Expedient Total Syntheses of Rhein and
Diacerhein via Fries Rearrangement
Steve Tisserand,† Rachid Baati,† Marc Nicolas,‡ and
Charles Mioskowski*,†
Universite´ Louis Pasteur, Faculte´ de Pharmacie, UMR 7514,
Laboratoire de Synthe`se Bio-Organique, 74 route du Rhin,
67401 Illkirch-Graffenstaden, France, and Laboratoires
Pierre Fabre (Plantes et Industrie), 16 rue Jean Rostand,
81600 Gaillac, France
FIGURE 1. Structure of rhein (1), diacerhein (2), aloe-emodin
(3), and aloin (4).
Received May 7, 2004
SCHEME 1. Retrosynthetic Plan for the Synthesis
of Rhein (1)
Abstract: Short and practical total syntheses of rhein (1)
and diacerhein (2) have been achieved via a Fries rearrange-
ment and bis-carbonylation strategy followed by cyclization
in molten salt, starting from dibromoester 7.
Isolated in the free state and as the glucoside in Rheum
polygonaceae species (rhubarb), Senna leaves, and several
species of Cassia (Peguminosae),1 rhein (1, Figure 1) is
well-known for its applications in antiarthritic drugs.2
Indeed, rhein is recognized to be the active metabolite of
diacerhein (2), which inhibits interleukin-1 activity by
reducing the collagenase production in articular cartilage.
Rhein (1) is also known to inhibit superoxide anion
production, chemotaxis, phagocytic activity of neutro-
phils, macrophage migration, and phagocytosis.2 Diacer-
hein (2) has been produced by semisynthesis on industrial
scale via oxidation of the natural occurring aloin (4).3
However, this route affords compounds which are difficult
to purify and, importantly, may be contaminated with
the mutagenic byproduct aloe-emodin (3). To overcome
this crucial problem, several innovative strategies have
been designed for the total synthesis of rhein and related
anthraquinones.
Fries rearrangement followed by bis-carbonylation. More-
over, our synthetic plan avoids any intermediates con-
taining the undesirable hydroxymethyl group at the C-8
position of the anthraquinone core, precluding mutagenic
aloe-emodin (3) as a contaminate. Scheme 1 outlines our
strategy toward the synthesis of the target.
The cyclization precursor 5 could be derived from
dibromobenzophenone 6 via a bis-carbonylation process.
This key building block 6 could conveniently be obtained
by a Fries rearrangement of precursor 7 which in turn
could easily be synthesized starting from the cheap and
commercially available materials 1,3,5-tribromobenzene
8 and anisic acid 9.
The synthesis began with the preparation of 3,5-
dibromophenol 10 from 1,3,5-tribromobenzene 8 by reac-
tion with potassium methoxide in DMF at 80 °C (Scheme
2).8 Methyl ether deprotection was performed by treat-
ment with BBr3 using a standard method (98%, overall
yield).9
Phenol 10 was then coupled to anisic acid 9 in the
presence of trifluoroacetic anhydride10 affording key ester
7 in quantitative yield.13 With 7 in hand, we were able
Approaches, based on Diels-Alder reactions,4 tandem
processes5,6 (Stobbe condensation or Michael addition
followed by cyclization), or organometallic routes7 (con-
densation of lithium salts with benzynes) are often
lengthy and low yielding. In this paper, we report an
efficient and practical synthesis of rhein (1) and diacer-
hein (2) using a highly convergent approach based on a
† Universite´ Louis Pasteur.
‡ Laboratoires Pierre Fabre (Plantes et Industrie).
(1) (a) Rhein: The Merck Index, 11th ed.; Merck: Rahway, NJ, 1989;
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Harborne FRS, J. B., Baxter, H., Eds.; John Wiley & Sons Ltd.: New
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Tetrahedron 1967, 23, 515.
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1982, 115, 1089. (d) Martin, R.; Demerseman, P. Synthesis 1989, 25.
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(13) See the Supporting Information for the optimization.
(2) Pencer, C. M.; Wilde, M. I. Drugs 1997, 53, 98.
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Carcasona, A.; Grimminger, W.; Hietala, P.; Witthohn, K.; Zaeske, H.
Ger. Offen. 4120990, 07 Jan 1993.
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1993, 58, 7906.
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Tetrahedron Lett. 1994, 35, 289. (b) Unesh, R. Z.; Bipin, P.; Nagaraj,
R. A. Chem. Ind. 1988, 4, 124.
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10.1021/jo049228l CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/17/2004
8982
J. Org. Chem. 2004, 69, 8982-8983