Total synthesis of cavicularin and riccardin C: Addressing the synthesis of an arene that adopts a boat configuration

Article abstract of DOI:10.1002/anie.200500466

(Chemical Equation Presented) A transannular ring contraction induced by the addition of an aryl radical intermediate to a proximal arene facilitated the construction of the highly strained macrocyclic core of cavicularin (1). The precursor, an iodinated

Full text of DOI:10.1002/anie.200500466

Angewandte
Chemie
Natural Product Synthesis
Total Synthesis of Cavicularin and Riccardin C:
Addressing the Synthesis of an Arene That
Adopts a Boat Configuration**
David C. Harrowven,* Timothy Woodcock, and
Peter D. Howes
From a structural perspective cavicularin (1), from the
liverwort Cavicularia densa,[1] is one of the most unusual
natural products to have been isolated in the last decade. It
comprises a macrocyclic core that contains dibenzyl and
dihydrophenanthrene units conjoined by a biaryl bond and an
ether linkage. This core imparts such strain on the system that
one of the arenes, ring A, adopts a boatlike configuration and
is twisted out of the plane by some 158 in the solid state.
Herein, we describe the first total synthesis of cavicularin (1),
in which a radical-induced transannular ring contraction
features as a key step (Scheme 1).
Scheme 1. Synthetic strategy to cavicularin (1).
In planning the synthesis of cavicularin, we identified two
problems that required special consideration: one was the
obvious kinetic barrier to closure of the strained macrocycle;
[*] Dr. D. C. Harrowven, T. Woodcock
School of Chemistry, University of Southampton
Highfield, Southampton, SO171BJ (UK)
Fax: (+44)2380-596805
E-mail: dch2@soton.ac.uk
Dr. P. D. Howes
GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage, SG12NY (UK)
[**] Financial support from GlaxoSmithKline, Pfizer, and the EPSRC is
gratefully acknowledged. Dr. Mark Bunnage (Pfizer) is thanked for
helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 3899 –3901
DOI: 10.1002/anie.200500466
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
the other was a thermodynamic constraint imposed by the
need to distort arene A. We felt that both of these problems
could be resolved by employing a radical-induced, trans-
annular ring-contraction strategy, such as 2!3 (Scheme 1).[2]
In particular, by employing a larger and less-strained macro-
cycle as a precursor the kinetic burden would be transferred
to the ring-contraction step, in which the close proximity of
the aryl radical intermediate to arene D offered good
prospects for a favorable outcome. It also seemed likely
that cyclization could proceed without significant distortion of
arene A. Indeed, that would occur in the second phase of the
reaction with the collapse of 3 to cavicularin trimethyl ether,
with the thermodynamic cost of bending the arene compen-
sated by the rearomatization of arene D.[3,4]
Our synthesis began with the protection of isovanillin as
its dioxolane acetal 4. Union of 4 with 4-fluorobenzaldehyde
then gave diaryl ether 5,[6] which was reduced with sodium
borohydride to the corresponding alcohol. Bromination with
CBr4/PPh3 additionally unmasked the latent aldehyde func-
tion to give 6, which, on sequential treatment with PPh3 and
neopentyl glycol, led to the suitably functionalized AD ring
system 7 (Scheme 2).
Scheme 3. Synthesis of the BC ring system. DCC=dicyclohexylcarbo-
diimide, DMAP=4-dimethylaminopyridine, DIBALH=diisobutylalumi-
num hydride, R=o-tolyl.
the phenol group as its methyl ether and removal of the acetal
functions then provided dialdehyde 16, which underwent
macrocyclization on treatment with low-valent titanium to
yield (Z)-17 (Scheme 4).[9]
We were now in a position to address the synthesis of
riccardin C (20) and cavicularin (1). Catalytic hydrogenation
of 17 using palladium on carbon simultaneously effected
hydrogenolysis of the aryl iodide to give riccardin C trimethyl
ether (18). Deprotection of the phenolic groups with boron
tribromide then gave riccardin C (20) in 86% yield.[10,11]
Reduction of the alkene in 17 also proceeded smoothly to
give 19 without concomitant reduction of the aryl iodide.[12]
A
Scheme 2. Synthesis of the AD ring biaryl ether 7. DMF=N,N-dime-
thylformamide, PPTS=pyridinium p-toluenesulfonate.
solution of macrocycle 19 in toluene was then heated at 908C
with TTMSS and AIBN to induce homolysis of the carbon–
iodine bond.[13] This procedure gave an inseparable mixture of
riccardin C trimethyl ether (18) and cavicularin trimethyl
ether in 2:1 ratio. Exposure of the mixture to boron
tribromide provided riccardin C (20) and cavicularin (1),
which were readily separated by column chromatography.
Pleasingly, data recorded on our synthetic samples matched
those reported for the natural products.[1,10,11]
In summary, we have completed the first total synthesis of
cavicularin (1), a cyclic dibenzyldihydrophenanthrene ether
from Cavicularia densa, in which one of the arenes is under
such strain that it is forced to adopt a boat configuration. The
key step involved the addition of an aryl radical intermediate
to a proximal arene to facilitate a transannular ring contrac-
tion with concomitant bending of aromatic ring A
(Scheme 1). The macrocyclic precursor 19 was also trans-
formed into riccardin C (20) to complete the shortest syn-
thesis of this natural product described to date.[11]
Construction of the BC ring system began with the
protection of 3-hydroxybenzaldehyde as its neopentyl glycol
acetal 8. Coupling of 8 and 2-bromo-5-methoxybenzoic acid
in the presence of DCC then gave ester 9, which, on heating in
the presence of the Herrmann catalyst, underwent cyclization
to benzo[c]chromen-6-ones 10 and 11 (Scheme 3).[6] Though
low-yielding, the rapidity with which this sequence led to the
BC ring system of cavicularin (1) offered practical advantages
over the alternative routes investigated. Most notably,
reduction of 10 with DIBALH provided lactol 12, which
was appropriately functionalized for union with 7 and primed
to facilitate regioselective iodination of arene C at a later
stage.
The coupling of phosphonium salt 7 and lactol 12 by using
standard Wittig protocols proved troublesome at first. How-
ever, through the simple expedient of adding 18-crown-6 to
the reaction mixture, stilbene 13 was formed in 66% yield as a
mixture of E and Z isomers in 2:1 ratio.[7] Next, reduction of
the alkene gave phenol 14, which was selectively iodinated
under basic conditions to give tetraarene 15.[8] Protection of
Received: February 7, 2005
Published online: May 18, 2005
3900
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Angewandte
Chemie
[3] A related reaction has been used in the synthesis of [5]helicenes
that provides precedent for this hypothesis; see: a) D. C.
Harrowven, M. I. T. Nunn, D. R. Fenwick, Tetrahedron Lett.
2002, 43, 3189 – 3191; b) D. C. Harrowven, M. I. T. Nunn, D. R.
Fenwick, Tetrahedron Lett. 2002, 43, 7345 – 7347.
[4] The mechanism of rearomatization has been the subject of much
discussion; for some leading references, see: a) D. C. Har-
rowven, B. J. Sutton, S. Coulton, Tetrahedron 2002, 58, 3387 –
3400; b) A. L. J. Beckwith, V. W. Bowry, W. R. Bowman, E.
Mann, J. Parr, J. M. D. Storey, Angew. Chem. 2004, 116, 97 – 100;
Angew. Chem. Int. Ed. 2004, 43, 95 – 98.
[5] a) G. W. Yeager, D. N. Schissel, Synthesis 1991, 63 – 68; b) O.
Dann, J. Ruff, H.-P. Wolff, H. Griessmeier, Liebigs Ann. Chem.
1984, 409 – 425; c) G. M. Keserꢀe, Z. Dienes, M. Nogradi, M.
Kajtar-Peredy, J. Org. Chem. 1993, 58, 6725 – 6728.
[6] a) D. E. Ames, A. Opalko, Tetrahedron 1984, 40, 1919 – 1926;
b) T. Harayama, H. Yasuda, Heterocycles 1997, 61 – 64;
c) A. V. R. Rao, T. K. Chakraborty, S. P. Joshi, Tetrahedron
Lett. 1992, 33, 4045 – 4048; d) G. Bringmann, D. Menche, J.
Muehlbacher, M. Reichert, N. Saito, S. S. Pfeiffer, B. H. Lip-
shutz, Org. Lett. 2002, 4, 2833 – 2836.
[7] T. Eicher, S. Fey, W. Puhl, E. Bꢀchel, A. Speicher, Eur. J. Org.
Chem. 1998, 877 – 888.
[8] K. J. Edgar, S. N. Falling, J. Org. Chem. 1990, 55, 5287 – 5291.
[9] For a related macrocyclization reaction leading to bazzanin A
tetramethyl ether, see: A. Speicher, J. Kolz, R. P. Sambanje,
Synthesis 2002, 2503 – 2512.
[10] Riccardin C was first isolated from the liverwort Reboulia
hemisphaerica, see: a) Y. Asakawa, R. Matsuda, Phytochemistry
1982, 21, 2143 – 2144; b) Y. Asakawa, M. Toyota, Z. Taira, T.
Takemoto, M. Kido, J. Org. Chem. 1983, 48, 2164 – 2167; it
displays in vitro cytotoxicity against nasal epidermoid carcinoma
cells and weak inhibitory activity against HIV-1 reverse tran-
scriptase, see: c) T. Yoshida, T. Hashimoto, S. Takaoka, Y. Kan,
M. Tori, Y. Asakawa, J. M. Pezzuto, T. Pengsuparp, G. A.
Cordell, Tetrahedron 1996, 52, 14487 – 14500.
[11] For previous total syntheses of riccardin C, see: a) A. Gottsegen,
M. Nogradi, B. Vermes, M. Kajtar-Peredy, E. Bihatsi-Karsai, J.
Chem. Soc. Perkin Trans. 1 1990, 315 – 320; b) A. Gottsegen, M.
Nogradi, B. Vermes, M. Kajtar-Peredy, E. Bihatsi-Karsai,
Tetrahedron Lett. 1988, 29, 5039 – 5040, and reference [6].
[12] D. C. Harrowven, B. J. Sutton, S. Coulton, Org. Biomol. Chem.
2003, 1, 4047 – 4057.
[13] C. Chatgilialoglu, Organosilanes in Radical Chemistry, Wiley,
Chichester, UK, 2003.
Scheme 4. Total synthesis of cavicularin (1) and riccardin C (20).
Ts =p-toluenesulfonyl, TTMSS=tris(trimethylsilyl)silane, AIBN=azo-
bis(isobutyronitrile).
Keywords: arenes · macrocycles · radical reactions ·
.
ring contraction · total synthesis
[1] M. Toyota, T. Yoshida, Y. Kan, S. Takaoka, Y. Asakawa,
Tetrahedron Lett. 1996, 37, 4745 – 4748.
[2] D. C. Harrowven, M. I. T. Nunn, D. R. Fenwick, Tetrahedron
Lett. 2002, 43, 3185 – 3187.
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