Efficient route to 4a-methyltetrahydrofluorenes: A total synthesis of (±)-dichroanal B via intramolecular Heck reaction

Article abstract of DOI:10.1021/jo052454q

An efficient new route based on intramolecular Heck cyclization of the diene 11 was developed to prepare the 4a-methyltetrahydrofluorene diterpenoids and utilized for the total synthesis of (±)-dichroanal B with significantly improved overall yield.

Full text of DOI:10.1021/jo052454q

Efficient Route to 4a-Methyltetrahydrofluorenes:
A Total Synthesis of (()-Dichroanal B via
Intramolecular Heck Reaction
Lo¨ıc Planas, Muneto Mogi, Hirofumi Takita,
Tetsuya Kajimoto, and Manabu Node*
Department of Pharmaceutical Manufacturing Chemistry, 21
Century COE program, Kyoto Pharmaceutical UniVersity,
Misasagi, Yamashina, Kyoto 607-8414, Japan
node@mb.kyoto-phu.ac.jp
ReceiVed NoVember 28, 2005
FIGURE 1. Natural products with a 4a-methylhydrofluorene skeleton.
In the report by Banerjee et al.,9 (()-4 was prepared in a
total of 27 steps with less than 5% overall yield via an
intramolecular Heck reaction of the exo-olefin 10 (Scheme 1a).
We sought to construct the 4a-methyltetrahydrofluorene skeleton
using the diene 11, which could be readily prepared from
commercially available â-cyclocitral (Scheme 1b).
To confirm the synthetic feasibility of the intramolecular Heck
cyclization,10 a test reaction was carried out with the substrate
diene 12 (Scheme 2). The Pd(0)-catalyzed reaction proceeded
smoothly in acetonitrile at 60 °C. The obtained isomers, 13a,b,
underwent selective hydrogenation using Wilkinson’s catalyst,11
providing the desired 4a-methyltetrahydrofluorene 14. While
the result was satisfactory, a computational model suggested
that substrate 12 is expected to have a planar half-chair
conformation as the most stable form, in which the arylpalladium
is distant from the olefin. To explain the reaction mechanism,
the diene moiety should take a “boatlike” conformation with
increased temperature to bring the arylpalladium species and
the olefin in close contact (Figure 2).
An efficient new route based on intramolecular Heck
cyclization of the diene 11 was developed to prepare the
4a-methyltetrahydrofluorene diterpenoids and utilized for the
total synthesis of (()-dichroanal B with significantly im-
proved overall yield.
During the past decade, several diterpenoids with the 4a-
methyltetra-(or hexa-)hydrofluorene skeleton, such as taiwan-
iaquinols A (1) and B (2),1 dichroanals A (3) and B (4),2
standishinal (5),3 and taiwaniaquinols C (6), D (7),4 E (8), and
F (9),5 were isolated from salVia dichroantha, thuja standishii,
taiwania cryptomerioides, and other related plants (Figure 1).
Although little is known about their bioactivities, standishinal
is known to demonstrate aromatase inhibitory activities,6 and,
therefore, this class of compounds may be promising candidates
for the treatment of breast cancer.7
Several syntheses with different strategies have been reported
for the construction of the 4a-methylhydrofluorenes,8 and the
first total synthesis of (()-dichroanal B (4) was recently
disclosed.9 Its synthesis, however, requires multiple steps, and
the overall yield is considerably low. We herein report a new
strategy to construct the six-five-six ring system and an
application of the methodology to the total synthesis of (()-4,
with a shorter synthetic route and much improved overall yield.
The new methodology to prepare the 4a-methyltetrahydro-
fluorene skeleton was adopted for the total synthesis of (()-4.
The synthesis started with the preparation of the aryl bromide
18 in four steps from commercially available 2′,3′-dihydroxy-
4′-methoxyacetophenone 15 (Scheme 3). A Grignard reaction
(8) (a) Ghatak, U. R.; Chakravarty, J. Tetrahedron Lett. 1966, 7, 2449-
2458. (b) Ghatak, U. R.; Chakravarty, J.; Banerjee, A. K. Tetrahedron 1968,
24, 1577-1593. (c) Ghatak, U. R.; Chakravarty, J.; Dasgupta, R.;
Chakraborti, P. C. J. Chem. Soc., Perkin Trans. 1 1975, 2438-2445. (d)
Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1992, 57, 5937-5947. (e)
Ishibashi, H.; Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org. Chem.
2000, 65, 9022-9027. (f) Ishibashi, H.; Kobayashi, T.; Takamatsu, D.
Synlett 1999, 1286-1288. (g) Bailey, W. F.; Daskapan, T.; Rampalli, S. J.
Org. Chem. 2003, 68, 1334-1338. (h) Mukhopadhya, J. K.; Pal, S.; Ghatak,
U. R. Synth. Commun. 1995, 25, 1641-1657. (i) Lomberget, T.; Bentz, E.;
Bouyssi, D.; Balme, G. Org. Lett. 2003, 5, 2055-2057.
(1) Lin, W.-H.; Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1995, 40, 871-
873.
(2) Kawazoe, K.; Yamamoto, M.; Takaishi, Y.; Honda, G.; Fujita, T.;
Sezik, E.; Yesilada, E. Phytochemistry 1999, 50, 493-497.
(3) Ohtsu, H.; Iwamoto, M.; Ohishi, H.; Matsunaga, S.; Tanaka, R.
Tetrahedron Lett. 1999, 40, 6419-6422.
(4) Chang, C.-I.; Chien, S.-C.; Lee, S.-M.; Kuo, Y.-H. Chem. Pharm.
Bull. 2003, 51, 1420-1422.
(5) Chang, C.-I.; Chang, J.-Y.; Kuo, C.-C.; Pan, Y.-H.; Kuo, Y.-H. Planta
Med. 2005, 71, 72-76.
(6) Iwamoto, M.; Ohtsu, H.; Tokuda, H.; Nishino, H.; Matsunaga, S.;
Tanaka, R. Bioorg. Med. Chem. 2001, 9, 1911-1921.
(7) Minami, T.; Iwamoto, M.; Ohtsu, H.; Ohishi, H.; Tanaka, R.;
Yoshitake, A. Planta Med. 2002, 68, 742-745.
(9) Banerjee, M.; Mukhopadhay, R.; Achari, B.; Banerjee, A. K. Org.
Lett. 2003, 5, 3931-3933.
(10) For reviews, see: (a) Link, J. T. Org. React. 2002, 60, 157-534.
(b) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-2964. (c)
Guiry, P. J.; Kiely, D. Curr. Org. Chem. 2004, 8, 781-794.
(11) Ward, D. E. Can. J. Chem. 1987, 65, 2380-2384.
10.1021/jo052454q CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/28/2006
2896
J. Org. Chem. 2006, 71, 2896-2898

SCHEME 1
FIGURE 2. Proposed mechanism via a “boatlike” conformation.
SCHEME 4
SCHEME 2
SCHEME 3
SCHEME 5
with MeMgBr, followed by reduction using BF3‚Et2O/Et3SiH,
afforded the isopropyl derivative 16. The hydroxyl groups were
protected as isopropyl ether, and the selective bromination of
17 using NBS provided the aryl bromide 18. The diene substrate
11 was prepared as follows (Scheme 4). The reaction of
â-cyclocitral with 18 using n-butyllithium afforded the alcohol
19. Dehydration of the newly generated hydroxyl group using
triflic anhydride in the presence of pyridine provided the
pyridium salt 20, which after elimination with DABCO,
provided the diene 21 as a mixture of Z/E isomers. Configura-
tion of the double bond in the major isomer of 21 was
determined to be Z by NOE experiments. Demethylation of 21
using sodium hydride and dodecanthiol, an odorless sulfur
reagent developed by our group,12 afforded the phenol 22 in
high yield, which was then converted to the triflate 11 with
triflic anhydride.
of 11, was accomplished with high yield (92% from the Z
isomer) and provided 23 as an inseparable mixture of the double
bond isomers, which were selectively hydrogenated using
Wilkinson’s calatyst to afford 24. Finally, deprotection of the
phenolic groups, followed by the formylation reaction, led to
the formation of (()-dichroanal B.
In conclusion, a new efficient method to prepare a 4a-
methyltetrahydrofluorene system was developed via an intramo-
lecular Heck cyclization of the novel diene 11. The methodology
was applied to the synthesis of (()-dichroanal B and allowed
to achieve a remarkably shorter synthesis (eight steps from
â-cyclocitral) with an improved yield (36% from 18), compared
to the previously reported total synthesis.9 This methodology
also provides the opportunity for a convenient construction of
The diene substrate 11 was utilized for the construction of
the 4a-methyltetrahydrofluorene skeleton and the synthesis of
(()-dichroanal B (4) (Scheme 5). The key step, Heck cyclization
(12) Nishide, K.; Ohsugi, S.; Miyamoto, T.; Kumar, K.; Node, M.
Monatsh. Chem. 2004, 135, 189-200.
J. Org. Chem, Vol. 71, No. 7, 2006 2897

(M + H)+ calcd for C25H38O2, 370.2872; found, 370.2869. Anal.
Calcd for C25H38O2: C, 81.03; H, 10.34. Found: C, 80.87; H, 10.52.
(()-Dichroanal B (4). To a solution of 24 (30 mg, 0.081 mmol)
in dichloromethane (1 mL) was slowly added 1 M boron trichloride
solution in dichloromethane (400 µL, 0.405 mmol) at 0 °C. After
stirring for 1 h, dichloromethyl methyl ether (11 µL, 1.12 mmol)
was added. The reaction mixture was stirred for 3 h at 0 °C,
quenched with water, and then extracted with ethyl acetate. The
organic phase was washed with water, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The crude product
was purified by short-column chromatography on silica gel (hexane/
chiral 4a-methyltetrahydrofluorene. The asymmetric synthesis
using related diene substrates is in progress.
Experimental Section
5,6-Diisopropoxy-7-isopropyl-1,1,4a-trimethyl-2,3,4,4a-tet-
rahydro-1H-fluorene (24). To a suspension of 11 (170 mg, 0.33
mmol, Z/E, 80/20), potassium carbonate (226 mg, 1.64 mmol), and
1,3-bis(diphenylphosphino)propane (54 mg, 0.13 mmol) in N,N-
dimethylformamide (3.3 mL) was rapidly added palladium acetate
(14.7 mg, 0.07 mmol). The mixture was stirred for 15 min at room
temperature and 17 h at 100 °C. After the reaction mixture was
quenched with water and extracted with ethyl acetate, the organic
phase was washed with water and brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The crude
product was purified by chromatography on silica gel (hexane/
diethyl ether, 95/5), providing 23 (83 mg, 92%) as a colorless oil
along with unreacted (E)-11 (25 mg). To a solution of the obtained
mixture of 23 and (E)-11 (26 mg of 23, 0.07 mmol) in benzene (2
mL) was added RhCl(PPh3)3 (25 mg, 0.027 mmol) under a nitrogen
atmosphere. The nitrogen was replaced with hydrogen, and the
solution was stirred for 15 h. The reaction mixture was concentrated
and purified by chromatography on silica gel (hexane/diethyl ether,
95/5), providing 24 (24 mg, 92%) as a colorless solid. Recrystal-
lization from ethyl acetate gave an analytically pure product as
colorless crystals: mp 86-87 °C. 1H NMR (400 MHz, CDCl3): δ
1.12 (d, J ) 6.0 Hz, 3H), 1.16 (d, J ) 6.8 Hz, 3H), 1.17 (d, J )
6.2 Hz, 3H), 1.21 (d, J ) 7.0 Hz, 3H), 1.22 (s, 3H), 1.26 (s, 3H),
1.28 (d, J ) 6.2 Hz, 3H), 1.29 (d, J ) 6.2 Hz, 3H), 1.45 (s, 3H),
1.60 (m, 2H), 1.93 (m, 2H), 2.48 (m, 2H), 3.37 (sept, J ) 7.0 Hz,
1H), 4.31 (sept, J ) 6.2 Hz, 1H), 5.09 (sept, J ) 6.2 Hz, 1H), 6.25
(s, 1H), 6.86 (s, 1H). 13C NMR (400 MHz, CDCl3): δ 19.9, 21.6,
22.4, 22.4, 22.8, 23.0, 23.8, 24.8, 25.9, 26.5, 31.8, 35.6, 37.6, 42.7,
52.5, 70.9, 74.0, 112.0, 120.4, 138.4, 142.2, 143.7, 144.4,145.8,
163.8. IR (CHCl3, cm-1): 2966, 2932, 2361, 1421, 1111. HRMS
1
ethyl acetate, 1/1), providing (()-4 (20 mg, 80%) as an oil. H
NMR (400 MHz, C5D5N): δ 1.05-1.15 (m, 1H), 1.15-1.30 (m,
1H), 1.24 (s, 3H), 1.30 (s, 3H), 1.50-1.70 (m, 2H), 1.66 (d, J )
7.1 Hz, 6H), 1.73 (s, 3H), 1.94 (q, J ) 13.7, 1H), 2.93 (dd, J )
1.3, 12.6 Hz, 1H), 4.47 (sept, J ) 7.1 Hz, 1H), 5.05 (br s, 2H),
7.59 (s, 1H), 10.96 (s, 1H). 13C NMR (400 MHz, CDCl3): δ 20.1,
20.7, 23.0, 23.1, 25.9, 27.4, 31.9, 36.2, 36.7, 43.4, 51.5, 120.9,
121.3, 139.5, 139.7, 141.3, 143.0, 150.8, 167.5, 192.2. IR (CHCl3,
cm-1): 3524, 2964, 2934, 1670, 1589, 1458, 1275. HRMS (M +
H)+ calcd for C20H26O3, 314.1882; found, 314.1879.
Acknowledgment. This work was supported by a grant from
the Japanese Society for the Promotion of Science and, in part,
by Frontier Research Program and the 21st Century Center of
Excellence Program, “Development of Drug Discovery Frontier
Integrated from Tradition to Proteome”, of the Ministry of
Education, Culture, Sports and Technology, Japan.
Supporting Information Available: Experimental procedures
and compound characterizations for 11, 13a,b, 14, 16-22 and
1H and 13C NMR spectra for 4, 11, 13a,b, 14, 16-22, and 24.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052454Q
2898 J. Org. Chem., Vol. 71, No. 7, 2006