Total synthesis of zoanthenol

Article abstract of DOI:10.1002/anie.200904537

Reaching home plate: The first total synthesis of zoanthenol, an aromatic member of the zoanthamine alkaloid family with potent anti-platelet activity for human platelet aggregation, has been achieved using an intermediate in the total synthesis of norzoa

Full text of DOI:10.1002/anie.200904537

Angewandte
Chemie
DOI: 10.1002/anie.200904537
Natural Product Synthesis
Total Synthesis of Zoanthenol**
Yu Takahashi, Fumihiko Yoshimura, Keiji Tanino,* and Masaaki Miyashita*
The zoanthamine alkaloids, a family of marine metabolites
produced by the zoanthid Zoanthus sp., not only have a novel
array of structures with stereochemical complexity, but also
exhibit distinctive biological and pharmacological properties.
For example, norzoanthamine (1), isolated from the colonial
studies of the zoanthamine alkaloids, we have achieved the
first total syntheses of 1[4a,c] and 2.[4c] These syntheses involved
a stereoselective synthesis of the crucial triene precursor
using sequential three-component coupling reactions, a key
intramolecular Diels–Alder reaction, and subsequent bis-
(amino)acetalization as the key synthetic steps.[4a] Recently,
Kobayashi and co-workers reported the second total synthesis
of 1, which involved an elegant intramolecular Diels–Alder
reaction for the construction of the AB ring system as the key
step.[5]
Having achieved the efficient chemical syntheses of
norzoanthamine and zoanthamine, we focused on the syn-
thesis of zoanthenol (3),[6] a member of the zoanthamine
alkaloids which is unique as it has an aromatic ring. As with
the norzoanthamine derivatives, zoanthenol has been found
to exhibit potent anti-platelet activity for human platelet
aggregation.[7] In spite of synthetic studies by a number of
research groups, employing a variety of distinct strategies, the
total synthesis of 3 has yet to be successfully completed.[8–10]
Herein, we report the first total synthesis of zoanthenol 3,
using a synthetic intermediate 11 in our synthesis of 1,[4a,c] and
the development of an efficient synthetic route from the
commercially available norzoanthamine hydrochloride
(1·HCl) to 3.
The only difference in the structures of zoanthenol and
zoanthamine is the oxidation pattern of the A ring; therefore,
we thought that 3 might be directly synthesized by oxidative
aromatization of 2. To this end, we initially examined the
viability of the transformation on the tetracyclic enone 4 as a
model substrate. Two efficient procedures were found that
successfully effected this transformation (Scheme 1). Thus,
zoanthid Zoanthus sp. by Uemura et al., can suppress the loss
of the weight of, and strengthen, bones in ovariectomized
mice without problematic side effects[1] and thus is a promis-
ing candidate for an anti-osteoporotic drug. Furthermore,
zoanthamine (2), isolated by Rao, Faulkner and co-workers,
exhibits potent inhibitory activity toward phorbol myristate-
induced inflammation, along with powerful analgesic
effects.[2] The remarkable biological properties of norzoanth-
amine and zoanthamine, combined with their novel molecular
architectures, make this family of alkaloids extremely attrac-
tive as synthetic targets.[3] As part of our ongoing synthetic
[*] Y. Takahashi, Dr. F. Yoshimura, Prof. Dr. K. Tanino,
Prof. Dr. M. Miyashita[+]
Division of Chemistry, Graduate School of Science
Hokkaido University, Sapporo 060-0810 (Japan)
[+] Present address:
Department of Applied Chemistry, Faculty of Engineering
Kogakuin University, Hachioji 192-0015 (Japan)
Fax: (+81)42-628-4870
E-mail: bt13149@ns.kogakuin.ac.jp
Scheme 1. Model studies on oxidative aromatization of the tetracyclic
enone 4. Reagents and conditions: a) For 5: CuBr2, LiBr, CH3CN, 608C,
83% yield. b) For 6: Yb(OTf)3, Ac2O, O2 (1 atm), dioxane, 708C, 86%
yield. Tf=trifluoromethanesulfonyl.
[**] Dr. Eri Fukushi, Mr. Kenji Watanabe (GC-MS and NMR Laboratory,
Graduate School of Agriculture, Hokkaido University), and Dr.
Yasuhiro Kumaki (High-Resolution NMR Laboratory, Graduate
School of Science, Hokkaido University) are acknowledged for their
NMR spectroscopy and mass spectrometry measurements. Finan-
cial support from the Ministry of Education, Culture, Sports, Science
and Technology (Japan), a Grant-in-Aid for Scientific Research (A)
(No. 12304042), a Grant-in-Aid for Scientific Research on Priority
Areas (A) “Exploitation of Multi-Element Cyclic Molecules” (No.
13029003), and the Global COE Program (Project No. B01: Catalysis
as the Basis for Innovation in Materials Science)) is gratefully
acknowledged.
when enone 4 was treated with CuBr2 in CH3CN in the
presence of LiBr,[11] compound 5, now containing an aromatic
ring, was obtained as a single product in 83% yield. The
stereochemical structure of 5 was unambiguously confirmed
using NOE measurements, which indicated that epimeriza-
tion at the C19 benzylic position did not occur at all. A second
procedure for the aromatization of 4, by treatment with Ac2O
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904537.
Angew. Chem. Int. Ed. 2009, 48, 8905 –8908
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8905

Communications
and Yb(OTf)3 in dioxane under an oxygen atmosphere, also
derived from diketone A, by a regioselective dehydrogen-
À
À
produced the aromatic acetate 6 in high yield (86%),
whereupon oxygen was found to be critical for this reaction.
Although the reaction mechanism for the latter oxidation is
not clear at present, a related air oxidation of 4-oxo-4,5,6,7-
tetrahydroindoles with Ac2O and TsOH (4-methyl benzene-
sulfonic acid), leading to 4-acetoxyindoles, was reported
recently by Ishikawa and Saito.[12]
Having established these two efficient synthetic proce-
dures using tetracyclic enone 4, we studied the oxidative
aromatization of zoanthamine and its synthetic intermediate
7 as potential routes to the total synthesis of zoanthenol
(Scheme 2). Although we investigated the reaction conditions
in detail for these transformations, particularly focusing on
the reaction temperature, solvent, and Lewis acid (e.g.
ation reaction at the C15 C16 and C18 C19 bonds. The
crucial construction of the AB ring system, culminating in the
total synthesis of zoanthenol (Scheme 3, D), would be
achieved by stereoselective introduction of a methyl group
at the C19 position.
Indeed, we were able to accomplish the first total
synthesis of 3, using our new synthetic strategy (Scheme 4),
starting from the tricyclic ketoacid 11.[4] First, 11 was
converted into dihydronorzoanthamine (12) by treatment
with aqueous acetic acid at 1008C in 76% yield. The crucial
precursor for the aromatization step, bis(enone) 13, was
successfully derived from 12 using the Ito–Saegusa method.[14]
Thus, the treatment of 12 with LDA (8 equiv) and TMSCl
(6 equiv) in THF at À508C regioselectively furnished trime-
thylsilyl enol ethers on the ketone functionalities
in the AB ring system; subsequent treatment of
the bis(silyl enol ether) with Pd(OAc)2 and CaCO3
in CH3CN afforded the desired bis(enone) 13 in
good yield. As the labile silyl enol ether in the B
ring was readily hydrolyzed by acetic acid gen-
erated in situ, addition of CaCO3 was critical
during the latter reaction.[15] The key aromatiza-
tion step was successfully performed by treatment
of 13 with TFA at 508C for 1.5 h to produce the
long-awaited aromatic compound 14, that is,
norzoanthenol.[16] It should be noted that this is
the first isolation and characterization of norzoan-
thenol (14); isolation of norzoanthenol from
natural sources has not yet been reported.
The remaining task for the total synthesis of
zoanthenol is the regio- and stereoselective intro-
duction of a methyl group onto the B ring. For this
purpose, the phenolic compound 14 was initially
Scheme 2. Attempts toward the oxidative aromatization of zoanthamine, zoanth-
amine hydrochloride (2·HCl), and its synthetic intermediate 7. Boc=tert-butoxycar-
bonyl.
Sc(OTf)3), we were unable to obtain any of the corresponding
aromatized compounds (3, 8–10) from zoanthamine, zoanth-
amine hydrochloride (2·HCl), or their synthetic intermediate
7. When the oxidation was performed using CuBr2 and LiBr,
only a trace amount of starting material was recovered;
Yb(OTf)3-mediated oxidation resulted in the formation of
unidentified degradation products. Because copper salts have
been known to be coordinated by amines, we postulated that
the aminoacetal moiety in the substrates might be labile and
decompose under the reaction conditions. Therefore, we
decided not to consider this route further.
We then turned our attention to the aminoacetalization
steps in the total synthesis of norzoanthamine (1).[4] This
Scheme 3. Isoaromatization route to zoanthenol.
synthesis involved removal of the tert-butoxy carbonyl group
and formation of an iminium ion by treatment with aqueous
acetic acid, and subsequent aqueous TFA (trifluoroacetic
acid)-mediated hydrolysis of the methyl ester and lactoniza-
tion. In these reactions, the use of Brønsted acids did not
affect the aminoacetal moiety or the ABC ring system to any
appreciable extent. Therefore, we proposed a synthetic route
for the construction of aromatic ring C using a Brønsted acid
mediated isoaromatization[13] of the bis(enone) B, by way of a
double tautomerization (Scheme 3). Bis(enone) B could be
transformed into its TBS ether (15) in 57% overall yield from
12. The stereoselective introduction of the methyl group at
the C19 position in the desired product (16) was successfully
performed by treatment of 15 with LDA (lithium diisopro-
pylamide; 1.5 equiv)[18] in THFat À788C followed by addition
of MeI (20 equiv). Finally, desilylation of the TBS ether 16
with TASF (tris(dimethylamino)sulfonium difluorotrimethyl-
silicate)[19] in acetone furnished the crude zoanthenol which
8906 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 8905 –8908

Angewandte
Chemie
Scheme 4. Total synthesis of zoanthenol. Reagents and conditions: a) AcOH (aq.), 1008C, 76%. b) TMSCl, LDA, THF, À508C. c) Pd(OAc)2,
CaCO3, CH3CN, 558C. d) TFA, 508C. e) TBSNO3, pyridine, THF, RT, 57% (4 steps). f) LDA, THF, À788C, then MeI. g) TASF, acetone, RT, 53% (2
steps). TASF=tris(dimethylamino)sulfonium difluorotrimethylsilicate, TBS=tert-butyldimethylsilyl, TFA=trifluoroacetic acid, TMS=trimethylsilyl,
LDA=lithium diisopropylamide.
was purified by reverse-phase HPLC (MeOH/H2O, 1:1) to
give the pure zoanthenol in 53% yield in two steps. The
spectroscopic data of the synthetic compound were in agree-
ment with those of the natural product, including optical
rotation
([a]2D0 = + 7.0 degcm3 gÀ1 dmÀ1
(c = 0.18 gcmÀ3
,
CHCl3); natural zoanthenol:[6] [a]2D0 = + 7.1 degcm3 gÀ1 dmÀ1
(c = 0.24 gcmÀ3, CHCl3)), IR, 1H and 13C NMR spectroscopy,
and mass spectrometry.
Although the proposed structure of 3 was successfully
verified by the present synthesis, we should point out that all
of the aromatic compounds (14–16), as well as 3, are highly
air-sensitive, probably resulting in oxidation at the benzylic
position, and ultimately decomposition. For example, approx-
imately one third of zoanthenol decomposed during the 36 h
13C NMR acquisition time in CDCl3 (neutralized by basic
Al2O3), and circa 30% of neat TBS ether 16 decomposed over
several days of refrigerated storage (À208C). Therefore, to
minimize oxidative decomposition in air, these compounds
were handled under an argon atmosphere with studious care
taken in their isolation and purification.
We also studied an alternative synthetic approach from
commercially available norzoanthamine hydrochloride
(1·HCl)[20] to zoanthenol, because Uemura and co-workers
have reported the efficient conversion of the former into
(15S)-15,16-dihydronorzoanthamine (17),[1c] the C15 epimer
of 12, by simple catalytic hydrogenation (Scheme 5). Thus,
norzoanthamine hydrochloride was hydrogenated over Pd/C
in methanol to produce 17 (95% yield), which was trans-
formed into the TBS ether 15 by a four-step reaction
sequence, similar to that from 12 to 15, in 54% overall
yield. All of the spectral data for ether 15 was identical with
that of the compound previously synthesized from 11
(Scheme 4). In this way, we have established an alternative,
Scheme 5. Conversion of norzoanthamine hydrochloride into zoanthe-
nol. Reagents and conditions: a) Pd/C, H2 (1 atm), MeOH, RT, then
Et3N, 95%. b) TMSCl, LDA, THF, À508C. c) Pd(OAc)2, CaCO3, CH3CN,
558C. d) TFA, 508C. e) TBSNO3, pyridine, THF, RT, 54% (4 steps).
efficient, synthetic route from commercially available nor-
zoanthamine hydrochloride to zoanthenol. The overall yield
was 27% in seven steps.
In conclusion, we have achieved the first total synthesis of
zoanthenol (3), which features the key TFA-promoted
isoaromatization of the bis(enone) 13 to the aromatic
compound norzoanthenol (14). We have established another
efficient synthetic route for zoanthenol, starting from com-
mercially available norzoanthamine hydrochloride (1·HCl),
Angew. Chem. Int. Ed. 2009, 48, 8905 –8908
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8907

Communications
[8] a) G. Hirai, H. Oguri, M. Hirama, Chem. Lett. 1999, 141 – 142;
b) S. M. Moharram, G. Hirai, K. Koyama, H. Oguri, M. Hirama,
Tetrahedron Lett. 2000, 41, 6669 – 6673; c) G. Hirai, H. Oguri,
S. M. Moharram, K. Koyama, M. Hirama, Tetrahedron Lett.
2001, 42, 5783 – 5787; d) G. Hirai, Y. Koizumi, S. M. Moharram,
H. Oguri, M. Hirama, Org. Lett. 2002, 4, 1627 – 1630; e) G. Hirai,
H. Oguri, M. Hayashi, K. Koyama, Y. Koizumi, S. M. Moharram,
M. Hirama, Bioorg. Med. Chem. Lett. 2004, 14, 2647 – 2651; f) N.
Sugano, Y. Koizumi, G. Hirai, H. Oguri, S. Kobayashi, S.
Yamashita, M. Hirama, Chem. Asian J. 2008, 3, 1549 – 1557.
[9] D. R. Williams, D. C. Ihle, T. A. Brugel, S. Patnaik, Heterocycles
2006, 70, 77 – 82.
[10] a) D. C. Behenna, J. L. Stockdill, B. M. Stoltz, Angew. Chem.
2007, 119, 4155 – 4158; Angew. Chem. Int. Ed. 2007, 46, 4077 –
4080; b) J. L. Stockdill, D. C. Douglas, B. M. Stoltz, Tetrahedron
Lett. 2009, 50, 3182 – 3184; c) J. L. Stockdill, D. C. Douglas, B. A.
McClory, B. M. Stoltz, Tetrahedron 2009, 65, 6571 – 6575.
[11] D. Bondon, Y. Pietrasanta, B. Pucci, Tetrahedron Lett. 1977, 18,
821 – 824.
in seven steps. The chemistry described herein opens up a
completely new chemical avenue to 3, to the hitherto
unknown norzoanthenol, and to aromatic members of the
zoanthamine alkaloids and their synthetic derivatives.
Received: August 14, 2009
Published online: October 19, 2009
Keywords: alkaloids · isoaromatization · natural products ·
.
total synthesis · zoanthenol
[1] a) S. Fukuzawa, Y. Hayashi, D. Uemura, A. Nagatsu, K.
Yamada, Y. Ijuin, Heterocycl. Commun. 1995, 1, 207 – 214;
b) M. Kuramoto, K. Hayashi, Y. Fujitani, K. Yamaguchi, T. Tsuji,
K. Yamada, Y. Ijuin, D. Uemura, Tetrahedron Lett. 1997, 38,
5683 – 5686; c) M. Kuramoto, K. Hayashi, K. Yamaguchi, M.
Yada, T. Tsuji, D. Uemura, Bull. Chem. Soc. Jpn. 1998, 71, 771 –
779.
[12] M. Arai, Y. Miyauchi, T. Miyahara, T. Ishikawa, S. Saito, Synlett
2009, 122 – 126.
[2] a) C. B. Rao, A. S. R. Anjaneyula, N. S. Sarma, Y. Venkatates-
warlu, R. M. Rosser, D. J. Faulkner, M. H. M. Chen, J. Clardy, J.
Am. Chem. Soc. 1984, 106, 7983 – 7984; b) C. B. Rao, A. S. R.
Anjaneyulu, N. S. Sarma, Y. Venkatateswarlu, R. M. Rosser,
D. J. Faulkner, J. Org. Chem. 1985, 50, 3757 – 3760.
[3] For an excellent review of synthetic studies of the zoanthamine
alkaloids, see: D. C. Behenna, J. L. Stockdill, B. M. Stoltz,
Angew. Chem. 2008, 120, 2400 – 2421; Angew. Chem. Int. Ed.
2008, 47, 2365 – 2386.
[4] a) M. Miyashita, M. Sasaki, I. Hattori, M. Sakai, K. Tanino,
Science 2004, 305, 495 – 499; b) M. Miyashita, Pure Appl. Chem.
2007, 79, 651 – 655; c) F. Yoshimura, M. Sasaki, I. Hattori, K.
Komatsu, M. Sakai, K. Tanino, M. Miyashita, Chem. Eur. J. 2009,
15, 6626 – 6644.
[5] a) Y. Murata, D. Yamashita, K. Kitahara, Y. Minasako, A.
Nakazaki, S. Kobayashi, Angew. Chem. 2009, 121, 1428 – 1431;
Angew. Chem. Int. Ed. 2009, 48, 1400 – 1403; b) D. Yamashita, Y.
Murata, N. Hikage, K. Takao, A. Nakazaki, S. Kobayashi,
Angew. Chem. 2009, 121, 1432 – 1434; Angew. Chem. Int. Ed.
2009, 48, 1404 – 1406.
[13] The isoaromatization of 6-alkylidene-2-cyclohexen-1-one deriv-
atives to 2-alkylphenols has been reported by several groups:
a) T. Kobayashi, S. Kumazawa, T. Kato, Y. Kitahara, Chem. Lett.
1975, 301 – 304; b) E. Campbell, J. J. Martin, J. Bordber, E. F.
Kleinman, J. Org. Chem. 1996, 61, 4806 – 4809; c) K. Yoshida, R.
Narui, T. Imamoto, Chem. Eur. J. 2008, 14, 9706 – 9713.
[14] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011 – 1013.
[15] Other acid scavengers, such as MS4A, K2CO3, and 2,6-di-tert-
butylpyridine, were fruitless.
[16] As 13 and 14 were labile on silica gel, the crude products were
directly used in the subsequent reactions.
[17] G. H. Hakimelahi, Z. A. Proba, K. K. Ogilvie, Tetrahedron Lett.
1981, 22, 4775 – 4778.
[18] Use of an excess amount of LDA resulted in the formation of a
C19-dimethylated compound as the major product, along with
16.
[19] K. A. Scheidt, H. Chen, B. C. Follows, S. R. Chemler, D. S.
Coffey, W. R. Roush, J. Org. Chem. 1998, 63, 6436 – 6437.
[20] Norzoanthamine hydrochloride (1·HCl) is commercially avail-
able from Wako Pure Chemical Industries Ltd., and also can be
easily prepared by treatment of norzoanthamine with HCl in
methanol.[1c]
[6] A. H. Daranas, J. J. Fernꢀndez, J. A. Gavꢁn, M. Norte, Tetrahe-
dron 1999, 55, 5539 – 5546.
[7] R. M. Villar, J. Gil-Longo, A. H. Daranas, M. L. Souto, J. J.
Fernꢀndez, S. Peixinho, M. A. Barral, G. Santafꢂ, J. Rodriguez,
C. Jimꢂnez, Bioorg. Med. Chem. 2003, 11, 2301 – 2306.
8908 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 8905 –8908