.5), 101 (24), 45
(100); HMRS (EIMS) calcd for C7H12O4 160.0735, found
160.0738.
To a strirred solution of this anthraquinone in THF (6 mL)
and H2O (2.5 mL) were added n-Bu4NBr (35 mg, 5%) and
Na2S2O4 (4!555 mg, 12.75 mmol) portionwise over 1 h.
The mixture was then treated with aqueous KOH (3.5 mL,
42.5 mmol) and stirred for 15 min, after which time Me2SO4
(4 mL, 42.5 mmol) was added dropwise. The reaction
mixture was stirred at rt overnight. It was then diluted in
3.1.10. 5-Acetoxy-1,4-dihydroxy-2-methoxyanthra-
quinone (30). To a stirring ice-cold solution of BTI
(76 mg, 0.18 mmol) in dry CH2Cl2 (3 mL) was added
dropwise a solution of 1-hydroxy-2-methoxy-5-acetoxy-
anthraquinone (25a) (50 mg, 0.16 mmol) in dry CH2Cl2
(2 mL) and diene 7a (56 mL, 0.32 mmol). After 3 h at rt, the

N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
1559
CH2Cl2 (20 mL) and quenched with H2O (50 mL). The
aqueous phase was extracted with CH2Cl2 (3!40 mL). The
combined organic layers were washed with brine (80 mL),
dried over Na2SO4, and evaporated. The crude mixture was
purified by column chromatography, eluting with hex-
ane/EtOAc [(5:1)/(1:1)], to give 1-benzyloxy-2,5,9,10-
tetramethoxyanthracene (303 mg, 35%): mp 130–131 8C;
IR (KBr) 2931, 2831 cmK1; 1H NMR (CDCl3, 200 MHz) d
3.95 (s, 3H), 4.01 (s, 3H), 4.02 (s, 3H), 4.08 (s, 3H), 5.08 (s,
2H), 6.74 (d, JZ7.6 Hz, 1H), 7.32–7.48 (m, 5H), 7.68 (m,
2H), 8.12 (d, JZ8.9 Hz, 1H), 8.27 (dd, JZ1.9, 9.6 Hz, 1H);
13C NMR (CDCl3, 50.3 MHz) d 156.2, 149.6, 149.2, 146.4,
140.3, 138.1, 129.0, 128.8, 128.2, 127.7, 125.3, 124.2,
121.8, 120.7, 116.8, 115.5, 115.1, 103.1, 76.6, 63.4, 63.3,
57.0, 56.0; LSIMS m/z (rel intensity) 404 (MC, 33), 405
(MHC, 17), 313 (M-BnC, 100); HMRS (LSIMS) calcd for
C25H24O5 404.1624, found 404.1618.
solution in THF (1 mL) was added and the resulting mixture
was stirred for 1 h. The THF solvent was then removed by
evaporation and replaced with pentane. The mixture was
filtered through Celite and evaporated to furnish a ca. 3:1
mixture of 23b and 28b, as estimated by 1H NMR analysis.
A solution of this mixture thus estimated to contain 114 mg
of 23b (0.49 mmol) in toluene (2 mL) was added dropwise
to a stirred solution of commercial 2,5-dichlorobenzo-
quinone (44 mg, 0.25 mmol) in toluene (1 mL). The
reaction mixture was stirred at rt for 24 h, after which
time the solvent was evaporated, the residue was diluted in
CH2Cl2 and treated with silica gel for 6 h. After filtration
and extensive trituration of the silica gel with CH2Cl2,
evaporation gave a red solid, which was purified by column
chromatography, eluting with light petroleum/Et2O (4:1), to
give 36b (14.7 mg, 22%): IR (NaCl) 1668, 1634, 1584 cmK1
;
1H NMR (CDCl3, 250 MHz) d 3.53 (s, 3H), 5.36 (s, 2H),
7.18 (s, 1H), 7.40 (d, JZ8.5 Hz, 1H), 7.72 (d, JZ8.5 Hz,
1H), 12.22 (s, 1H); 13C NMR (CDCl3, 75.5 MHz) d 188.2,
152.5, 152.3, 145.4, 135.6, 124.0, 122.3, 119.7, 119.2,
116.0, 95.1, 56.8; EIMS m/z (rel intensity) 268 (MC, 100),
237 (27); HMRS (EIMS) calcd for C12H9O5Cl 268.0138,
found 268.0140.
A solution of this anthracene (238 mg, 0.70 mmol) in THF
(23 mL) was stirred for 24 h in the presence of 10% wt Pd-C
(87 mg) under an atmosphere of hydrogen. This mixture
was filtered through Celite, and evaporated to give a residue,
which was purified by column chromatography, eluting with
hexane/EtOAc (4:1), to give 32 (67 mg, 30%): mp 134 8C;
IR (KBr) 3341, 2934, 2838 cmK1 1H NMR (CDCl3,
;
3.1.15. 2-Methoxy-1-(tripropylsilyloxy)-naphthalene
(38). To a stirred solution of 2-methoxynaphthol 6a
(500 mg, 2.87 mmol)42 in CH2Cl2 (30 mL) was added
dropwise at 0 8C the triethylamine (0.5 mL, 3.37 mmol).
After stirring for 30 min, Pr3SiCl (609 mg, 3.16 mmol) was
added dropwise at 0 8C. The mixture was stirred at rt for
100 min, after which time it was diluted with CH2Cl2
(20 mL), washed with 1M H3PO4 (30 mL), water (30 mL),
dried over Na2SO4, and evaporated at rt to furnish pure 38 in
quantitative yield (1 g): IR (NaCl) 3062, 2952, 2865,
200 MHz) d 3.99 (s, 3H), 4.05–4.07 (m, 9H), 6.70 (d, JZ
7.6 Hz, 1H), 7.26–7.39 (m, 2H), 7.72 (d, JZ8.9 Hz, 1H),
7.94 (d, JZ9.6 Hz, 1H), 9.56 (s, 1H); 13C NMR (CDCl3,
50.3 MHz) d 156.4, 149.8, 145.2, 141.7, 139.5, 126.3, 125.6,
123.5, 117.1, 116.8, 116.4, 114.8, 113.5, 102.9, 63.7, 63.3,
57.2, 56.0; LSIMS m/z (rel intensity) 314 (MC, 33) 337
(MNaC, 17), 299 (M-MeC, 100).
3.1.13. 1,2,5-Trimethoxyanthraquinone (33).76 To a stir-
ring ice-cold solution of 33 (50 mg, 0.16 mmol) in CH2Cl2
(10 mL) was added BTI (75 mg, 0.17 mmol) as a solid, in
one portion. After 2 min, the diene 7a (33 mL, 0.19 mmol) in
solution in CH2Cl2 (200 mL) was added dropwise. The
mixture was stirred at rt for 1 h, after which time it was
diluted with CH2Cl2 (20 mL), washed with saturated
aqueous NaHCO3 (2!20 mL), 1M H3PO4 (20 mL), brine
(20 mL), dried over Na2SO4, and evaporated at rt. The
resulting brownish oil was purified by column chromato-
graphy, eluting with hexane/Et2O (1:1), to furnish 33
(21 mg, 48%) as a red solid: mp 186–188 8C; IR (KBr)
1
1626 cmK1; H NMR (CDCl3, 300 MHz) d 0.72 (m, 6H),
0.87 (m, 9H), 1.34 (m, 6H), 3.81 (s, 3H), 7.15 (d, JZ8.1 Hz,
1H), 7. 23 (m, 1H), 7.34 (m, 2H), 7.63 (d, JZ8.1 Hz, 1H),
7.99 (dd, JZ8.2, 1.1 Hz, 1H); 13C NMR (CDCl3,
75.5 MHz) d 145.4, 139.0, 129.8, 128.8, 127.5, 125.3,
123.8, 121.9, 121.1, 114.5, 56.3, 18.5, 17.6, 16.8; EIMS m/z
(rel intensity) 330 (MC, 41), 272 (100); HMRS (EIMS)
calcd for C20H30O2Si 330.2015, found 330.2012.
3.1.16. 2-Chloro-5-hydroxy-6-methoxy-3-tripropylsila-
nyl-[1,4]naphthoquinone (39). To a stirred ice-cooled
solution of naphthoquinone 36a (40 mg, 0.17 mmol) in
DMF (5 mL) was added triethylamine (47 mL, 0.34 mmol).
After stirring for 30 min, Pr3SiCl (74 mL, 0.34 mmol) was
added dropwise at 0 8C. The mixture was stirred at rt for
90 min, after which time it was diluted with water (20 mL).
The aqueous phase was extracted with ether (3!20 mL),
and the combined organic layers were dried over Na2SO4,
and evaporated at rt. The residue was purified by column
chromatography, eluting with hexane/Et2O (2:1), to afford
39 (13.3 mg, 20%): IR (NaCl) 3408, 2925, 2854, 1668,
1
1663 cmK1; H NMR (CDCl3, 200 MHz) d 3.88 (s, 3H),
4.03 (s, 3H), 4.05 (s, 3H), 6.49 (d, JZ10.3 Hz, 1H), 7.13
(d, JZ7.4 Hz, 1H), 7.57 (dd, JZ8.1, 8.1 Hz, 1H), 7.98 (dd,
JZ1.0, 8.4 Hz, 1H), 8.10 (d, JZ10.3 Hz, 1H); 13C NMR
(CDCl3, 50.3 MHz) d 181.0, 178.7, 160.0, 157.1, 152.8,
140.9, 133.8, 129.8, 126.4, 122.5, 119.0, 118.1, 117.5,
111.6, 64.1, 62.7, 54.4; LSIMS m/z (rel intensity) 298 (MC,
21), 299 (MHC, 97), 321 (MHC, 100).
3.1.14. 2-Chloro-5-hydroxy-6-methoxymethylnaphtho-
quinone (36b). To a solution of i-Pr2NH (184 mL,
1.3 mmol) in THF (1 mL) was added dropwise at K78 8C
n-BuLi (576 mL, 1.44 mmol). After 40 min at this tempera-
ture, the mixture was allowed to warm up to rt for 10 min,
and then cooled down again to K78 8C. To this solution of
LDA was added dropwise methyl 2-methoxymethyl-3-
butenoate (28b, 200 mg, 1.25 mmol) in solution in THF
(1 mL). After 40 min, TMSCl (793 mL, 6.25 mmol) in
1
1632 cmK1; H NMR (CDCl3, 300 MHz) d 0.87 (m, 6H,
CH2-Pr), 1.04 (m, 9H, CH3-Pr), 1.62 (m, 6H, CH2-Pr), 4.00
(s, 3H, OCH3), 7.08 (d, JZ8.5 Hz, 1H, H-4), 7.75 (d, JZ
8.5 Hz, 1H, H-3), 12.43 (s, 1H, OH); 13C NMR (CDCl3,
75.5 MHz) d 188.2, 176.1, 154.6, 152.4, 148.0, 144.9, 123.1,
121.9, 115.0, 114.5, 56.4, 29.8, 21.3, 14.3; EIMS m/z (rel
intensity) 280 (MC, 100), 265 [(M-Pr3)C, 65].

1560
N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
3.1.17. 2-Chloro-6-methoxy-5-triethylsilanyloxy-[1,4]-
naphthoquinone (40). A solution of naphthoquinone 36a
(40 mg, 0.17 mmol), Ag2O (158 mg, 0.26 mmol) and Et3-
SiCl (42.8 mL, 0.26 mmol) in CHCl3 (5 mL) was refluxed
for 12 h. The mixture was filtered through Celite and
evaporated at rt to afford quantitatively 40 (71 mg), which
was used without any further purification: 1H NMR (CDCl3,
300 MHz) d 0.81 (m, 6H), 0.97 (m, 9H), 3.90 (s, 3H), 7.01
(s, 1H), 7.07 (d, JZ8.7 Hz, 1H), 7.83 (d, JZ8.7 Hz, 1H);
13C NMR (CDCl3, 75.5 MHz) d 180.9, 175.5, 156.5, 145.4,
143.6, 136.7, 123.9, 122.1, 121.0, 113.1, 54.7, 5.7, 4.6.
1-hydroxy-1,2-benziodoxol-3(1H)-one (80 mg, 0.3 mmol)
in THF (2 mL). To the resulting colorless solution was
added dropwise at rt a solution of enal 5b (63 mg,
0.25 mmol) in THF (2 mL). The resulting mixture gradually
became blue and then black. After 2 h, it was diluted with
Et2O (10 mL), washed with saturated aqueous NaHCO3
(2!5 mL), 10% HCl (10 mL), brine (10 mL), dried over
Na2SO4, and evaporated. The residue was purified by
column chromatography, eluting with light petroleum/
acetone (4:1), to give 46 (20 mg, 32%): IR (KBr) 3430,
2930, 1680, 1608, 753 cmK1; 1H NMR (CDCl3, 250 MHz)
d 2.19 (s, 3H, b-CH3), 2.63 (d, JZ17.4 Hz, 1H, g-CH2),
3.12 (d, JZ17.4 Hz, 1H, g-CH2), 3.17 (s, 3H, OCH3), 3.48
(s, 1H, OH), 5.73 (d, JZ9.8 Hz, 1H, H-3), 6.73 (d, JZ
9.8 Hz, 1H, H-4), 7.25–7.28 (m, 1H), 7.32–7.36 (m, 1H),
7.95 (d, JZ7.6 Hz, 1H), 9.51 (s, 1H, CHO); 13C NMR
(CDCl3, 62.9 MHz) d 189.4, 160.9, 136.6, 136.3, 132.7,
130.4, 128.7, 128.1, 127.3, 127.1, 126.9, 80.9, 80.2, 52.3,
49.8, 16.4; EIMS m/z (rel intensity) 256 (MC, 55), 224
(100), 195 (73); HMRS (EIMS) calcd for C16H16O3
256.1099, found 256.1103.
3.1.18.
2-(4-Hydroxy-3-methoxynaphtalen-1-yl)-3-
methylbut-2-enal (42). 3-Benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride (41, 1.4 mg, 0.005 mmol) and
Et3N (4 mL, 0.03 mmol) were successively added to a
solution of 5b (25 mg, 0.098 mmol) in absolute ethanol
(2 mL). The reaction mixture was heated at 80 8C for 2.5 h,
after which time ethanol was evaporated. The residue was
then diluted with CH2Cl2 (10 mL), washed with saturated
aqueous Na2CO3 (10 mL), brine (20 mL), dried over
Na2SO4, and evaporated. The resulting crude oil was
purified by column chromatography, eluting with light
petroleum/Et2O (1:1), to give 42 as a light red gum (23 mg,
3.1.21. Treatment of epoxide 48 with zinc. A suspension
of 48 (17 mg, 0.06 mmol), zinc powder (20 mg,
0.31 mmol), ammonium chloride (10 mg, 0.18 mmol) in a
4:1 mixture of EtOH/H2O (7 mL) was heated at 80 8C for
20 min, after which time it was filtered. The filtration pellet
was rinsed with Et2O, and the filtrates were washed with
brine (10 mL), dried over Na2SO4 and evaporated at rt. The
residue was purified by PLC, eluting with light petroleum/
Et2O (2:3), to afford 46 (17 mg, 14%).
1
90%): IR (NaCl) 3408, 2928, 1694, 1350 cmK1; H NMR
(CDCl3, 250 MHz) d 1.71 (s, 3H, CH3), 2.47 (s, 3H, CH3),
3.97 (s, 3H, OCH3), 6.03 (s, 1H, H-3), 6.94 (s, 1H), 7.30 (d,
JZ8.3 Hz, 1H), 7.42 (m, 2H), 8.17 (d, JZ7.6 Hz, 1H),
10.36 (s, 1H, CHO); 13C NMR (CDCl3, 62.9 MHz) d 190.7,
158.7, 140.8, 139.5, 137.1, 128.0, 125.8, 125.4, 124.8,
124.7, 124.3, 121.8, 115.0, 57.2, 25.3, 19.9; LSIMS m/z (rel
intensity) 279 (MNaC, 28); 256 (MC, 100); HMRS
(LSIMS) calcd for C16H16O3 256.1099, found 256.1101.
3.1.22. Treatment of epoxide 48 with SmI2. To a slurry
suspension of Sm powder (84 mg, 0.55 mmol) and molecu-
˚
lar sieves 4 A in THF (4 mL) was added at rt diiodomethane
3.1.19. 5-(2-Methoxy-1-oxo-1,2-dihydro-naphthalen-2-
yl)-4-methyl-trimethylsilanyloxy-pent-3-enenitrile (43).
To a stirred solution of 5b (150 mg, 0.59 mmol), KCN
(3 mg, 0.08 mmol) and 18-crown-6 (8 mg, 0.05 mmol) in
CH2Cl2 (6 mL) was added dropwise at 0 8C Me3SiCN
(94 ml, 0.71 mmol). The reaction mixture was stirred at 0 8C
for 45 min, after which time it was evaporated and directly
submitted to column chromatography, eluting with light
petroleum/Et2O (2:1), to give 43 as a pale yellow oil (77 mg,
37%): IR (NaCl) 2935, 2360, 1686 cmK1; 1H NMR (CDCl3,
250 MHz) d 0.16 (s, 9H, TMS), 1.67 (s, 3H, b-CH3), 1.79 (s,
3H, b-CH3), 2.46 (s, 2H, g-CH2), 2.50 (s, 2H, g-CH2), 3.17
(s, 3H, OCH3), 3.18 (s, 3H, OCH3), 4.93 (d, JZ8.5 Hz, 1H,
CHCN), 4.99 (d, JZ7.9 Hz, 1H, CHCN), 5.26 (d, JZ
8.5 Hz, 1H, H-a), 5.32 (d, JZ7.3 Hz, 1H, H-a), 6.09 (d, JZ
10.1 Hz, 1H, H-4), 6.79 (d, JZ10.1 Hz, 1H, H-3), 7.24 (d,
JZ7.6 Hz, 1H, H-5), 7.37 (t, JZ7.6 Hz, 1H, H-7), 7.59 (t,
JZ7.6 Hz, 1H, H-6), 8.02 (d, JZ7.6 Hz, 1H, H-8); 13C
NMR (CDCl3, 62.9 MHz) d 200.0, 137.1, 136.9, 135.0,
135.0, 134.9, 134.9, 129.9, 129.3, 129.1, 128.3, 126.9,
126.8, 125.8, 82.3, 57.9, 53.4, 48.6, 48.3, 18.7, 18.5, -0.4;
EIMS m/z (rel intensity) 355 (MC, 7), 173 (100); HMRS
(EIMS) calcd for C20H25NO3Si 355.1603, found 355.1601.
(30 mL, 0.37 mmol). The resulting olive-green slurry was
stirred for 2 h, after which time the deep blue solution of
SmI2 thus formed was cooled to K90 8C, and treated with a
solution of 48 (100 mg, 0.37 mmol) in THF/MeOH (4:1,
2.5 mL). The resulting brown mixture was stirred for 10 min
at K90 8C, quenched at this temperature with H2O and then
warmed to rt. The mixture was then further diluted in H2O
and extracted four times with Et2O (4!10 mL). The
combined organic layers were washed with saturated
aqueous sodium thiosulfate (5 mL) and H2O (2!5 mL),
dried over Na2SO4, and evaporated to give a residue which
was purified by column chromatography, eluting with light
petroleum/Et2O (1:1), to furnish 46 (13 mg, 14%).
3.1.23. Epoxide 48. To a suspension of 5b (120 mg,
0.47 mmol) and Na2CO3 (49.8 mg, 0.47 mmol) in a mixture
of EtOH/H2O (4:1, 7 mL) was added dropwise at 0 8C a
30% aqueous solution of H2O2 (400 mL). After the addition
was complete, the ice-bath was removed and the mixture
was stirred at rt for 3 h. The mixture was then evaporated,
and the residue was diluted with CH2Cl2 (10 mL), washed
with H2O (10 mL), brine (10 mL), dried over Na2SO4, and
evaporated at rt. The resulting oil was purified by column
chromatography, eluting with ligth petroleum/Et2O (2:3), to
afford the epoxide 48 as a 1:1 mixture of diastereosomers
(85 mg, 67%, light yellow oil). These isomers were
separated by PLC, eluting with light petroleum/acetone
(3:1), to furnish 48a as the fastest moving isomer and 48b.
3.1.20. 9b-Hydroxy-3a-methoxy-2-methyl-3a,9b-di-
hydro-3H-cyclopenta[a]naphthalene-1-carbaldehyde
(46)—treatment of enal 5b with tetra-n-butylammonium
oxido-l3-iodane (45). Tetrabutylammonium fluoride
(270 mL in THF, 0.3 mmol) was added to a suspension of

N. Lebrasseur et al. / Tetrahedron 61 (2005) 1551–1562
1561
1
48a: H NMR (CDCl3, 250 MHz) d 1.42 (s, 3H, g-CH3),
support of the Centre National de la Recherche Scientifique
through the French IGERT program and the Robert A.
Welch Foundation (Grant D-1365) are gratefully acknowl-
edged, as well as Simafex (www.simafex.com) for the gifts
of several batches of BTI reagent.
2.10 (d, JZ14.6 Hz, 1H), 2.31 (d, JZ14.6 Hz, 1H), 3.18 (s,
3H, OCH3), 6.13 (d, JZ10.0 Hz, 1H, H-3), 6.72 (d, JZ
10.0 Hz, 1H, H-4), 7.24 (d, JZ7.9 Hz, 1H), 7.39 (m, 1H),
7.60 (t, JZ1.5, 7.8 Hz, 1H), 7.99 (d, JZ8.5 Hz, 1H), 9.28
(d, JZ5.2 Hz, 1H, CHO); EIMS m/z (rel intensity) 272
1
(MC, 15), 157 (100). 48b: H NMR (CDCl3, 250 MHz) d
1.48 (s, 3H, g-CH3), 1.88 (d, JZ14.6 Hz, 1H), 2.20 (d, JZ
14.6 Hz, 1H), 3.18 (s, 3H, OCH3), 6.18 (d, JZ10.0 Hz, 1H,
H-3), 6.82 (d, JZ10.0 Hz, 1H, H-4), 7.24 (d, JZ6.1 Hz,
1H), 7.39 (m, 1H), 7.60 (t, JZ1.5, 7.8 Hz, 1H), 8.03 (d, JZ
8.5 Hz, 1H), 9.37 (d, JZ4.9 Hz, 1H, CHO); EIMS m/z (rel
intensity) 272 (MC, 15), 157 (100).
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Acknowledgements
The authors thank the French Ministry of Research for G.-
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