General route to 4a-methylhydrofluorene diterpenoids: Total syntheses of (±)-taiwaniaquinones D and H, (±)-taiwaniaquinol B, (±)-dichroanal B, and (±)-dichroanone

Article abstract of DOI:10.1021/jo052589w

A general and convergent route for the synthesis of the 4a-methylhydrofluorene diterpenoids has been established through a common hexahydrofluorenone intermediate (10) obtained via Pd(0)-catalyzed reductive cyclization of a substituted 2-(2-bromobenzyl) methylene cyclohexane (13). The strategy has been successfully utilized for the synthesis of (±)-taiwaniaquinones D (3) and H (5), (±)-taiwaniaquinol B (1), (±)-dichroanal B (7), and (±)-dichroanone (8).

Full text of DOI:10.1021/jo052589w

General Route to 4a-Methylhydrofluorene Diterpenoids: Total
Syntheses of (()-Taiwaniaquinones D and H, (()-Taiwaniaquinol B,
(()-Dichroanal B, and (()-Dichroanone
Mainak Banerjee, Ranjan Mukhopadhyay, Basudeb Achari, and Asish Kr. Banerjee*
Medicinal Chemistry DiVision, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road,
Kolkata-700 032, India
ashisbanerjee@iicb.res.in
ReceiVed December 16, 2005
A general and convergent route for the synthesis of the 4a-methylhydrofluorene diterpenoids has been
established through a common hexahydrofluorenone intermediate (10) obtained via Pd(0)-catalyzed
reductive cyclization of a substituted 2-(2-bromobenzyl) methylene cyclohexane (13). The strategy has
been successfully utilized for the synthesis of (()-taiwaniaquinones D (3) and H (5), (()-taiwaniaquinol
B (1), (()-dichroanal B (7), and (()-dichroanone (8).
Introduction
Recently a large number of highly rearranged abietane-type
diterpenoids possessing the uncommon 4a-methyl tetra- (or
hexa-) hydrofluorene skeleton were isolated mainly from a
common Taiwanese pine tree, Taiwania cryptomerioides.1 These
include taiwaniaquinols B (1)1a and D (2),1c and taiwaniaquino-
nes D (3),1b F (4),1c and H (5)1d (Figure 1). A few more
structurally related diterpenoids such as dichroanals A (6) and
B (7), and dichroanone (8) were isolated from SalVia dichroan-
tha.2 Another novel diterpenoid, standishinal (9), was obtained
from Thuja standishii.3 Though the bioactivities of this family
of compounds are yet to be examined comprehensively,
preliminary studies1d revealed that taiwaniaquinone D (3)
possesses antitumoral cytotoxic activity, and standishinal (9)
has promising antitumor4 and aromatase inhibitory5 potential.
The published results on their bioactivities and the unique
(1) (a) Lin, W.-H.; Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1995, 40,
871-873. (b) Lin, W.-H.; Fang, J.-M.; Cheng, 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.; Yesilada, E. Phytochemistry 1999, 50, 493-497.
(3) Ohtsu, H.; Iwamoto, M.; Ohishi, H.; Matsunaga, S.; Tanaka, R.
Tetrahedron Lett. 1999, 40, 6419-6422.
FIGURE 1. 4a-Methylhydrofluorene diterpenoids.
structural pattern make them attractive synthetic targets. Reports
on the syntheses of the basic 4a-methyl hydrofluorene skeleton
are relatively few,6-10 though a large volume of literature exists
on the synthesis of the gibberellin group of diterpenoids
possessing a bridged hydrofluorene nucleus.11 In the course of
our studies on the synthesis of rearranged polycyclic diter-
penoids12 we have recently disclosed12a in a preliminary account
the first total syntheses of dichroanal B (7) and dichroanone
(4) Iwamoto, M.; Ohtsu, H.; Tokuda, H.; Nishino, H.; Matsunaga, S.;
Tanaka, R. Bioorg. Med. Chem. 2001, 9, 1911-1921.
(5) (a) Minami, T.; Iwamoto, M.; Ohtsu, H.; Ohishi, H.; Tanaka, R.;
Yoshitake, A. Planta Med. 2002, 68, 742-745. (b) Hanson, J. R. Nat. Prod.
Rep. 2004, 21, 312-320.
10.1021/jo052589w CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/10/2006
J. Org. Chem. 2006, 71, 2787-2796
2787

Banerjee et al.
SCHEME 1. Retrosynthetic Analysis
SCHEME 2. Synthesis of the Basic Hexahydrofluorene Skeleton 27aa
a Reagents and conditions: (a) KOtBu, tBuOH, NaI, reflux, 6 h. (b) LiOH, MeOH, H2O, rt, 12 h. (c) SiO2, 80 °C, 4 h, 64% over two steps. (d) Me2CuLi,
BF3‚Et2O, Et2O, -30 to 0 °C, 1 h, 94%. (e) NaH, DMSO, MePPh3I, THF, -10 to 10 °C, 1.5 h, 92%. (f) Pd(PPh3)4, HCOONa, DMF, 95-100 °C, 30 h, 60%.
(g) Pd/C (10%), H2, EtOH, 12 h. (h) Recrystallization, 72% over two steps.
(8) using Pd(0)-catalyzed reductive intramolecular cyclization6a
as the key step to construct the basic hydrofluorenone inter-
mediate (10). This crucial intermediate has the potential for
being equally effective for the synthesis of other rearranged
abietane-type diterpenoids such as taiwaniaquinol B (1)13 and
taiwaniaquinones D (3) and H (5). We describe herein our efforts
directed toward this goal as well as the details of our earlier
work on the synthesis of 7 and 8.
Results and Discussion
In a short retrosynthetic plan (Scheme 1), the hydrofluorene
diterpenoids 1 and 3 could be obtained from the common
hexahydrofluorenone intermediate 10 through trimethoxyhy-
drofluorenone 11. As described already, 7 and 8 (and hence 5)
are also derivable from 10, prepared in turn from the basic 4a-
methyl hydrofluorene 12. The latter is conveniently obtainable
through Pd(0)-catalyzed reductive Heck reaction6a of the exo-
olefin 13, which could be generated from Hagemann’s ester
(14a) and an appropriately substituted benzyl bromide 15.
Synthesis of Common Intermediate 10. The required benzyl
bromide (15) was obtained from commercially available vanillin
using a sequence of standard reactions,12a,14 with 27% yield over
seven steps (see Supporting Information). For the construction
of the 4a-methyl hydrofluorene 12, we adopted an established
route15 involving alkylation of Hagemann’s ester 14a to give
the alkylated product 23a (Scheme 2) in good yield. Attempted
(6) (a) Mukhopadhyaya, J. K.; Pal, S.; Ghatak, U. R. Synth. Commun.
1995, 25, 1641-1657. (b) Ghatak, U. R.; Chakravarty, J. Tetrahedron Lett.
1966, 7, 2449-2458. (c) Ghatak, U. R.; Chakravarty, J.; Banerjee, A. K.
Tetrahedron 1968, 24, 1577-1593. (d) Ghatak, U. R.; Chakravarty, J.;
Dasgupta, R.; Chakraborti, P. C. J. Chem. Soc, Perkin Trans. 1 1975, 2438-
2445. (e) Chakravarty, J.; Dasgupta, R.; Ray, J. K.; Ghatak, U. R. Proc.
Indian Acad. Sci. 1977, 86A, 317-325. (f) Chakraborti, P. C.; Ghosh, S.;
Kanjilal, P. R.; Satyanarayana, G. O. S. V.; Ghatak, U. R. Indian J. Chem.
1979, 18B, 183-185.
(7) Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1992, 57, 5937-5947.
(8) (a) Ishibashi, H.; Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org.
Chem. 2000, 65, 9022-9027. (b) Ishibashi, H.; Kobayashi, T.; Takamasu,
D. Synlett 1999, 1286-1288.
(9) Bailey, W. F.; Daskapan, T.; Rampalli, S. J. Org. Chem. 2003, 68,
1334-1338.
(10) Lomberget, T.; Bentz, E.; Bouyssi, D.; Blame, G. Org. Lett. 2003,
5, 2055-2057.
(11) Mander, L. N. Nat. Prod. Rep. 2003, 20, 49-69 and references
therein.
(12) (a) Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. K.
Org. Lett. 2003, 5, 3931-3933; Org. Lett. 2004, 6, 143 (correction). (b)
Sengupta, S.; Mukhopadhyay, R.; Achari, B.; Banerjee, A., Kr. Tetrahedron
Lett. 2005, 46, 1515-1519. (c) Sengupta, S.; Mukhopadhyay, R.; Achari,
B.; Banerjee, A. K. J. Org. Chem. 2005, 70, 7694-7700.
(13) The total synthesis of taiwaniaquinol B (1) via a domino intra-
molecular Friedel-Crafts acylation reaction has recently been reported
(see: Fillion, E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127, 13144-13145).
(14) Burger, A. P. N.; Brandt, E. V.; Roux, D. G. Phytochemistry 1983,
22, 2813-2817.
2788 J. Org. Chem., Vol. 71, No. 7, 2006

General Route to 4a-Methylhydrofluorene Diterpenoids
TABLE 1. Results of Heck Cyclization Reaction on Olefin 13a
yield (%)
12 (cis:trans)
entry
1
catalyst (mol %)
reducing agent (equiv)
HCOONa (1)
temp (°C)
80-85
time (h)
24
26
Pd(OAc)2 (5)
PPh3 (20)
56b (85:15)
32b
2
3
Pd(PPh3)4 (5)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(OAc)2 (120)
Pd(OAc)2 (10)
PPh3 (10)
HCOONa (1)
HCOONa (1.5)
HCOONH4 (1.1)
95-100
130
95-100
reflux
80
30
24
30
24
24
60 (85:15)
42 (80:20)
36 (85:15)
no reaction
32b (85:15)
26
31
28
4
5c
6c
HCOONa (1)
24b
Bu4NBr (4 equiv)
a DMF used as solvent except for entry 5 where THF was used. b Based on recovered starting material. c Et3N (5 equiv) used as base.
SCHEME 3. Synthesis of Hexahydrofluorenone 33a
a Reagents and conditions: (a) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C, 1 h, 92%. (b) AlCl3, PhNO2, 58-60 °C, 4 h, 64-67%. (c) MeMgI, THF, reflux, 2 h,
64%. (d) MeLi, Et2O, -78 °C, 1 h, 99%. (e) H2, Pd/C, HClO4 (cat.), EtOH, 30 min, 61%. (f) MeI, K2CO3, acetone-MeOH (2:1), rt, 12 h, 97%. (g) PCC,
Celite, benzene, reflux, 4 h, 40% (of 33) based on recovery of 32.
hydrolytic decarboxylation of 23a to synthesize cyclohexenone
24 proved unsatisfactory using usual conditions6c,15 (refluxing
with aqueous ethanolic KOH), producing a complex mixture
of products presumably due to oxidative side reactions involving
the heavily oxygenated aromatic ring. However, the alkylated
methyl ester 23b, obtained in 92% yield from the methyl ester
analogue 14b16 of Hagemann’s ester, underwent smooth hy-
drolysis with aqueous methanolic LiOH. The resulting crude
acid produced the desired cyclohexenone 24 when heated as a
slurry with silica gel. Treatment of 24 with Me2CuLi furnished
the cyclohexanone 25, which on Wittig olefination afforded the
FIGURE 2. Selected ROESY and HMBC correlations in 27a.
olefin 13 in excellent yield. Conversion of the bicyclic
intermediate to a tricyclic product was next accomplished via
relatively low yield and stereochemical nonselectivity in the
cyclization of 13. However cleavage of the O-benzyl ether in
12a,b and careful recrystallization of the resulting isomeric
mixture from methanol afforded the desired epimer 27a, also
the major isomer, in pure form. NMR spectral analysis of the
product supported the cis ring fusion originally assumed on the
basis of analogy with similar ring systems. The methyl singlet
at δ 1.62, showing a prominent HMBC correlation peak with
Pd(0)-catalyzed cyclization in the presence of a hydride
donor.6a,17 Initially, the reaction was attempted in dry DMF in
the presence of 5 mol % Pd(OAc)2 and 20 mol % PPh3, but
this surprisingly afforded an inseparable mixture of epimeric
hydrofluorenes 12a and 12b in a ratio of ca. 85:15 (as
1
determined by H NMR) along with a substantial amount of
the debrominated product 26, in contrast to that reported for
an aromatic carbon signal (δ 145.2), was easily assigned to the
the sterically uncongested analogues.6a The ring fusion in the
ring juncture substituent (Figure 2). The δ 1.12 methyl signal
showed ROESY cross-peaks with this as well as the other
methyl signal (at δ 0.88). The signal for the ring juncture
methine proton (δ 1.84) showed cross-peaks with both the δ
1.12 and 1.62 methyl signals in the ROESY spectrum. The
benzylic proton signal, on the other hand, showed distinct
ROESY correlation peak only with the δ 0.88 methyl singlet.
major isomer (12a) was assigned as cis by analogy with reports
on similar systems.6a Attempts to achieve better yields of 12a
by changing the reaction condition6a,17,18 or the hydride donor
proved unfruitful (Table 1). The buttressing effect19 of the
benzyloxy and the o-methoxy substituents in addition to the
cyclohexylmethyl residue appeared to be responsible for the
The results suggest a cis ring fusion with the two â-methyl
(15) Pal, S.; Mukhopadhyaya, J. K.; Ghatak, U. R. J. Org. Chem. 1994,
groups axially oriented on the cyclohexane ring. This also
59, 2687-2694.
(16) Begbie, A. L.; Golding, B. T. J. Chem. Soc., Perkin Trans. 1 1972,
602-605.
(17) Link, J. T. Org. React. 2002, 60, 157-534 and references therein.
(18) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291-5294.
(19) (a) Schlosser, M. Eur. J. Org. Chem. 2001, 3975-3984. (b)
Westheimer, F. H. In Steric Effects in Organic Chemistry; Newman, M.
S., Ed.; Wiley: New York, 1956; pp 523-555.
J. Org. Chem, Vol. 71, No. 7, 2006 2789

Banerjee et al.
SCHEME 4. Synthesis of Common Hexahydrofluorenone 10a
a Reagents and conditions: (a) SiO2, 80 °C, 4 h, 96% based on recovery of 30. (b) Ac2O, Et3N, DMAP, 0 °C, 1 h, 93%. (c) H2, Pd/C (10 mol %), EtOH,
6 h, 95%. (d) PCC, Celite, benzene, reflux, 10 h, 86% (of 10) based on recovery of 37.
SCHEME 5. Synthesis of Dichroanal B (7)a
a Reagents and conditions: (a) NaBH4, CeCl3‚7H2O, -40 to 0 °C, 1 h. (b) SOCl2/pyridine, -10 °C, 2 h, 96% over two steps. (c) K2CO3, MeI, acetone-
MeOH (2:1), rt, 12 h, 94%. (d) NBS, CH3CN, rt, 16 h, 92%. (e) n-BuLi, DMF, THF, -78 °C, 4 h, 60%. (f) PhSH, NMP, K2CO3, 160 °C, 20 min, 91%.
SCHEME 6. Synthesis of (()-Dichroanone (8)a
a Reagents and conditions: (a) NBS, CH3CN, rt, 24 h, 82%. (b) NaOMe, CuI, MeOH, DMF, 110 °C, 20 min. (c) CAN, CH3CN-H2O (2:1), 10 min, 62%
in two steps.
SCHEME 7. Synthesis of (()-Taiwaniaquinone H (5)a
explains the Jvic values observed (8.4,10.2 Hz) for the methine
proton as the dihedral angles determined from a model study
for the proposed structure are 36° and 162°.
Acetylation of 27a (to 28) was thereafter carried out and
followed with Fries rearrangement20 to obtain the desired
2-acetyl phenol 29 (Scheme 3). After some experimentation
a Reagents and conditions: (a) K2CO3, MeI, acetone-MeOH (2:1),
reflux, 10 h, 58%. (b) NaOMe, CuI, MeOH, DMF, 110 °C, 20 min, 89%.
(c) AgO, HNO3, dioxane, rt, 30 min, 67%.
based on the choice of Lewis acid, solvent, or reaction
temperature, use of 1.2 equiv AlCl3 in dry nitrobenzene at 58-
60 °C proved to be the most effective, affording 29 in good
yield (minor amount of the deacetylated product 27a was also
encountered, which could be recycled). Treatment of 29 with
excess of MeMgI in dry THF under reflux afforded the unstable
benzylic alcohol 30 in moderate yield; however, the yields were
almost quantitative when MeLi was used as the alkylating agent.
The product was immediately subjected to acid-catalyzed
hydrogenolysis21 (to 31) followed by methylation to afford 32.
Benzylic oxidation of 32 however proved difficult using a
variety of reagents (PCC/Celite,22 CrO3 in Ac2O-AcOH,23
CrO3/1,3-dimethyl pyrazole,24 or PDC with TBHP25), which
produced either a complex mixture of products or higher yields
of the over oxidation6c product 34.
of 35 and thereafter hydrogenation of the resulting acetate 36
furnished 37. Benzylic oxidation of the hydrofluorene 37
delivered the desired intermediate 10. PCC proved to be the
best oxidizing agent, producing 86% of the desired ketone based
on recovery of the starting material (conversion 52%) with a
minor amount of the over oxidation product 38.
Following the same sequence of reactions, the epimeric
mixture of the cyclized products 12a and 12b (ca. 85:15) was
directly converted to the more stable cis-ketone 10, eliminating
the necessity for separation of the epimeric intermediates. The
cis ring fusion for 10, assumed on the basis of analogy,6c,26
received support from the NOESY spectrum also. Thus the
singlet for the ring juncture methine proton showed cross-peaks
with two methyl singlets, including that for the angular methyl.
Synthesis of (()-Dichroanal B (7). With a convenient
synthesis of the ketone 10 accomplished, our next task was to
An alternative approach was therefore adopted to convert 30
to the common intermediate 11 (Scheme 4). Thus, heating 30
as a slurry with silica gel produced the styrene 35. Acetylation
(20) (a) Gammill, R. B. Tetrahedron Lett. 1985, 26, 1385-1388. (b)
Blatt, A. H. Org. React. 1942, 1, 342-369.
(21) Burdeska, K. Synthesis 1982, 940.
(22) (a) Ghosh, A. K.; Mukhopadhyay, C.; Ghatak, U. R. J. Chem. Soc.,
Perkin Trans. 1 1994, 327-332. (b) Rathore, R.; Saxena, N.; Chandraseka-
ran, S. Synth. Commun. 1986, 16, 1493-1498.
(23) (a) Nakayama, M.; Shinke, S.; Matsushita, Y. Bull. Chem. Soc. Jpn.
1979, 52, 184-185. (b) Harms, W. M.; Eisenbraun, E. J. Org. Prep. Proced.
Int. 1972, 4, 67-72. (c) Burnham, J. W.; Duncan, W. P.; Eisenbraun, E. J.;
Keen, G. W.; Hamming, M. C. J. Org. Chem. 1974, 39, 1416-1420.
(24) (a) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem.
1978, 43, 2057-2059. (b) Smith, A. B., III; Liverton, N. J.; Hrib, N. J.;
Sivaramakrishnan, H.; Winzenberg, K. J. Am. Chem. Soc. 1986, 108, 3040-
3048.
(25) Chidambaram, N.; Chandrasekaran, S. J. Org. Chem. 1987, 52,
5048-5051.
(26) (a) Ghosh, S.; Ghatak, U. R. J. Org. Chem. 1981, 46, 1486-1490.
(b) Parham, W. E.; Czuba, L. J. J. Org. Chem. 1969, 34, 1899-1904.
2790 J. Org. Chem., Vol. 71, No. 7, 2006

General Route to 4a-Methylhydrofluorene Diterpenoids
SCHEME 8. Attempted Ring Bromination of 10a
a Reagents and conditions: (a) NBS, CH3CN, rt, 3 days, 98%.
SCHEME 9. Attempted Synthesis of 11 from 32a
a Reagents and conditions: (a) NBS, CH3CN, rt, 12 h, 92%. (b) NaOMe, CuI, DMF-MeOH, 110 °C, 2 h, 80%. (c) PCC, Celite, benzene, reflux, 10 h.
convert it to different hydrofluorene natural products. For the
synthesis of dichroanal B (7), reduction of 10 was carried out
under controlled condition,27 followed by dehydration with
SOCl2/pyridine28 to afford the acetate 39 (Scheme 5). Subse-
quent hydrolysis of 39 and methylation of the resulting phenol
yielded the tetrahydrofluorene 40. Introduction of the aldehyde
group in 40 was realized by bromination with NBS29 to 41
followed by formylation,30 and the resulting product 42 was
smoothly converted31 to (()-dichroanal B (7) through depro-
tection of the catechol dimethyl ether residue by heating with
thiophenol. The synthetic product exhibited spectral data identi-
cal to those reported2 for the natural material.
Synthesis of (()-Dichroanone (8). Only three reactions were
required to complete the synthesis of the norditerpenoid (()-
dichroanone (8) from 39 (Scheme 6). The acetate 39 was
smoothly transformed to the bromo derivative 43, which on
treatment with NaOMe in MeOH and DMF in the presence of
CuI32 produced the unstable dimethoxy phenol intermediate 44.
This was immediately subjected to oxidation with CAN33 in
the presence of acetonitrile-water to afford (()-dichroanone
(8) in good yield, identified by comparison of the spectral data
with those for the natural product.2
followed by oxidation with an acidic solution of freshly prepared
AgO34 in dioxane. The spectral data of the synthetic compound
were in good agreement with those reported for the natural
product.1d
Synthesis of Taiwaniaquinol B (1). With the aim of
converting 10 to the trimethoxy ketone 11 as the stepping stone
to 1 and 3, we subjected 10 to ring bromination with NBS
(Scheme 8). To our dismay this delivered, instead of the desired
46, the R-bromo ketone 47 exclusively. Similar result was also
obtained with the dimethoxy ketone 33. In an alternative way,
bromination could be carried out on the electron rich hexahy-
drofluorene derivative 32 to get the desired bromo compound
48 in excellent yield (Scheme 9). However, the introduction of
the 9-oxo group, attempted using a variety of oxidizing
agents22-25 and under different reaction conditions, could not
be effected satisfactorily. Conversion of the bromo derivative
48 to the trimethoxy derivative 49 followed by attempted
oxidation to the desired ketone 11 also led to a mixture of
intractable products.
A promising route for the total synthesis of taiwaniaquinol
B (1) was thereafter developed (Scheme 10) by employing the
dimethoxy benzyl alcohol 50 as the substrate for bromination.
The common intermediate 10 was hydrolyzed and methylated
in situ to form the ketone 33. This on controlled reduction27
afforded the alcohol 50, a single isomer of unknown stereo-
chemistry. Unlike the ketone 10, it could be brominated at low
temperature to produce 51 in good yield. This was then oxidized
using Jones reagent to the ketone 52, which was successfully
converted to the trimethoxy derivative 11. Silver(II) oxide
oxidation of 11 smoothly afforded the quinone 53, which was
easily reduced35 to (()-taiwaniaquinol B (1). The spectral data
of the synthetic product matched closely with those of the natural
product.1a
Synthesis of (()-Taiwaniquinone H (5). The synthesis of
the diterpenoid taiwaniaquinone H (5) was achieved (Scheme
7) either by simple methylation of dichroanone (8) or, more
conveniently, by conversion of 41 to the corresponding tri-
methoxy derivative 45 with NaOMe in the presence of CuI
(27) (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227. (b)
Boutin, R. H.; Rapoport, H. J. Org. Chem. 1986, 51, 5320-5327.
(28) Allen, W. S.; Bernstein, S. J. Am. Chem. Soc. 1955, 77, 1028-
1032.
(29) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano,
A. J. Org. Chem. 1995, 60, 5328-5331.
(30) Maddaford, S. P.; Charlton, J. L. J. Org. Chem. 1993, 58, 4132-
4138.
(31) Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1997, 38, 8749-
8752.
(32) Sishido, K.; Goto, K.; Miyoshi, S.; Takaishi, Y.; Shibuya, M. J.
Org. Chem. 1994, 59, 406-414.
(33) Horiguchi, Y.; Toeda, A.; Tomoda, K.; Suzuki, H.; Sano, T. Chem.
Pharm. Bull. 1998, 46, 1356-1363.
(34) (a) Kende, A. S.; Tsay, Y.-G.; Mills, J. E. J. Am. Chem. Soc. 1976,
98, 1967-1969. (b) Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972,
94, 227-231.
(35) . Reagents for Organic Synthesis; Fieser, L. F., Fieser, M., Eds.;
John Wiley and Sons Ltd.: Chichester, 1967; Vol. 1, pp 1081-1083.
J. Org. Chem, Vol. 71, No. 7, 2006 2791

Banerjee et al.
SCHEME 10. Synthesis of Taiwaniaquinol B (1)a
a Reagents and conditions: (a) K2CO3, MeI, acetone-MeOH (2:1), 96%. (b) NaBH4/CeCl3, EtOH, -40 to 0 °C, 1 h, 98%. (c) NBS/CH3CN, 0 °C, 16 h,
78%. (d) Jones reagent, acetone, 0 °C, 1 h, 98%. (e) NaOMe/CuI, MeOH-DMF, 110 °C, 1 h, 78%. (f) AgO/HNO3, dioxane, rt, 30 min, 82%. (g) Na2S2O4,
ether-H2O, 2 h, 67%.
SCHEME 11. Synthesis of Taiwaniaquinone D (3)a
a Reagents and conditions: (a) 1,3-Dithiane (3 equiv), n-BuLi (2.5 equiv), -78 °C to rt, 16 h. (b) CAN (2.4 equiv), CH3CN-H2O (2:1), 30 min. (c) AgO
(4 equiv), dioxane-H2O, HNO3 6 N, 30 min. (d) MeI, CH3CN-H2O (5:1), 12 h. (e) KHSO4, 205 °C, 30 min, 82%. (f) TMSCl, NaI, CH2Cl2, 0 °C to rt,
2 h.
Synthesis of Taiwaniaquinone D (3). Conceptually, taiwa-
niaquinol B (1) appeared to be the most promising intermediate
to 3, requiring only the addition of a formyl group to carbonyl
with minor alterations in the aromatic substituents. However,
initial attempts to introduce a formyl group at the 9-oxo
functionality of 1 by umpolung reaction with 1,3-dithiane and
n-BuLi36 resulted only in the recovery of the starting material.
Attributing this to the reduced electrophilicity of the carbonyl
center due to conjugation with the initially generated quinol
dianion, we chose 11 as the substrate for the reaction, which
indeed afforded (Scheme 11) the desired dithiane alcohol 54, a
single isomer of undetermined stereochemistry, in very good
yield. Attempted transformation of 54 to the R-hydroxy formyl
quinone 55 with CAN or AgO resulted only in desulfurization,
furnishing the hydroxy aldehyde 56. The deprotection of 54 was
in fact best achieved37 by stirring with MeI in acetonitrile-
water. Unfortunately, oxidation of 56 with CAN or AgO gave
back the ketone 11. Literature survey reveals that tertiary
alcohols are prone to undergo fragmentation with the reagent.38
We therefore decided to test the R,â-unsaturated aldehyde (57)
as the substrate for oxidation. Dehydration of 56 was smoothly
achieved by heating the compound with fused KHSO4,39
furnishing 57 in 82% yield (18-20% when SOCl2-pyridine
was used). Though the projected transformation of the sterically
congested trimethoxy aldehyde 57 to the corresponding p-
benzoquinone derivative 58 proved elusive, oxidation with CAN
produced a dark red product in moderate yield (54% based on
recovery of 57), identified as the o-quinone derivative 59 from
the presence of a long-range UV absorption peak. Demethylation
of 59 with TMSCl40 and NaI at room temperature then smoothly
delivered the (()-taiwaniaquinone D (3), identified by spectral
comparison with the natural product.1b
Conclusion
In conclusion, we have developed a convenient route for the
total synthesis of a number of hydrofluorene natural products
(38) Trahanovsky, W. S.; Macaulay, D. B. J. Org. Chem. 1973, 38,
1497-1499.
(36) Ranu, B. C.; Jana, U. J. Org. Chem. 1999, 64, 6380-6386.
(37) (a) Tanako, S.; Hatakeyama, S.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1977, 68-69. (b) Fetizon, M.; Jurion, M. J. Chem. Soc., Chem.
Commun. 1972, 382-383.
(39) Ghosh, A. K.; Ray, C.; Ghatak, U. R. Tetrahedron Lett. 1992, 33,
655-658.
(40) Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra, R. J.
Org. Chem. 1979, 44, 1247-1251.
2792 J. Org. Chem., Vol. 71, No. 7, 2006

General Route to 4a-Methylhydrofluorene Diterpenoids
1188 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.76 (3H, s), 1.21 (6H,
d, J ) 6.8 Hz), 1.25 (3H, s), 1.42 (3H, s), 1.47-1.75 (4H, m),
1.80-1.97 (1H, m), 2.10 (1H, s), 2.16-2.25 (1H, m), 2.39 (3H,
s), 2.96 (1H, sept, J ) 6.8 Hz), 3.85 (3H, s), 7.45 (1H, s); 13C
NMR (CDCl3, 75 MHz) δ 18.0, 20.7, 23.0 (2C), 24.5, 27.7, 31.2,
31.8, 32.6, 34.2, 37.3, 42.4, 61.1, 65.4, 116.6, 135.8, 142.6, 147.4,
149.1, 151.4, 168.1, 207.0; Mass (EI) m/z 358 (M+), 316, 301, 247,
234. Anal. Calcd for C22H30O4: C, 73.71; H, 8.44. Found: C, 74.00;
H, 8.56.
and their analogues. The protocol was followed to realize the
total synthesis of (()-dichroanal B (7), (()-dichroanone (8),
(()-taiwaniaquinol B (1), and (()-taiwaniaquinones D (3) and
H (5). The methodology is general and applicable to the other
natural products of similar skeleton.
Experimental Section
6-Benzyloxy-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahy-
dro-1H-fluorene (12a,b). To a solution of 13 (7.6 g, 0.018 mol)
in 130 mL of dry DMF were added palladium(0) tetrakistri-
phenylphosphine (1 g, 0.88 mmol) and sodium formate (1.2 g, 0.018
mol), and the suspension was heated at 95-100 °C for 30 h. The
reaction mixture was cooled, diluted with water, and extracted with
ethyl acetate (3 × 30 mL). The combined organic extracts were
washed with brine, dried, and concentrated. The crude product was
carefully column chromatographed over silica gel (petroleum ether)
to give 12a,b (cis:trans ) 85:15) (3.8 g, 60%) as a white solid:
mp 55-56 °C; IR (KBr) ν 2925, 1483, 1257, 1059 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.89 (3H, s), 1.13 (3H, s), 1.24-1.45 (4H,
m), 1.54-1.68 (1H, m), 1.63 (3H, s), 1.71-1.89 (2H, m), 2.66-
2.78 (2H, m), 3.87 (3H, s), 5.06 (2H, s), 6.75 (1H, d, J ) 8 Hz),
6.81 (1H, d, J ) 8 Hz), 7.30-7.40 (3H, m), 7.46 (2H, d like, J )
7.1 Hz) [additional small peaks at 0.95 (3H, s) and 1.02 (3H, s)
are attributed to the trans-isomer]; 13C NMR (CDCl3, 75 MHz) δ
18.7, 25.8, 30.4, 31.0, 32.2, 33.8, 34.8, 35.4, 47.2, 57.1, 60.8, 71.2,
112.7, 119.3, 127.3 (2C), 127.7, 128.5 (2C), 135.7, 137.6, 145.9,
146.4, 150.8 (one carbon signal undetermined due to overlap);
[additional small peaks at 20.0, 20.2, 21.1, 29.8, 33.1, 33.4, 36.8,
41.5, 47.1, 61.0, 71.1, 112.1, and 120.0 are attributed to the trans-
isomer]. Mass (EI) m/z 351 (M+ + 1), 350 (M+), 260, 228. Anal.
Calcd for C24H30O2: C, 82.24; H, 8.63. Found: C, 81.98; H, 8.60.
The debrominated product 26 (1.55 g, 25%) was also eluted out
with petroleum ether as a colorless viscous liquid.
Further elution with 10% EtOAc in petroleum ether afforded
the R-hydroxy ketone 38 (52 mg, 6%) as a white solid, and 315
mg (40%) of starting material (37) was also recovered.
6-Acetoxy-7-isopropyl-5,6-dimethoxy-1,1,4a-trimethyl-2,3,4,4a-
tetrahydro-1H-fluorene (39). To a stirred solution of 10 (430 mg,
1.2 mmol) in ethanol (30 mL) was added CeCl3‚7H2O (447 mg,
1.2 mmol), and the temperature was brought down to -40 °C.
NaBH4 (45.6 mg, 1.2 mmol) was added portionwise to the stirred
solution, the temperature was allowed to come to 0 °C, and the
stirring was continued for 1 h. The reaction mixture was quenched
with saturated NH4Cl solution and extracted with ethyl acetate (2
× 15 mL). The combined organic extracts were washed with brine
and dried. The solvent was evaporated to afford the crude alcohol
(420 mg, 1.17 mmol). The alcohol was taken in dry CH2Cl2 (20
mL) and cooled to -10 °C. Pyridine (0.56 mL, 7 mmol) was added
followed by SOCl2 (0.19 mL, 2.6 mmol) dropwise. The reaction
mixture was stirred at the same temperature for 2 h and then
quenched by adding excess saturated NH4Cl solution. The organic
part was separated out and the aqueous part was extracted with
CH2Cl2 (2 × 25 mL). The combined organic extracts were washed
with 2 N HCl, water, and brine and dried. The solvent was
evaporated and the crude product was purified by column chro-
matography over silica gel (1% ethyl acetate in petroleum ether)
to furnish 39 (394 mg, 96%) as a white solid: mp 80-82 °C; IR
1
(KBr) ν 2961, 2936, 1769, 1211, 1194 cm-1; H NMR (CDCl3,
300 MHz) δ 1.02-1.26 (2H, m, overlapped), 1.21 (6H, d, J ) 6.9
Hz), 1.23 (3H, s), 1.27 (3H, s), 1.46 (3H, s), 1.57-1.64 (2H, m),
1.88-1.98 (1H, m), 2.35 (3H, s), 2.35-2.44 (1H, m, overlapped),
2.95 (1H, sept, J ) 6.9 Hz), 3.82 (3H, s), 6.26 (1H, s), 6.96 (1H,
s); 13C NMR (CDCl3, 75 MHz) δ 19.5, 20.7, 21.4, 23.3 (2C), 25.4,
27.5, 31.4, 35.4, 36.8, 42.4, 52.2, 61.3, 113.2, 120.4, 138.8, 140.3,
141.5, 143.7, 147.3, 165.0, 169.2; Mass (EI) m/z 342 (M+), 301,
300, 285, 231. Anal. Calcd for C22H30O3: C, 77.16; H, 8.83.
Found: C, 76.97; H, 8.88.
6-Hydroxy-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahy-
dro-1H-fluorene (27a). A well-stirred suspension of 12a,b (3.5 g,
0.01 mol) and Pd/C (10% w/w, 600 mg) in dry ethanol (30 mL)
was fitted to a source of hydrogen (1 atm) and stirred vigorously
for 12 h. The mixture was filtered through a pad of Celite and
washed with ethanol. The combined filtrates were concentrated and
the residue was column chromatographed over silica gel (2% EtOAc
in petroleum ether) to give a cis-trans mixture (85:15) of 27a,b.
Recrystallization of the diastereomeric mixture from methanol in
cold condition afforded the pure cis-phenol 27a (1.82 g, 72%) as
a white solid: mp 94-95 °C; IR (KBr) ν 3283, 2929, 1358, 1251
7-Isopropyl-5,6-dimethoxy-1,1,4a-trimethyl-2,3,4,4a-tetrahy-
dro-1H-fluorene (40). The acetyl tetrahydrofluorene 39 (171 mg,
0.5 mmol) and K2CO3 (276 mg, 2 mmol) were taken in 2:1 mixture
of acetone and methanol (6 mL) and the mixture was stirred for 1
h. Then CH3I (0.31 mL, 5 mmol) was added and the reaction
mixture was stirred for 16 h more. The solvent was evaporated,
and the residue was dissolved in a mixture of water (10 mL) and
ethyl acetate (10 mL). The aqueous part was extracted with ethyl
acetate (2 × 10 mL). The combined organic extracts were washed
with brine, dried and concentrated. Column chromatography of the
residue over silica gel (1% EtOAc in petroleum ether) afforded 40
(144 mg, 92%) as a white solid: mp 68-70 °C; IR (KBr) ν 2963,
2933, 1448, 1408, 1023 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.02-
1.26 (2H, m, overlapped), 1.22-1.26 (12H, four overlapped methyl
signals), 1.46 (3H, s), 1.56-1.63 (2H, m), 1.91-1.97 (1H, m), 2.44
(1H, bd, J ) 12.9 Hz), 3.31 (1H, sept, J ) 6.9 Hz), 3.82 (3H, s),
3.90 (3H, s), 6.23 (1H, s), 6.88 (1H, s); 13C NMR (CDCl3, 75 MHz)
δ 19.6, 21.5, 23.9 (2C), 25.5, 26.8, 31.5, 35.4, 36.8, 42.5, 52.2,
60.3, 60.7, 112.8, 120.4, 138.8, 141.2, 143.7, 147.7, 148.8, 164.0;
Mass (EI) m/z 315 (M+ + 1), 314 (M+), 299, 271, 245. Anal. Calcd
for C21H30O2 C, 80.21; H, 9.62. Found: C, 79.93; H, 9.58.
8-Bromo-7-isopropyl-5,6-dimethoxy-1,1,4a-trimethyl-2,3,4,4a-
tetrahydro-1H-fluorene (41). NBS (76.9 mg, 0.432 mmol) was
added portion wise to a stirred solution of 40 (123 mg, 0.36 mmol)
in dry acetonitrile (6 mL) at -5 °C and the mixture was stirred for
16 h at room temperature. The acetonitrile was removed in a
1
cm-1; H NMR (CDCl3, 600 MHz) δ 0.88 (3H, s), 1.12 (3H, s),
1.27 (1H, bd, J ) 13.0 Hz), 1.38 (1H, dt, J ) 3.0, 13.0 Hz), 1.42-
1.47 (2H, m), 1.58-1.68 (1H, m, overlapped), 1.62 (3H, s), 1.72-
1.78 (1H, m), 1.84 (1H, dd, J ) 8.4, 10.5 Hz), 2.67 (1H, dd, J )
10.5, 15.0 Hz), 2.72 (1H, dd, J ) 8.4, 15.0 Hz), 3.80 (3H, s), 5.29
(1H, s, exchangeable), 6.73 (1H, d, J ) 7.8 Hz), 6.82 (1H, d, J )
7.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 18.8, 25.5, 29.8, 30.8, 32.2,
33.7, 35.1, 35.3, 47.2, 57.6, 61.8, 113.8, 120.7, 134.9, 143.9, 145.2,
147.8; Mass (EI) m/z 261 (M+ + 1), 260 (M+), 245. Anal. Calcd
for C17H24O2: C, 78.42; H, 9.29. Found: C, 78.62; H, 9.36.
6-Acetoxy-7-isopropyl-5-methoxy-1,1,4a-trimethyl-1,2,3,4,4a,9a-
hexahydro-fluoren-9-one (10). Celite (4.36 g) was heated to 140
°C under vacuum for 2 h and cooled. To it dry benzene (40 mL)
was added followed by PCC (1.98 g, 9.2 mmol), and the slurry
was stirred for 15 min to make a homogeneous mixture. Then a
solution of hydrofluorene 37 (792 mg, 2.3 mmol) in dry benzene
(40 mL) was added, and the reaction mixture was refluxed for 10
h. After cooling, the reaction mixture was filtered through a pad
of Celite, and the bed was washed with benzene. The combined
organic extracts were washed with water and brine, then dried and
concentrated. Column chromatography of the crude product over
silica gel (4% EtOAc in petroleum ether) afforded 10 (428 mg,
52%) as a white solid: mp 78 °C; IR (KBr) ν 2964, 1776, 1710,
J. Org. Chem, Vol. 71, No. 7, 2006 2793

Banerjee et al.
vacuum and the residue was chromatographed over silica gel
s), 1.57-1.65 (2H, m), 1.87-1.96 (1H, m), 2.35 (3H, s), 2.35-
2.42 (1H, m, overlapped), 3.56-3.60 (1H, m), 3.78 (3H, s), 6.40
(1H, s); 13C NMR (CDCl3, 75 MHz) δ 19.3, 20.76, 20.83, 21.2,
25.2, 31.3, 35.7, 36.8, 42.3, 53.7, 61.3, 121.1, 137.7, 141.0, 142.0,
144.5, 147.2, 166.1, 168.8 (two carbon signals remained undistin-
guished); Mass (EI) m/z 422/420 (M+, Br ) 81/79), 380, 378, 365,
363, 311, 309. Anal. Calcd for C22H29BrO3: C, 62.71; H, 6.94.
Found: C, 62.53; H, 7.08.
(petroleum ether) to afford 41 (143 mg, 92%) as a white solid:
mp 104-105 °C; IR (KBr) ν 2959, 2934, 1448, 1338, 1021 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.02-1.19 (2H, m), 1.23 (3H, s),
1.29 (3H, s), 1.35 (3H, d, J ) 6.8 Hz), 1.37 (3H, d, J ) 6.8 Hz),
1.44 (3H, s), 1.58-1.64 (2H, m), 1.87-1.97 (1H, m), 2.40-2.45
(1H, m), 3.61-3.65 (1H, m), 3.83 (3H, s), 3.85 (3H, s), 6.37 (1H,
s); 13C NMR (CDCl3, 75 MHz) δ 19.4, 21.2, 21.28, 21.35, 25.4,
31.4, 35.6, 36.7, 42.5, 53.7, 60.0, 60.5, 121.1, 138.6, 139.1, 144.7,
148.7, 150.5, 164.9 (two carbon signals remained undistinguished
due to overlap); Mass (EI) m/z 394/392 (M+, Br ) 81/79), 379,
377, 325, 323, 277. Anal. Calcd for C21H29BrO2: C, 64.12; H, 7.43.
Found: C, 64.33; H, 7.59.
(()-Dichroanone (8). To a well-stirred suspension of CuI (19
mg, 0.01 mmol) in dry DMF (0.2 mL) was added a freshly prepared
solution of NaOMe in dry methanol (8.5 mg of Na in 0.3 mL of
methanol) and the mixture was heated to 90 °C. Then a solution of
43 (35 mg, 0.083 mmol) in dry DMF (0.2 mL) was added to the
hot suspension dropwise; the mixture was heated at 110 °C for 30
min and then cooled. The reaction mixture was diluted with water
and extracted with ethyl acetate (3 × 10 mL) and the combined
organic extracts were washed with brine and dried. The solvent
was evaporated to give the unstable phenol 44 (28 mg) as a sticky
liquid (immediately produces a red color when exposed to air),
which was dissolved in acetonitrile-water (2 mL, 2:1) and kept at
-5 °C. Then a solution of CAN (125 mg, 0.25 mmol) in
acetonitrile-water (1 mL, 2:1) was added and the mixture was
allowed to stir for 30 min. The solvent was evaporated, and the
residue was diluted with water and extracted with ethyl acetate.
The organic phase was washed with brine, dried, and concentrated.
The crude product was purified by preparative TLC to afford 8
(16 mg, 65%) as an amorphous red solid: mp 102-104 °C; IR
2-Isopropyl-3,4-dimethoxy-4b,8,8-trimethyl-5,6,7,8-tetrahy-
dro-4bH-fluorene-1-carbaldehyde (42). To a stirred solution of
41 (110 mg, 0.28 mmol) in dry THF (6 mL) was added n-BuLi
(0.21 mL, 1.6 M in hexane) slowly during 5 min at -78 °C and
the mixture was stirred for 2 h. Then a cold solution of DMF (0.11
mL, 1.4 mmol) in dry THF (2 mL) was added dropwise through a
cannulae and the mixture was stirred for 4 h at the same
temperature. The reaction mixture was quenched with an excess
of saturated NH4Cl solution and allowed to come to room
temperature, the THF layer was separated and concentrated, and
the residue was taken in ether (25 mL). The aqueous part was
extracted with ether (2 × 20 mL). The combined ether extracts
were washed with brine and dried. The solvent was evaporated to
dryness and the residue was chromatographed (silica gel, petrol/
EtOAc, 98:2) to afford 42 (56 mg, 60%) as a white solid: mp 82-
83 °C; IR (KBr) ν 2936, 1681, 1035 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.04-1.18 (2H, m), 1.25 (3H, s), 1.31 (3H, s), 1.42-1.44
(9H, overlapped signals of two methyl doublets and a methyl
singlet), 1.56-1.74 (2H, m), 1.88-1.97 (1H, m), 2.46 (1H, bd, J
) 12.8 Hz), 3.81 (3H, s), 3.86-3.95 (1H, m, overlapped), 3.94
(3H, s), 7.09 (1H, s), 10.62 (1H, s); 13C NMR (CDCl3, 75 MHz) δ
19.4, 21.0, 23.3, 23.4, 25.3, 26.3, 31.4, 35.8, 36.4, 42.5, 51.2, 60.0,
60.5, 120.1, 123.2, 141.7, 143.4, 145.4, 148.8, 152.9, 168.8, 192.2;
Mass (EI) m/z 343 (M+ + 1), 342(M+), 327, 273. Anal. Calcd for
C22H30O3: C, 77.16; H, 8.83. Found: C, 76.90; H, 8.66.
1
(KBr) ν 3271, 2934, 1639, 1318, 1090 cm-1; H NMR (CDCl3,
300 MHz) δ 1.04-1.16 (2H, m), 1.23-1.25 (9H, three overlapped
methyl signals), 1.29 (3H, s), 1.45 (3H, s), 1.58-1.73 (2H, m),
1.85-2.00 (1H, m), 2.38 (1H, dd, J ) 2.0, 13.0 Hz), 3.22 (1H,
sept, J ) 7.0 Hz), 6.45 (1H, s), 7.30 (1H, s); 13C NMR (CDCl3, 75
MHz) δ 19.0, 20.0 (2C), 20.1, 23.9, 24.7, 30.9, 37.0, 37.3, 43.4,
55.3, 118.0, 122.7, 147.8, 148.9, 152.4, 177.1, 178.2, 185.7; Mass
(EI) m/z 300 (M+), 285 (M+ - Me), 231, 173. Anal. Calcd for
C19H24O3: C, 75.97; H, 8.05. Found: C, 76.08; H, 8.13.
7-Isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-2,3,4,4a-tet-
rahydro-1H-fluorene (45). The same procedure as described for
the conversion of 43 to 44 (during the synthesis of 8) was followed
to synthesize 45 from 41 (30 mg, 0.076 mmol). After usual workup,
column chromatography of the residue over silica gel (1% EtOAc
in petroleum ether) afforded 45 (23.4 mg, 89%) as a white solid:
mp 82-84 °C; IR (KBr) ν 2938, 1453, 1409, 1046 cm-1; 1H NMR
(CDCl3, 600 MHz) δ 1.09-1.16 (2H, m), 1.23 (3H, s), 1.26 (3H,
s), 1.33 (3H, d, J ) 6.9 Hz), 1.34 (3H, d, J ) 6.9 Hz), 1.46 (3H,
s), 1.59-1.63 (2H, m), 1.91-1.96 (1H, m), 2.42-2.45 (1H, m),
3.45 (1H, sept, J ) 6.9 Hz), 3.82 (3H, s), 3.83 (3H, s), 3.85 (3H,
s), 6.35 (1H, s); 13C NMR (CDCl3, 150 MHz) δ 19.5, 21.6, 22.25,
22.28, 25.5, 25.6, 31.5, 35.5, 36.8, 42.5, 52.3, 60.2, 60.5, 62.0,
116.8, 130.3, 132.7, 145.0, 145.7, 147.2, 149.3, 162.9; Mass (ESI)
m/z 367 (M+ + Na), 345 (M+ + 1). Anal. Calcd for C22H32O3: C,
76.70; H, 9.36. Found: C, 76.41; H, 9.52.
(()-Taiwaniaquinone H (5). A mixture of 45 (16 mg, 0.046
mmol) and freshly prepared silver(II) oxide (35 mg, 0.275 mmol)
taken in dry dioxane (1 mL, freshly distilled over Na) was sonicated
for 5 min. Then 6 N HNO3 (0.1 mL) was added slowly (the solid
AgO dissolved during the addition of acid to from a clear yellow
solution) to the reaction mixture. The mixture was stirred for 30
min, then diluted with water and extracted with ether (2 × 10 mL).
The combined ethereal extracts were washed several times with
brine, dried and concentrated. Column chromatography over silica
gel (petroleum ether/EtOAc, 97:3) of the crude product gave 5 (9.8
mg, 67%) as a red amorphous solid: mp 75-76 °C; IR (KBr) ν
2934, 1645, 1536, 1260 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.06-
1.12 (2H, m), 1.22-1.25 (9H, three overlapped methyl signals),
1.28 (3H, s), 1.45 (3H, s), 1.56-1.67 (2H, m), 1.91-1.93 (1H,
m), 3.25 (1H, sept, J ) 7.0 Hz), 3.99 (3H, s), 6.38 (1H, s); 13C
NMR (CDCl3, 150 MHz) δ 19.1, 20.1, 20.68, 20.70, 24.5, 24.8,
31.0, 36.7, 37.2, 43.4, 55.6, 61.4, 116.7, 136.0, 145.8, 150.6, 157.3,
The debrominated product 40 (28 mg, 32%) was also recovered
(eluted with 1% EtOAc in petroleum ether).
(()-Dichroanal B (7). A mixture of 42 (26 mg, 0.076 mmol),
K2CO3 (4.2 mg, 0.03 mmol), thiophenol (15.6 µL, 0.152 mmol),
and dry NMP (0.3 mL) was heated in a tightly capped vessel at
160 °C for 30 min and then cooled. The reaction mixture was
poured into 2 N HCl solution (10 mL) and extracted with ethyl
acetate (3 × 5 mL). The combined organic extracts were washed
with water and brine, dried, and concentrated. The crude product
was purified by preparative TLC to furnish 7 (20.7 mg, 87%) as a
yellow solid: mp 148-150 °C; IR (KBr) ν 3444, 3284, 2921, 1641,
1
1551, 1274 cm-1; H NMR (pyridine-d5, 300 MHz) δ 1.08-1.17
(2H, m,), 1.20 (3H, s), 1.26 (3H, s), 1.41-1.57 (2H, m), 1.62 (6H,
d, J ) 7.0 Hz), 1.68 (3H, s), 1.84-1.89 (1H, m), 2.88 (1H, bd, J
) 12.5 Hz), 4.43 (1H, sept, J ) 7.0 Hz), 5.27 (2H, bs, exchange-
able), 7.54 (1H, s), 10.91 (1H, s); 13C NMR (pyridine-d5, 75 MHz)
δ 19.6, 20.2, 22.6, 22.7, 25.5, 27.0, 31.5, 35.8, 36.2, 43.0, 51.0,
120.5, 120.9, 139.0, 139.2, 140.8, 142.6, 167.0, 191.7 (the 142.6
ppm signal may represent two carbon peaks as suggested for the
natural product);2 Mass (EI) m/z 315 (M+ + 1), 314 (M+), 299,
245, 91. Anal. Calcd for C20H26O3: C, 76.40; H, 8.33. Found: C,
76.59; H, 8.26.
6-Acetoxy-8-bromo-7-isopropyl-5-methoxy-1,1,4a-trimethyl-
2,3,4,4a-tetrahydro-1H-fluorene (43). The same procedure as
described for 41 was followed to synthesize 43 from 39 (171 mg,
0.5 mmol). The reaction mixture was stirred for 24 h. The
acetonitrile was evaporated and the residue chromatographed (silica
gel, petrol/EtOAc, 99:1) to afford 43 (172 mg, 92%) as a white
1
solid: mp 128-130 °C; IR (KBr) ν 2962, 1776,1193 cm-1; H
NMR (CDCl3, 300 MHz) δ 1.09-1.24 (2H, m, overlapped), 1.24
(3H, s), 1.30 (9H, bs, overlapped three methyl signals), 1.46 (3H,
2794 J. Org. Chem., Vol. 71, No. 7, 2006

General Route to 4a-Methylhydrofluorene Diterpenoids
175.7, 178.8, 186.3; Mass (ESI) m/z 315 (M+ + 1). Anal. Calcd
for C20H26O3: C, 76.40; H, 8. 33. Found: C, 76.56; H, 8.38.
7-Isopropyl-5,6-dimethoxy-1,1,4a-trimethyl-1,2,3,4,4a,9a-
hexahydro-fluoren-9-one (33). The same procedure as described
for the conversion of 39 to 40 was followed to synthesize 33 from
10 (300 mg, 0.84 mmol). Column chromatography of the residue
over silica gel afforded 33 (265 mg, 96%) as a white solid: mp
76-77 °C; IR (KBr) 3473, 2972, 1708, 1461, 1313 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.77 (3H, s), 1.22 (6H, d, J ) 6.9 Hz), 1.26
(3H, s), 1.41 (3H, s), 1.38-1.43 (1H, m, overlapped), 1.48-1.78
(3H, m), 1.88-1.96 (1H, m), 2.06 (1H, s), 2.12-2.22 (1H, m),
3.28 (1H, sept, J ) 6.9 Hz), 3.89 (3H, s), 3.90 (3H, s), 7.36 (1H,
s); 13C NMR (CDCl3, 75 MHz) δ 17.8, 23.2, 23.3, 24.3, 27.0, 30.7,
31.3, 32.7, 34.0, 37.0, 42.1, 59.8, 60.2, 65.0, 116.0, 133.0, 143.2,
149.8, 152.0, 156.5, 206.8; Mass (EI) m/z 331 (M+ + 1), 330 (M+),
315, 261, 248, 247. Anal. Calcd for C21H30O3: C, 76.33; H, 9.15.
Found: C, 76.19; H, 9.03.
7-Isopropyl-5,6-dimethoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-
hexahydro-1H-fluoren-9-ol (50). To a stirred solution of 33 (240
mg, 0.73 mmol) in ethanol (20 mL) was added CeCl3‚7H2O (272
mg, 0.73 mmol) and temperature was brought down to -40 °C.
Then NaBH4 (27.6 mg, 0.73 mmol) was added portionwise, the
temperature of the mixture was allowed to come to 0 °C. The
mixture was stirred for 1 h and then quenched by adding excess
saturated NH4Cl solution and extracted with ethyl acetate (3 × 10
mL). The combined organic extracts were washed with brine, dried
and concentrated to furnish the crude alcohol. Column chromatog-
raphy over silica gel (petroleum ether/EtOAc, 99:1) gave 50 (235
mg, 98%) as a white solid: mp 96-98 °C; IR (KBr) ν 3520, 2961,
2932, 2865, 1450, 1409, 1313, 1024 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.17 (3H, s), 1.20 (3H, d, J ) 7.0 Hz), 1.21 (3H, d, J )
7.0 Hz), 1.28 (3H, s), 1.41-1.67 (4H, m, overlapped), 1.61 (3H,
s), 1.72-1.80 (2H, m), 2.05 (1H, bd, J ) 11.8 Hz), 3.29 (1H, sept,
J ) 7.0 Hz), 3.82 (3H, s), 3.86 (3H, s), 4.99 (1H, d, J ) 5.1 Hz),
6.98 (1H, s); 13C NMR (CDCl3, 75 MHz) δ 19.5, 23.5, 23.7, 25.3,
26.9, 29.8, 31.4, 32.8, 36.9, 37.8, 46.5, 59.7, 60.1, 60.2, 77.7, 116.7,
139.7, 141.9, 144.4, 149.9, 150.9; Mass (EI) m/z 332 (M+), 317,
314, 299. Anal. Calcd for C21H32O3: C, 75.86; H, 9.70. Found: C,
75.68; H, 10.03.
to give 52 (146 mg, 98%) as a white solid: mp 67-68 °C; IR
(KBr) ν 2951, 1708, 1303, 1022 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.73 (3H, s), 1.23 (3H, s), 1.33-1.37 (9H, s, overlapped three
methyl signals), 1.44-1.73 (4H, m), 1.76-1.85 (1H, m), 2.10 (1H,
s), 2.28-2.37 (1H, m), 3.76-3.85 (1H, m, overlapped), 3.85 (3H,
s), 3.92 (3H, s); 13C NMR (CDCl3, 75 MHz) δ 18.2, 20.8, 20.9,
24.6, 31.5, 31.7, 32.5, 34.2, 37.7, 41.0, 59.7, 60.3, 65.9, 115.0,
130.5, 141.6, 149.6, 153.6, 158.8, 204.5 (one carbon peak was not
distinguished); Mass (EI) m/z 410/408 (M+, Br isotopes), 395, 393,
328, 326. Anal. Calcd for C21H29BrO3: C, 61.61; H, 7.14. Found:
C, 61.83; H, 7.27.
7-Isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-1,2,3,4,4a,9a-
hexahydro-fluoren-9-one (11). To a well-stirred suspension of CuI
(84 mg, 0. 44 mmol) in dry DMF (1 mL) was added a freshly
prepared 1.2 M solution of sodium methoxide in dry methanol (34
mg of Na in 2 mL of methanol) and the mixture was heated to 90
°C. Then a solution of 52 (120 mg, 0.293 mmol) in dry DMF (2
mL) was added to the hot suspension dropwise and the mixture
was heated to 110 °C. The heating was continued for 30 min. The
reaction mixture was cooled, diluted with water and extracted with
ethyl acetate (3 × 15 mL). The combined organic extracts were
washed with brine, dried and concentrated. Column chromatography
of the residue over silica gel (petroleum ether/EtOAc, 98:2) afforded
11 (54 mg, 78%) as a white solid: mp 93-95 °C; IR (KBr) ν
2931, 1697, 1465, 1270, 1040 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.78 (3H, s), 1.24 (3H, s), 1.31 (6H, d, J ) 7.0 Hz), 1.38 (3H,
s), 1.45-1.75 (4H, m), 1.80-1.89 (1H, m), 2.03 (1H, s), 2.22-
2.32 (1H, m), 3.49 (1H, sept, J ) 7.0 Hz), 3.84 (3H, s), 3.88 (3H,
s), 3.89 (3H, s); 13C NMR (CDCl3, 75 MHz) δ 18.1, 21.9 (2C),
24.6, 25.3, 31.5 (2C), 32.7, 34.2, 37.5, 41.9, 59.9, 60.3, 62.1, 65.6,
124.8, 134.8, 146.2, 152.7, 152.9, 158.6, 204.7; Mass (EI) m/z 361
(M+ + 1), 345, 278, 277, 247. Anal. Calcd for C22H32O4: C, 73.30;
H, 8.95. Found: C, 72.99; H, 8.81.
2-Isopropyl-3-methoxy-4b,8,8-trimethyl-4b,5,6,7,8,8a-hexahy-
dro-fluorene-1,4,9-trione (53). The same procedure as described
for 5 (from 45) was followed to synthesize 53 from 11 (28 mg,
0.078 mmol). Column chromatography of the residue over silica
gel (petroleum ether/EtOAc, 97:3) of the crude product gave 53
(21 mg, 82%) as a yellow liquid: IR (neat) ν 2948, 2872, 1726,
1
1656, 1586, 1462, 1143 cm-1; H NMR (MeOH-d4, 300 MHz) δ
8-Bromo-7-isopropyl-5,6-dimethoxy-1,1,4a-trimethyl-
2,3,4,4a,9,9a-hexahydro-1H-fluoren-9-ol (51). The same proce-
dure as described for 41 was followed to synthesize 51 from 50
(200 mg, 0.6 mmol) except that the mixture was stirred at 0-5 °C
for 16 h. Acetonitrile was removed in a vacuum and the residue
was column chromatographed over silica gel (petroleum ether) to
afford 51 (190 mg, 78%) as a white solid: mp 111-112 °C; IR
0.96 (3H, s), 1.23-1.25 (9H, three overlapped methyl signals),
1.35-1.54 (2H, m, overlapped), 1.48 (3H, s), 1.58-1.72 (1H, m),
1.74-1.83 (1H, m), 1.99 (2H, t like, J ) 7.0 Hz), 2.12 (1H, s),
3.26 (1H, sept, J ) 7.0 Hz), 4.01(3H, s); 13C NMR (MeOH-d4, 75
MHz) δ 18.3, 20.7, 20.8, 24.9, 25.6, 27.9, 31.3, 33.1, 35.7, 36.9,
44.2, 61.6, 66.2, 135.5, 138.4, 158.9, 171.9, 184.5, 185.7, 206.7;
Mass (EI) m/z 332 (M+ + 2), 330 (M+), 315, 249, 247. Anal. Calcd
for C20H26O4: C, 72.70; H, 7.93. Found: C, 72.49; H, 8.07.
(()-Taiwaniaquinol B (1). The quinone 53 (18 mg, 0.054 mmol)
was dissolved in the minimum volume of ether (0.1 mL) and a
solution of sodium dithionite (94 mg, 0.54 mmol) in water (0.1
mL) was added. The biphasic solution was stirred vigorously for 2
h, diluted with water and extracted with ether (2 × 5 mL). The
combined ether extracts were washed with brine, dried and
concentrated. The crude compound was immediately purified by
preparative TLC to afford (()-taiwaniaquinol B (1) (11.6 mg, 67%)
as a white solid: mp 140-141 °C (lit.21 142-144 °C); IR (KBr)
ν 3442, 3276, 2950, 1650, 1627, 1426, 1328, 1112 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.88 (3H, s), 1.26 (3H, s), 1.38 (6H, d, J )
7.0 Hz), 1.45 (3H, s), 1.51-1.76 (4H, m), 1.99-2.06 (2H, m), 2.12
(1H, s), 3.27 (1H, sept, J ) 7.0 Hz), 3.80 (3H, s), 5.28 (1H, s),
9.54 (1H, s); 13C NMR (CDCl3, 75 MHz) δ 17.5, 20.6 (2C), 24.4,
25.9, 28.8, 30.3, 33.0, 34.3, 36.5, 42.7, 62.1, 65.1, 118.3, 126.1,
138.4, 142.7, 151.1, 152.2, 211.1; Mass (EI) m/z 332 (M+), 317,
249, 149. Anal. Calcd for C20H28O4: C, 72.26; H, 8.49. Found: C,
72.43; H, 8.33.
(KBr) ν 3547, 2939, 2869, 1449, 1336, 1094 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.16 (3H, s), 1.29 (3H, s), 1.34 (6H, d, J )
6.9 Hz), 1.56-1.67 (4H, m, overlapped), 1.59 (3H, s), 1.72-1.88
(2H, m), 1.95-1.98 (1H, m), 3.57 (1H, sept, J ) 6.9 Hz), 3.81
(3H, s), 3.83 (3H, s), 5.15 (1H, d, J ) 5.6 Hz); 13C NMR (CDCl3,
75 MHz) δ 19.5, 21.0, 21.2, 25.1, 29.8, 31.4, 32.8, 36.7, 37.0, 48.4,
58.5, 60.0, 60.2, 78.9, 115.2, 139.2, 139.5, 145.8, 150.0, 153.7 (one
carbon signal could not be distinguished); Mass (EI) m/z 412/410
(M+, Br isotopes), 397, 395, 379, 361, 330, 315, 248, 199. Anal.
Calcd for C21H31BrO3: C, 61.31; H, 7.60. Found: C, 61.42; H,
7.87.
8-Bromo-7-isopropyl-5,6-dimethoxy-1,1,4a-trimethyl-
1,2,3,4,4a,9a-hexahydro-fluoren-9-one (52). To a stirred solution
of 51 (150 mg, 0.365 mmol) in acetone (3 mL) at 0 °C was added
freshly prepared Jones reagent (0.44 mL, 0.438 mmol) dropwise
and the mixture was stirred for 2 h. Then few drops of 2-propanol
were added and the mixture was allowed to stir for few minutes
until the color of the Jones reagent disappeared. The reaction
mixture was diluted with ether (10 mL) and water (5 mL). The
ethereal part was separated out and the aqueous part was extracted
with ether (2 × 5 mL). The combined ether extracts were washed
with brine, dried and concentrated. The residue was column
chromatographed over silica gel (3% EtOAc in petroleum ether)
9-{[1,3]Dithian-2-yl}-7-isopropyl-5,6,8-trimethoxy-1,1,4a-tri-
methyl-2,3,4,4a,9,9a-hexahydro-1H-fluoren-9-ol (54). To a stirred
solution of 1,3-dithiane (200 mg, 1.67 mmol) in dry THF (4 mL)
J. Org. Chem, Vol. 71, No. 7, 2006 2795

Banerjee et al.
was added n-BuLi (0.87 mL, 1.6 M in hexane) dropwise at -25
°C and the stirring was continued at the same temperature for 90
min. Then the mixture was cooled to -78 °C and a solution of 11
(200 mg, 0.56 mmol) in dry THF (2 mL) was added dropwise.
The reaction mixture was stirred at that temperature for 4 h. Then
it was allowed to reach room temperature slowly and left overnight.
After quenching the reaction mixture with ice water, the product
was extracted with ethyl acetate (2 × 20 mL). The combined
organic extracts were washed successively with water and brine
and then dried. Evaporation of the solvent and purification of the
crude product over neutral alumina (2% EtOAc in petroleum ether)
afforded 54 (224 mg, 84%) as white fluffy solid: mp 52-54 °C;
372 (M+), 343, 303, 275. Anal. Calcd for C23H32O4: C, 74.16; H,
8.66. Found: C, 74.08; H, 8.72.
7-Isopropyl-8-methoxy-1,1,4a-trimethyl-5,6-dioxo-2,3,4,4a,5,6-
hexahydro-1H-fluorene-9-carbaldehyde (59). To a stirred solution
of 57 (15 mg, 0.040 mmol) in THF-acetonitrile (0.45 mL, 2:1) at
0 °C was added a solution of CAN (55 mg, 0.10 mmol) in
acetonitrile-water (0.45 mL, 1:2) dropwise and the mixture was
stirred for 10 min. The solvent was removed and the residue was
diluted with ethyl acetate (5 mL) and water (2 mL). The organic
part was separated, and the aqueous part was extracted with ethyl
acetate (2 × 5 mL). The combined organic extracts were washed
with brine, dried and concentrated. The crude product was purified
by preparative TLC to give quinone 59 (3.6 mg, 26%, 54% based
on recovery of 57), as dark red colored sticky liquid along with
the starting material 57 (7.6 mg, 51%). Data for 59: IR (CCl4) ν
1
IR (KBr) ν 3531, 2936, 1458, 1412, 1340, 1119, 1030 cm-1; H
NMR (pyridine-d5, 300 MHz) δ 1.38-1.41 (9H, three overlapped
methyl signals), 1.41 (3H, d, J ) 6.8 Hz), 1.20-1.50 (2H, m,
overlapped), 1.73 (3H, s), 1.86 (3H, s), 1.58-1.86 (4H, m,
overlapped), 1.93-1.99 (1H, m), 2.08-2.12 (1H, m), 2.55 (1H,
s), 2.67-2.87 (4H, m), 3.53 (1H, sept, J ) 7.0 Hz), 3.78 (3H, s),
3.82 (3H, s), 3.92 (3H, s), 5.42 (1H, s), 5.74 (1H, s, exchangeable);
13C NMR (pyridine-d5, 75 MHz) δ 18.9, 22.2, 22.3, 26.2, 26.8,
27.7, 29.8, 32.5, 32.8, 34.08, 34.13, 35.2, 37.9, 47.0, 59.7 (2C),
61.6, 62.7, 63.6, 87.7, 132.6, 134.1, 144.7, 146.5, 151.3, 154.6;
Mass (ESI) m/z 503 (M+ + Na), 463. Anal. Calcd for C26H40O4S2:
C, 64.96; H, 8.39. Found: C, 65.21; H, 8.31.
2928, 1699, 1645, 1459, 1385 cm-1; UV (in EtOH) λ
(ꢀ) 474
max
(348), 342 (5345), 273 (5766), 211 (20622); 1H NMR (CDCl3, 300
MHz) δ 1.17 (3H, s), 1.26-1.31 (9H, three overlapped methyl
signals), 1.47 (3H, s), 1.05-1.73 (4H, m, overlapped), 1.82-1.91
(1H, m), 2.42 (1H, bd, J ) 12.9 Hz), 3.05 (1H, sept, J ) 7.0 Hz),
3. 72 (3H, s), 10.31 (1H, s); 13C NMR (CDCl3, 75 MHz) 18.4,
20.7, 20.9, 21.6, 25.9, 26.4, 34.2, 36.0, 38.1, 43.9, 56.5, 61.7, 134.0,
134.4, 145.8, 150.4, 160.7, 172.0, 176.9, 182.7, 194.7; Mass (ESI)
m/z 365 (M+ + Na), 343 (M+ + 1). Anal. Calcd for C21H26O4: C,
73.66; H, 7.65. Found: C, 73.91; H, 7.79.
9-Hydroxy-7-isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-
2,3,4,4a,9,9a-hexahydro-1H-fluorene-9-carbaldehyde (56). To a
well-stirred solution of 54 (160 mg, 0.33 mmol) in CH3CN-H2O
(1.2 mL, 5:1 v/v) was added CH3I (0.2 mL, 3.3 mmol) and the
mixture allowed to stir for another 10 h. After removal of solvent,
the residue was taken in ether (25 mL), and the ether layer was
washed successively with Na2S2O3 (5%) and brine and dried. The
ethereal part was concentrated and the crude product was purified
by neutral alumina column chromatography (1% EtOAc in petro-
leum ether) to afford 56 (112 mg, 86%) as a white solid: mp 135-
136 °C; IR (KBr) ν 3436, 2939, 1724, 1459, 1337, 1046 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 0.91 (3H, s), 1.15 (3H, s), 1.19 (1H,
bs), 1.27 (3H, d, J ) 7.0 Hz), 1.33 (3H, d, J ) 7.0 Hz), 1.69 (3H,
s), 1.65-1.77 (2H, m, overlapped), 1.73-1.86 (2H, m), 2.01-2.06
(2H, m), 3.24 (1H, sept, J ) 7.0 Hz), 3.55 (3H, s), 3.72 (1H, bs,
exchangeable), 3.81 (3H, s), 3.86 (3H, s), 9.63 (1H, s); 13C NMR
(CDCl3, 75 MHz) δ 19.2, 21.9 (2C), 25.0, 25.8, 31.3, 31.7, 34.0,
36.3, 36.7, 48.4, 59.0, 59.9, 60.0, 62.5, 89.2, 129.4, 133.9, 146.0,
147.0, 149.4, 155.1, 201.6; Mass (EI) m/z 390 (M+), 374, 362, 361,
345, 331, 277, 263, 247, 237. Anal. Calcd for C23H34O5: C, 70.74;
H, 8.78. Found: C, 71.01; H, 8.89.
7-Isopropyl-5,6,8-trimethoxy-1,1,4a-trimethyl-2,3,4,4a-tet-
rahydro-1H-fluorene-9-carbaldehyde (57). The hydroxy aldehyde
56 (80 mg, 0.205 mmol) was fused with KHSO4 (1 g) at 200-205
°C during 30 min. After cooling to room temperature, the solid
residue was dissolved in water (2 mL) and extracted with ethyl
acetate (2 × 10 mL). The combined organic extracts were washed
with brine, dried and concentrated. Column chromatography of the
residue over silica gel (1% EtOAc in petroleum ether) afforded 57
(62.5 mg, 82%) as a white solid: mp 162-165 °C; IR (KBr) ν
2940, 1698, 1455, 1034 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.16
(3H, s), 1.21-1.31 (1H, m, overlapped), 1.31-1.38 (9H, three
overlapped methyl signals), 1.46 (3H, s), 1.51-1.65 (3H, m), 1.85-
1.89 (1H, m), 2.50 (1H, bd, J ) 12.7 Hz), 3.36 (1H, sept, J ) 7.0
Hz), 3.53 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 10.50 (1H, s); 13C
NMR (CDCl3, 75 MHz) δ 18.9, 22.1 (2C), 22.9, 25.9, 26.6, 34.2,
35.1, 36.6, 42.7, 53.7, 60.0, 60.1, 62.5, 129.0, 133.6, 133.7, 143.8,
146.1, 146.7, 151.6, 162.1, 197.3; Mass (EI) m/z 373 (M+ + 1),
(()-Taiwaniaquinone D (3). To a stirred mixture of 59 (3.4
mg, 0.01 mmol) and NaI (3 mg, 0.02 mmol) in dry CH2Cl2 (0.1
mL) at 0 °C was added a solution of TMSCl (15 µL, 0.12 mmol)
in CH2Cl2 (0.1 mL) dropwise and the mixture was stirred for 1 h.
One drop of methanol was added to the reaction mixture and
allowed to stir for 30 min. The mixture was diluted with CH2Cl2
(1 mL) and water (1 mL). The organic part was separated out and
the aqueous part was extracted twice with CH2Cl2 (2 × 2 mL).
The combined organic extracts were washed with 5% NaHCO3,
water and brine, dried, and concentrated. The product was purified
by preparative TLC to give quinone 3 (2.3 mg, 71%) as a red
1
gum: IR (CCl4) ν 3363, 2921, 2852, 1700, 1639, 1315 cm-1; H
NMR (CDCl3, 500 MHz) δ 1.18 (3H, s), 1.21-1.24 (6H, two
overlapped methyl signals), 1.32 (3H, s), 1.48 (3H, s), 1.67-1.75
(2H, m), 1.86-1.97 (1H, m), 2.44 (1H, br d, J ) 13.0 Hz), 3.19
(1H, sept, J ) 7.0 Hz), 7.21 (1H, s, exchangeable), 10.42 (1H, s);
13C NMR (CDCl3, 150 MHz) δ 18.3, 19.9, 21.4, 24.0, 25.7, 33.7,
35.3, 38.1, 43.4, 55.9, 123.2, 134.4, 147.2, 147.8, 152.2, 176.6,
177.3, 185.1, 194.1 (the 19.9 ppm signal may represent two carbon
peaks as suggested for the natural product);1b Mass (ESI) m/z 351
(M+ + Na). Anal. Calcd for C20H24O4: C, 73.15; H, 7.37. Found:
C, 73.49; H, 7.48.
Acknowledgment. We are grateful to Late Prof. U. R.
Ghatak of this institute for his excellent suggestions and criticism
and to CSIR (New Delhi) for the award of a Research
Fellowship to M.B.
Supporting Information Available: Scheme S1 (containing
compounds 15-22); experimental procedures for 13, 15, 17-25,
28-37, and 47-49; alternative procedures for 5 and 56; spectral
1
data of 26 and 38; H and 13C NMR spectra of compounds 12ab,
27a, 10, 7, 8, 45, 5, 50-52, 11, 53, 1, 54, 56, 59, and 3. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO052589W
2796 J. Org. Chem., Vol. 71, No. 7, 2006