An enantiospecific route towards taiwaniaquinoids. First synthesis of (-)-taiwaniaquinone H and (-)-dichroanone

Article abstract of DOI:10.1039/b916209g

A new methodology for the enantiospecific synthesis of taiwaniaquinoids, based on a thermal 6π electrocyclization, is reported. Under this procedure, 4a-methylhexahydrofluorene terpenoids bearing an A/B trans-configuration has been prepared for the first

Full text of DOI:10.1039/b916209g

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An enantiospecific route towards taiwaniaquinoids. First synthesis
of (-)-taiwaniaquinone H and (-)-dichroanone†
Enrique Alvarez-Manzaneda,*a Rachid Chahboun,a Eduardo Cabrera,a Esteban Alvarez,a Ali Haidour,a
Jose Miguel Ramos,a Ramo´n Alvarez-Manzaneda,b Yahia Charrahc and Hakima Es-Samtia
Received 7th August 2009, Accepted 21st September 2009
First published as an Advance Article on the web 21st October 2009
DOI: 10.1039/b916209g
A new methodology for the enantiospecific synthesis of taiwaniaquinoids, based on a thermal 6p
electrocyclization, is reported. Under this procedure, 4a-methylhexahydrofluorene terpenoids bearing
an A/B trans-configuration has been prepared for the first time. This methodology also makes it
feasible to synthesize taiwaniaquinoids with an A/B cis-configuration and 4a-methyltetrahydrofluorene
terpenoids. Accordingly, the first synthesis of (-)-taiwaniaquinone G, (-)-taiwaniaquinone H and
(-)-dichroanone has been achieved.
Introduction
Several rearranged terpenoids possessing the uncommon
4a-methyltetra- (and hexa-)hydrofluorene skeleton have been
described during the past decade. These compounds, known as
taiwaniaquinoids, were isolated from certain species of East Asian
conifers. Among these, let us mention taiwaniaquinones A (1),1a
D (2),1b G (3)1d and H (4),1d and taiwaniaquinols A (5),1a B (6)1a
and C (7),1a isolated from Taiwania cryptomerioides,1 dichroanone
(8), obtained from Salvia dichroantha,2 and standishinal (9), found
in Thuja standishii (Fig. 1).3 Hexahydrofluorene derivatives with
an A/B trans-, e.g. compounds 1 and 3, or cis-configuration,
e.g. compound 6, have been isolated. Moreover, in some cases,
one carbon is lost in the course of the biosynthesis to give
norditerpenoids, such as compounds 4 and 8.
Although not much is known about their bioactivities, recent
studies have revealed that taiwaniaquinones A (1) and D (2), and
taiwaniaquinols A (5) and C (7) exhibit cytotoxic activity,1d and
that standishinal (9) is a potential antitumor agent for treating
breast cancer due to its aromatase inhibitory activity.4
Fig. 1 Some representative taiwaniaquinoids.
These promising biological activities and the peculiar carbotri-
cyclic structure of this family of compounds have motivated
the development of varied synthetic approaches. Four main
strategies have been utilized for the construction of the core
6,5,6-ABC tricyclic skeleton of taiwaniaquinoids. An A-AB-ABC
approach5 was used by McFadden and Stoltz for synthesiz-
ing (+)-dichroanone (8), the antipode of the natural product;
the 5-membered B ring was formed via a novel asymmetric
palladium-catalyzed allylation.6 The C-ABC strategy, involv-
ing a bis-cyclization process, was utilized in the synthesis of
( )-taiwaniaquinol B (6) reported by Fillion and Fishlock, through
a domino intramolecular acylation carbonyl a-tert-alkylation
reaction.7 The same strategy was utilized by Li and Chiu, who
synthesized compound 6 via an intramolecular acid-promoted
sequential cationic cyclization.8 The AC-ABC approach is cur-
rently the most widely utilized strategy for synthesizing this type
of terpenoid. The process usually involves the utilization of a
monoterpene synthon, such as b-cyclocitral or cyclogeranic acid,
together with a phenol derivative to construct the 4a-methyl- (or
hexa-)hydrofluorene skeleton. Node et al.9 and Banerjee et al.10
utilized intramolecular Heck reactions to prepare some com-
pounds of this family of metabolites. Trauner et al. described an
interesting synthetic approach toward taiwaniaquinoids utilizing a
Nazarov cyclization.11 Recently, She et al. described the synthesis
of compounds 6 and 8 using an acid-promoted Friedel–Crafts
acylation/alkylation process, which allows the elaboration of the
ABC tricyclic skeleton in one step.12 Very recently, our group
described a very short synthesis of ( )-taiwaniaquinone H (4) and
aDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Instituto de
Biotecnolog´ıa, Universidad de Granada, 18071, Granada, Spain. E-mail:
eamr@ugr.es; Fax: +34 958 24 80 89; Tel: +34 958 24 80 89
bDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de
Almer´ıa, 04120, Almer´ıa, Spain
cLaboratoire de Pharmacologie et Toxicologie, Faculte´ de Medecine et
Pharmacie, Universite Mohammed V-Suissi, Rabat, Morocco
† Electronic supplementary information (ESI) available: Experimental
procedures for compounds 17, 18, 22, 28, 33 and 37, and copies of 1H
and 13C NMR for all novel compounds. See DOI: 10.1039/b916209g
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( )-dichroanone (8), through an intramolecular Friedel–Crafts
alkylation13 (Scheme 1).
Scheme 2 Retrosynthetic analysis.
Scheme 1 Previously reported strategies starting from a monoterpene
(AC-ABC approach)
All the previously reported approaches are total syntheses.
Moreover, all these methods are restricted to synthesizing com-
pounds with an A/B cis-configuration or a cyclopentane double
bond, such as compounds 6 and 8, respectively. Our group recently
communicated the first route towards taiwaniaquinoids bearing
an A/B trans-configuration via a thermal 6p electrocyclization;
furthermore, this new procedure, which utilizes chiral precursors
with the same absolute configuration on the AB junction carbons,
makes it feasible to address the enantiospecific synthesis of natural
taiwaniaquinoids.14
Scheme 3 Synthesis of triene 12. (a) I2, PPh3, CH2Cl2, rt, 3.5 h (83%).
(b) (i) O3, CH2Cl2, -78 ◦C, 3 h. (ii) Me2S, -78 ◦C–rt, 12 h (75%). (c) DBU,
benzene, rt, 12 h (90%). (d) H2SO4, dioxane, rt, 4 h (73%). (e) TMSOTf,
PriNEt2, CH2Cl2, 0 ◦C, 30 min (quant.).
Diol 15 has previously been obtained by lipase-catalyzed kinetic
resolution after the acid cyclization of homofarnesyl acetate
(2 steps, 27% overall yield);15 we have prepared diol 15 in 96%
yield after reduction of commercial (+)-sclareolide with KBH4.14
Treatment of compound 15 with the I2–PPh3 system, following
a methodology previously reported by our group,16 caused the
simultaneous regioselective dehydration of tertiary alcohol and the
transformation of primary alcohol into the corresponding iodide,
giving compound 14.17 Ozonolysis of this afforded 1,6-diketone
16 in good yield,18 which was converted into b-hydroxy ketone 13
by treating it with DBU in benzene. Transformation of hydroxy
derivative 13 into dienone 17 was not a trivial task, the dehydration
probably being difficult due to the strong hydrogen bond in
the molecule. Table 1 shows the most representative attempts to
achieve this goal. Treatment with SOCl2 and pyridine in CH2Cl2 at
-58 ◦C for 10 min gave chloroketone 18 in 60% yield (entry 2). The
same compound results in high yield after treatment with conc.
HCl in CH2Cl2 at room temperature for 1 h (entry 6). Dienone 17
and chloroketone 18 were obtained in low yield by treating hydroxy
derivative 13 with POCl3 and pyridine in CH2Cl2 (entry 3). The
best result was achieved utilizing conc. H2SO4 in dioxane at room
temperature, which afforded dienone 17 in 73% yield (entry 4).
Chloroketone 18 was completely converted into dienone 17 by
treating it with DBU in benzene at room temperature for 1 h.
In this paper, we report our studies on the synthesis towards
this family of compounds, utilizing the 6p electrocyclization
strategy, and its possible application to obtaining different types
of taiwaniaquinoids.
Results and discussion
The synthetic strategy planned is shown in Scheme 2. Phenol 10
is postulated as an adequate precursor for synthesizing the target
compounds. The isopropyl group would be introduced utilizing the
ester group of methyl salicylate derived from ketoester 11, which
is obtained from the enone resulting from the electrocyclization
of silyl enol ether 12. This will be obtained from the conjugated
dienone formed after the dehydration of ketol 13, resulting from
the intramolecular aldol condensation of diketone derived from
the oxidative rupture of the homoallylic iodide 14, which can be
easily prepared from diol 15.
The synthesis of silyl enol ether 12 is depicted in Scheme 3,
in which key steps are the transformation of diol 15 into the
homoallylic iodide 14 and the intramolecular aldol condensation
with simultaneous dehydrohalogenation of diketone 16, affording
the hydroxyketone 13.
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Table 1 Dehydration of b-hydroxyketone 13
sequence (35% overall yield). These precedents forced us to
investigate new strategies to achieve the target quinone.
A first approach to compound 3 is depicted in Scheme 5. The
sequence involves the introduction of the oxygenated functions
on the C ring through successive formylation and Baeyer–Villiger
oxidations. Treatment of the methyl ether 22 with Cl2CHOMe and
TiCl4 gave aldehyde 23, which was converted into formiate 24 by
treating it with MCPBA. Further formylation of this compound
took place with the simultaneous removal of isopropyl group,
affording aldehyde 25.
Entry
Reaction conditions
Compound (%)
1
2
3
TsOH, benzene, 85 ◦C, 10 min
SOCl2, pyridine, CH2Cl2, -58 ◦C, 10 min
POCl3, pyridine, CH2Cl2, -36 ◦C–reflux,
10 min
Complex mixture
18a (60)
17 (20), 18a (35)
4
5
6
Conc. H2SO4, dioxane, rt, 4 h
BF3·Et2O, CH2Cl2, rt, 5 h
17 (73)
13
Conc. HCl, CH2Cl2, rt, 1 h
18a (97)
a Treatment of chloroketone 18 with DBU in benzene at room temperature
for 1 h gave dienone 17 in 95% yield.
Triene 12 was finally obtained in quantitative yield after treatment
with TMSOTf and PriNEt2 in dichloromethane at 0 ◦C.
Scheme 4 shows the transformation of silyl enol ether 12 into
the tricyclic precursor 10 of taiwaniaquinoids. The key step is the
6p electrocyclization of triene 12 leading to enone 19, which has a
tricyclic system of taiwaniaquinoid. Refluxing triene 12 in xylene
for 4 h gave a,b-enone 19, which when treated with LDA and
NCCOOMe in THF afforded b-ketoester 11, obtained as a 1 : 1
mixture of epimers. Treatment of the latter with DDQ (1.5 equiv.)
in dioxane under reflux led to the methyl salicylate 20, which
was then transformed into hydroxyphenol 21 when treated with
MeMgBr (4 equiv.). Treatment of this compound with Et3SiH and
CF3COOH gave the desired phenol 10.
Scheme 5 Functionalization of the C ring. Reagents and conditions:
(a) MeI, K2CO3, acetone, reflux, 17 h (97%). (b) (i) Cl2CHOMe, TiCl4,
CH2Cl2, -20 ◦C, 13 h. (ii) H2O (87%). (c) MCPBA, CH2Cl2, 0 ◦C, 1 h
(97%). (d) (i) Cl2CHOMe, TiCl4, CH2Cl2, -20 ◦C, 15 h. (ii) H2O (87%).
A straightforward transformation of phenol 10 into taiwani-
aquinone G (3) has been developed (Scheme 6).
Scheme 6 Synthesis of (-)-taiwaniaquinone G (3) from phenol 10.
Reagents and conditions: (a) Fremy’s salt, acetone, rt, pH 7 buffer, 15 h
(94%). (b) Br2, AcOH, rt, 5 min (89%). (c) MeONa, MeOH, rt, 30 min
(97%).
Scheme 4 Synthesis of intermediate 10 from triene 12. Reagents and
conditions: (a) xylene, reflux, 4 h (92%). (b) (i) LDA, THF, -78 ◦C. (ii)
NCCOOMe, THF, -78 ◦C–-36 ◦C, 3 h, (97%). (c) DDQ (1.5 eq), dioxane,
reflux, 30 min (94%). (d) MeMgBr (4 eq), THF, rt, 13 h (97%). (e) Et3SiH,
CF3COOH, CH2Cl2, -40 ◦C, 1 h (95%).
Treatment of compound 10 with Fremy’s salt gave quinone
26 in high yield. The direct introduction of the methoxy group
onto the quinone ring under the diverse previously reported
conditions, e.g. HgCl2, I2, MeOH19 or Fe2(SO4)3, MeOH,20 was
unsuccessful. Methoxy quinone 3 was finally obtained after
treatment of bromoquinone 27 with MeONa in MeOH. In this
way, phenol 10 was converted into taiwaniaquinone G (3) in
a 3-step sequence in 81% overall yield. The optical rotation of
synthetic taiwaniaquinone G (3) ([a]2D5: -91.4◦; c 1.1, CHCl3) was
similar to that reported for the natural product ([a]2D2: -120.8◦;
c 0.29, CHCl3); the spectroscopic properties were identical to those
previously described.1d
Next, the functionalization of the aromatic C ring was under-
taken. We selected taiwaniaquinone G (3) as the target compound
because it is the most immediate terpenoid bearing an A/B trans-
configuration and it has not yet been synthesized. All preceding
authors have utilized phenolic precursors with a substitution
pattern quite different from that of intermediate 10. Most of
them used 1,3-7,11 or 3,4-dihydroxy10 derivatives, which were trans-
formed into the final compound after a 2- or 3-step sequence in
45–52% yield. McFadden and Stoltz,6 and She et al.12 utilized a
3-hydroxy precursor, which afforded quinone 8 in a 3-step
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After this, we were interested in exploring the utilization of this
new strategy to develop the enantiospecific synthesis of a wider
range of taiwaniaquinoids, including A/B trans- and cis-fused
4a-methylhexahydrofluorene and 4a-methyltetrahydrofluorene
derivatives. First, the direct oxidation of A/B trans-fused
4a-methylhexahydrofluorene derivatives, such as quinones 26 and
3, to the corresponding 4a-methyltetrahydrofluorene derivatives
was unsuccessfully essayed; thus, compounds 26 and 3 remained
unaltered after refluxing for 48 h with DDQ in dioxane.
phenol 36 in almost quantitative yield, which, after methylation,
was converted into the 4a-methyltetrahydrofluorene 38 following
the same treatment utilized for 33. The isopropyl group was then
introduced by treating the O-methyl derivative 38 with n-BuLi
and acetone. At this point, it should be noted that, following
the same procedure described for quinones 26 and 3, treatment
of compounds 33 and 37 with DDQ in refluxing dioxane did not
afford the desired 4a-methyltetrahydrofluorene derivatives, but the
starting materials remained unaltered.
Next, we investigated the introduction of a functional group
into the cyclopentane B ring of A/B trans-fused derivatives, which
would allow us to synthesize compounds such as 1, 5, 7 or 9.
With this purpose in mind, we attempted the preparation of
the corresponding oxocyclopentane derivatives. The oxidation of
several compounds resulting from the hydroxyl group protection
of phenol 10 was then investigated. The unaltered starting material
was recovered when the methyl ether derived from 10 was treated
with different oxidizing reagents under mild conditions; a complex
mixture of compounds resulted when the reaction conditions
were forced. Acetoxy derivative 28 exhibited a similar behaviour;
however, treatment of this with Na2CrO4, Ac2O, AcONa and
AcOH in benzene at 70 ◦C allowed the isolation of diacetoxy
derivative 29 in low yield (Scheme 7). This result revealed that the
methyne of the isopropyl group is more easily oxidized than is the
cyclopentane methylene.
Scheme 9 Synthesis of intermediate 30. Reagents and conditions: (a) MeI,
K2CO3, acetone, reflux, 8 h (98%). (b) (i) NBS, CCl4, hn, Bz2O2, 60 ◦C,
30 min. (ii) Amberlyst A-15, CH2Cl2, reflux, 1 h (90%). (c) MeMgBr, THF,
rt, 15 min (96%). (d) ZnI2, NaBH3CN, CH2Cl2, 0 ◦C, 2 h (96%). (e) DDQ,
dioxane, reflux, 1 h (98%). (f) MeI, K2CO3, acetone, reflux, 6 h (96%). (g) (i)
NBS, CCl4, hn, Bz2O2, 60 ◦C, 30 min. (ii) Amberlyst A-15, CH2Cl2, reflux,
1 h (93%). (h) (i) n-BuLi, THF, -20 ◦C, 30 min. (ii) Acetone, HMPA, 0 ◦C,
3 h (84%).
Next, the preparation of oxocyclopentane 32 following the
synthetic proposal depicted in Scheme 8 was tackled. Treatment
of methyl ether 30 with MCPBA in CH2Cl2 at 0 ◦C for 30 min
and the further treatment of crude epoxide with BF3·Et2O in
CH2Cl2 at 0 ◦C for 30 min led to ketone 39, with an A/B
cis-configuration, as revealed by nOe experiments. This compound
is a suitable intermediate for the enantiospecific synthesis of A/B
cis-fused taiwaniaquinoids, such as taiwaniaquinol B (6). All
attempts to epimerize ketone 39 to the corresponding trans isomer
32 were unsuccessful (Scheme 10).
Scheme 7 Oxidation of acetoxy derivative 28 with Na2CrO4.
In view of the failure to achieve direct oxidation of the
cyclopentane ring, an alternative route towards the oxo deriva-
tive 32, via rearrangement of epoxide 31, derived from the
4a-methyltetrahydrofluorene 30, was planned (Scheme 7).
Scheme 8 A possible route towards A/B trans-fused oxocyclopentane
derivatives.
Then, the synthesis of intermediate 30 was addressed. Scheme 9
shows two alternative procedures developed to synthesize the
methoxy derivative 30. In both sequences, the isopropyl group
was introduced after the elaboration of the cyclopentane double
bond. The first route started from salicylate 20; treatment of its O-
methyl derivative 33 with NBS and Bz2O2 in CCl4 under irradiation
followed by refluxing with cationic resin in CH2Cl2 gave the
4a-methyltetrahydrofluorene 34 in good yield. The introduction of
the isopropyl group to give the desired compound 30 was achieved
in a similar way to that commented on above for compound
10. In the second procedure, the a,b-enone 19 was the starting
material. Refluxing this ketone with DDQ in dioxane afforded
Scheme 10 Synthesis of oxocyclopentane derivative 39.
An alternative route towards A/B trans-fused taiwaniaquinoids
with a functionality in the cyclopentane B ring could be achieved
via the hydroboration–oxidation of intermediate 30. The axial
angular methyl would direct the a attack of borane, thus providing
a cyclopentane substitution pattern similar to that of standishinal
(9). Under this assumption, we investigated an approach to this
taiwaniaquinoid (Scheme 11). Treatment of the methoxy derivative
30 with Cl2CHOMe and TiCl4 gave aldehyde 40 in high yield;
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an A/B cis-configuration as well as 4a-methyltetrahydrofluorene
derivatives. Utilizing this, the first enantiospecific synthesis
of (-)-taiwaniaquinone G (3), (-)-taiwaniaquinone H (4) and
(-)-dichroanone (8), and an approach to (-)-standishinal (9) have
been developed. The elaboration of A/B trans-fused taiwani-
aquinoids bearing a functionality in the cyclopentane B ring,
which presents some difficulties, is currently under study.
Scheme 11 Hydroboration of the cyclopentane double bond. Reagents
and conditions: (a) (i) Cl2CHOMe, TiCl4, CH2Cl2, -30 ◦C, 10 h. (ii) H2O
(96%). (b) (i) B2H6, THF, -78 ◦C–-35 ◦C, 14 h. (ii) NaOH, H2O, EtOH,
H2O2 30%, rt, 8 h (81%, 41 : 42 4 : 1).
Experimental
further reaction of this with B2H6 followed by alkaline H2O2
led to diols 41 and 42 in a 4 : 1 relation. Compound 42 is an
immediate precursor of (-)-standishinal (9). In obtaining diol 41
and ketone 39, the considerable stability of the A/B cis-fused
4a-methylhexahydrofluorene system was apparent.
For the experimental procedure and analytical data concerning
compounds 3, 10–16, 19–21 and 26–27 see ref. 14.
(4bS,8aS)-2-Isopropyl-1-methoxy-4b,8,8,-trimethyl-5,6,7,8,8a,9-
hexahydro-4bH-fluoren-4-carbaldehyde (23)
Of course, the methoxy derivative 30 is a suitable pre-
cursor to synthesize taiwaniaquinoids bearing the 4a-methyl-
tetrahydrofluorene skeleton. Scheme 12 shows the sequence devel-
oped to prepare (-)-taiwaniaquinone H (4) and (-)-dichroanone
(8). Phenol 43 was transformed almost quantitatively into quinone
44 by treatment with CAN in CH2Cl2 at room temperature for 1 h.
Introduction of the methoxy group of compound 4 via bromo
derivative 45 was carried out in a similar way to that utilized
for quinone 26. Treatment of methoxy derivative 4 with KOH in
MeOH at room temperature for 15 h gave (-)-dichroanone (8)
in 88% yield.21 This sequence constitutes the first enantiospecific
synthesis of (-)-taiwaniaquinone H (4) and (-)-dichroanone (8).
The optical rotations of synthetic 4 ([a]2D5: -11.9; c 0.56, CHCl3)
and 8 ([a]2D5: -88.7; c 0.79, CHCl3) were similar to those reported for
Cl2CHOMe (0.5 mL, 5.52 mmol) and TiCl4 (0.3 mL, 2.73 mmol)
were added to a solution o◦f compound 22 (320 mg, 1.12 mmol)
in CH2Cl2 (15 mL) at -20 C under argon and the mixture was
stirred at this temperature for 13 h, at which time TLC showed no
starting material. Then, water (5 mL) was added and the mixture
was stirred for a further 10 min. It was extracted with ether (2 ¥
20 mL) and the organic phase was washed with water (5 ¥ 10 mL),
brine (10 mL) and dried over anhydrous Na2SO4. The solvent was
removed under vacuum and the crude residue was purified by
flash chromatography column on silica gel (10% ether/hexanes),
affording aldehyde 23 (305 mg, 87%) as a yellow syrup. [a]2D5 = -9.0
(c 2.6, CHCl3); 1H NMR (CDCl3, 500 MHz) d: 0.99 (s, 3H), 1.07
(s, 3H), 1.20 (d, J = 6.9 Hz, 3H), 1.21 (ddd, J = 13.6, 13.6, 4.2 Hz,
1H), 1.24 (d, J = 6.9 Hz, 3H), 1.25 (s, 3H), 1.53 (dt, J = 13.4,
3.4 Hz, 1H), 1.69 (m, 2H), 1.76 (bd, J = 12.9, 6.1 Hz, 1H), 1.88
(qt, J = 13.5, 4.0 Hz, 1H), 2.44 (dt, J = 12.0, 3.2 Hz, 1H), 2.67 (dd,
J = 14.1, 12.9 Hz, 1H), 2.85 (dd, J = 14.1, 6.1 Hz, 1H), 3.27 (h,
J = 6.9 Hz, 1H), 3.86 (s, 3H), 7.63 (s, 1H), 10.63 (s, 1H). 13C NMR
(CDCl3, 125 MHz) d: 20.1 (CH2), 21.1 (CH3), 21.5(CH3), 23.3
(CH3), 23.4 (CH3), 26.9 (CH), 27.2 (CH2), 33.1 (C), 31.2 (CH3),
38.6 (CH2), 40.8 (CH2), 48.2 (C), 59.4 (OCH3), 60.4 (CH), 125.4
(CH), 127.7 (C), 134.1 (C), 139.2 (C), 158.1 (C), 159.3 (C), 190.6
(CHO). IR (cm-1) n: 1684, 1471, 1259; HRMS [FAB, (M + Na)+]
m/z: calcd for C21H30O2Na 337.2143, found: 337.2156.
the natural products ([a]2D5: -9.0; c 0.29, CHCl3 and [a]2D5: -99.3;
1d
c 0.67, dioxane,2 respectively); their spectroscopic properties were
identical to those previously described.1d,2
8-(4bS,8aS)-2-Isopropyl-1-methoxy-4b,8,8-trimethyl-5,6,7,8,8a,9-
hexahydro-4bH-fluoren-4-yl) formate (24)
m-Chloroperoxybenzoic acid (MCPBA, 75%; 123 mg, 0.5 mmol)
was added at 0 ◦C to a stirred solution of 23 (147 mg, 0.468 mmol)
in CH2Cl2 (10 mL) and the reaction was stirred for 1 h, at which
time TLC indicated no starting material remaining. The reaction
was quenched with sat. aq Na2SO3 (0.5 mL) and stirred for an ad-
ditional 10 min. Then, it was poured into ether/water (20 : 7 mL),
and the organic phase was washed with sat. aq NaHCO3 (10 ¥
8 mL) and brine, dried over Na2SO4 and concentrated to give 24
(150 mg, 97%) as a colourless oil. [a]2D5 = -23.3 (c 1.8, CHCl3); 1H
NMR (CDCl3, 500 MHz) d: 0.96 (s, 3H), 1.03 (s, 3H), 1.10 (s, 3H),
1.17 (d, J = 6.9 Hz, 3H), 1.18 (ddd, J = 13.6, 13.6, 4.2 Hz, 1H),
1.21 (d, J = 6.9 Hz, 3H), 1.50 (dt, J = 13.0, 3.2 Hz, 1H), 1.55 (dd,
J = 13.1, 3.9 Hz, 1H), 1.62 (m, 1H), 1.75 (bd, J = 12.8, 6.1 Hz,
1H), 1.78 (qt, J = 13.6, 4.0 Hz, 1H), 2.16 (dt, J = 12.4, 3.1 Hz,
1H), 2.63 (dd, J = 14.6, 12.8 Hz, 1H), 2.82 (dd, J = 14.6, 6.1 Hz,
Scheme 12 Synthesis of (-)-taiwaniaquinone H (4) and (-)-dichroanone
(8) from intermediate 30. Reagents and conditions: (a) BBr3, CH2Cl2,
-78–0 ◦C, 2 h (64%). (b) CAN, CH2Cl2, rt, 1 h (96%). (c) Br2, AcOH, rt,
5 min (82%). (d) MeONa, MeOH, rt, 30 min (95%). (e) KOH, MeOH, rt,
15 h (88%).
Conclusions
In summary, a new synthetic strategy towards taiwaniaquinoids,
based on a thermal 6p electrocyclization, is described. This
procedure, which enables the preparation of natural enantiomers,
is the first reported to synthesize taiwaniaquinoids with an A/B
trans-configuration; it also allows the synthesis of terpenoids with
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1H), 3.26 (h, J = 6.9 Hz, 1H), 3.79 (s, 3H), 6.66 (s, 1H), 8.28 (s,
1H). 13C NMR (CDCl3, 125 MHz) d: 19.8 (CH3), 19,9 (CH2), 23.5
(CH3), 23.8 (CH3), 26.9 (CH), 27.4 (CH2), 33.1 (C), 33.2 (CH3),
36.3 (CH2), 41.2 (CH2), 46.6 (C), 59.9 (OCH3), 60.7 (CH), 118.1
(CH), 135.9 (C), 140.3 (C), 140.7 (C), 144.1 (C), 152.2 (C), 160.3
(OCHO); IR (cm-1) n: 1742, 1474, 1132; HRMS [FAB, (M + Na)+]
m/z: calcd for C21H30O3Na 353.2093, found: 353.2101.
117.7 (CH), 125.2 (CH), 133.3 (C), 136.1 (C), 144.5 (C), 156.8 (C),
168.5 (C), 169.6 (C); IR (cm-1) n: 1763, 1458, 1368, 1246; HRMS
[FAB, (M + Na)+] m/z: calcd for C23H32O4Na 395.2198, found:
395.2203.
(R)-Methyl-1-methoxy-4b,8,8-trimethyl-5,6,7,8-tetrahydro-4bH-
fluoren-2-carboxylate (34)
(4bS)-4-(dichloromethoxy)-1-methoxy-4b,8,8,-trimethyl-
5,6,7,8,8a,9-hexahydro-4bH-fluorene-3-carbaldehyde (25)
NBS (260 mg, 1.45 mmol) and (BzO)2 (6 mg) was added under
an argon atmosphere to a solution of compound 33 (400 mg,
1.32 mmol) in CCl4 (20 mL) and the mixture was stirred at 60 ◦C
under light irradiation for 30 min, at which time TLC revealed
no starting material. The mixture was filtered through a silica gel
column (50% ether/hexanes) and the solvent removed affording
a crude residue (394 mg). This was dissolved in CH2Cl2 (20 mL),
Amberlyst A-15 (100 mg) was added, and the mixture was refluxed
for 1 h, at which time TLC showed only a product. The solvent was
evaporated under vacuum and the crude residue purified by silica
gel column (10% ether/hexanes), giving compound 34 (360 mg,
Cl2CHOMe (0.5 mL, 3.31 mmol) and TiCl4 (0.3 mL, 1.82 mmol)
were added to a solution of compound 24 (105 mg, 0.318 mmol)
◦
in CH2Cl2 (15 mL) at -20 C under argon and the mixture was
stirred at this temperature for 15 h, at which time TLC showed no
starting material. Then, water (5 mL) was added and the mixture
was stirred for a further 10 min. It was extracted with ether (2 ¥
20 mL) and the organic phase was washed with water (5 ¥ 10 mL),
brine (10 mL) and dried over anhydrous Na2SO4. The solvent was
removed under vacuum and the crude residue was purified by
flash chromatography column on silica gel (10% ether/hexanes),
affording aldehyde 25 (305 mg, 87%) as a yellow oil. [a]2D5 = -46.4
(c 1.5, CHCl3); 1H NMR (CDCl3, 500 MHz) d: 0.99 (s, 3H), 1.05
(s, 3H), 1.13 (s, 3H), 1.19 (ddd, J = 13.7, 13.7, 4.5 Hz, 1H), 1.53
(dd, J = 13.4, 3.0 Hz, 1H), 1.60 (ddd, J = 12.9, 12.9, 3.8 Hz, 1H),
1.77 (dd, J = 12.9, 6.3 Hz, 1H), 1.79 (qt, J = 13.9, 3.8 Hz, 1H),
2.42 (dt, J = 12.8, 3.2 Hz, 1H), 2.66 (dd, J = 14.1, 13.0 Hz, 1H),
2.88 (dd, J = 14.7, 6.2 Hz, 1H), 3.94 (s, 3H), 7.05 (s, 2H), 10.30
(s, 1H). 13C NMR (CDCl3, 125 MHz) d: 19.3 (CH3), 19,9 (CH2),
21.1 (CH3), 27.3 (CH2), 33.19 (C), 33.22 (CH3), 35.9 (CH2), 41.1
(CH2), 47.7 (C), 59.6 (OCH3), 62.2 (CH), 112.9 (CH), 127.3 (C),
137.4 (C), 145.9 (C), 153.1 (C), 156.8 (C), 189.0 (CHO). IR (cm-1)
n: 1685, 1601, 1579, 1472, 1412, 1385, 1284, 1251, 1220, 1115,
1091, 1074, 1004, 820, 703; HRMS [FAB, (M + Na)+] m/z: calcd
for C22H30O3 Cl2Na 435.1470, found: 435.1482.
1
90%) as a colourless oil. [a]2D5 = +18.8 (c 3.1, CHCl3); H NMR
(CDCl3, 400 MHz) d: 0.98 (ddd, J = 13.2, 13,2, 3,5 Hz, 1H), 1.11
(ddd, J = 13.4, 13.4, 4.0 Hz, 1H), 1.24 (s, 3H), 1.32 (s, 3H), 1.36 (s,
3H), 1.60–1.69 (m, 2H), 1.96 (qt, J = 13.6, 3.2 Hz, 1H), 2.13 (dd,
J = 12.8, 1.6 Hz, 1H), 3.90 (s, 3H), 3.96 (s, 3H), 6.51 (s, 1H), 7.02
(d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H); 13C NMR (CHCl3,
100 MHz) d: 19.6 (CH2), 23.1 (CH3), 25.2 (CH3), 31.2 (CH3), 35.7
(C), 37.7 (CH2), 42.6 (CH2), 51.7 (C), 52.0 (OCH3), 62.3 (OCH3),
116.5 (CH), 116.7 (CH), 122.2 (C), 127.8 (CH), 135.5 (C), 153.1
(C), 162.0 (C), 164.4 (C), 167.2 (C); IR (cm-1) n: 1727, 1458, 1291,
1224, 1121; HRMS [FAB, (M + Na)+] m/z: calcd for C19H24O3Na
323.1623, found: 323.1614.
(R)-2-(1-Methoxy-4b,8,8-trimethyl-5,6,7,8-tetrahydro-4bH-
fluoren-2-yl)propan-2-ol (35)
Methyl magnesium bromide (1.4 M in 3 : 1 toluene–THF, 1.3 mL,
1.86 mmol) was added at 0 ◦C under argon to a solution of
compound 34 (280 mg, 0.93 mmol) in anhydrous ether (15 mL),
and the mixture was stirred for 15 min, at which time TLC showed
no starting material. Then, water (2 mL) was added carefully to
quench the reaction and the mixture was extracted with ether
(3 ¥ 20 mL). The organic phase was washed with water (2 ¥
10 mL), brine (10 mL) and dried over anhydrous Na2SO4. After
removing the solvent under vacuum, alcohol 35 (270 mg, 96%)
was obtained as a colourless syrup. [a]2D5 = +3.8 (c 2.3, CHCl3);
1H NMR (CDCl3, 400 MHz) d: 0.99 (ddd, J = 13.3, 13.3, 3.7 Hz,
1H), 1.13 (ddd, J = 12.9, 12.9, 3.9 Hz, 1H), 1.25 (s, 3H), 1.32 (s,
3H), 1.36 (s, 3H), 1.62 (s, 3H), 1.63 (s, 3H), 1.59-1.70 (m, 2H), 1.96
(qt, J = 13.8, 3.4 Hz, 1H), 2.13 (dd, J = 12.8, 1.8 Hz, 1H), 4.15
(s, 3H), 6.50 (s, 1H), 6.92 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz,
1H); 13C NMR (CDCl3, 100 MHz) d: 19.7 (CH2), 23.5 (CH3), 25.3
(CH3), 30.9 (CH3). 31.2 (CH3), 31.3 (CH3), 35.7 (C), 38.1 (CH2),
42.7 (CH2), 50.7 (C), 61.6 (OCH3), 73.0 (C), 116.1 (CH), 117.1
(CH), 122.0 (CH), 133.2 (C), 137.3 (C), 151.0 (C), 157.1 (C), 164.0
(C). IR (cm-1) n: 3527, 1458, 1416, 1367, 1268, 1217, 1055, 1021,
820, 672; HRMS [FAB, (M + Na)+] m/z: calcd for C20H28O2Na
323.1987, found: 323.1995.
(4bS,8aS)-2-Isopropyl acetate-4b,8,8-trimethyl-5,6,7,8a,
9-hexahydro-4bH-fluoren-1-yl acetate (29)
To a solution of 28 (130 mg, 0.41 mmol) in benzene (8 mL) was
added sodium chromate (201mg, 1.24 mmol, 3 eq.), sodium acetate
(68 mg, 0.82 mmol), acetic acid (1 mL) and acetic anhydride
(2 mL), and the mixture was heated at 70 ◦C for 20 h. Then, water
was added to quench the reaction and the mixture was extracted
with ether (2 ¥ 20 mL). The organic phase was washed with water
(6 ¥ 10 mL), sat. aq NaHCO3 (5 ¥ 10 mL), brine and dried over
anhydrous Na2SO4. The solvent was removed and the residue
crude purified by flash silica gel column (10% ether/hexanes),
affording 32 mg of diacetate 29 (21%) as a colourless oil. [a]D25
=
-8.0 (c 0.4, CHCl3);1H NMR (CDCl3, 500 MHz) d: 0.93 (s, 3H),
1.00 (s, 3H), 1.03 (s, 3H), 1.09–1.20 (m, 2H), 1.37 (ddd, J = 12.6,
12.6, 3.9 Hz, 1H), 1.4–1.52 (m, 1H), 1.59 (m, 1H), 1.65 (bd, J =
10.8, 8.2 Hz, 1H), 1.79 (s, 3H) 1.80 (s, 3H), 1.95 (s, 3H), 2.98 (dt,
J = 12.7, 3.2 Hz, 1H), 2.32 (s, 3H), 2.39 (dd, J = 10.8, 8.2 Hz,
2H), 6.80 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H). 13C NMR
(CDCl3, 125 MHz) d: 20.0 (CH2), 21.0 (CH3), 21.2 (CH3), 21.7
(CH3), 22.1 (CH3), 26.9 (CH2), 27.0 (CH3), 27.8 (CH3), 33.1 (C),
33.2 (CH3), 35.5 (CH2), 41.5 (CH2), 46.2 (C), 59.6 (CH), 80.8 (C),
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(4bS,8aS)-4b,8,8-Trimethyl-5,6,7,8,8a,9- hexahydro-4bH-
fluoren-1-ol (36)
mixture was stirred for a further 3 h, at which time TLC showed
no starting material. The mixture was poured into ice (30 mL) and
extracted with ether (2 ¥ 20 mL). The organic phase was washed
with water (10 mL), brine (10 mL) and dried over anhydrous
Na2SO4. Evaporation of solvent under vacuum afforded a crude
residue, which after purification by flash chromatography column
on silica gel (10% ether/hexanes) gave compound 35 (437 mg,
84%) as a colourless syrup.
DDQ (2.28 g, 10.05 mmol) was added to a solution of compound
19 (1.6 g, 6.7 mmol) in dioxane (20 mL) and the mixture was stirred
under reflux for 1 h, at which time TLC showed no ketone 19.
The solvent was evaporated under vacuum and the crude residue
was purified by flash chromatography column on silica gel (20%
hexanes/ether), affording phenol 36 (1.55 g, 98%) as a yellow oil.
[a]2D5 = -23.7 (c 2.0, CHCl3); 1H NMR (CDCl3, 500 MHz) d: 0.90
(s, 3H), 0.96 (s, 3H), 0.97 (s, 3H), 1.39 (ddd, J = 12.8, 3.7 Hz, 1H),
1.47 (dt, J = 13.6, 3.1 Hz, 1H), 1.51-1.62 (m, 2H), 1.66 (dd, J =
12.4, 6.2 Hz, 1H), 1.76 (qt, J = 13.4, 3.5 Hz, 1H), 1.97 (dt, J =
12.5, 2.8 Hz, 1H), 2.45 (dd, J = 14.1, 12.4 Hz, 1H), 2.62 (dd, J =
14.1, 6.2 Hz, 1H), 5.12 (bs, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.59
(d, J = 7.3 Hz, 1H), 6.94 (dd, J = 8.0, 7.3 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) d: 18.9 (CH2), 20.0 (CH3), 20.5 (CH3), 24.3
(CH2), 32.0 (CH3), 32.2 (C), 34.7 (CH2), 40.6 (CH2), 59.0 (CH),
111.6 (CH), 111.8 (CH), 126.0 (C), 126.8 (CH), 151.0 (C), 156.9
(C).); IR (cm-1) n: 3405, 1719, 1586, 1459, 1369, 1263, 1099, 787;
HRMS [FAB, (M + Na)+] m/z: calcd for C16H22ONa 253.1568,
found: 253.1580.
(R)-7-Isopropyl-8-methoxy-1,1,4a-trimethyl-2,3,4,4a-tetrahydro-
1H-fluorene (30)
◦
NaBH3CN (684 mg, 9.4 mmol, 10 eq.) was added at 0 C under
argon to a solution of compound 35 (283 mg, 0.94 mmol) in
freshly distilled CH2Cl2 (20 mL) and the mixture was stirred for
2 min at this temperature. Then, ZnI2 (514 mg, 2.82 mmol) was
added and the mixture was stirred for a further 2 h, at which time
TLC showed no compound 35. The mixture was filtered through
a silica gel column (5% ether/hexanes) and the solvent evaporated
to give compound 30 (257 mg, 96%) as a colourless oil. [a]D25
=
+20.0 (c 0.56, CHCl3); 1H NMR (CDCl3, 400 MHz) d: 1.10 (ddd,
J = 13.3, 13.3, 3.7 Hz, 1H), 1.17 (ddd, J = 12.8, 12.8, 3.9 Hz, 1H),
1.24 (d, J = 6.9 Hz, 3H), 1.26 (s, 3H), 1.27 (d, J = 6.9 Hz, 3H), 1.33
(s, 3H), 1.38 (s, 3H), 1.60-1.71 (m, 2H), 1.97 (qt, J = 13.8, 3.2 Hz,
1H), 2.13 (bd, J = 12.8 Hz, 1H), 3.38 (h, J = 6.9 Hz, 1H), 3.86 (s,
3H), 6.51 (s, 1H), 6.98 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz,
1H); 13C NMR (CDCl3, 100 MHz) d: 19.8 (CH2), 23.6 (CH3), 23.7
(CH3), 23.9 (CH3), 25.4 (CH3), 26.6 (CH3), 31.3 (CH3), 35.6 (C),
38.2 (CH2), 42.8 (CH2), 50.9 (C), 61.8 (OCH3), 116.7 (CH), 117.2
(CH), 122.3 (CH), 133.6 (C), 138.7 (C), 150.6 (C), 155.2 (C), 163.5
(C). IR (cm-1) n: 1470, 1249, 1054, 1023, 814, 671; HRMS [FAB,
(M + Na)+] m/z: calcd for C20H28ONa 307.2038, found: 307.2045.
(R)-8-Methoxy-1,1,4a-trimethyl-2,3,4,4a-tetrahydro-1H-fluorene
(38)
NBS (500 mg, 2.8 mmol, 1.2 eq.) and (BzO)2 (10 mg) was added
under argon atmosphere to a solution of compound 37 (570 mg,
2.33 mmol) in CCl4 (40 mL) and the mixture was stirred at 60 ◦C
under light irradiation for 30 min, after which time TLC revealed
the absence of starting material. The mixture was filtered through
a silica gel column (10% ether/hexanes) and the solvent removed
affording a crude residue. This was dissolved in CH2Cl2 (40 mL),
Amberlyst A-15 (100 mg) was added, and the mixture was refluxed
for 1 h, at which time TLC showed only a product. The solvent
was evaporated under vacuum and the residue purified by silica
gel column (10% ether/hexanes), giving compound 38 (252 mg,
(4aS,9aR)-7-Isopropyl-8-methoxy-1,1,4a-trimethyl-2,3,4,4a-
tetrahydro-1H-fluoren-9(9aH)-one (39)
m-Chloroperoxybenzoic acid (MCPBA, 75%; 114 mg, 0.49 mmol)
was added at 0 ◦C to a stirred suspension of 30 (93 mg, 0.327 mmol)
and solid NaHCO3 (84 mg, 1 mmol) in CH2Cl2 (12 mL), and the
reaction was stirred for 30 min, at which time TLC indicated no
starting material remaining. The reaction was quenched with sat.
aq Na2SO3 (2 mL) and stirred for an additional 10 min. Then,
it was poured into ether/water (20 : 7 mL), and the phases were
shaken and separated; the organic phase was washed with sat.
aq NaHCO3 (10 ¥ 7 mL) and brine, dried over Na2SO4 and
concentrated to give a crude product as a mixture of epoxide
derivatives.
1
93%) as a yellow syrup. [a]2D5 = +35.9 (c 1.5, CHCl3); H NMR
(CDCl3, 400 MHz) d: 0.91 (ddd, J = 13.2, 13.2, 3.4 Hz, 1H), 1.03
(ddd, 12.8, 12.8, 3.8 Hz, 1H), 1.16 (s, 3H), 1.23 (s, 3H), 1.28 (s,
3H), 1.51-1.61 (m, 2H), 1.89 (qt, J = 13.7, 3.4 Hz, 1H), 2.60 (dd,
J = 12.9, 1.8 Hz, 1H), 3.80 (s, 3H), 6.45 (s, 1H), 6.66 (d, J =
8.1 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 7.03 (bd, J = 8.1, 7.3 Hz,
1H); 13C NMR (CDCl3, 100 MHz) d: 18.7 (CH2), 22.3 (CH3), 24.3
(CH3), 30.2 (CH3), 34.5 (C), 37.0 (CH2), 41.7 (CH2), 50.4 (C),
54.3 (OCH3), 107.3 (CH), 113.0 (CH), 115.5 (CH), 124.2 (CH),
129.2 (C), 151.6 (C), 156.3 (C), 161.6 (C); IR (cm-1) n: 3078, 1592,
1573, 1478, 1478, 1439, 1272, 1248, 1076, 1032, 862, 784, 740, 671;
HRMS [FAB, (M + Na)+] m/z: calcd for C17H22ONa 265.1568,
found: 265.1549.
A solution of this crude product (89 mg) in CH2Cl2 (8 mL)
was added at 0 ◦C BF3·Et2O (45%, 0.1 mL, 0.788 mmol) and the
mixture was stirred for 30 min, at which time TLC showed no
30. Water (1 mL) was added and the mixture was stirred for an
additional 15 min, then it was extracted with ether (2 ¥ 10 mL), the
organic phase was washed with water, sat. aq NaHCO3 (2 ¥ 7 mL),
brine, dried over Na2SO4 and concentrated to give the ketone 39
(R)-2-(1-Methoxy-4b,8,8-trimethyl-5,6,7,8-tetrahydro-4bH-
fluoren-2-yl)propan-2-ol (35) (from 38)
n-BuLi (2.4 M, 1 mL, 2.4 mmol) was added to a solution of
1
compound 38 (420 mg, 1.72 mmol) in anhydrous THF (15 mL) at
(79 mg, 81%) as a yellow oil. [a]2D5 = -68 (c 0.94, CHCl3); H
◦
-20 C under argon atmosphere, and the mixture was stirred at
NMR (CDCl3, 500 MHz) d: 0.67 (s, 3H), 1.20 (d, J = 6.9 Hz,
6H), 1.21 (s, 3H), 1.24 (s, 3H), 1.28–1.37 (m, 2H), 1.44 (m, 1H),
1.55–1.65 (m, 2H), 2.10 (m, 1H), 2.14 (s, 1H), 3.38 (h, J = 6.9 Hz,
1H), 3.95 (s, 3H), 7.08 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz,
this temperature for 20 min. Then HMPA (1 mL, 5.73 mmol) was
◦
added and the reaction mixture was warmed to 0 C for 30 min
and dry acetone (0.5 mL, 6.81 mmol) was added at 0 ◦C and the
5152 | Org. Biomol. Chem., 2009, 7, 5146–5155
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1H); 13C NMR (CDCl3, 100 MHz) d: 18.4 (CH2), 23.57 (CH3),
23.64 (CH3), 24.7 (CH3), 26.3 (CH3), 32.4 (CH3), 33.5 (CH2), 33.9
(C), 34.8 (CH2), 38.7 (CH2), 41.5 (C), 62.2 (OCH3), 66.1 (CH),
117.2 (CH), 127.8 (C), 133.1 (CH), 140.3 (C), 155.1 (C), 161.9 (C),
206.6 (C). IR (cm-1) n: 1704, 1595, 1474, 1409, 1291, 1247, 1175,
1026, 827; HRMS [FAB, (M + Na)+] m/z: calcd for C20H28O2Na
323.1987, found: 323.1998.
J = 7.8, 2.9 Hz, 1H), 6.90 (s, 1H). Assignable signals to isomer 42:
1.16 (s, 3H), 1.20 (s, 3H), 1.82 (br d, J = 8.8 Hz, 1H), 1.94 (brd,
J = 13.7 Hz, 1H), 3.28 (h, J = 6.9 Hz, 1H), 3.47 (bs, 1H), 3.82 (s,
3H), 4.75 (dd, J = 4.9, 3.9 Hz, 2H), 5.17 (bs, 1H), 7.21 (s, 1H); 13
C
NMR (CDCl3, 125 MHz) d: 18.7 (CH2), 22.2 (CH3), 22.5 (CH3),
25.9 (CH3), 29.7 (CH), 29.8 (CH3), 31.9 (C), 32.0 (CH3), 36.5
(CH2), 39.3 (CH2), 44.1 (C), 59.7 (CH), 64.3 (CH2), 66.0 (OCH3),
75.1 (CH), 117.7 (CH), 128 (C), 133.4 (C), 136.8 (C), 139.8 (C),
153.1 (C); IR (cm-1) n: 3421, 1459, 1224, 1031, 757; HRMS [FAB,
(M + Na)+] m/z: calcd for C21H32O3Na 355.2249, found: 355.2249.
(S)-2-Isopropyl-1-methoxy-4b,8,8-trimethyl-5,6,7,8-tetrahydro-
4bH-fluoren-4-carbaldehyde (40)
Cl2CHOMe (0.7 mL, 7.7 mmol, 10 eq.) and TiCl4 (0.43 mL,
(R)-Isopropyl-4b,8,8-trimethyl-5,6,7,8-tetrahydro-4bH-fluoren-1-
ol (43)
3.85 mmol, 5 eq.) were added to a solution of compound 30
◦
(220 mg, 0.77 mmol) in CH2Cl2 (20 mL) at -30 C under argon
and the mixture was stirred at this temperature for 10 h, at which
time TLC showed no starting material. Then, water (5 mL) was
added and the mixture was stirred for a further 10 min. It was
extracted with ether (2 ¥ 20 mL) and the organic phase was washed
with water (5 ¥ 10 mL), brine (10 mL) and dried over anhydrous
Na2SO4. The solvent was removed under vacuum and the crude
residue was purified by flash chromatography column on silica gel
(10% ether/hexanes), affording aldehyde 40 (231 mg, 96%) as a
yellow syrup. [a]2D5 = +9.5 (c 0.5, CHCl3); 1H NMR (CDCl3, 400
MHz) d: 0.92 (ddd, J = 13.2, 13.2, 3.4 Hz, 1H), 1.05 (ddd, J =
12.8, 12.8, 3.8 Hz, 1H), 1.18 (s, 3H), 1.25 (d, J = 6.9 Hz, 3H), 1.31
(d, J = 6.9 Hz, 3H), 1.37 (s, 3H), 1.38 (s, 3H), 1.56 (dt, J = 13.2,
3.1 Hz, 1H), 1.61 (brd, J = 12.4 Hz, 1H), 1.89 (qt, J = 13.8, 2.9 Hz,
1H), 2.11(bd, J = 12.4 Hz, 1H), 3.83 (s, 3H), 3.65 (h, J = 6.9 Hz,
1H), 6.44 (s, 1H), 7.49 (s, 1H), 10.41 (s, 1H); 13C NMR (CDCl3,
125 MHz) d: 19.6 (CH2), 23.2 (CH3), 23.4 (CH3), 23.5 (CH3), 25.1
(CH3), 25.8 (CH3), 31.1 (CH), 36.1 (C), 37.9 (CH2), 42.6 (CH2),
51.5 (C), 61.9 (OCH3), 117.5 (CH), 118.0 (CH), 134.6 (C), 140.4
(C), 142.0 (C), 152.2, 154.9 (C), 169.1 (C), 192.0 (CHO); IR (cm-1)
n: 1684, 1603, 1450, 1274; HRMS [FAB, (M + Na)+] m/z: calcd
for C21H28O2Na 335.1987, found: 335.1972.
BBr3 (0.25 mL, 2.08 mmol) was added at -78 ◦C to a solution of
compound 30 (150 mg, 0.53 mmol) in CH2Cl2 (15 mL) and the
mixture was stirred at 0 ◦C for 2 h, at which time TLC showed
no starting material. The mixture was poured onto ice (10 g) and
extracted with ether (30 mL). The organic phase was washed with
water (5 ¥ 10 mL), brine (3 ¥ 10 mL) and dried over anhydrous
Na2SO4. The solvent was removed under vacuum and the crude
residue was purified by flash chromatography column on silica
gel (10% ether/hexanes) affording phenol 43 (92 mg, 64%) as a
colourless oil. [a]D25 = +12.0 (c 0.3, CHCl3); 1H NMR (CDCl3, 600
MHz) d: 0.93 (ddd, J = 13.2, 13.2, 3.4 Hz, 1H), 1.04 (ddd, J =
12.8, 12.8, 3.6 Hz, 1H), 1.12 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H),
1.20 (d, J = 6.9 Hz, 3H), 1.23 (s, 3H), 1.28 (s, 3H), 1.51-1.56 (dt,
J = 13.2, 3.1 Hz, 1H), 1.58 (bd, J = 12.8 Hz, 1H), 1.88 (qt, J =
13.7, 3.3 Hz, 1H), 2.04 (bd, J = 12.8, 1.5 Hz, 1H), 3.13 (h, J =
6.9 Hz, 1H), 4.60 (s, 1H), 6.37 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H),
6.92 (d, J = 7.6 Hz, 1H); 13C NMR (CHCl3, 125 MHz) d: 19.7
(CH2), 22.9 (CH3), 22.9 (CH3), 23.5 (CH3), 25.3 (CH3), 26.9 (CH),
31.2 (CH3), 35.6 (C), 38.1 (CH2), 42.7 (CH2), 51.3 (C), 113.8 (CH),
115.2 (CH), 122.2 (CH), 128.3 (C), 131.9 (C), 145.5 (C), 154.6 (C),
163.2 (C); IR (cm-1) n: 3473, 1718, 1576, 1459, 1295, 807. HRMS
[FAB, (M + Na)+] m/z: calcd for C19H26ONa 293.1881, found:
293.1873.
(4aS,9S,9aR)-5-(Hydroxymethyl)-7-isopropyl-8-methoxy-1,1,4a-
trimethyl-2,3,4,4a,9,9a-hexahydro-1H-fluoren-9-ol (41) and
(4aS,9R,9aS)-5-(hydroxymethyl)-7-isopropyl-8-methoxy-1,1,4a-
trimethyl-2,3,4,4a,9,9a-hexahydro-1H-fluoren-9-ol (42)
(S)-2-Isopropyl-4b,8,8-trimethyl-5,6,7,8-tetrahydro-4bH-fluoren-
1,4-dione (44)
1M B2H6–THF (1.27 mL, 0.7 mmol) was added to a solution of
compound 40 (100 mg, 0.32 mmol) in anhydrous THF (10 mL) at
-78 ◦C, under argon, and the temperature was raised to -35 ◦C for
14 h, at which time TLC showed no starting material. Then, EtOH
(0.6 mL), 4 M NaOH in EtOH (0.3 mL) and 30% H2O2 1 mL) were
added and the mixture was stirred at room temperature for 8 h. The
solvent was evaporated and ether (20 mL) was added. The organic
phase was washed with water (3 ¥ 6 mL), brine (2 ¥ 5 mL) and
dried over anhydrous Na2SO4. After removing the solvent under
vacuum the crude residue was purified by flash chromatography
column on silica gel (20% ether/hexanes), affording the mixture
of diols 41–42 (86 mg, 81%), in a 4 : 1 proportion, as a yellow
syrup. [a]2D5 = +45.0 (c 1.3, CHCl3). 1H NMR (CDCl3, 500 MHz)
d: Assignable signals to isomer 41: 1.00 (ddd, J = 13.7, 13.7 Hz,
1H), 1.15 (s, 3H), 1.19 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 1.36 (d,
J = 6.9 Hz, 3H), 1.38-1.44 (m, 1H), 1.46 (s, 3H), 1.53-1.68 (m,
4H), 1.77 (d, J = 7.8 Hz, 1H), 2.88 (d, J = 2.9 Hz, 1H), 3.34 (h,
J = 6.9 Hz, 1H), 3.87 (s, 3H), 4.71 (d, J = 4.9 Hz, 2H), 5.25 (dd,
CAN (350.6 mg, 0.64 mmol) was added to a solution of compound
43 (87 mg, 0.32 mmol) in CH2Cl2 (10 ml) and the mixture was
stirred at room temperature for 1 h, at which time TLC showed no
starting material. The mixture was extracted with ether (20 mL)
and the organic phase was washed with water (4 ¥ 10 mL), brine
(3 ¥ 10 mL) and dried over anhydrous Na2SO4. After evaporating
the solvent, the crude residue was purified on silica gel (10%
ether/hexanes) affording quinone 44 (88 mg, 96%) as a red syrup.
[a]2D5 = -16.8 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) d: 0.98–
1.04 (m, 2H), 1.05 (d, J = 6.9 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H),
1.16 (s, 3H), 1.21 (s, 3H), 1.37 (s, 3H), 1.54 (dd, J = 13.7, 3.3 Hz,
1H), 1.62 (dd, J = 13.5, 2.4 Hz, 1H), 1.86 (qt, J = 13.8, 3.4 Hz,
1H), 2.34 (dd, J = 13.0, 2.0 Hz, 1H), 2.99 (h, J = 6.9 Hz, 1H),
6.27 (bs, 1H), 6.32 (s, 1H); 13C NMR (CHCl3, 100 MHz) d: 18.0
(CH2), 19.0 (CH3), 20.6 (CH3), 20.7 (CH3), 23.8 (CH3), 25.3 (CH),
29.3 (CH3), 35.3 (C), 36.1 (CH2), 42.3 (CH2), 54.5 (C), 115.4 (CH),
130.8 (CH), 144.4 (C), 151.4 (C), 152.0 (C), 173.9 (C), 182.5 (C),
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184.6 (C); IR (cm-1) n: 2962, 2933, 2872, 1685, 1653; HRMS [FAB,
(M + Na)+] m/z: calcd for C19H24O2Na 307.1674, found: 307.1690.
NMR (CDCl3, 500 MHz) d: 1.04–1.17 (m, 2H), 1.231 (s, 3H),
1.234 (d, J = 7.0 Hz, 3H), 1.238 (d, J = 7.0 Hz, 3H), 1.25 (s,
3H), 1.46 (s, 3H), 1.62 (m, 2H), 1.70 (ddd, J = 13.2, 5.4, 2.4 Hz,
1H), 1.91 (qt, J = 13.9, 3.5 Hz, 1H), 2.36 (ddd, J = 12.4, 4.9,
2.1 Hz, 1H), 3.21 (h, J = 7.0 Hz, 1H), 6.43 (s, 1H), 7.31 (br s,
1H). 13C NMR (CDCl3, 125 MHz) d: 19.1 (CH2), 20.1 (CH3),
20.11 (CH3), 20.2 (CH3), 24.0 (CH3), 24.8 (CH3), 31.0 (CH), 37.1
(C), 37.4 (CH2), 43.5 (CH2), 55.4 (C), 118.1 (CH), 122.8 (C),
147.8 (C), 148.9 (C), 152.5 (C), 177.1 (C), 178.3 (C), 185.8 (C).
IR (cm-1) n: 3350, 1638, 1528, 1455, 1367, 1318, 966. HRMS
[FAB, (M + Na)+] m/z: calcd for C19H24O3Na 323.1623, found:
323.1609.
(S)-3-Bromo-2-isopropyl-4b,8,8-trimethyl-5,6,7,8-tetrahydro-
4bH-fluoren-1,4-dione (45)
Bromine (0,10 ml, 1.95 mmol) was added to a solution of quinone
44 (82 mg, 0.28 mmol) in acetic acid (5 mL) and the mixture
was stirred at room temperature for 5 min, at which time TLC
showed no quinone 44. Then, 5% NaHSO3 (1 mL) was added
and the mixture was stirred for a further 5 min, and extracted
with ether (25 mL). The organic phase was washed with water
(5 ¥ 10 mL), brine (10 mL) and dried over anhydrous Na2SO4.
The solvent was removed under vacuum and the resulting crude
residue was purified by flash chromatography on silica gel (10%
ether/hexanes) giving the bromo derivative 45 (84 mg, 82%) as
Acknowledgements
1
a yellow syrup; [a]2D5 = -19.1 (c 1.3, CHCl3); H NMR (CDCl3,
The authors thank the Spanish Ministry of Science and Innova-
tion (Project CTQ2006-12697) and the Regional Government of
Andalucia (Project P07-FQM-03101 and aids to the group FQM-
348) for financial support.
400 MHz) d: 0.96–1.07 (m, 2H), 1.16 (s, 3H), 1.21 (s, 3H), 1.25
(d, J = 6.9 Hz, 3H), 1.27 (d, J = 6.9 Hz, 3H), 1.38 (s, 3H),
1.55 (dt, J = 13.7, 3.3 Hz, 1H), 1.64 (dd, J = 13.5, 2.3 Hz, 1H),
1.86 (qt, J = 13.8, 3.4 Hz, 1H), 2.36 (dd, J = 13.4, 2.5 Hz, 1H),
3.39 (h, J = 6.9 Hz, 1H), 6.31 (s, 1H), 7.19 (s, 1H); 13C NMR
(CHCl3, 125 MHz) d: 18.0 (CH2), 18.93 (CH3), 18.96 (CH3), 19,1
(CH3), 23.8 (CH3), 29.8 (CH), 33.0 (CH3), 35.7 (C), 36.1 (CH2),
42.3 (CH2), 55.3 (C), 115.4 (CH), 137.0 (C), 145.0 (C), 149.0 (C),
150.0 (C), 173.2 (C), 175.4 (C), 181.3 (C); IR (cm-1) n: 2960, 2925,
2851, 1687, 1656, 1533, 1459, 1255, 1086, 1037, 802, 666; HRMS
[FAB, (M + Na)+] m/z: calcd for C19H23O2BrNa 385.0779, found:
385.0791.
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(-)-Taiwaniaquinone H (4)
Sodium methoxide (68 mg, 1.26 mmol) was added to a solution
of bromide 45 (78 mg, 0.21 mmol) in methanol (8 mL) and the
mixture was stirred at room temperature for 30 min. The mixture
was diluted with ether (20 mL) and the organic phase was washed
with water (2 ¥ 6 mL), brine (6 mL) and dried over anhydrous
Na2SO4. Evaporation of solvent under vacuum gave compound
4 (63 mg, 95%) as a red syrup. [a]2D5 = -11.9 (c 0.56, CHCl3);1H
NMR (CDCl3, 500 MHz) d: 1.05–1.14 (m, 2H), 1.21 (s, 3H), 1.220
(d, J = 7.0 Hz, 3H), 1.223 (d, J = 7.0 Hz, 3H), 1.27 (s, 3H), 1.45
(s, 3H), 1.62 (m, 1H), 1.69 (ddd, J = 13.1, 5.4, 2.5 Hz, 1H), 1.93
(qt, J = 13.9, 3.4 Hz, 1H), 2.41 (ddd, J = 10.1, 4.9, 2.9 Hz, 1H),
3.26 (h, J = 7.0 Hz, 1H), 3.99 (s, 3H), 6.38 (s, 1H). 13C NMR
(CDCl3, 125 MHz) d: 19.2 (CH2), 20.2 (CH3), 20.77 (CH3), 20.79
(CH3), 24.6 (CH3), 24.9 (CH3), 31.0 (CH), 36.7 (C), 37.3 (CH2),
43.5 (CH2), 55.8 (C), 61.4 (CH3), 116.8 (CH), 136.2 (C), 145.9 (C),
150.7 (C), 157.4 (C), 175.7 (C), 178.9 (C), 186.3 (C). IR (cm-1) n:
1644, 1538, 1451, 1058, 864. HRMS [FAB, (M + Na)+] m/z: calcd
for C20H26O3Na 337.1780, found: 337.1793.
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17 Synthesis of compound 14 has also been reported by Hagiwara et al.
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and the mixture was stirred at room temperature for 15 h. Then,
2 N HCl (3 mL) was added slowly and the mixture was diluted
with ether (20 mL). The organic phase was washed with water and
brine, dried over Na2SO4 and concentrated to afford quinone 8
1
(46 mg, 88%) as a red syrup. [a]2D5 = -88.7; c 0.79, CHCl3); H
5154 | Org. Biomol. Chem., 2009, 7, 5146–5155
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18 Ozonolysis of compound 14 to give diketone 16 has also been
accomplished by Hagiwara’s group (ref. 17a). However, these authors
reported low yields for this transformation, probably due to the small
quantity of starting material they utilized.
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This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5146–5155 | 5155
©