Efficient asymmetric synthesis of abeo-abietane-type diterpenoids by using the intramolecular Heck reaction

Article abstract of DOI:10.1021/jo901972b

(Chemical Equation Presented) The synthesis of the abeo-abietane-type diterpenoids, i.e., (-)-dichroanal B, (-)-dichroanone, and taiwaniaquinone H, was achieved by using the intramolecular asymmetric Heck reaction. Our synthetic routes required fewer steps and gave a much higher overall yield and ee within shorter steps than those for racemic and antipodal forms reported to date (10, 12, and 13 steps with an overall yield of 50%, 40%, and 39%, and 94%, 98%, and 98% ee, respectively). 2009 American Chemical Society.

Full text of DOI:10.1021/jo901972b

pubs.acs.org/joc
Efficient Asymmetric Synthesis of abeo-Abietane-Type Diterpenoids by
Using the Intramolecular Heck Reaction
Manabu Node,* Minoru Ozeki, Loıc Planas, Masashi Nakano, Hirofumi Takita,
Daisuke Mori, Shinji Tamatani, and Tetsuya Kajimoto
Department of Pharmaceutical Manufacturing Chemistry, 21st COE Program, Kyoto Pharmaceutical
University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
node@mb.kyoto-phu.ac.jp
Received September 24, 2009
The synthesis of the abeo-abietane-type diterpenoids, i.e., (-)-dichroanal B, (-)-dichroanone, and
taiwaniaquinone H, was achieved by using the intramolecular asymmetric Heck reaction. Our
synthetic routes required fewer steps and gave a much higher overall yield and ee within shorter steps
than those for racemic and antipodal forms reported to date (10, 12, and 13 steps with an overall yield
of 50%, 40%, and 39%, and 94%, 98%, and 98% ee, respectively).
Introduction
and taiwaniaquinone D and H (4) using an intramolecular
reductive Heck reaction.1e,f Later, Fillion and Fishlock
adopted an intramolecular Friedel-Crafts/R-tert-alkylation
domino reaction for the synthesis of taiwaniaquinol B.1g
Moreover, Trauner’s group reported the total synthesis of 3,
4, taiwaniaquinol B, and taiwaniaquinone D using the
Nazarov triflation reaction.1h She’s group recently reported
the formal synthesis of 3 and taiwaniaquinol B.1i Meanwhile,
we also achieved the synthesis of 1 and 2 using an acid-
catalyzed aldol reaction and intramolecular Heck reaction,
respectively.1d,j Very recently, Alvarez-Manzaneda’s group
reported the facile synthesis of 3 and 4.1k In spite of these
successful results of total synthesis, no asymmetric synthesis
has been reported to date, except for that by Stoltz and his
colleagues.1l However, it should be noted that (þ)-3 synthe-
sized therein was the antipode of the naturally occurring
compound. Against this background, we embarked on a
study of abeo-abietane-type diterpenes using an intramole-
cular asymmetric Heck reaction of triflate 6, as shown in
Scheme 1. Herein, we report the first synthesis of the natural
form of (-)-2, (-)-3, and (-)-4 using the asymmetric intra-
molecular Heck reaction.
Recently, diterpenes having an abeo-abietane (4a-methyl-
tetrahydrofluorene) skeleton were identified as a new type of
naturally occurring product. Among them, standishinal (1,
Figure 1) isolated from Thuja standishii by Tanaka has been
evaluated as a potential antitumor agent for treating breast
cancer postmenopause because of its appreciable inhibitory
activity against aromatase.1a-d Thus, other diterpenes pos-
sessing the same skeleton are expected to have promising
activities for the treatment of female hormone-dependent
cancers. Banerjee and his colleagues succeeded in the synth-
esis of dichroanal B (2), dichroanone (3), taiwaniaquinol B,
(1) (a) Ohtsu, H.; Iwamoto, M.; Ohishi, H.; Matsunaga, S.; Tanaka, R.
Tetrahedron Lett. 1999, 40, 6419–6422. (b) Minami, T.; Iwamoto, M.; Ohtsu,
H.; Ohishi, H.; Tanaka, R.; Yoshitake, A. Planta Medica 2002, 68, 742–745.
(c) Iwamoto, M.; Ohtsu, H.; Tokuda, H.; Nishino, H.; Matsunaga, S.;
Tanaka, R. Bioorg. Med. Chem. 2001, 9, 1911–1921. (d) Katoh, T.; Akagi,
T.; Noguchi, C.; Kajimoto, T.; Node, M.; Tanaka, R.; Nishizawa, M.; Ohtsu,
H.; Suzuki, N.; Saito, K. Bioorg. Med. Chem. 2007, 15, 2736–2748. (e)
Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. Org. Lett.
2003, 5, 3931–3933. (f) Banerjee, M.; Mukhopadhyay, R.; Achari, B.;
Banerjee, A. K. J. Org. Chem. 2006, 71, 2787–2796. (g) Fillion, E.; Fishlock,
D. J. Am. Chem. Soc. 2005, 127, 13144–13145. (h) Liang, G.; Xu, Y.; Speiple,
I. B.; Trauner, D. J. Am. Chem. Soc. 2006, 128, 11022–11023. (i) Tang, S.;
Xu, Y.; He, J.; He, Y.; Zheng, J.; Pan, X.; She, X. Org. Lett. 2008, 10, 1855–
1858. (j) Planas, L.; Mogi, M.; Takita, H.; Kajimoto, T.; Node, M. J. Org.
Chem. 2006, 71, 2896–2898. (k) Alvarez-Manzaneda, E.; Chahboun, R.;
Cabrera, E.; Alvarez, E.; Alvarez-Manzaneda, R.; Meneses, R.; Es-Samti,
Results and Discussion
Initially, we planed to apply the asymmetric version of the
intramolecular Heck reaction to the synthesis of dl-2
ꢀ
H.; Fernandez, A. J. Org. Chem. 2009, 74, 3384–3388. (l) McFadden, R.; M.,
Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738–7739.
190 J. Org. Chem. 2010, 75, 190–196
Published on Web 12/07/2009
DOI: 10.1021/jo901972b
r
2009 American Chemical Society

Node et al.
JOCArticle
FIGURE 1. Structures of abeo-abietane-type diterpenoids.
FIGURE 2. Equilibration of atropisomers.
SCHEME 1. Synthetic Strategy of abeo-Abietanes
(Scheme 1).1j Namely, dienylalkyloxybenzene derivative pre-
pared by the condensation of β-cyclocitral (5) and aryllithium
was converted to the corresponding triflate via O-dealkylation
and subsequent triflation. Thereafter, the asymmetric Heck
reaction with a chiral ligand could annelate the B-ring to form
the abeo-abietane skeleton. Further transformation of functional
groups should afford the desired natural product.
TABLE 1. Solvent Effect in the Intramolecular Asymmetric Heck
Reaction of 6
€
Inspection with the Buchi molecular model of substrate 6
suggested the existence of two atropisomers, which is a
disadvantage for the asymmetric reaction; however, the
atropisomers were not analyzed by HPLC with a chiral
column.2 Thus, to evaluate the energy barrier that exists
between two stable conformations, the triflate group of
6 was replaced with N-Boc-L-phenylalanine to give the
R-amino ester 9, the atropisomers of which were observed
only at low temperature (-70 °C) in 1H NMR spectroscopic
analysis (see the Supporting Information). As the atrop-
isomers were not observed at temperatures higher than
-40 °C, the fast equilibrium between two atropisomers in 6
was confirmed. This phenomenon could be explained by con-
sidering the distorted boat-type conformation, which reduced
the energy barrier between the atropisomers, as shown in
Figure 2.1j Thus, it was confirmed that 6 could be employed
as a substrate in the asymmetric Heck reaction, which should
generally be performed at temperatures higher than 60 °C.
The asymmetric intramolecular Heck reaction of 6 (a
mixture of E/Z isomers) was conducted as a model experi-
ment under Shibasaki’s condition where (S)-BINAP and
potassium carbonate were adopted as a chiral ligand and
base, respectively.3 Fortunately, the annulated products
conditions
entrya
solvent
time (h)
yield (%)b
7/8
% ee (8)c
1
2
3
4
5
6
toluene
THF
40
18
70
90
89
90
87
82
38/62
12/88
52/48
25/75
80/20
35/65
49
58
69
97
96
97
MeCN
DMF
DMA
NMPd
17
7.5
7.5
7.5
aThe starting material 6 of Z/E 84/16 (entries 1 and 3) and Z/E 91/9,
(entries 2 and 4-6) was used. bThe yield was calculated from the Z
isomer. cThe ee value was determined by chiral HPLC. dNMP = N-
methylpyrrolidinone.
7 and 8 were attained in 70% yield with 49% ee at 60 °C
(Table 1, entry 1).4 Changing the solvent from toluene to
aprotic polar solvents shortened the reaction period and
increased both chemical and optical yields at the same
temperature (Table 1, entries 2-6). The reaction in DMF
gave the most satisfactory result, i.e., 90% yield with 97% ee
(Table 1, entry 4). Since the dissociation of palladium and
triflate in the Pd-complex could accelerate the Heck reac-
tion with DMF as a solvent, high enatioselectivity in the
(2) The atropisomers did not separate at room temperature. The details of
the existence of atropisomers will be published elsewhere.
(3) Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem.
Soc. 1993, 115, 8477–8478.
(4) The fate of the E-isomer was not traced, i.e., neither recovery of the
E-isomer nor its decomposed products were detected.
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SCHEME 2. Synthetic Route of 10
TABLE 2. Heck Reaction of 10 with Chiral Ligands Having C2-Symmetry
aThe numerical values show chemical yields (%) in the Heck reaction. The subsequent hydrogenation proceeded quantitatively.
amide-type solvent (DMF, DMA, and NMP) could be
obtained by a route involving a cation intermediate.5
The intramolecular asymmetric Heck reaction of triflate 10
(a mixture of E/Z isomers) was tried using palladium(II)
acetate, chiral BINAP, and cesium carbonate in DMF at
100 °C, the hydrogenated product of which showed 76% ee
(Table 2, entry 1). Marked temperature dependence to im-
prove the ee was not observed in the Heck reaction with chiral
BINAP (Table 2, entries 2-4). Among several other chiral
phosphorus ligands having C2-symmetry, such as (S)-6-MeO-
BIP, (S,S)-chiraphos, and (S)-MOP, Synphos (17) exhibited a
further improvement in ee and reaction time (Table 2, entries
5-8). This result could be attributed to the smaller dihedral
angle of 17 (75°), which afforded more potent interaction
between the ligand and substrate than that of BINAP (80°).9
Moreover, temperature dependence was also observed in the
reaction. Finally, it was found that the Heck reaction of 10
and successive hydrogenation gave 18 in good yield (<86% in
2 steps) with excellent ee (94-98% ee) when (R)-17 was used
as a ligand.10 The absolute configuration of (þ)-18 was con-
firmed to be S by single-crystal X-ray diffraction analysis after
Finally, we applied the intramolecular Heck reaction to the
asymmetric synthesis of (-)-2and (-)-3isolated from the roots of
Salvia dichroantha6 and (-)-4 from Taiwania cryptomerioides.7
Initially, we designed substrate 10 bearing a rigid acetonide group
in the catechol moiety because the flexible isopropyl group
employed in the racemic synthesis of 2 retarded the access of
the palladium complex to a bulky chiral ligand. 10 was prepared
by modifying a previously reported method1j (Scheme2).Namely,
11, commercially available, was treated with acetone in the
presence of BF3 Et2Otogivetheacetonide12, of which bromina-
3
tion with NBS afforded 13 in excellent yield. After lithiation of the
bromide 13 with n-butyllithium, the aryllithium generated was
reacted with β-cyclocitral (5) to afford the benzylic alcohol 14.
Dehydration of 14 by treatment with methanolic hydrochloric
acid gave the diene 15 as a mixture of E and Z isomers (ca. 1:4).
After demethylation of the methyl ether in 15 with dodecane thiol
and sodium hydride in DMF,8 the obtained phenolic compound
16 was converted to the triflate 10.
(9) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.;
Yanagi, K.; Moriguchi, K. Organometallics 1993, 12, 4188–4196.
(10) For economical reasons, the intermediate 18 (83%, 76% ee) obtained
by the Heck reaction with (R)-BINAP and successive hydrogenation was
recrystallized two times from isopropanol to increase the optical purity until
>98% ee. The recrystallized 18 (17%, 94-98% ee) was used for synthesis of
(-)-2, (-)-3, and (-)-4.
(5) Brown, J. M.; Hii, K. K. Angew. Chem., Int. Ed. 1996, 35, 657–659.
(6) Kawazoe, K.; Yamamoto, M.; Takaishi, Y.; Honda, G.; Fujita, T.;
Sezik, E.; Yesilada, E. Phytochemistry 1999, 50, 493–497.
(7) Chang, C.-I.; Chang, J.-Y.; Kuo, C.-C.; Pan, W.-Y.; Kuo, Y.-H.
Planta Med. 2005, 71, 72–76.
(8) Node, M.; Kajimoto, T. Heteroatom Chem. 2007, 18, 572–583.
192 J. Org. Chem. Vol. 75, No. 1, 2010

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SCHEME 3. Synthesis of (-)-2, (-)-3, and (-)-4a
aReagents and conditions: (a) Pd(OAc)2 (0.3 equiv), (R)-Synphos (0.4 equiv), Cs2CO3, DMF, then H2, RhCl(PPh3); (b) HCl, MeOH, 60 °C; (c) BCl3,
CHCl2OCH3 (5 equiv), CH2Cl2, 0 °C; (d) NBS; (e) CuI, NaOMe, DMF, MeOH, 100 °C; (f) BBr3 (4 equiv), CH2Cl2, -78 to 0 °C; (g) DDQ (1.1 equiv),
CH2Cl2; (h) Me3OBF4, DIEA, CH2Cl2.
deriving to 19 with NBS. Because the E-isomer of 10 also
afforded the desired product in 46% yield under Heck condi-
tions, which indicated the existence of equilibrium between E/Z
isomers, the E/Zmixture was used without any separation in the
reactions.11
saturated aqueous solution of sodium hydrogen carbonate and
extracted with diethyl ether. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (hexane/ethyl acetate = 19/1) to afford 6 (1.39 g, 91%,
1
E/Z = 9/91 mixture). Colorless oil; H NMR of the Z-isomer
Finally, the acetonide of 18 (94.2%ee) was subjected to
deprotection with HCl-MeOH followed by a Friedel-Crafts-
type reaction with dichloromethoxymethane in the presence of
BCl3 to give (-)-2([R]D -15.3 (dioxane), lit. [R]D -8.26) in92%
yield. Treatment of 19 (98%ee) with sodium methoxide in the
presence of CuI followed by removal of the acetonide and
oxidation with DDQ afforded (-)-3 ([R]D -97 (dioxane), lit.
[R]D -99.36), which was further transformed to (-)-4 ([R]D
-36.9 (CHCl3), lit. [R]D -9.07) on treatment with Meerwein
reagent (Scheme 3).
(400 MHz, CDCl3) δ 7.35-7.15 (m, 4H), 6.36 (s, 1H), 5.63 (m,
1H), 2.21 (m, 2H), 1.60 (t, J = 6.4 Hz, 2H), 1.42 (s, 3H), 1.18 (s,
6H);13C NMR ofthe Z-isomer(100 MHz, CDCl3) δ 151.3, 147.6,
134.5, 132.7, 131.2, 130.7, 128.2, 127.6, 121.1, 114.1, 36.7, 36.3,
27.3 (2C), 24.0, 22.9; IR (CHCl3) 2961, 2930, 1421, 1248, 1140,
903 cm-1; HRMS calcd for C17H19F3O3S (Mþ) 360.1007, found
360.1002.
1,1,4a-Trimethyl-2,4a-dihydro-1H-fluorene (7) and 1,1,4a-
Trimethyl-4,4a-dihydro-1H-fluorene (8). Potassium carbonate
(128.0 mg, 0.93 mmol), (S)-BINAP (34.0 mg, 0.056 mmol),
and palladium acetate (6.2 mg, 0.028 mmol) were added to a
solution of 6 (66.8 mg, 0.19 mmol, E/Z = 9/91) in DMF (2.0
mL), and the resulting mixture was stirred for 10 min at room
temperature under an argon atmosphere. The reaction mixture
was allowed to warm to 60 °C and stirred for 7.5 h. After the
reacton was complete, the mixture was poured into water and
extracted with chloroform. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (hexane) to afford the products 7 and 8 as a regioiso-
meric mixture (31.8 mg, 90% from the Z-isomer of 6). This
regioisomer could be separated by silica gel column chromato-
graphy into 7 and 8.
Conclusions
In conclusion, we found an intramolecular asymmetric
Heck reaction to be applicable to substrates which seem to
exist as a mixture of two atropisomers. Using this reaction,
we succeeded in the first asymmetric synthesis of naturally
occurring abeo-abietane-type diterpenoids, (-)-2, (-)-3, and
(-)-4, in 10, 12, and 13 steps with an overall yield of 50%,
40%, and 39%, respectively. Our routes gave a much higher
overall yield and ee within shorter steps than those for
racemic and antipodal forms reported to date.
Experimental Section
7: colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.3
Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.17 (dt, J = 7.3, 1.4 Hz, 1H),
7.12 (dt, J = 7.3, 1.4 Hz, 1H), 6.42 (s, 1H), 6.04 (ddd, J = 9.7,
2.7, 1.0 Hz, 1H), 5.56 (ddd, J = 9.7, 5.0, 2.7 Hz, 1H), 2.20 (ddd,
J = 17.1, 5.0, 1.0 Hz, 1H), 1.97 (dt, J = 17.1, 2.3 Hz, 1H), 1.44 (s,
3H), 1.36 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
163.5, 152.7, 142.3, 131.6, 126.7, 125.2, 124.4, 121.3, 121.2,
120.8, 53.3, 43.4, 35.2, 29.4, 27.1, 26.8; IR (CHCl3) 3007, 2964,
1603, 1466 cm-1; EI-MS m/z 210 (Mþ, 22), 195 (100), 180 (28),
165 (41), 152 (13), 89 (16), 76 (10); HRMS calcd for C16H18 (Mþ)
210.1409, found 210.1414. Anal. Calcd for C16H18: C, 91.37; H,
8.63. Found: C, 91.09; H, 8.65.
2-(2,6,6-Trimethylcyclohex-2-enylidenemethyl)phenyl Trifluoro-
methanesulfonate (6). N-phenylbis(trifluoromethanesulfonimide)
(1.88 g, 5.04 mmol) was added to a solution of C (960 mg,
4.20 mmol) in dichloromethane (15 mL) at room temperature
under a nitrogen atmosphere. The mixture was allowed to cool to
0 °C, and triethylamine (1.52 mL, 10.5 mmol) was added drop-
wise to the reaction mixture, which was stirred for 14 h at room
temperature. The reaction mixture was then poured into a
(11) The heating experiment of E-10 in the absence of the palladium
catalyst did not afford Z-10. The ee value of the product from the mixture of
the E- and Z-isomers was as high as that from the Z-isomer only. Therefore,
the ee value from the E-isomer should be equal to that from the Z-isomer.
(S)-8: colorless oil; [R]23D -197.3 (c 1.65, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.21 (dt, J = 7.5, 1.2,
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Node et al.
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1
1H), 7.13 (dt, J = 7.5, 1.2 Hz, 1H), 6.47 (s, 1H), 5.67 (ddd, J =
10.1, 5.8, 2.0 Hz, 1H), 5.54 (ddd, J = 10.1, 2.9, 0.7 Hz, 1H), 2.49
(dd, J = 16.6, 5.8 Hz, 1H), 1.83 (br dt, J = 16.6, 2.0 Hz, 1H),
1.38 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.3, 153.7, 143.1, 137.5, 126.6 (2C), 124.2, 122.6,
121.3, 120.8, 49.7, 37.3, 36.4, 30.0, 28.6, 23.7; IR (CHCl3) 3007,
2963, 2912, 2866, 1468, 1367 cm-1; EI-MS m/z 210 (Mþ, 39), 195
(100), 180 (39), 165 (56), 152 (15), 128 (12), 115 (12), 89 (27), 76
(14); HRMS calcd for C16H18 (Mþ) 210.1409, found 210.1413.
[97% ee, HPLC: Chiralcel OJ, n-hexane/i-PrOH = 200/1, 0.3
mL/min, tR = 16.3 min [(-)-8], 18.3 min [(þ)-8).]
Colorless oil; H NMR of the Z-isomer (400 MHz, CDCl3) δ
6.43 (s, 1H), 6.32 (s, 1H), 5.52 (m, 1H), 3.86 (s, 3H), 2.92 (sept,
J = 7.0 Hz, 1H), 2.21-2.17 (m, 2H), 1.68 (s, 6H), 1.56 (t, J = 6.4
Hz, 2H), 1.52 (dd, J = 3.3, 2.0 Hz, 3H), 1.20 (d, J = 7.0 Hz, 6H),
1.14 (s, 6H); 13C NMR of the Z-isomer (100 MHz, CDCl3) δ
146.8, 145.0, 139.2, 136.8, 132.4, 128.4, 125.9, 123.9, 121.3,
117.7, 117.4, 60.0, 37.4, 36.0, 28.5, 27.4, 25.8 (2C), 24.1, 23.0,
22.6, 22.5 (2C); IR (CHCl3) 3005, 2966, 1701, 1418, 1366, 1240
cm-1; EI-MS m/z 356 (Mþ, 100), 341 (51), 325 (9), 313 (13), 283
(17), 235 (23); HRMS calcd for C23H32O3 (Mþ) 356.2351, found
356.2348. Anal. Calcd for C23H32O3: C, 77.49; H, 9.05. Found:
C, 77.21; H, 8.96.
4-Isopropyl-7-methoxy-2,2-dimethylbenzo[1,3]dioxole (12).
Acetone (9.6 mL, 130.78 mmol) and boron trifluoride (6.60
mL, 52.31 mmol) were added to a solution of 111 (2.38 g, 13.01
mmol) in diethyl ether (15.0 mL) at °C, and the resulting mixture
was stirred at room temperature for 21.5 h under an argon
atmosphere. After the reaction was complete, the mixture was
quenched with water at 0 °C and extracted with chloroform. The
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/ethyl
7-Isopropyl-2,2-dimethyl-5-(2,6,6-trimethylcyclohexe-2-enyl-
idenemethyl)benzo[1,3]dioxol-4-ol (16). 1-Dodecanethiol (28.0
mL, 117.59 mmol) was added dropwise to a suspension of
sodium hydride (5.13 g, 117.59 mmol, 55% in mineral oil) in
DMF (15.0 mL) at 0 °C, and the solution was stirred for 10 min
under an argon atmosphere. After 10 min, the solution of 15
(4.19 g, 11.76 mmol) in DMF (15.0 mL) was added dropwise to
the resulting mixture at 0 °C, and the reaction mixture was
stirred at 120 °C for 17.5 h. After the reaction was complete, the
reaction mixture was quenched with an aqueous solution of 1 M
hydrochloric acid at 0 °C and extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to remove the solvent. The residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate = 100/1) to afford 16 (3.91 g, 97%, E/Z = 20/80).
1
acetate = 24/1) to afford 12 (2.70 g, 93%). Colorless oil; H
NMR (400 MHz, CDCl3) δ 6.60 (d, J = 8.6 Hz, 1H), 6.42 (d,
J = 8.6 Hz, 1H), 3.85 (s, 3H), 2.95 (sept, J = 7.0 Hz, 1H), 1.69 (s,
6H), 1.22 (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
146.0, 141.9, 134.6, 126.1, 123.6, 118.3, 105.8, 56.2, 28.2, 25.8
(2C), 22.3 (2C); IR (CHCl3) 2964. 1506, 1448, 1286, 1219, 1126
cm-1; EI-MS m/z 222 (Mþ, 32), 207 (100), 167 (13); HRMS
calcd for C13H18O3 (Mþ) 222.1256, found 222.1260. Anal. Calcd
for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.33; H, 8.09.
5-Bromo-7-isopropyl-4-methoxy-2,2-dimethylbenzo[1,3]dioxole
(13). N-Bromosuccinimide (3.34 g, 18.80 mmol) was added to a
solution of 12 (3.80 g, 17.08 mmol) in dichloromethane (70.0
mL) at 0 °C, and the reaction mixture was stirred at room
temperature for 1.5 h under an argon atmosphere. After the
reacton was complete, silica gel was added to the mixture, and
the mixture was concentrated in vacuo to remove the solvent.
The residue was purified by column chromatography on silica
gel (hexane/ethyl acetate = 30/1) to afford 13 (5.02 g, 98%).
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 6.82 (s, 1H), 3.94 (s,
3H), 2.92 (sept, J = 7.0 Hz, 1H), 1.69 (s, 6H), 1.19 (d, J = 7.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 145.6, 138.5, 137.7,
125.7, 122.0, 118.6, 106.3, 60.0, 28.1, 25.6 (2C), 22.0 (2C); IR
(CHCl3) 2963, 1483, 1441, 1377, 1273, 1117 cm-1; EI-MS m/z
302 (Mþ þ 2, 56), 300 (Mþ, 57), 287 (99), 285 (100); HRMS calcd
for C13H17BrO3 (Mþ) 300.0361, found 300.0366; Anal. Calcd
for C13H17BrO3: C, 51.84; H, 5.69. Found: C, 51.59; H, 5.72.
7-Isopropyl-4-methoxy-2,2-dimethyl-5-(2,6,6-trimethylcyclo-
hexe-2-enylidenemethyl)benzo[1,3]dioxole (15). n-Buthyllithium
(4.32 mL, 11.22 mmol, 2.6 M in hexane) was added dropwise to a
solution of 13 (3.07 g, 10.20 mmol) in THF (30.0 mL) at -78 °C,
and the solution was stirred for 1 h under an argon atmosphere.
β-Cyclocitral (2.06 mL, 10.20 mmol, 80% pure) was added
dropwise at -78 °C, and the mixture was stirred for 0.5 h at
the same temperature and stirred for another 2 h at 0 °C. After
the reaction was complete, the reaction mixture was quenched
with a saturated aqueous solution of ammonium chloride and
extracted with chloroform. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo to give the crude material. A methanol solution of
hydrogen chloride (5-10%, 8.0 mL) was added to the crude
material at 0 °C, and the resulting solution was stirred for 15 min
at the same temperature. The reaction mixture was then diluted
with water and extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo to remove the solvent. The residue
was purified by column chromatography on silica gel (hexane/
ethyl acetate = 30/1) to afford 15 (3.16 g, 87%, E/Z = 20/80).
1
Colorless oil; H NMR of the Z-isomer (400 MHz, CDCl3) δ
6.40 (s, 1H), 6.24 (s, 1H), 5.04 (m, 1H), 5.03 (s, 1H, OH), 2.92
(sept, J = 7.0 Hz, 1H), 2.24-2.19 (m, 2H), 1.69 (s, 6H), 1.58 (t,
J = 6.4 Hz, 2H), 1.52-1.50 (m, 3H), 1.20 (d, J = 7.0 Hz, 6H),
1.17 (s, 6H); 13C NMR of the Z-isomer (100 MHz, CDCl3) δ
149.5, 144.7, 135.2, 133.1, 131.7, 130.3, 122.1, 120.6, 119.1,
118.0, 115.9, 37.6, 36.0, 28.2, 28.0, 27.2, 25.6 (2C), 23.8, 22.4
(2C), 22.1; IR (CHCl3) 3518, 2963, 2924, 1452, 1377, 1248, 1151
cm-1; EI-MS m/z 342 (Mþ, 49), 327 (100), 299 (9), 285 (8), 221
(25); HRMS calcd for C22H30O3 (Mþ) 342.2195, found
342.2188.
7-Isopropyl-2,2-dimethyl-5-(2,6,6-trimethylcyclohexe-2-enyl-
idenemethyl)benzo[1,3]dioxol-4-yl trifluoromethanesulfonate (10).
Triflic anhydride (1.75 mL, 10.41 mmol) was slowly added to a
solution of 16 (2.38 g, 6.94 mmol) in pyridine (20.0 mL) at 0 °C,
and the reaction mixture was stirred at the same temperature for
1.5 h and stirred for another 2.0 h at room temperature under an
argon atmosphere. After the reacton was complete, the reaction
mixture was quenched with water at 0 °C and extracted with
chloroform. The organic layer was dried over anhydrous so-
dium sulfate and concentrated in vacuo to remove the solvent.
The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate = 50/1) to afford 10 (3.10 g, 94%, E/Z =
20/80). Colorless oil; 1H NMR of the Z-isomer (400 MHz,
CDCl3) δ 6.52 (s, 1H), 6.22 (s, 1H), 5.58 (m, 1H), 2.96 (sept, J =
7.0 Hz, 1H), 2.22-2.18 (m, 2H), 1.70 (s, 6H), 1.58 (t, J = 6.4 Hz,
2H), 1.47 (m, 3H), 1.20 (d, J = 7.0 Hz, 6H), 1.14 (s, 6H); 13C NMR
of the Z-isomer (100 MHz, CDCl3) δ 149.9, 148.9, 145.1, 138.3,
131.4, 129.0, 128.8, 128.0, 127.2, 121.3, 120.3, 114.4, 36.6, 36.0,
28.6, 27.2, 25.6 (2C), 23.9, 22.6, 22.1, 22.0 (2C); IR (CHCl3) 2966,
2926, 1450, 1418, 1250, 1140, 1109, 1049 cm-1; EI-MS m/z 474
(Mþ, 55), 356 (100), 341 (67), 285 (87); HRMS calcd for
C23H29F3O5S (Mþ) 474.1687, found 474.1684.
(S)-4-Isopropyl-2,2,7,7,10a-pentamethyl-8,9,10,10a-tetrahy-
dro-7H-fluoreno[3,4-d][1,3]dioxole [(þ)-18]. Palladium acetate
(6.1 mg, 0.027 mmol) was added to a suspension of 10 (64.0
mg, 0.135 mmol), cesium carbonate (176.3 mg, 0.541 mmol),
and (R)-synphos (17) (34.5 mg, 0.054 mmol) in DMF (2 mL).
The reaction mixture was stirred for 26 h at 80 °C under an argon
atmosphere. After the reacton was complete, the mixture was
quenched with water, and the resulting mixture was extracted
194 J. Org. Chem. Vol. 75, No. 1, 2010

Node et al.
JOCArticle
1
with ethyl acetate. The organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. The crude product was purified by column chromato-
graphy on silica gel (hexane/diethyl ether = 50/1) to afford the
cyclized products as a regioisomeric mixture (33.1 mg, 72%).
RhCl(PPh3)3 (23.6 mg, 0.026 mmol) was added to a solution of
the cyclic compounds (33.1 mg, 0.102 mmol) in methanol (1.0
mL) under a nitrogen atmosphere. The nitrogen was replaced
with hydrogen, and the resulting mixture was stirred for 24.5 h at
room temperature. After the reacton was complete, the solvent
was concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/diethyl ether = 50/1) to
afford 18 (33.1 mg, 99%). Colorless crystal; mp 89-91 °C (i-
(i-PrOH); [R]26 þ39.5 (c 1.59, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 6.33 (s, 1H), 3.42 (sept, J = 7.2 Hz, 1H), 2.31 (dd, J =
13.2, 3.2 Hz, 1H), 1.90 (tq, J = 13.0, 3.3 Hz, 1H), 1.65 (d, J = 0.8
Hz, 6H), 1.56-1.64 (m, 2H), 1.42 (s, 3H), 1.31-1.28 (m, 9H),
1.22 (s, 3H), 1.16-1.07 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
162.7, 144.1, 141.3, 136.5, 132.6, 126.3, 121.3, 117.6, 106.7, 76.7,
51.7, 42.6, 36.4, 35.6, 31.6, 31.2, 25.64, 25.62, 25.4, 20.9, 20.5,
19.3; IR (CHCl3) 3018, 2937, 1427, 1375, 1333, 1267, 1238,
1196 cm-1; EI-MS m/z 404 (Mþ, 64), 406 (61), 391 (31), 389 (31),
337 (85), 335 (88), 58 (100); HRMS calcd for C22H29BrO2 (Mþ)
404.1350, found 404.1354. Anal. Calcd for C22H29BrO2: C,
65.18; H, 7.21. Found: C, 65.38; H, 7.25.
(S)-4-Isopropyl-5-methoxy-2,2,7,7,10a-pentamethyl-8,9,10,10a-
tetrahydro-7H-fluoreno[3,4-d]dioxole [(þ)-20]. Copper iodide
(177 mg, 0.93 mmol) and a suspension of sodium methoxide
(1.0 mL, 4.63 mmol, 28% in methanol) in DMF/methanol = 1/1
(10 mL) were added to a solution of (þ)-19 (313 mg, 0.77 mmol,
98% ee) in DMF (5.0 mL) at room temperature, and the
resulting mixture was stirred at 100 °C for 28 h. The reaction
mixture was added to water and extracted with diethyl ether.
The organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo to remove the
solvent. The residue was purified by column chromatography
on silica gel (hexane/ethyl acetate = 50/1) to afford (þ)-20 (272
PrOH); [R]26 þ68.2 (c 2.67, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 6.59 (s, 1H), 6.22 (s, 1H), 3.30 (sept, J = 7.0 Hz, 1H),
2.32 (dd, J = 13.0, 1.5 Hz, 1H), 1.91 (tq, J = 13.0, 3.3 Hz, 1H),
1.66 (s, 6H), 1.55-1.64 (m, 2H), 1.43 (s, 3H), 1.25 (s, 6H), 1.23
(d, J = 7.0 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.11 (dt, J = 13.0,
4.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 161.5, 142.6, 141.3,
136.8, 132.1, 127.5, 120.8, 116.8, 109.7, 50.2, 42.6, 36.5, 35.4,
31.3, 28.4, 25.8 (2C), 25.5, 22.5, 22.4, 21.1, 19.4; IR (CHCl3)
2999, 2963, 2934, 1602, 1429, 1375, 1332 cm-1; EI-MS m/z 326
(Mþ, 100), 311 (70), 283 (16), 268 (21), 257 (55); HRMS calcd for
C22H30O2 (Mþ) 326.2246, found 326.2247. Anal. Calcd for
C22H30O2: C, 80.94; H, 9.26. Found: C, 80.82; H, 9.45. [98%
mg, 99%). Colorless crystal; mp 135-138 °C (i-PrOH); [R]26
D
ee, HPLC: Chiralcel OD f OD-H, n-hexane, 0.1 mL/min, tR
72 min [(-)-18], 75 min [(þ)-18.]
=
þ47.9 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.32 (s,
1H), 3.78 (s, 3H), 3.32-3.25 (sept, J = 7.2 Hz, 1H), 2.32-2.26
(dd, J = 12.8, 1.6 Hz, 1H), 1.96-1.84 (tq, J = 13.6, 3.2 Hz, 1H),
1.65 (d, J = 4.0 Hz, 6H), 1.63-1.53 (m, 2H), 1.42 (s, 3H),
1.31-1.27 (m, 9H), 1.21 (s, 3H), 1.15-1.07 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 160.4, 144.3, 143.7, 138.2, 132.4, 127.4,
121.4, 117.1, 76.7, 62.6, 50.6, 50.5, 42.7, 36.5, 35.4, 31.3, 25.6,
25.5, 25.0, 21.4, 21.3, 21.1, 19.4; IR (CHCl3) 3034, 3009, 2936,
2361, 2341, 1452, 1429, 1375, 1335, 1234, 1209, 1198 cm-1; EI-
MS m/z 356 (Mþ, 80), 341 (37), 287 (100), 143 (10); HRMS calcd
for C23H32O3 (Mþ) 356.2351, found 356.2344. Anal. Calcd for
C23H32O3: C, 77.49; H, 9.05. Found: C, 77.22; H, 9.00.
(-)-Dichroanal B [(-)-2]. A solution of (þ)-18 (33.5 mg, 0.10
mmol, 94% ee) in a hydrogen chloride methanol solution (3.0
mL, 5-10%) was stirred for 1 h at room temperature and then
for another 8 h at 60 °C. After the reacton was complete, the
mixture was concentrated in vacuo to remove the solvent. Next,
boron trichloride (309 μL, 0.31 mmol, 1 M in dichloromethane)
was added dropwise to a solution of the residue in dichloro-
methane (3.0 mL), and subsequent dichloromethyl methyl ether
(46.6 μL, 0.52 mmol) was then added dropwise at -78 °C, and
the resulting mixture was stirred for 1 h at the same temperature
and for another 11 h at 0 °C. After the reacton was complete, the
mixture was quenched with an aqueous solution of 1 M hydro-
chloric acid and extracted with chloroform. The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo to remove the solvent. The residue
was purified by column chromatography on silica gel (hexane/
ethyl acetate = 6/1) to afford (-)-2 (30.8 mg, 95%). Yellow
amorphous; [R]21D -15.3 (c 0.61, dioxane); 1H NMR (400 MHz,
C5D5N) δ 10.93 (s, 1H), 7.56 (s, 1H), 4.95 (br s, 2H), 4.44 (sept,
J = 7.1 Hz, 1H), 2.90 (dd, J = 12.8, 1.5 Hz, 1H), 1.91 (qt, J =
13.7, 3.1 Hz, 1H), 1.70 (s, 3H), 1.63 (d, J = 7.1 Hz, 6H),
1.60-1.56 (m, 1H), 1.53-1.49 (m, 1H), 1.27 (s, 3H), 1.21 (s,
3H), 1.18-1.05 (m, 2H); 13C NMR (100 MHz, C5D5N) δ 192.2,
167.5, 150.8, 143.0, 141.3, 139.7, 139.5, 121.3, 120.9, 51.5, 43.4,
36.7, 36.2, 31.9, 27.4, 25.9, 23.1, 23.0, 20.7, 20.1; IR (CHCl3)
3524, 2969, 2934, 1670, 1589, 1458, 1275 cm-1; EI-MS m/z 314
(Mþ, 36), 300 (45), 283 (36), 271 (12), 258 (18), 245 (100), 231
(34); HRMS calcd for C20H26O3 (Mþ) 314.1882, found
314.1890.
(-)-Dichroanone [(-)-3]. Boron tribromide (0.58 μL, 0.58
mmol) was added dropwise to a solution of (þ)-20 (41 mg,
0.12 mmol, 98% ee) in dichloromethane (5.0 mL) at 0 °C, and
the reaction mixture was stirred for 1 h at the same temperature
and then for another 14 h at room temperature under an argon
atmosphere. After the reacton was complete, the mixture was
quenched with an aqueous solution of 1 M hydrochloric acid at
0 °C and extracted with chloroform. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo to remove the solvent. Then, 2,3-di-
chloro-5,6-dicyano-p-benzoquinone (32 mg, 0.14 mmol) was
added to a solution of the residue in dichloromethane (3.0
mL) at room temperature, and the reaction mixture was stirred
at room temperature for 1 h under an argon atmosphere. After
the reacton was complete, the mixture was quenched with water
and extracted with chloroform. The organic layer was washed
with brine, dried over anhydrous sodium sulfate, and concen-
trated in vacuo. The residue was purified by column chromato-
graphy on silica gel (hexane/diethyl ether = 14/1) to afford
(S)-5-Bromo-4-isopropyl-2,2,7,7,10a-pentamethyl-8,9,10,10a-
tetrahydro-7H-fluoreno[3,4-d][1,3]dioxole [(þ)-19]. N-Bromo-
succinimide (67 mg, 0.38 mmol) was added to a solution of
(þ)-18 (112 mg, 0.32 mmol) in dichloromethane (3.0 mL) at
0 °C, and the reaction mixture was stirred for 2 h at the
same temperature. The reaction mixture was quenched with
an aqueous solution of 1 M hydrochloric acid and extracted
with chloroform. The organic layer was washed with brine, dried
over anhydrous sodium sulfate, and concentrated in vacuo to
remove the solvent. The residue was purified by column chro-
matography on silica gel (hexane/ethyl acetate=100/1) to give
(þ)-19 (134 mg, 97%). Colorless crystal; mp 140-150 °C
(-)-3 (33 mg, 94%). Red amorphous; [R]21 -97.8 (c 0.14,
D
dioxane); 1H NMR (400 MHz, CDCl3) (H of OH was not
detected) δ 6.45 (s, 1H), 3.22 (sept, J=7.0 Hz, 1H), 2.38 (dq,
J = 13.0, 2.5 Hz, 1H), 1.92 (tq, J = 14.0, 3.5 Hz, 1H), 1.71 (br
dq, J = 13.0, 2.5 Hz, 1H), 1.67-1.60 (m, 1H), 1.46 (s, 3H), 1.29
(s, 3H), 1.24 (s, 3H), 1.24 (dd, J = 7.0, 1.8 Hz, 6H), 1.15-1.06
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 185.7, 178.2, 177.1,
152.4, 148.9, 147.7, 122.7, 118.0, 55.3, 43.3, 37.3, 37.0, 30.9, 24.7,
23.9, 20.1, 20.0, 19.0; IR (CHCl3) 3368, 2964, 2930, 2872, 2856,
1717, 1636, 1526, 1470, 1458, 1369, 1319 cm-1; EI-MS m/z 300
(Mþ, 93), 285 (85), 267 (9), 257 (29), 232 (48), 231 (79); HRMS
calcd for C19H24O3 (Mþ) 300.1725, found 300.1723.
J. Org. Chem. Vol. 75, No. 1, 2010 195

Node et al.
JOCArticle
(-)-Taiwaniaquinone H [(-)-4]. N,N-Diisopropylethylamine
(6.5 μL, 0.038 mmol) and Meerwein reagent (5.1 mg, 0.034
mmol) were added to a solution of (-)-3 (9.4 mg, 0.031 mmol,
98% ee) in dichloromethane (1.0 mL) at room temperature, and
the reaction mixture was stirred for 7 h under an argon atmo-
sphere. After the reacton was complete, the mixture was
quenched with an aqueous solution of 1 M hydrochloric acid
at 0 °C and extracted with chloroform. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo to remove the solvent. The residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate = 9/1) to afford (-)-4 (9.8 mg, 99%). Orange amor-
mixture was quenched with a saturated aqueous solution of
ammonium chloride and extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo to remove the
solvent. The residue was purified with silica gel column chro-
matography (hexane/diethyl ether = 24/1) to give 9 (75 mg,
28%). Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.34-7.12
(m, 8H), 6.94 (d, J = 7.9 Hz, 1H), 6.22 (s, 1H), 5.57 (s, 1H), 5.01
(d, J = 8.1 Hz, 1H, NH), 4.82-4.76 (m, 1H), 3.30 (dd, J = 11.0,
5.4 Hz, 1H), 3.12 (dd, J = 11.0, 6.9 Hz, 1H), 2.22-2.17 (m, 2H),
1.53 (t, J = 6.4 Hz, 2H), 1.42 (br s, 3H), 1.41 (s, 9H), 1.11 (s, 3H),
1.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 155.1, 149.8,
148.0, 136.1, 133.5, 132.0, 131.8, 129.7, 128.8, 127.6, 127.3,
125.8, 121.6, 115.84, 115.77, 80.1, 54.67, 54.65, 38.8, 37.1,
36.1, 28.5, 27.7, 24.0, 23.2; IR (CHCl3) 2926, 1759, 1713, 1497,
1456, 1367, 1163 cm-1; EI-MS m/z 475 (Mþ, 1), 419 (29), 374 (8),
360 (19), 228 (45), 213 (67), 172 (100); HRMS calcd for
C30H37NO4 (Mþ) 475.2723, found 475.2722.
phous; [R]21 -36.9 (c 0.30, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 6.38 (s, 1H), 3.99 (s, 3H), 3.25 (sept, J = 7.0 Hz,
1H), 2.40 (dq, J = 13.1, 2.6 Hz, 1H), 1.92 (tq, J = 13.8, 3.4 Hz,
1H), 1.72-1.66 (m, 1H), 1.65-1.59 (m, 1H), 1.44 (s, 3H), 1.27 (s,
3H), 1.24, 1.23 (each d, J = 7.0 Hz, 3H), 1.22 (s, 3H), 1.08 (tt,
J = 13.5, 3.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 186.3,
178.8, 175.7, 157.3, 150.5, 145.8, 136.0, 116.7, 61.3, 55.6, 43.3,
37.2, 36.7, 30.9, 24.8, 24.5, 20.7, 20.6, 20.1, 19.1; IR (CHCl3)
3031, 1643, 1533, 1236, 1197 cm-1; EI-MS m/z 314 (Mþ, 100),
299 (97), 285 (14), 271 (24), 255 (57), 245 (56); HRMS calcd for
C20H26O3 (Mþ) 314.1882, found 314.1889.
O-[2-(2,6,6-Trimethylcyclohex-2-enylidenemethyl)phenyl]-2-
(R)-tert-butoxycarbonylamino-3-phenylpropionate (9). To a so-
lution of C (131 mg, 0.57 mmol) in dichloromethane (5.0 mL)
were added N-Boc-D-phenylalanine (274 mg, 1.03 mmol) and
WSC (220 mg, 1.15 mmol) at room temperature, and the
mixture was stirred for 14 h at the same temperature under a
nitrogen atmosphere. After the reacton was complete, the
Acknowledgment. This research was financially sup-
ported in part by the Frontier Research Program and the
21st Century COE Program of the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
Supporting Information Available: 1H NMR and 13C NMR
spectra for all new compounds, an ORTEP for 19, and complete
experimental details following the general procedures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
196 J. Org. Chem. Vol. 75, No. 1, 2010