A very efficient route toward the 4a-methyltetrahydrofluorene skeleton: short synthesis of (±)-dichroanone and (±)-taiwaniaquinone H

Article abstract of DOI:10.1021/jo900153y

A very expedient and efficient new route toward taiwaniaquinoids, bearing the 4a-methyltetrahydrofluorene skeleton, is reported. Key steps are the intramolecular Friedel - Crafts alkylation of an aryldiene and the degradative oxidation of a methylenedioxy

Full text of DOI:10.1021/jo900153y

A Very Efficient Route toward the 4a-Methyltetrahydrofluorene
Skeleton: Short Synthesis of (()-Dichroanone and
(()-Taiwaniaquinone H
Enrique Alvarez-Manzaneda,* Rachid Chahboun, Eduardo Cabrera, Esteban Alvarez,
Ramo´n Alvarez-Manzaneda,‡ Ricardo Meneses, Hakima Es-Samti, and Antonio Ferna´ndez
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad de Granada, 18071 Granada, Spain
eamr@ugr.es
ReceiVed January 23, 2009
A very expedient and efficient new route toward taiwaniaquinoids, bearing the 4a-methyltetrahydrofluorene
skeleton, is reported. Key steps are the intramolecular Friedel-Crafts alkylation of an aryldiene and the
degradative oxidation of a methylenedioxy group; the latter process could also be utilized for building
the 2-hydroxy-1,4-benzoquinone unit, which is frequently found in natural products. Utilizing this new
methodology, (()-dichroanone (7) (three steps, 77% overall yield) and (()-taiwaniaquinone H (6) (four
steps, 70% overall yield) have been synthesized from commercial R- (11a) or ꢀ-cyclocitral (11b).
Introduction
Taiwaniaquinoids are a family of tricyclic diterpenoids
bearing an unusual 4a-methyltetra- (and hexa-)hydrofluorene
skeleton, which were isolated during the past decade from
different East Asian conifers, such as Taiwania cryptomeri-
oides,1 SalVia dichroantha,2 and Thuja standishii.3 They include
taiwaniaquinol A (1), B (2),1a and C (3),1c taiwaniaquinone A
(4),1a D (5),1b and H (6),1d dichroanone (7),2 dichroanal B (8),
and standishinal (9) (Figure 1).3 Although only a few prelimi-
nary studies of the bioactivity of some of these compounds have
been reported, taiwaniaquinols A (1) and C (3) and taiwan-
iaquinones A (4) and D (5) are known to exhibit potent cytotoxic
activity against KB epidermoid carcinoma cancer cells;1d
standishinal (9) shows aromatase inhibitory activity4 and is
‡ Universidad de Almer´ıa.
(1) (a) Lin, W.-H.; Fang, J.-M.; Chang, Y.-S. Phytochemistry 1995, 40, 871–
873. (b) Lin, W.-H.; Fang, J.-M.; Chang, Y.-S. Phytochemistry 1996, 42, 1657–
1663. (c) Chang, C.-I.; Chien, S.-C.; Lee, S.-M.; Kuo, Y.-H. Chem. Pharm. Bull.
2003, 51, 1420–1422. (d) Chang, C.-I.; Chang, J.-Y.; Kuo, C.-C.; Pan, W.-Y.;
Kuo, Y.-H. Planta Med. 2005, 71, 72–76.
(2) Kawazoe, K.; Yamamoto, M.; Takaishi, Y.; Honda, G.; Fujita, T.; Sezik,
E. Phytochemistry 1999, 50, 493–497.
FIGURE 1. Some representative taiwaniaquinoids.
(3) Ohtsu, H.; Iwamoto, M.; Ohishi, U.; Matsunaga, S.; Tanaka, R.
Tetrahedron Lett. 1999, 40, 6419–6422.
(4) Iwamoto, M.; Ohtsu, H.; Tokuda, H.; Nishino, H.; Matsunaga, S.; Tanaka,
R. Bioorg. Med. Chem. 2001, 9, 1911–1921.
therefore a promising candidate to be employed in the treatment
of breast cancer.5
3384 J. Org. Chem. 2009, 74, 3384–3388
10.1021/jo900153y CCC: $40.75 2009 American Chemical Society
Published on Web 04/06/2009

Synthesis of (()-Dichroanone and (()-Taiwaniaquinone H
SCHEME 1. Direct Transformation of Aryldiene 10 into Taiwaniaquinoids
In addition to possessing promising biological activities, the
unique carbotricyclic structure of this family of compounds has
attracted varied synthetic approaches. Fillion reported a total
synthesis of (()-taiwaniaquinol B (2) based on an interesting
domino acylation/alkylation step.6 Dichroanone (7) was syn-
thesized by Stoltz via a novel asymmetric palladium-catalyzed
alkylation.7 The most efficient processes toward this class of
compounds utilize a monoterpene synthon, such as ꢀ-cyclocitral
(11a) or cyclogeranic acid, together with a phenol derivative
to construct the 4a-methyltetra- or (hexa-)hydrofluorene skel-
eton. The cyclopentane B ring of the target compounds has been
elaborated through intramolecular Heck reactions, as Banerjee8a,b
and Node8c used in their syntheses of dichroanone (7), or via
Nazarov cyclizations, as Trauner reported in a synthetic ap-
proach to this family of compounds.9 The synthesis of standishi-
nal (9) has been achieved starting from p-formylanisol.10
Recently, She reported the synthesis of taiwaniaquinol B (2)
and dichroanone (7) featuring an interesting domino Friedel-
Crafts acylation/alkylation step.11 Very recently, our group has
reported a new synthetic strategy toward these types of
compounds based on a thermal 6π electrocyclization.12
basis of NOE experiments. The dienes 14a-e were efficiently
transformed into the 4a-methyltetrahydrofluorene derivatives
15a-e by treating them with SnCl4 in dichloromethane at room
temperature. Compounds 14a-c underwent cyclization even at
low temperatures, and so these dienes are more suitably obtained
for characterization purposes by treating the corresponding
alcohols 13a-e with cationic resin. This synthetic sequence
constitutes the most efficient procedure yet reported for achiev-
ing the 4a-methyltetrahydrofluorene skeleton of taiwaniaquinoids.
We next applied this new methodology to the synthesis of
dichroanone (7) and taiwaniaquinone H (6). The O-methyl
derivative 20 of the commercially available sesamol (3,4-
methylenedioxyphenol) was chosen as a suitable aromatic
synthon for our purposes. Although achieving the rupture of
the methylenedioxy group entails some difficulty, which has
greatly limited its use as a protective group in organic synthesis,
our previous studies on the degradative oxidation of methyl-
enedioxybenzenes encouraged us to work to overcome this
difficulty.15 Scheme 2 shows the synthesis of compound 19, an
immediate precursor of the target compounds 6 and 7, starting
from the tricyclic derivative 15e, obtained after a two-step
sequence from ꢀ-cyclocitral (11a) (91% overall yield) (Table
1, entry 5).
Results and Discussion
When methyl ether 15e was reacted with n-BuLi and then
with acetone, the hydroxy derivative 17 resulted in 75% yield,
and the starting material was partially recovered (17%). Alcohol
17 showed a considerable tendency to undergo dehydration
under acidic conditions, leading to the isopropylene derivative
18; the rapid transformation of alcohol 17 into compound 18
was observed in the NMR chloroform solutions. Compound 19
was obtained in high yield, after removal of the hydroxyl group
by cationic reduction with ZnI2 and NaBH3CN. The carbon-
carbon double bond was also reduced when Et3SiH and
trifluoroacetic acid were utilized.
Alternatively, the intermediate 19 was synthesized starting
from the aryllithium derivative of bromide 23. This compound
was prepared from the methoxy derivative 20, following the
same procedure utilized for the methyl ether 15e; finally, the
treatment of the isopropyl derivative 22 with NBS afforded
the bromide 23 (Scheme 3).
The condensation of aryllithium derived from bromide 23
with ꢀ-cyclocitral (11a) leads to alcohol 24a and then to diene
25 and to the cyclized compound 19, utilizing the above-
described procedure (Scheme 4). Aryldienes 14a-e, or 25, were
also expected to be formed after the condensation of R-cycloci-
tral (11b) and the corresponding aryllithium. This supposition
was confirmed by utilizing the bromide 23 as the aromatic
synthon; thus, the treatment of aldehyde 11b with the aryllithium
derived from 23 gave the homoallyl alcohol 24b as a 1:1 mixture
of diastereoisomers. This alcohol was converted into the diene
25 under the same conditions utilized for 24a.
As part of our research into the synthesis of taiwaniaquinoids
we are exploring new routes toward these types of compounds,
involving fewer steps and utilizing readily accessible synthons.
Bearing this in mind, we planned a possible synthesis of
taiwaniaquinoids (Scheme 1). The key intermediate would be
the aryldiene 10, which under acidic conditions would lead to
the arylallyl cation I, which will undergo a fast intramolecular
Friedel-Crafts alkylation, thus providing the 4a-methyltetrahy-
drofluorene skeleton.
The scheme in Table 1 shows the implementation of this
synthetic proposal, utilizing different aromatic synthons with
increasing electronic densities. The treatment of ꢀ-cyclocitral
(11a) with the aryllithium derived from the corresponding
bromobenzenes 12a-e gave in excellent yield the allyl alcohols
13a-e. These were quickly converted into the aryldienes 14a-e
after treatment with SnCl4 in dichloromethane at 0 °C. Com-
pounds 14a-e were characterized as the Z stereoisomer on the
(5) Minami, T.; Iwamoto, M.; Ohtsu, H.; Ohishi, H.; Tanaka; Yoshitake, A.
Planta Med. 2002, 68, 742–745.
(6) Fillion, E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127, 13144–13145.
(7) McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738–
7739.
(8) (a) Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. Org.
Lett. 2003, 5, 3931–3933. (b) Banerjee, M.; Mukhopadhyay, R.; Achari, B.;
Banerjee, A. K. J. Org. Chem. 2006, 71, 2787–2796. (c) Planas, L.; Mogi, M.;
Takita, H.; Ajimoto, T.; Node, M. J. Org. Chem. 2006, 71, 2896–2898.
(9) Liang, G.; Xu, Y.; Sciple, I. B.; Trauner, D. J. Am. Chem. Soc. 2006,
126, 11022–11023.
(10) Katoh, T.; Ahagi, T.; Noguchi, C.; Kajimoto, T.; Node, M.; Tanaka,
R.; Nishizawa, M.; Ohtsu, H.; Suzuki, N.; Saito, K. Bioorg. Med. Chem. 2007,
15, 2736–2748.
(11) Tang, S.; Xu, Y.; He, J.; Zheng, J.; Pan, X.; She, X. Org. Lett. 2008,
10, 1855–1858.
(12) Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez, E.;
Haidour, A.; Ramos, J. M.; Alvarez-Manzaneda, R.; Hmamouchi, M.; Es-Samti,
H. Chem. Commun. 2009, 592–594.
(13) Blatchly, J. M.; McOmie, J. F. W.; Searle, J. B. J. Chem. Soc. C 1969,
1350–1355.
(14) Bernet, A.; Seifert, K. HelV. Chim. Acta 2006, 89, 784–796.
(15) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Corte´s, M.;
Armstrong, V. Tetrahedron 1999, 55, 15181–15208.
J. Org. Chem. Vol. 74, No. 9, 2009 3385

Alvarez-Manzaneda et al.
TABLE 1. Construction of the Core 6,5,6-ABC Tricyclic Skeleton of Taiwaniaquinoidsa
a Reagents and conditions: (a) 12, n-BuLi, THF, -78 °C, 30 min; 11a, 15 min; (b) SnCl4, CH2Cl2, 0 °C to rt, 1-2 h; (c) Amberlyst A-15, CH2Cl2, rt,
20-75 min. b Bromobenzenes 12a-c are commercially available. For compounds 12d and 12e see refs 13 and 14, respectively. c Yields obtained after
treatment with cationic resin. d Yields from alcohols.
SCHEME 2. Synthesis of Intermediate 19a
SCHEME 3. Synthesis of Aromatic Synthon 23a
a Reagents and conditions: (a) n-BuLi, TMEDA, THF, 0 °C, 30 min;
acetone, 0 °C, 2 h, 72%; (b) ZnI2, NaBH3CN, CH2Cl2, 0 °C to rt, 2 h, 92%;
(c) NBS, CH2Cl2, rt, 5 min, 94%.
allows the efficient transformation of methylenedioxybenzenes
into the corresponding o-quinones by treating them with DDQ
and TsOH in refluxing dioxane. When methyl ether 19 was
reacted under these conditions for 1 h 30 min, dichroanone (7)
was obtained in high yield. Next, the transformation of this
quinone into taiwaniaquinone H (6) was addressed. Methylation,
utilizing MeI in basic medium, afforded a complex mixture;
our objective was attained after treatment with Me2SO4 and
K2CO3 in acetone under reflux.
a Reagents and conditions: (a) n-BuLi, THF, -20 °C, 20 min; acetone,
HMPA, 0 °C, 4 h, 75%; (b) ZnI2, NaBH3CN, CH2Cl2, 0 °C to rt, 2 h, 98%.
Finally, the transformation of compound 19 into taiwan-
iaquinoids 6 and 7 was undertaken (Scheme 5). As indicated
above, we had previously developed an oxidative process which
3386 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of (()-Dichroanone and (()-Taiwaniaquinone H
SCHEME 4. Synthesis of Intermediate 19 Starting from the
Aromatic Synthon 23a
Phenyl(2,6,6-trimethylcyclohex-1-enyl)methanol (13a). Colorless
oil. 1H NMR (CDCl3, 500 MHz) δ: 1.08 (s, 3H), 1.19 (s, 3H), 1.38
(s, 3H), 1.50-1.60 (m, 2H), 1.62-1.69 (m, 2H), 1.93 (br s, 1H),
1.99 (t, J ) 6.2 Hz, 2H), 5.42 (s, 1H), 7.21 (ddd, J ) 7.5, 7.5, 0.9
Hz, 2H), 7.32 (dd, J ) 7.6, 7.5 Hz, 2H), 7.43 (dd, J ) 7.6, 0.9 Hz,
1H). 13C NMR (CDCl3, 125 MHz) δ: 19.3 (CH2), 21.6 (CH3), 28.6
(CH3), 28.9 (CH3), 33.6 (CH2), 34.8 (C), 39.7 (CH2), 70.7 (CH),
125.9 (2CH), 126.1 (CH), 128.0 (2CH), 133.8 (C), 140.4 (C), 144.9
(C). IR (film): 3424, 1664, 1602, 1493, 1451, 1363, 1311, 1217,
1031, 974, 753 cm -1. HRMS (FAB) m/z: calcd for C16H22ONa
(M + Na+) 253.1568, found 253.1555.
General Procedure for the Preparation of Aryldienes 14a-e.
To a solution of allyl alcohols 13a-e (1 mmol) in dry CH2Cl2 (10
mL) was added Amberlyst 15 ion-exchange (0.5 g), and the reaction
mixture was stirred for specified time (15-75 min), at which time
TLC showed no starting material. The reaction mixture was filtered,
and the solvent was removed under vacuum to yield the aryldienes
14a-e (see Table 1).
(Z)-(2,6,6-Trimethylcyclohex-2-enylidenemethyl)benzene (14a).
Colorless syrup. 1H NMR (CDCl3, 500 MHz) δ: 1.20 (s, 6H), 1.49
(br s, 3H), 1.60-1.70 (m, 2H), 2.26 (br s, 2H), 5.60 (br s, 1H),
6.48 (s, 1H), 7.18-7.36 (m, 5H). 13C NMR (CDCl3, 125 MHz) δ:
23.2 (CH3), 23.9 (CH2), 27.2 (2CH3), 35.8 (C), 37.2 (CH2), 121.3
(CH), 125.9 (CH), 127.6 (CH), 128.2 (C), 128.4 (C), 128.9 (CH),
129.2 (CH), 132.1 (C), 140.6 (C), 147.7 (C). IR (film): 1609, 1493,
1445, 1380, 1359, 1339, 1287, 1195, 1126, 1082, 1029, 979, 850,
821, 753, 719, 704 cm -1. HRMS (FAB) m/z: calcd for C16H20Na
(M + Na+) 235.1463, found 235.1458.
a Reagents and conditions: (a) 23, n-BuLi, THF, -78 °C, 60 min; 11a
or 11b, 15 min (96% from 11a; 98% from 11b); (b) SnCl4, CH2Cl2, 0 °C,
5 min; rt, 2 h, 94%; (c) SnCl4, CH2Cl2, 0 °C to rt; (d) Amberlyst A-15,
CH2Cl2, rt, 15 min, 92%.
SCHEME 5. Synthesis of Dichroanone (7) and
Taiwaniaquinone H (6)a
General Procedure for the Preparation of 4a-Methyltetrahy-
drofluorene Derivatives 15a-e. To a solution of allyl alcohols
13a-e (1 mmol) in dry CH2Cl2 (10 mL) was added at 0 °C the
Lewis acid (1.5 mmol), and the reaction mixture was stirred for 5
min and the cooling bath was removed. Then it was stirred at room
temperature for a specified time (1-2 h), at which time TLC showed
no starting material. The reaction mixture was cooled at 0 °C, water
(1 mL) was added to quench the reaction, and the solvent was
removed under vacuum. The crude was fractionated in water-ether
(50 mL), extracted with ether (2 × 20 mL), and washed with water
(2 × 10 mL), satd aqueous NaHCO3 (2 × 10 mL), water (10 mL),
and brine (10 mL). The dried organic layers were evaporated, and
the residue was directly purified by flash chromatography (hexanes/
ether mixture) to yield 4a-methyltetrahydrofluorene derivatives
15a-e (see Table 1).
a Reagents and conditions: (a) DDQ, TsOH, dioxane, reflux, 1 h 20 min,
84%; (b) Me2SO4, K2CO3, acetone, rt, 2 h, 90%.
Conclusion
A very expedient and efficient new route toward taiwan-
iaquinoids, starting from commercial R- (11b) or ꢀ-cyclocitral
(11a), has been developed. Utilizing this methodology, (()-
dichroanone (7) (three steps, 77% overall yield) and (()-
taiwaniaquinone H (6) (four steps, 70% overall yield) have been
synthesized. After construction of the tricyclic skeleton of the
target compounds, via the intramolecular Friedel-Crafts alky-
lation of an aryldiene, the methylenedioxy benzene fragment
of the resulting intermediate was directly converted into the
2-hydroxy-1,4-benzoquinone moiety through an oxidative deg-
radation achieved by treatment with DDQ and TsOH in refluxing
dioxane. The latter process could also be utilized for building
the 2-hydroxy-1,4-benzoquinone unit, which is frequently found
in natural products.
1,1,4a-Trimethyl-2,3,4,4a-tetrahydro-1H-fluorene (15a). Color-
1
less syrup. H NMR (CDCl3, 500 MHz) δ: 0.99 (ddd, J ) 13.1,
13.1, 3.8 Hz, 1H), 1.11 (ddd, J ) 13.1, 13.1, 3.9 Hz, 1H), 1.25 (s,
3H), 1.30 (s, 3H), 1.37 (s, 3H), 1.54-1.70 (m, 2H), 1.97 (qt, J )
13.8, 3.4 Hz, 1H), 2.16 (d, J ) 10.2 Hz, 1H), 6.36 (s, 1H), 7.12
(ddd, J ) 7.3, 7.3, 1.2 Hz, 1H), 7.19 (ddd, J ) 7.4, 7.4, 1.2 Hz,
1H), 7.24 (d, J ) 7.3 Hz, 1H), 7.28 (d, J ) 7.4 Hz, 1H). 13C NMR
(CDCl3, 125 MHz) δ: 19.8 (CH2), 23.4 (CH3), 25.2 (CH3), 31.2
(CH3), 35.5 (C), 38.0 (CH2), 42.6 (CH2), 50.9 (C), 120.4 (CH2),
120.7 (CH), 120.9 (CH), 123.9 (CH), 126.2 (CH), 142.1 (C), 155.2
(C), 164.1 (C). IR (film): 1606, 1467, 1370, 1290, 1187, 1014, 969,
873, 849, 747, 671 cm -1. HRMS (FAB) m/z: calcd for C16H20Na
(M + Na+) 235.1463, found 235.1471.
Experimental Section
General Procedure for the Preparation of Allyl Alcohols
13a-e. To a solution of bromobenzenes 12a-e (1.2 mmol) in dry
THF (10 mL) was added n-butyllithium (1.3 mmol) at -78 °C under
an argon atmosphere, and the reaction mixture was stirred at this
temperature for 30 min. Then a solution of R- (11b) or ꢀ-cyclocitral
(11a) (1 mmol) in dry THF (10 mL) was added and the mixture
stirred for a further 15 min (monitored by TLC). The reaction was
quenched with water (1 mL), the solvent was removed under
vacuum, and then the mixture was extracted with ether (2 × 15
mL). The combined organic extracts were washed with water (10
mL) and brine (10 mL), dried over anhydrous Na2SO4, and
concentrated under vacuum to yield a crude product which was
directly purified by flash chromatography (hexanes/ether mixture)
to yield the desired allyl alcohols 13a-e (see Table 1).
(3-Isopropyl-2-methoxy-4,5-methylenedioxyphenyl)(2,6,6-tri-
methylcyclohex-1-enyl)methanol (24a). Alcohol 24a was synthe-
sized following the general procedure described above for alcohols
13a-e (reaction time: 1 h, 96%). White solid. Mp: 149-151 °C.
1H NMR (CDCl3, 600 MHz) δ: 0.83 (s, 3H), 1.18 (s, 3H), 1.30 (d,
J ) 6.6 Hz, 3H), 1.36 (d, J ) 6.6 Hz, 3H), 1.47 (ddd, J ) 12.6,
11.4, 3.6 Hz, 1H), 1.52 (ddd, J ) 9.1, 6.6, 3.1 Hz, 1H), 1.61-1.72
(m, 2H), 1.68 (s, 3H), 2.02-2.13 (m, 2H), 3.28 (h, J ) 6.6 Hz,
1H), 3.48 (d, J ) 1.8 Hz, 1H), 3.83 (s, 3H), 5.57 (d, J ) 1.8 Hz,
1H), 5.91 (d, J ) 5.2 Hz 2H), 6.59 (s, 1H). 13C NMR (CDCl3, 150
MHz) δ: 19.4 (CH2), 21.27 (CH3), 21.34 (CH3), 22.7 (CH3), 25.4
(CH3), 28.1 (CH), 28.9 (CH3), 33.7 (CH2), 34.7 (C), 39.8 (CH2),
62.0 (CH3), 68.7 (CH), 100.9 (CH2), 106.3 (CH), 124.9 (C), 129.0
J. Org. Chem. Vol. 74, No. 9, 2009 3387

Alvarez-Manzaneda et al.
(C), 134.5 (C), 136.0 (C), 143.5 (C), 145.4 (C), 150.8 (C). IR (KBr):
(()-Dichroanone (7). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) (0.415 g, 1.82 mmol) and p-toluensulfonic acid (0.3 g, 1.57
mmol) were added to a solution of 19 (0.5 g, 1.52 mmol) in 1,4-
dioxane (15 mL), and the reaction mixture was stirred at reflux for
1 h 20 min, at which time TLC indicated no 19. Then the reaction
mixture was diluted with ether (40 mL) and washed with water (3
× 10 mL), satd aqueous NaHCO3 (2 × 10 mL), water (10 mL),
and brine (10 mL). The organic phase was dried over anhydrous
Na2SO4 and concentrated under vacuum to yield a crude product
which was directly purified by flash chromatography (hexanes/ether,
-1
2958, 2929, 2871, 2828, 1456, 1418, 1334, 1118, 1047 cm
.
HRMS (FAB) m/z: calcd for C21H30O4Na (M + Na+) 369.2042,
found 369.2031.
(Z)-3-Isopropyl-4-methoxy-1,2-methylenedioxy-5-(2,6,6-trimeth-
ylcyclohex-2-enylidenemethyl)benzene (25). Diene 25 was synthe-
sized from 24a or 24b following the general procedure described
above for dienes 14a-e (reaction time: 15 min, 92%). Colorless
1
syrup. H NMR (CDCl3, 500 MHz) δ: 1.07 (s, 6H), 1.23 (d, J )
7.1 Hz, 6H), 1.48 (m, 2H), 1.50 (s, 3H), 2.12 (br s, 2H), 3.24 (h,
J ) 7.1 Hz, 1H), 3.58 (s, 3H), 5.48 (br s, 1H), 5.82 (s, 2H), 6.28
(s, 1H), 6.42 (s, 1H). 13C NMR (CDCl3, 125 MHz) δ: 21.4 (2CH3),
22.8 (CH3), 23.9 (CH2), 25.3 (CH3), 27.3 (CH3), 27.3 (CH), 35.8
(C), 37.1 (CH2), 61.2 (CH3), 100.6 (CH2), 108.0 (CH), 117.6 (C),
123.9 (C), 126.0 (C), 128.7 (C), 131.8 (C), 143.1 (C), 144.5 (C),
146.7 (C), 149.8(C). IR (film): 1620, 1503, 1480, 1455, 1424, 1343,
1266, 1192, 1157, 1040, 1007, 937, 867, 811, 758 cm -1. HRMS
(FAB) m/z: calcd for C21H28O3Na (M + Na+) 351.1936, found
351.1928.
1
9:1) to yield 383 mg of dichroanone (7) (84%) as red crystals. H
NMR (CDCl3, 500 MHz) δ: 1.04-1.13 (m, 2H), 1.21 (s, 3H), 1.219
(d, J ) 7.0 Hz, 3H), 1.222 (d, J ) 7.0 Hz, 3H), 1.26 (s, 3H), 1.44
(s, 3H), 1.61 (m, 1H), 1.68 (ddd, J ) 13.1, 5.4, 2.5 Hz, 1H), 1.91
(qt, J ) 13.9, 3.4 Hz, 1H), 2.40 (ddd, J ) 10.1, 4.9, 2.9 Hz, 1H),
3.24 (h, J ) 7.0 Hz, 1H), 3.98 (s, 3H), 6.37 (s, 1H). 13C NMR
(CDCl3, 125 MHz) δ: 19.2 (CH2), 20.2 (CH3), 20.76 (CH3), 20.78
(CH3), 24.6 (CH3), 24.9 (CH3), 31.0 (CH), 36.8 (C), 37.3 (CH2),
43.5 (CH2), 55.7 (C), 61.4 (CH3), 116.8 (CH), 136.1 (C), 145.9
(C), 150.7 (C), 157.4 (C), 175.7 (C), 178.9 (C), 186.4 (C). IR (film):
3348, 1638, 1527, 1367, 1317, 966 cm -1. HRMS (FAB) m/z: calcd
for C19H24O3Na (M + Na+) 323.1623, found 323.1614.
Synthesis of Compound 19 from Alcohols 24a,b. To a solution
of 24a or 24b (235 mg, 0.68 mmol) in dry CH2Cl2 (10 mL) was
added at 0 °C tin(IV) chloride (0.12 mL, 1.02 mmol), the reaction
mixture was stirred for 5 min, and the cooling bath was removed.
The mixture was stirred at room temperature for 2 h, at which time
TLC showed no starting material. The reaction mixture was cooled
at 0 °C, water (0.8 mL) was added to quench the reaction, and the
solvent was removed under vacuum. The crude was fractionated
into water-ether (40 mL) and extracted with ether (2 × 15 mL).
The recombined organic phases were washed with water (2 × 10
mL), satd aqueous NaHCO3 (2 × 10 mL), water (10 mL), and brine
(10 mL). The dried organic layers were evaporated, and the residue
was directly purified by flash chromatography (hexanes/ether, 95:
5) to yield 209 mg of 19 (94%) as a colorless oil. 1H NMR (CDCl3,
500 MHz) δ: 1.00-1.10 (m, 2H), 1.15 (s, 3H), 1.21 (s, 3H), 1.23
(d, J ) 6.9 Hz, 3H), 1.24 (d, J ) 6.9 Hz, 3H), 1.36 (s, 3H),
1.49-1.58 (m, 2H), 1.85 (qt, J ) 13.7, 2.9 Hz, 1H), 2.21 (d, J )
12.7 Hz, 1H), 3.25 (h, J ) 6.9 Hz, 1H), 3.71 (s, 3H), 5.82 (d, J )
7.8 Hz, 2H), 6.27 (s, 1H). 13C NMR (CDCl3, 125 MHz) δ: 19.5
(CH2), 21.4 (CH3), 21.6 (2CH3), 25.2 (CH), 25.6 (CH3), 31.4 (CH3),
35.6 (C), 36.8 (CH2), 42.7 (CH2), 50.8 (C), 63.7 (CH3), 100.8 (CH2),
117.3 (CH), 122.0 (C), 128.3 (C), 132.7 (C), 138.1 (C), 143.7 (C),
144.9 (C), 161.0 (C). IR (film): 1451, 1423, 1332, 1267, 1184, 1139,
1059, 962, 859, 772 cm -1. HRMS (FAB) m/z: calcd for
C21H28O3Na (M + Na+) 351.1936, found 351.1925.
(()-Taiwaniaquinone H (6). K2CO3 (200 mg, 1.45 mmol) was
added to a solution of dichroanone (7) (150 mg, 0.5 mmol) in
acetone (10 mL), and the reaction was kept stirring at room
temperature for 5 min. Dimethyl sulfate (183 mg, 1.45 mmol) was
added, and the reaction mixture was stirred at room temperature
for 2 h. The solvent was evaporated under vacuum, and the crude
reaction mixture was diluted with ether-water (20-5 mL), washed
with water and brine, dried, and concentrated to give a crude product
which was directly purified by flash column chromatography
(hexanes/ether, 95:5) to yield taiwaniaquinone H (6) (141 mg, 90%)
1
as a yellow oil. H NMR (CDCl3, 500 MHz) δ: 1.04-1.15 (m,
2H), 1.232 (s, 3H), 1.234 (d, J ) 7.0 Hz, 3H), 1.239 (d, J ) 7.0
Hz, 3H), 1.25 (s, 3H), 1.45 (s, 3H), 1.63 (m, 2H), 1.71 (ddd, J )
13.2, 5.4, 2.4 Hz, 1H), 1.92 (qt, J ) 13.9, 3.5 Hz, 1H), 2.37 (ddd,
J ) 12.4, 4.9, 2.1 Hz, 1H), 3.21 (h, J ) 7.0 Hz, 1H), 6.44 (s, 1H),
7.30 (br s, 1H). 13C NMR (CDCl3, 125 MHz) δ: 19.1 (CH2), 20.09
(CH3), 20.10 (CH3), 20.19 (CH3), 24.0 (CH3), 24.8 (CH3), 30.96
(CH), 37.06 (C), 37.4 (CH2), 43.47 (CH2), 55.4 (C), 118.1 (CH),
122.8 (C), 147.8 (C), 148.9 (C), 152.5 (C), 177.2 (C), 178.3 (C),
185.8 (C). IR (film): 1645, 1537, 1451, 1058 cm -1. HRMS (FAB)
m/z: calcd for C20H26O3Na (M + Na+) 337.1780, found 337.1778.
Synthesis of Compound 19 from Diene 25. To a solution of 25
(310 mg, 0.94 mmol) in dry CH2Cl2 (10 mL) was added at 0 °C
tin(IV) chloride (0.17 mL, 1.45 mmol), the reaction mixture was
stirred for 5 min, and the cooling bath was removed. The mixture
was stirred at room temperature for 2 h, at which time TLC showed
no starting material. The reaction mixture was cooled at 0 °C, water
(1 mL) was added to quench the reaction, and the solvent was
removed under vacuum. The crude product was fractionated into
water-ether (40 mL) and extracted with ether (2 × 20 mL). The
combined organic phases were washed with water (2 × 10 mL),
satd aqueous NaHCO3 (2 × 10 mL), water (10 mL), and brine (10
mL). The dried organic layers were evaporated, and the residue
was directly purified by flash chromatography (hexanes/ether, 95:
5) to yield 289 mg of 19 (94%).
Acknowledgment. This paper is dedicated to the memory
of Dr. Chahboun’s father. We thank the Spanish Ministry of
Science and Technology (Project No. CTQ2006-12697) and the
Junta de Andalucia for financial support.
Supporting Information Available: . Experimental proce-
dures and spectroscopic data for compounds 13b-e, 14b-e,
1
15b-e, 16-19, and 21-23 and copies of H NMR and 13C
NMR spectra for compounds 6, 7, 13a-e, 14a-e, 15a-e,
16-19, 21-23, 24a,b, and 25. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO900153Y
3388 J. Org. Chem. Vol. 74, No. 9, 2009