Enantioselective total synthesis of (-)-euxanmodinb: An axially chiral natural product with an anthraquinone-xanthone composite structure

Article abstract of DOI:10.1002/asia.201100187

The first total synthesis of (-)-euxanmodinB is described. An axially chiral, enantiomerically pure biphenyl, available by enzymatic desymmetrization of I-symmetric biaryl diacetate, was used as the key chiral biaryl building block. Two annulation reactions allowed the construction of the xanthone-anthraquinone composite structure with full stereochemical control.

Full text of DOI:10.1002/asia.201100187

COMMUNICATION
DOI: 10.1002/asia.201100187
Enantioselective Total Synthesis of (ꢀ)-Euxanmodin B: An Axially Chiral
Natural Product with an Anthraquinone–Xanthone Composite Structure
[
a]
[b]
[a]
[a]
Nobuyuki Takahashi, Takeshi Kanayama, Kumi Okuyama, Hiroko Kataoka,
[
b]
[a]
[b]
Haruhiko Fukaya, Keisuke Suzuki,* and Takashi Matsumoto*
Dedicated to the 150th Anniversary of the Department of Chemistry, The University of Tokyo
Densely functionalized biaryl structures are common
acetate II would serve as a versatile synthetic platform
toward various axially chiral biaryl structures by multi-direc-
tional elaboration, by exploiting well-discriminated function-
alities. It is noteworthy that the enzymatic process is com-
patible with a broad substrate variation in I (X, Y, and Z),
and selection of the suitable enzyme allows access to both
enantiomers of II (Figure 1).
[1]
motifs embedded in biologically active natural products,
[2]
[3]
such as korupensamine A and knipholone. They often
have atropisomerism with restricted rotation around the
biaryl axis, which could have biological relevance and pro-
vide us with synthetic challenges, including construction of
sterically congested biaryl linkages in a regio- and enantio-
controlled manner.
As an alternative, we have reported the enzyme-cata-
lyzed, enantioselective hydrolysis of biphenyl diacetate I as
an effective route to access such axially chiral biaryl struc-
[4]
tures. We anticipated that the axially chiral biaryl mono-
Figure 1. Schematic representation of enzymatic desymmmetrization.
[
a] N. Takahashi, Dr. K. Okuyama, H. Kataoka, Prof. Dr. K. Suzuki
Department of Chemistry
Tokyo Institute of Technology
[
5]
To demonstrate this concept, euxanmodin A and B were
selected as natural products, which were isolated from an
Asian plant, Ploiarium alternifolium (Bonnetiaceae). They
are the composites of two biologically active tricyclic natural
2
-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
Fax : (+81)3-5734-2788
E-mail: ksuzuki@chem.titech.ac.jp
[6]
[7]
[
b] T. Kanayama, H. Fukaya, Prof. Dr. T. Matsumoto
School of Pharmacy
products, euxanthone and emodin, which differ in their
connectivity (Figure 2). Regarding the axial stereochemistry
of these compounds, the [a]D value was recorded for euxan-
modin A, but not for euxanmodin B. As we were interest-
ed in the atropisomerism and also the relationship to the
biological activities, we embarked on the asymmetric synthe-
sis of these natural products.
Tokyo University of Pharmacy and Life Sciences
Horinouchi, Hachioji, Tokyo, 192-0392 (Japan)
Fax : (+81)42-676-3257
[5]
E-mail: tmatsumo@toyaku.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100187.
1752
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Chem. Asian J. 2011, 6, 1752 – 1756

Scheme 1 shows the overall strategy. Assuming the axial
stereochemistry of 1 is as shown, we contemplated correlat-
ing it to the axially chiral, enantiomerically pure biphenyl 2,
which is available by the enzymatic desymmetrization ap-
[4a]
proach as discussed above. Given the case, suitable proto-
cols were required to assemble the tricyclic skeletons at
both sides of the molecule. We reasoned that the xanthone
could be constructed by an SNAr cyclization [Equa-
[8]
tion (1)], while the anthraquinone would be accessible by
the ring expansion of a benzocyclobutenone derivative
[
9]
[
Equation (2)].
Scheme 2 shows the preparation of the key biaryl building
block 6, and this starts from the enzyme-catalyzed, enantio-
[4a]
selective hydrolysis of s-symmetric biaryl diacetate 3.
Figure 2. Structures of euxanmodin A and B.
Herein, we describe the first total synthesis of (ꢀ)-euxan-
modin B (1), which proved indeed to have highly stable
axial stereochemistry.
Scheme 2. Reagents and conditions: unless otherwise indicated, the reac-
tions were performed at ambient temperature. a) PPL; b) TBSCl, imida-
zole, CH
2
Cl
2
, 4.5 h (95%); c) [Pd
A
H
U
T
E
N
N
3
)
4
] (25 mol%), AcOH, 808C, 12 h
CH Cl MeOH, 4 h (81%);
+
ꢀ
(
90%); d) BnMe
3
N ICl
2
,
3
,
2
2
,
+
ꢀ
e) (MeO)
g) (MeO)
2
2
SO
SO
2
2
, K
, K
2
CO
CO
3
4
N F , THF, 30 min;
2
3
NaOH (2m), 1,4-dioxane, 10 h; i) MOMCl, iPr
2
tive, over 2 steps). PPL=porcine pancreas lipase; MOM=methoxymeth-
yl; THF=tetrahydrofuran; TBS=tert-butyldimethylsilyl.
Upon exposure to porcine pancreas lipase (PPL, Sigma
Type II; phosphate buffer (pH 7, 0.1m), iPr O, 35 8C, 11 h),
2
diacetate 3 underwent smooth hydrolysis, thus affording
1
9
mono-acetate (S)-2 in quantitative yield, ½aꢁ =+83 (c=1.0,
D
CHCl ). The enantiomeric excess of 2 proved to be excellent
3
[10]
(
>99% ee). The obtained chiral mono-acetate (S)-2 was
protected as a tert-butyldimethylsilyl (TBS) ether, which was
[11]
subjected to the palladium-catalyzed deallylation,
in
which an acyl migration occurred to give phenol 4 in excel-
lent yield. The next task was the regioselective installation
of an iodine atom at the ortho-position of the phenol in 4;
Scheme 1. Retrosynthesis.
Chem. Asian J. 2011, 6, 1752 – 1756
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www.chemasianj.org
1753

T. Matsumoto and K. Suzuki et al.
COMMUNICATION
+
ꢀ
2
this was nicely achieved by using BnMe N ICl to afford
iodide 5.
an aryl anion species to aldehydes 10a/b without affecting
the benzocyclobutenone moiety; this was achieved by the
Grignard reagent prepared from iPrMgBr·LiCl and iodide
3
[12]
A conventional protection/deprotection se-
quence converted iodide 5 into the key intermediate 6,
which proved to be enantiomerically pure by HPLC analysis
>99% ee).
Scheme 3 illustrates the synthesis of alcohol 11, which
possesses the full carbon/oxygen constituents of the target.
Upon treatment of iodide 6 with nBuLi (ꢀ788C, 5 min) fol-
[17,18]
12.
The addition reaction of 10a and separation by
[13]
(
silica-gel column chromatography afforded the isomeric ad-
ducts 11a (19%) and 11b (57%). The same reaction of 10b
gave the other adducts 11c and 11d (inseparable) in 56%
[19]
combined yield.
The obtained adducts 11a–d possessed the potential pre-
cursor to the anthraquinone–xanthone moieties, ready for
completing the synthesis. Among the possibilities, we opted
to construct the anthraquinone framework first (Scheme 4).
Heating of benzocyclobutenol 11a (mesitylene, 1658C, 11 h)
triggered the smooth 4!6-ring expansion, and subsequent
air oxidation gave anthraquinone 13a in 76% yield. Follow-
ing the same protocol, isomer 11b gave the isomeric anthra-
quinone 13b in 76% yield. The isomer mixture 11c/11d
gave a mixture of anthraquinones 13a/13b in 73% com-
[19]
bined yield.
The next stage was construction of the xanthone frame-
work. The secondary alcohol in 13a was oxidized (IBX,
[16]
DMSO) to give benzophenone 14 in 81% yield. Oxida-
tion of the isomer 13b also gave the same compound 14.
After removal of the MOM groups (aq. HCl (2m), 1,4-diox-
ane, 508C), the S Ar cyclization was achieved by using
N
Cs CO and N,N-dimethylformamide (DMF; 508C, 3 h) to
2
3
[8]
give xanthone 15. Notably, the enantiomeric purity was
again preserved through these transformations as proven by
[20]
HPLC analysis of 15 (>99% ee).
Finally, the four methyl ether groups in 15 were detached
upon treatment with BBr . Interestingly, the quadruple de-
3
methylation proceeded in a stepwise manner, as illustrated
by the TLC monitoring for the time course of the deprotec-
tion (Scheme 4). Upon exposure of 15 to BBr at ꢀ788C,
3
the C(1’) methyl ether was quickly cleaved (TLC no. 1), and
then the C(7) methyl ether was cleaved at ꢀ108C (TLC no.
2
). During warming to room temperature, the C(8’) methyl
ether was cleaved (TLC no. 3), and prolonged stirring
room temperature, 11 h) cleaved the remaining C(3’)
methyl ether (TLC no. 4), thus affording the target 1 as an
(
Scheme 3. Reagents and conditions: a) nBuLi, THF, ꢀ788C, 5 min;
2
5
orange solid in 67% yield, ½aꢁ =ꢀ93 (c=0.35, CHCl ,
b) ꢀ788C, 7, THF, 10 min (89%); c) aq. H
2
SO
4
(4.0m), 1,4-dioxane,
D
3
[21]
1
5
08C, 9 h (9a: 41% and 9b: 41%); d) IBX, DMSO, RT, 3 h (10a: 95%
from 9a; 10b: 88% from 9b); e) iPrMgBr·LiCl, 12, THF, ꢀ408C!RT,
h, 10a!11a (19%) and 11b (57%); 10b!11c/11d (56%, insepara-
ble). IBX=ortho-iodoxybenzoic acid; DMSO=dimethyl sulfoxide.
>99% ee). The H NMR data of 1 agreed with that of the
reported data for the natural product, and further structural
4
[22]
proof was provided by X-ray analysis.
Concerning the atropisomeric stability, the rotational bar-
rier of the biaryl linkage is quite high; no racemization was
detected even after prolonged (6 h) heating in refluxing tol-
uene.
In summary, the first total synthesis of (ꢀ)-euxanmodin B
(1) was achieved starting from an axially chiral, enantiomer-
ically pure biphenyl substrate. Further studies are in prog-
ress, including the biological assay for nonracemic and race-
mic materials.
[14]
lowed by the addition of ketone 7, the desired adduct 11
was obtained in 89% yield as an inseparable mixture of dia-
stereomers. The dimethyl acetal and the methoxymethyl
(
MOM) group in 8 were cleaved (aq. H SO (4.0m), 1,4-di-
2 4
oxane, 508C) to give the corresponding alcohol 9. Two dia-
[
15]
stereomers 9a
and 9b (for the designation of a/b, see
Scheme 3) were separable by silica-gel column chromatogra-
phy, and were oxidized by using ortho-iodoxybenzoic acid
[16]
and dimethyl sulfoxide (IBX, DMSO) to give the corre-
sponding aldehydes 10a and 10b in high yields, respectively.
The next task was the regioselective nucleophilic addition of
1754
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Chem. Asian J. 2011, 6, 1752 – 1756

Enantioselective Total Synthesis of (ꢀ)-Euxanmodin B
Keywords: annulation reactions · asymmetric synthesis ·
biaryls · enzymes · natural products
[
1] Biaryls in Nature: A Multi-Faceted Class of Stereochemically, Bio-
synthetically, and Pharmacologically Intriguing Secondary Metabo-
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Progress in the Chemistry of Organic Natural Products, Vol. 82
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Eds.: W. Herz, H. Falk, G. W. Kirby, R. E. Moore), Springer, New
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[
2] Y. F. Hallock, K. P. Manfredi, J. W. Blunt, J. H. Cardellina, II. , M.
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[
[
3] E. Dagne, W. Steglich, Phytochemistry 1984, 23, 1729.
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moto, Synlett 2009, 931; b) T. Matsumoto, T. Konegawa, T. Naka-
mura, K. Suzuki, Synlett 2002, 122.
[
5] G. J. Bennett, H.-H. Lee, T. K. Lowrey, Tetrahedron Lett. 1990, 31,
7
51.
[
6] a) Dictionary of Natural Products, Vol. 2, (Ed.: J. Buckingham),
Chapman & Hall, London, 1994, pp. 1834–1835. For recent reports
on biological activities of euxanthone, see: b) D. V. Cꢃmara, V. S.
Lemos, T. J. Nagem, S. F. Cortes, Phytomedicine 2010, 17, 690; c) M.
Naidu, C.-Y. K. Kuan, W.-L. Lo, M. Raza, A. Tolkovsky, N.-K. Max,
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trakul, W. Chanakul, M. Pohmakotr, T. Jaipetch, C. Yoosook, J. Ka-
sisit, C. Napaswat, T. Santisuk, S. Prabpai, P. Kongsaeree, P. Tuchin-
da, Planta Med. 2006, 72, 1433.
[
7] a) R. H. Thomson, Naturally Occurring Quinones, 2nd ed., Academ-
ic Press, New York, 1971, pp. 418–419. For recent reports on biolog-
ical activities of emodin, see: b) Y. Feng, S. Huang, W. Dou, S.
Zhang, J. Chen, Y. Shen, J. Shen, Y. Leng, Br. J. Pharmacol. 2010,
1
61, 113; c) J.-C. Ko, Y.-J. Su, S.-T. Lin, J.-Y. Jhan, S.-C. Ciou, C.-M.
Cheng, Y.-F. Chiu, Y.-H. Kuo, M.-S. Tsai, Y.-W. Lin, Lung Cancer
010, 69, 155; d) T.-C. Kuo, J.-S. Yang, M.-W. Lin, S.-C. Hsu, J.-J.
2
Lin, H.-J. Lin, T.-H. Hsia, C.-L. Liao, M.-D. Yang, M.-J. Fan, W. G.
Wood, J.-G. Chung, J. Pharmacol. Exp. Ther. 2009, 330, 736.
[
[
8] L. Hintermann, R. Masuo, K. Suzuki, Org. Lett. 2008, 10, 4859.
9] a) L. S. Liebeskind, S. Iyer, C. F. Jewell, Jr., J. Org. Chem. 1986, 51,
3
065; b) H. W. Moore, B. R. Yerxa, Chemtracts 1992, 5, 273; c) T.
Suzuki, T. Hamura, K. Suzuki, Angew. Chem. 2008, 120, 2280;
Angew. Chem. Int. Ed. 2008, 47, 2248. Also See: d) T. Matsumoto, T.
Hamura, M. Miyamoto, K. Suzuki, Tetrahedron Lett. 1998, 39, 4853;
e) T. Hamura, M. Miyamoto, T. Matsumoto, K. Suzuki, Org. Lett.
2
002, 4, 229; f) I. Takemura, K. Imura, T. Matsumoto, K. Suzuki,
Org. Lett. 2004, 6, 2503; g) I. Takemura, K. Imura, T. Matsumoto, K.
Suzuki, Tetrahedron Lett. 2006, 47, 6673.
[
10] The reaction with three grams of diacetate 3 gave an almost quanti-
tative yield of mono-acetate (S)-2, in which to attain effective stir-
ring, ten batches of 300 mg scale reactions (24 mm diameter test
tube) were carried out in parallel and combined for the work-up
Scheme 4. Reagents and conditions: a) mesitylene, 1658C, 11 h; air, 10 h,
[
19]
1
1a!13a (76%); 11b!13b (76%), 11c/11d!13a/13b (73%)
b) IBX, DMSO, 508C, 3 h; (81% from 13a, 97% from 13b); c) aq. HCl
2.0m), 1,4-dioxane, 508C, 3 h; d) Cs CO DMF, 508C, 3 h (93%,
steps); e) BBr , CH Cl
, ꢀ788C!RT, 11 h (67%). DMF=N,N-dime-
thylformamide.
;
(
see the Supporting Information). The enantiomeric excess of bi-
(
2
2
3
,
phenyl (S)-2 was >99%, as determined by chiral HPLC analysis
3
2
2
(
1
Chiralpak IA (Daicel), 0.46ꢄ25 cm, hexane/2-propanol=9:1,
ꢀ1
.0 mLmin , 208C, 254 nm) t
R
: 14.5 min for (S)-2 (9.2 min for (R)-
2
).
[
[
[
11] K. Nakayama, K. Uoto, K. Higashi, T. Soga, T. Kusama, Chem.
Pharm. Bull. 1992, 40, 1718.
12] S. Kajigaeshi, T. Kakinami, H. Yamasaki, S. Fujisaki, M. Kondo, T.
Okamoto, Chem. Lett. 1987, 2109.
Acknowledgements
13] The enantiomeric excess of biphenyl 6 was >99%, as determined
by chiral HPLC analysis (Chiralpak IA (Daicel), 0.46ꢄ25 cm,
We thank Professor Takeo Taguchi, Tokyo University of Pharmacy and
Life Sciences, for valuable discussions. This work was supported from the
Ministry of Education, Culture, Sports, Science, and Technology, Japan
by Grant-in-Aid for Scientific Research [(Priority Area) No. 16073210;
ꢀ
1
hexane/2-propanol=99:1, 1.0 mLmin , 208C, 254 nm) t : 23.4 min
R
(21.5 min for ent-6).
[14] Ketone 7 was prepared as follows. For further details, see the Sup-
(
(
C), No. 22590018]. Support to N. T. by the Global COE program
Tokyo Institute of Technology) is gratefully acknowledged.
porting Information.
Chem. Asian J. 2011, 6, 1752 – 1756
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1755

T. Matsumoto and K. Suzuki et al.
COMMUNICATION
Synthesis of Ketone 7.
Also see: a) T. Hamura, T. Hosoya, H. Yamaguchi, Y. Kuriyama, M.
Tanabe, M. Miyamoto, Y. Yasui, T. Matsumoto, K. Suzuki, Helv.
Chim. Acta 2002, 85, 3589; b) S. Tsujiyama, K. Suzuki, Org. Synth.
2
007, 84, 272.
[
15] The relative stereochemistry of 9a was determined by X-ray crystal-
lography of the racemic material, (ꢂ)-9a. CCDC 811999 (for com-
pound (ꢂ)-9a), CCDC 812000 (for compound (ꢂ)-11b), and
CCDC 812001 (for compound (ꢂ)-1) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Stereochemistry of 11a–d.
[
[
[
20] The enantiomeric excess of biphenyl 15 was >99%, as determined
by using chiral HPLC analysis (Chiralpak IA (Daicel), 0.46ꢄ25 cm,
ꢀ
1
hexane/2-propanol 6:4, 1.0 mLmin , 208C, 254 nm) t
13.4 min for ent-15).
R
: 23.2 min
(
21] The enantiomeric excess of 1 was >99% by using chiral HPLC
analysis (Chiralpak AD-H (Daicel), 0.46ꢄ25 cm, hexane/2-propa-
ꢀ
1
nol=1:1, 1.0 mLmin , 308C, 254 nm) t
ent-1)].
R
: 11.7 min (6.8 min for
22] The xanthone–anthraquinone structure was confirmed by X-ray
crystallography of the racemic material (ꢂ)-1. For synthesis of (ꢂ)-
1, see the Supporting Information.
X-ray Crystal Structure of (ꢂ)-9a.
[
16] a) M. Frigerio, M. Santagostino, Tetrahedron Lett. 1994, 35, 8019;
b) M. Frigerio, M. Santagostino, S. Sputore, J. Org. Chem. 1999, 64,
4
537.
X-ray crystal structure of (ꢂ)-1.
[
17] a) A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396;
Angew. Chem. Int. Ed. 2004, 43, 3333; Also see: b) P. Knochel, W.
Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapount-
zis, V. A. Vu, Angew. Chem. 2003, 115, 4438; Angew. Chem. Int. Ed.
2
003, 42, 4302.
[
18] The corresponding aryl lithium and aryl zinc species were not fruit-
ful. The use of iPrMgBr instead of iPrMgBr·LiCl was less effective.
19] The relative stereochemistries of 11a–d were fully assigned. The
structure of 11b was based on the X-ray crystallography for racemic
material, (ꢂ)-11b. Alcohol 11a is epimeric to 11b at the secondary
alcohol center. The fact that the mixture of 11c/11d (3:1, as deter-
mined by NMR spectroscopy) was converted into 13a (55%) and
[
1
3b (18%) was the basis of correlating 11c to 13a, and that of 11d
to 13b.
Received: February 24, 2011
Published online: May 9, 2011
1756
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Chem. Asian J. 2011, 6, 1752 – 1756