First Total Synthesis of the 4a-Methyltetrahydrofluorene Diterpenoids (±)-Dichroanal B and (±)-Dichroanone

Article abstract of DOI:10.1021/ol035506b

(Matrix presented) A simple synthesis of the 4a-methyltetrahydrofluorene diterpenoids (±)-dichroanal B and (±)-dichroanone has been achieved through a common hexahydrofluorenone intermediate obtained via Pd(0)-catalyzed reductive cyclization of a substituted 2-(2-bromobenzyl) methylene cyclohexane.

Full text of DOI:10.1021/ol035506b

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3931-3933
First Total Synthesis of the
4a-Methyltetrahydrofluorene
Diterpenoids (±)-Dichroanal B and
(±)-Dichroanone
Mainak Banerjee, Ranjan Mukhopadhyay, Basudeb Achari, and
Asish Kr. Banerjee*
Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road,
Kolkata-700 032, India
ashisbanerjee@iicb.res.in
Received August 8, 2003
ABSTRACT
A simple synthesis of the 4a-methyltetrahydrofluorene diterpenoids (±)-dichroanal B and (±)-dichroanone has been achieved through a common
hexahydrofluorenone intermediate obtained via Pd(0)-catalyzed reductive cyclization of a substituted 2-(2-bromobenzyl) methylene cyclohexane.
Recently, three rearranged diterpenoids that possessed the
uncommon 4a-methyl tetra- (or -hexa)hydrofluorene skeleton
were isolated from SalVia dichroantha. They were designated
dichroanals A (1) and B (2) and dichroanone (3) (Figure
1).1 Several structurally related diterpenoids have also been
isolated that include standishinal (4) from Thuja standishii2
and taiwaniaquinols A (5) and B (6) from Taiwania cryp-
tomerioides.3 Although not much is known about their
bioactivities, preliminary studies on 4 indicated its promising
tumor-inhibiting potential.4,5 No synthesis of this rare group
of six-five-six tricyclic ring natural products has appeared
so far.
fluorenone intermediate 22, obtained by a simple and flexible
convergent route suitable for the preparation of other
members of this family.
There are several methods available for the preparation
of 4a-methylhydrofluorene. These include acid-catalyzed
cyclization of substituted benzyl cyclohexanols,6 inter- and
intramolecular (3 + 2) cycloaddition,7 and the cyclization
We report herein the first total synthesis of two 4a-
methyltetrahydrofluorene diterpenoids (()-dichroanal B (2)
and (()-dichroanone (3) employing a common hexahydro-
(1) Kawazoe, K.; Yamamoto, M.; Takaishi, Y.; Honda, G.; Fujita, T.;
Sezik, E.; Yesilada, E. Phytochemistry 1999, 50, 493-497.
(2) Ohtsu, H.; Iwamoto, M.; Ohishi, H.; Matsunaga, S.; Tanaka, R.
Tetrahedron Lett. 1999, 40, 6419-6422.
(3) Lin, W.-H.; Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1995, 40, 871-
873.
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Yoshitake, A. Planta Med. 2002, 68, 742-745.
(5) Iwamoto, M.; Ohtsu, H.; Tokuda, H.; Nishino, H.; Matsunaga, S.;
Tanaka, R. Bioorg. Med. Chem. 2001, 9, 1911-1921.
Figure 1. Natural 4a-methylhydrofluorene diterpenoids.
10.1021/ol035506b CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/16/2003

of an arylpalladium,8 arylradical,9 or aryllithium10 tethered
to methylene cyclohexane. Very recently, an efficient method
for constituting this skeleton by intramolecular Friedel-
Crafts cyclization of 1,3-bis-exocyclic diene has been
reported.11 We selected the strategy based on palladium-
catalyzed reductive cyclization8 of a substituted 2-(2-bro-
mobenzyl) methylene cyclohexane, which appeared to be the
most attractive.
Scheme 2. Synthesis of Phenol 18a
The synthesis began with the preparation of the appropriate
benzyl bromide 11 from vanillin using a standard sequence
of reactions that proceeded through the known12 aldehyde 7
(Scheme 1). We sought to prepare the (o-bromobenzyl)-
Scheme 1. Synthesis of Aromatic Bromide 11
the heavily oxygenated aromatic ring. To our satisfaction,
however, the alkylated methyl ester 13b, obtained in 92%
yield from the methyl ester analogue 12b14 of Hagemann’s
ester, underwent smooth hydrolysis with aqueous methanolic
LiOH, and the resulting crude acid on heating with a slurry
of silica gel in CH2Cl2 produced the desired cyclohexenone
14 through decarboxylation. Wittig olefination of 15 pro-
ceeded uneventfully, producing the alkene 16 in good overall
yield.
Conversion of the bicyclic intermediate to a tricyclic
product was next accomplished via Pd(0)-catalyzed cycliza-
tion in the presence of a hydride donor.8,15 This gave an
inseparable mixture of the epimeric hydrofluorenes 17a and
17b in a ratio of ca. 85:15 in 60% yield. A separation of the
epimers could, however, be realized after deprotection of
the O-benzyl ether mixture and recrystallization of the
resulting product, which afforded the major epimer 18a (mp
94 °C), assigned cis stereochemistry by analogy.8 The minor
epimer 18b could not be isolated in pure form.
cyclohexanone 15, a key intermediate for the olefin 16
(Scheme 2), from the cyclohexenone 14 by an established
route13 involving conjugate addition of a methyl group. While
alkylation of Hagemann’s ester 12a gave the alkylated
product6b,13 13a in 75% yield, its attempted hydrolytic
decarboxylation under the usual condition6b,13 of refluxing
with aqueous ethanolic KOH gave a complex mixture of
products presumably due to oxidative side reactions involving
(6) (a) Ghatak, U. R.; Chakravarty, J. Tetrahedron Lett. 1966, 7, 2449-
2458. (b) Ghatak, U. R.; Chakravarty, J.; Banerjee, A. K. Tetrahedron 1968,
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R.; Satyanarayana, G. O. S. V.; Ghatak, U. R. Indian J. Chem. 1979, 18B,
183-185.
With the tricyclic product 18a in hand as a single epimer,
our next task was to introduce an isopropyl group in the
aromatic ring and to convert the benzylic methylene group
to a ketone. This was best achieved via the sequence of
reactions described in Scheme 3. Thus, acetylation of 18a
followed by Fries rearrangement16 of the acetate 19 furnished
(7) Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1992, 57, 5937-5947.
(8) Mukhopadhyaya, J. K.; Pal, S.; Ghatak, U. R. Synth. Commun. 1995,
25, 1641-1657.
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Chem. 2000, 65, 9022-9027. (b) Ishibashi, H.; Kobayashi, T.; Takamasu,
D. Synlett 1999, 1286-1288.
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1334-1338.
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5, 2055-2057.
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602-605.
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Blatt, A. H. Org. React. 1942, 1, 342-369.
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3932
Org. Lett., Vol. 5, No. 21, 2003

fluorene 24. Introduction of the aldehyde group in 24 was
realized by bromination followed by formylation,21 and the
resulting dimethyl ether 26 was smoothly converted22 to (()-
2. The synthetic product exhibited spectral data identical to
those reported1 for the natural material.
Scheme 3. Synthesis of Hexahydrofluorenone 22
Only three reactions were required to complete the
synthesis of (()-dichroanone (3) from the intermediate
tetrahydrofluorene acetate 23 (Scheme 5). This product was
Scheme 5. Synthesis of Dichroanone (3)
the 2-acetylphenol 20. This, after condensation with MeLi,
dehydration with silica gel, and acetylation afforded the
acetate 21 in good yield after hydrogenation. Benzylic
oxidation of 21 with PCC-Celite in benzene at reflux17
provided the ketone 22 (mp 78 °C).
Following the same sequence of reactions, the epimeric
mixture of the cyclized products 17a and 17b (ca. 85:15)
was conveniently converted to 22 without separation of the
epimeric intermediates. The cis ring fusion for 22, assumed
on the basis of analogy,6b,18 received support from the
NOESY spectrum also. Thus, the singlet for the ring juncture
methine proton showed NOESY cross-peaks with two methyl
singlets, as reported1 for dichroanal A.
smoothly transformed to the bromo derivative 27, which on
heating with NaOMe in MeOH and DMF in the presence of
CuI23 produced the dimethoxy phenol intermediate 28. On
direct oxidation with CAN,24 28 afforded (()-dichroanone
(3) in good yield, identified by spectral comparison with the
natural product.1
In conclusion, the first synthesis of the 4a-methyltetrahy-
drofluorene diterpenoids (()-dichronal B and (()-dichroanone
has been realized through a simple and convergent route.
Extension of this methodology to the other members of the
group is in progress.
Finally, the ketone 22 was converted to the desired (()-
dichroanal B (2) as follows (Scheme 4). The reduction of
Acknowledgment. Authors are grateful to Prof. U. R.
Ghatak of the Indian Institute of Chemical Biology for his
excellent suggestions and criticism and CSIR for the award
of Research Fellowship to M.B.
Scheme 4. Synthesis of Dichroanal B (2)
Supporting Information Available: 1H and 13C NMR
spectra of compounds 2, 3, 16, 18a, 21-24, 26, and 27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035506B
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22 under controlled conditions19 afforded the crude alcohol,
which was directly subjected to dehydration with SOCl2/
pyridine.20 Subsequent hydrolysis of the acetate 23 and
methylation of the resulting phenol yielded the tetrahydro-
Org. Lett., Vol. 5, No. 21, 2003
3933