Total synthesis of atroviridin

Article abstract of DOI:10.1016/S0040-4039(03)00629-4

A total synthesis of atroviridin (1) based on biosynthetic principles is presented. The tetracyclic xanthone structure of the natural product was constructed by coupling aryl bromide 8 with aldehyde 7 and subsequent intramolecular conjugate addition on a quinone precursor. Bromide 8 was produced from aldehyde 9 via a sequence of steps involving Baeyer-Villiger oxidation and Claisen cyclization.

Full text of DOI:10.1016/S0040-4039(03)00629-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3281–3284
Total synthesis of atroviridin
Eric J. Tisdale, David A. Kochman and Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358,
USA
Received 17 January 2003; accepted 5 March 2003
Abstract—A total synthesis of atroviridin (1) based on biosynthetic principles is presented. The tetracyclic xanthone structure of
the natural product was constructed by coupling aryl bromide 8 with aldehyde 7 and subsequent intramolecular conjugate
addition on a quinone precursor. Bromide 8 was produced from aldehyde 9 via a sequence of steps involving Baeyer–Villiger
oxidation and Claisen cyclization. © 2003 Elsevier Science Ltd. All rights reserved.
Atroviridin (1)1 (Fig. 1) is a tetracyclic polyhydroxyl-
ated xanthone recently isolated from the stem bark of
Garcinia atroviridis, a lofty tree indigenous to Thailand.
Although the precise biological mode of action of this
natural product has not yet been reported, it is noted
that a decoction of the leaves of the parent tree has
been traditionally used for the treatment of earache.
products isolated from Garcinia-related tropical plants.2
Representative members of this family include osajax-
anthone (2),3 morellin (3),4 morellic acid (4)5 and late-
riflorone (5)6 (Fig. 1). All these compounds are
presumed to derive from benzophenone or benzophe-
none-like intermediates generated by means of a mixed
shikimate–acetate biosynthetic pathway that, upon an
intramolecular oxidative coupling or conjugate addi-
tion, produce a common xanthone scaffold.7 A series of
plant specific oxygenations, prenylations and pericyclic
reactions are postulated to bring about the final struc-
ture and are accountable for the observed biological
activities of these natural products. In continuation
with our synthetic studies in this area,8 we present
herein the first total synthesis of atroviridin (1).
From a structural standpoint, atroviridin (1) belongs to
a growing family of xanthone and xanthonoid natural
In step with the presumed biosynthetic pathway, atro-
viridin was thought to be accessible from benzophe-
none-like intermediate 6 through an intramolecular
conjugate addition (Fig. 2). Moreover, disconnection
across the C9ꢀC9a bond (xanthone numbering) sug-
gests a synthetic route toward 6 based on coupling of
aldehyde 7 with aryl bromide 8. The latter compound
was envisioned to arise from protected hydroquinone 99
by a sequence of steps including a Baeyer–Villiger
oxidation (introduction of O1 atom) and a Claisen
rearrangement (construction of C2ꢀC4% bond).10 Reduc-
tion of this plan to the synthesis of 1 is shown in
Schemes 1 and 2.
Figure 1. Selected xanthones from the Garcinia family of
plants.
The synthesis of aryl bromide 8 is shown in Scheme 1
and began with commercially available benzaldehyde
10. Regioselective bromination of 10 at the 9a position
(atroviridin numbering) with a slight excess of bromine
in acetic acid produced adduct 9 in 45% yield.9 Baeyer–
* Corresponding author. Tel.: +1-(858)-822-0456; fax: +1-(858)-822-
0386; e-mail: etheodor@ucsd.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00629-4

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E. J. Tisdale et al. / Tetrahedron Letters 44 (2003) 3281–3284
which was formed upon sitting, presumably via a spon-
taneous Claisen cyclization.13 Since this cyclization
event was found to be somewhat slow, requiring up to
2 days depending upon batch size, an improved proce-
dure was developed en route to chromenequinone 15.
According to the improved protocol, hydroquinone 13
was treated with CAN in 40% aqueous acetonitrile
transiently producing quinone 14, which was extracted
from the orange reaction mixture and, without further
purification, was heated at 40°C in toluene. This reac-
tion temperature was sufficient for the complete conver-
sion of compound 13 to the red-colored
chromenequinone 15 in 77% yield over two steps. We
also studied the effect of CoF3 on methyl ether 13 in
10% H2O/dioxane.14 Under these conditions the reac-
tion was consideralbly longer and offered no advan-
tages over the previously described CAN-mediated
oxidation. Reduction of quinone 15 with NaBH4 and
AcOH in THF yielded the resulting hydroquinone15
which was immediately converted to its MEM ether 8
using MEMCl and DIPEA (73% yield over two
steps).16
Figure 2. Strategic bond disconnections of atroviridin (1).
Completion of the total synthesis of atroviridin (1) by
union of bromide 8 with aldehyde 7 is shown in Scheme
2. To this end, commercially available 2,5-dihydroxy
Scheme 1. Reagents and conditions: (a) 1.1 equiv. Br2, AcOH,
4 h, 25°C, 45%; (b) 1.3 equiv. m-CPBA, CH2Cl2, 4 h, 25°C;
(c) 10% NaOH (aq.) in MeOH, 1 h, 25°C, 99% (over two
steps); (d) 1.2 equiv. 1,1-dimethylprop-2-ynyl methyl carbon-
ate (12), 1.3 equiv. DBU, 0.03 mol% CuCl2, CH3CN, 6 h,
0°C, 84%; (e) 2.5 equiv. CAN, 40% H2O in CH3CN, 0.5 h,
25°C; (f) PhCH3, 0.5 h, 40°C, 77% overall; (g) 2.2 equiv.
NaBH4, 22 equiv. AcOH, THF, 0.5 h, 25°C; (h) 2.5 equiv.
MEMCl, 2.8 equiv. DIPEA, CH2Cl2, 2 h, 0°C, 73% (over two
steps).
Villiger oxidation of 9 followed by hydrolysis of the
resulting formate ester under basic conditions afforded
phenol 11 in 99% yield.11 This compound was O-alkyl-
ated with 1,1-dimethylprop-2-ynyl methyl carbonate
(12) using DBU and catalytic CuCl2 in acetonitrile to
produce alkyne 13 (84% yield).12 Aiming to produce
quinone 14 we subjected methyl hydroquinone 13 to a
variety of oxidative demethylation conditions, including
cerium ammonium nitrate (CAN) or CoF3. Although
quinone 14 could be isolated, it was always found to be
contaminated with small amounts of cyclized adduct 15
Scheme 2. Reagents and conditions: (a) 2.2 equiv. TBSCl, 2.5
equiv. imid, CH2Cl2, 4 h, 25°C, 62%; (b) 1.3 equiv. n-BuLi,
Et2O, 1 h, −78 to 0°C, 52%; (c) 1.5 equiv. Dess–Martin
periodinane, CH2Cl2, 1 h, 25°C, 66%; (d) 5.0 equiv. ZnBr2,
CH2Cl2, 4 h, 25°C, 70%; (e) 2.5 equiv. IBX, 5% DMF in
CHCl3, 4 h, 25°C, 31%; (f) 2.2 equiv. TBAF, THF, 1 h, 25°C,
40%.

E. J. Tisdale et al. / Tetrahedron Letters 44 (2003) 3281–3284
3283
benzaldehyde (16) was protected as the corresponding
silyl ether 7 and subsequently alkylated with the lithium
salt of 8 to afford benzylic alcohol 17 in 52% yield.
Oxidation of 17 with Dess–Martin periodinane in
CH2Cl2 gave rise to benzophenone 18 in 66% yield.17
Deprotection of the MEM ethers of 18 was accom-
plished using an excess of ZnBr2 in CH2Cl2 producing
hydroquinone 19 in 70% yield.16 The stage was now set
for an oxidation of the hydroquinone ring and subse-
quent conjugate addition. Surprisingly, the desired oxi-
dation proved to be more problematic than expected.
Mild heterogeneous oxidants, such as MnO2 were
found to be completely ineffective.18 After several
experimental attempts we found that the best condi-
tions involved treatment of 19 with IBX in 5% DMF/
CHCl3 at ambient temperature producing quinone 20 in
31% yield.19 It was also possible to effect the same
oxidation with Dess–Martin periodinane in CH2Cl2.
Nonetheless, the Dess–Martin oxidation did not offer
an increase in yield or any other distinct advantage over
the IBX oxidation except for a more rapid reaction
time. With the red-colored quinone 20 in hand, the final
deprotection and sequential cyclization could be tested.
Along these lines, treatment of 20 with TBAF in THF
produced a brown solution which, over a 1 h period,
became increasingly yellow. This hypsochromic shift
suggested that the initially formed colored quinone 6
could react in situ to produce a less chromophoric
hydroquinone structure. Indeed, isolation, followed by
spectroscopic and analytical characterization of the
major product of this reaction confirmed the total
synthesis of atroviridin (1).
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2. The Garcinia species belongs to the Guttiferae family of
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In conclusion, we have presented an efficient and con-
vergent synthesis of atroviridin (1), a member of the
xanthone and xanthonoid natural products pool iso-
lated from the Garcinia species of tropical plants. Our
strategy highlights the use of a cerium ammonium
nitrate-mediated oxidative demethylation and tandem
Claisen cyclization to form chromenequinone 15. This
spontaneously occurring Claisen rearrangement is rare
in the literature and this occurrence may in fact be the
only case in which it has been used in the context of the
total synthesis of a natural product. Additionally, the
final deprotection protocol with concomitant annula-
tion to form atroviridin (1) mirrors a proposed biosyn-
thetic pathway for xanthone and xanthonoid natural
products.
13. The spontaneous propargylic Claisen rearrangement on
quinones has previoulsy been noted but its occurance in
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15. Pugh, C. Org. Lett. 2000, 2, 1329–1331.
Acknowledgements
Financial support from the NIH (CA085600) is grate-
fully acknowledged. We also thank the San Diego
Chapter of the ARCS Foundation for their support
through a graduate student fellowship to E.J.T.
16. Corey, E. J.; Gras, J.-L.; Ulrich, P. Tetrahedron Lett.
1976, 17, 809–812.
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