Synthetic studies of the Zoanthamine alkaloids: Total synthesis of zoanthenol based on an isoaromatization strategy

Article abstract of DOI:10.1002/asia.201000552

The total synthesis of zoanthenol, a unique aromatic member of the zoanthamine alkaloids, which has exhibited potent anti-platelet activities on human platelet aggregation, is described in full detail. The key step involves a Bronsted acid-promoted isoaromatization in the AB ring system to install the crucial aromatic ring. We have not only succeeded in the first total synthesis of zoanthenol, but also established an alternative efficient synthetic route from the commercially available norzoanthamine hydrochloride to zoanthenol. The mask of zoanthenol: The total synthesis of zoanthenol is described in full detail. Zoanthenol is an aromatic member of the zoanthamine alkaloids and it has potent anti-platelet activity for human aggregation. The key step involves a Bronsted acid-promoted isoaromatization in the AB ring system to install the crucial aromatic ring (see scheme).

Full text of DOI:10.1002/asia.201000552

FULL PAPERS
DOI: 10.1002/asia.201000552
Synthetic Studies of the Zoanthamine Alkaloids: Total Synthesis of
Zoanthenol Based on an Isoaromatization Strategy
Fumihiko Yoshimura, Yu Takahashi, Keiji Tanino,* and Masaaki Miyashita*[a]
Abstract: The total synthesis of zoanthenol, a unique aromatic member of the
zoanthamine alkaloids, which has exhibited potent anti-platelet activities on
human platelet aggregation, is described in full detail. The key step involves a
Brønsted acid-promoted isoaromatization in the AB ring system to install the cru-
cial aromatic ring. We have not only succeeded in the first total synthesis of zoan-
thenol, but also established an alternative efficient synthetic route from the com-
mercially available norzoanthamine hydrochloride to zoanthenol.
Keywords: alkaloids · isoaromatiza-
tion natural products total
synthesis · zoanthenol
·
·
Introduction
suppress the loss of bone weight and strength in ovariectom-
ized mice and has been expected to be a promising candi-
date for an anti-osteoporotic drug.[1c,d] On the other hand,
zoanthamine (2), isolated by Rao and Faulker et al. in
1984,[2] has exhibited potent inhibitory activity toward phor-
bol myristate-induced inflammation in addition to powerful
analgesic effects.[2b] The remarkable biological properties of
norzoanthamine (1) and zoanthamine (2), combined with
their novel molecular architectures make this family of alka-
loids extremely attractive targets for chemical synthesis.
Indeed, great synthetic efforts have been devoted to the
total synthesis of the zoanthamine alkaloids, which Stoltz
and co-workers recently described in their excellent
Review.[3]
The zoanthamine alkaloids, isolated from the genus Zoan-
thus sp., not only have a unique array of structural and ste-
reochemical complexity but also display a range of distinc-
tive biological and pharmaceutical properties. Namely, nor-
zoanthamine (1) isolated by Uemura et al. in 1995,[1] can
We have been engaged in synthetic studies of the zoantha-
mine alkaloids[4] and already achieved the first total synthe-
ses of norzoanthamine (1) in 2004[4b] and that of zoantha-
mine (2) in 2009, respectively.[4d] As shown in Scheme 1, the
total syntheses of norzoanthamine (1) and zoanthamine (2)
feature 1) the stereoselective synthesis of the requisite
triene 4 for an intramolecular Diels–Alder reaction using
the sequential three-component coupling reactions, and sub-
sequent photosensitized oxidation of the furan ring, 2) the
key intramolecular Diels–Alder reaction to construct the
ABC carbon framework bearing two quaternary asymmetric
carbon atoms, and 3) the crucial bis-(amino)acetalization for
the construction of the DEFG ring system.
[a] Dr. F. Yoshimura, Y. Takahashi, Prof. Dr. K. Tanino,
Prof. Dr. M. Miyashita+
Division of Chemistry
Graduate School of Science
Hokkaido University, Sapporo 060-0810 (Japan)
Fax : (+81)11-706-4920
[+] Present address:
Department of Applied Chemistry, Faculty of Engineering
Kogakuin University, Hachioji 192-0085 (Japan)
Fax : (+81)42-628-4870
Recently, Kobayashi et al. reported the second total syn-
thesis of 1, which involved an elegant intramolecular Diels–
Alder reaction to construct the AB ring system, and subse-
quent synthesis of the DEFG ring system including bis-
aminal structures as the key steps.[5]
E-mail: bt13149@ns.kogakuin.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000552.
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Chem. Asian J. 2011, 6, 922 – 931

egies.[8–10] However, until we accomplished the first synthesis
of 3 in 2009,[11] the total synthesis of 3 had seriously been
impeded, owing to its densely functionalized complex ster-
eostructure. In this article, we will discuss not only the first
total synthesis of zoanthenol (3), using a synthetic inter-
mediate 27 in our synthesis of norzoanthamine (1), and an
efficient alternative synthetic route from the commercially
available norzoanthamine hydrochloride to zoanthenol (3)
in full detail.[11]
Results and Discussion
The only difference in the structures of zoanthenol (3) and
zoanthamine (2) is the oxidation pattern of the A ring.
Therefore, we envisioned two possible routes toward the
total synthesis of zoanthenol. Namely, one is the straightfor-
ward synthesis of 3 from zoanthamine (2) by aromatization
of the A ring in the latter. The other includes aromatization
of the A ring in an appropriate synthetic intermediate in the
total syntheses of 1 and 2, and subsequent transformation
into zoanthenol (3). First, we set about synthetic studies of 3
based on the former strategy. The key issue in the synthesis
of zoanthenol (3) depended on, of course, development of
an efficient synthetic method that makes the construction of
the aromatic ring possible without affecting the densely
functionalized structure of zoanthamine (2).
Scheme 1. Strategy for the total synthesis of norzoanthamine (1) and
zoanthamine (2).
Having achieved the efficient total syntheses of 1 and 2,
we next focused on the synthesis of zoanthenol (3),[6] anoth-
er representative member of the zoanthamine alkaloids
bearing a unique aromatic ring. As with norzoanthamine de-
rivatives, Zoanthenol (3) has been reported to exhibit
potent anti-platelet activity on human platelet aggregation.[7]
The unique biological properties of zoanthenol (3), com-
bined with its novel chemical structure make this alkaloid
an extremely attractive target for total synthesis as well as
norzoanthamine (1) and zoanthamine (2). Indeed, a number
of research groups have extensively studied the chemical
synthesis of zoanthenol (3) based on their distinctive strat-
One-step oxidative aromatization approach
At first, we thought that zoanthenol (3) might be derived
from zoanthamine (2) by oxidative aromatization of the A
ring in one step. To probe such possibility effectively, we
chose tetracyclic enone 11 as a model compound. The requi-
site substrate 11 was synthesized from the diketo ester 7,[4]
the key intermediate in the total synthesis of 1 and 2, ac-
cording to Scheme 2. Thus, 7 was converted into the keto
Abstract in Japanese:
Scheme 2. Synthesis of the tetracyclic enone 11. a) K-Selectride, THF,
CH2Cl2, ꢀ788C, 89%; b) Ti
odinane, CH2Cl2, RT, 73% (2 steps); d) TMSCl, LiHMDS, THF, ꢀ658C;
e) Pd(OAc)2, CH3CN, 508C, 93% (2 steps); f) TBSOTf, Et3N, CH2Cl2,
ACHTUNGRTENN(UNG OEt)4, toluene, 1008C; c) Dess–Martin peri-
AHCTUNGTRENNUNG
ꢀ658C; g) LDA, THF, ꢀ558C, then MeI, ꢀ508C; h) AcOH (aq.), RT,
86% (3 steps).
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lactone 8 by treatment with K-Selectride in THF and
CH2Cl2 at ꢀ788C. After removal of the acetyl group in 8 by
the Supporting Information). The excellent preliminary
result led us to apply the Pucci procedure to zoanthamine
(2) and its synthetic intermediate 13[4] toward the synthesis
of zoanthenol (3). However, the reactions of 2, zoanthamine
hydrochloride,[16] and 13 gave a complex mixture in every
case under these reaction conditions, and none of the corre-
sponding aromatic compound was detected. In spite of
many attempts by screening the solvent effects and stoichi-
ometry of the reagents as well as the reaction temperature,
we were unable to obtain the targeted compounds. As
copper salts have been known to coordinate with amines, we
deduced that the aminoacetal moiety in these substrates
might be decomposed under the reaction conditions.
treatment with TiACHTUNGTRENNUNG
(OEt)4 in toluene at 1008C,[12] the resulting
alcohol was oxidized with Dess–Martin periodinane[13] to
afford the diketo lactone 9 in 65% overall yield from 7. Re-
gioselective introduction of a double bond into the A ring
was successfully performed by the Ito–Saegusa method,[14]
which involved regioselective formation of trimethylsilyl
enol ether in the A ring by treatment with lithium hexame-
thyldisilazide (LiHMDS) and trimethylsilyl chloride
(TMSCl) in THF at ꢀ658C, and subsequent oxidation of the
resulting trimethylsilyl (TMS) enol ether with PdACHTNUTRGNEUNG(OAc)2 in
CH3CN at 508C, provided the desired enone 10 in 93%
yield. The tetracyclic enone 10 was transformed into the tar-
geted compound 11 by a three-step reaction sequence:
1) conversion of the enone moiety into dienol TBS ether by
treatment with tert-butyldimethylsilyl trifluoromethanesulfo-
nate (TBSOTf) and Et3N in CH2Cl2 at ꢀ658C; 2) stereose-
lective introduction of a methyl group at the C19 position
by treatment of the TBS ether with lithium diisopropyla-
mide (LDA) and MeI in tetrahydrofuran (THF) at ꢀ508C;
3) hydrolysis of the resulting dienol TBS ether with aqueous
AcOH, in 86% overall yield from 10.
Stepwise dehydrogenation approach
We next examined another approach to construct the aro-
matic ring E, using homoannular dienol acetate B or its re-
gioisomer C, by means of dehydrogenation with DDQ or
chloranil as shown in Scheme 4, though an alternative possi-
With the model compound 11 in hand, we studied the key
oxidative aromatization of 11, which led to the aromatic
compound 12 (Scheme 3). Initial attempts to aromatize the
Scheme 4. Stepwise dehydrogenation approach to zoanthenol (3).
ble regioisomer D may not undergo aromatization. The
requisite dienol acetates B and/or C will probably be de-
rived from the dienone precursor A by treatment with an
appropriate base and acetic anhydride (Ac2O). In this con-
text, regioselective generation of dienolate anions from 3-
methyl-2-cyclohexenone derivatives have been reported in
the literature.[17] Alternatively, B and/or C may be derived
by acid-catalyzed enol acetylation of A.
Scheme 3. Attempts at one-step oxidative aromatization using CuBr2/
LiBr.
Toward this end, we first examined the reaction of the tet-
racyclic enone 11 (Scheme 5). Thus, when 11 was treated
with potassium hexamethyldisilazide (KHMDS) in THF at
ꢀ788C followed by an addition of Ac2O, a mixture of the
exocyclic dienol acetate 15 and endocyclic isomer 16 was ob-
tained in 20% and 33% yield, respectively. Interestingly, the
homoannular dienol acetate 18 was not produced under
these reaction conditions. As we expected, aromatization of
16 with DDQ (2 equiv) smoothly occurred in dioxane at
808C to afford the aromatic compound 17 in 85% isolated
yield. To improve the yield of 16, several bases were exam-
ined, however, the use of LDA and LiHMDS did not sub-
stantially affect the yield and ratio of the product 16:16
A ring by refluxing with an excess amount of 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) in benzene or diox-
ane merely resulted in recovery of the starting material.
After a number of trials, we eventually found that the proce-
dure of Pucci and co-workers[15] was effective for this partic-
ular transformation. Thus, when 11 was treated with CuBr2
(4 equiv) and LiBr (2 equiv) in CH3CN at 608C, the desired
product 12 was obtained as a single product in 83% yield.
The structure of 12 was unambiguously confirmed by NOE
measurements, which indicated that our apprehensive epi-
merization at the benzylic position did not occur at all (see
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Zoanthamine Alkaloids
the stoichiometry of catalyst,
and the reaction temperature as
well as the use of other Lewis
acids (e.g. ScACHTNUTRGENNG(U OTf)3). Soon, we
noticed that oxygen was of criti-
cal importance for this particu-
lar oxidation reaction. After a
number of experiments, we
eventually found that the aro-
matization of 11 smoothly oc-
curred under the following opti-
mized conditions, using a com-
bination of YbACHTNUTRGENNG(U OTf)3 (1 equiv),
Ac2O (10 equiv), and oxygen
(1 atm) in dioxane at 708C for
4 hours afforded the desired
product 17 in 86% yield
(Scheme 6). In addition, the ex-
periment confirmed that this ar-
omatization reaction was ex-
tremely retarded or did not
Scheme 5. Synthesis of dienol acetates and an aromatic compound.
(26%) and 15 (37%) with
LDA; exclusive formation of 15
(43%) with LiHMDS.
Encouraged by the experi-
ment that the dienol acetate 16
was an efficient precursor for
aromatization, we next focused
on the synthesis of 16 and/or 18
under acidic conditions. Howev-
er, all the reactions with TsOH
or camphorsulfonic acid (CSA)
in the presence of Ac2O did not
occur at all and only the start-
ing material was recovered un-
changed.
At this stage, we anticipated
that the use of a rare-earth
metal triflate might act as an ef-
fective catalyst for this particu-
Scheme 6. YbACHTNUTRGNE(UNG OTf)3-mediated oxidative aromatization to aromatic acetates.
lar transformation, since it is well known that rare-earth
metal triflates effectively catalyze acylation of alcohols with
acid anhydrides, and formation of geminal diacetate from al-
dehydes with Ac2O.[18] In addition, these catalysts are known
to be active even in the presence of Lewis bases containing
nitrogen and oxygen atoms,[19] and this seems to be ideally
suited for the highly functionalized zoanthamine alkaloids.
occur in the dark. Therefore, the following reaction mecha-
nism may be most probable (Scheme 7): 1) formation of the
enol acetate 16 in situ; 2) a Diels–Alder reaction with
oxygen leading to 21; 3) elimination of a hydroperoxide
anion from 22; 4) aromatization with a cross-conjugated
oxonium ion 23 giving rise to the product 17. A similar reac-
tion mechanism, including 1,4-adducts of enol acetates with
singlet oxygen, was recently reported by Ishikawa and
Saito;[21] this involved in air oxidation of 4-oxo-4,5,6,7-tetra-
hydroindoles with TsOH and Ac2O, leading to various 4-
acetoxyindoles.
Thus, when 11 was treated with Ac2O and YbACTHUNTRGNE(NUG OTf)3 in 1,2-
dichloroethane at 658C, surprisingly, the aromatic acetate
17[20] was directly obtained in 33% isolated yield, along with
the starting material (59%). Neither the expected dienol
acetates (16, 18) nor the exo-dienol acetate 15 was produced
under the conditions.
With this new methodology in hand for oxidative aromati-
zation, with the use of a YbACTHNUTRGNE(NUG OTf)3 catalyst, this methodolo-
The unexpected but gratifying result prompted us to in-
gy was applied to zoanthamine (2), zoanthamine hydrochlo-
ride (2·HCl), and its synthetic intermediate 13 toward the
total synthesis of zoanthenol (3; Scheme 6). However, disap-
vestigate Yb
ACHTUNGTRENNUNG(OTf)3-mediated aromatization of 11, thus lead-
ing to 17 in detail, particularly focusing on solvent effects,
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Scheme 8. Synthetic strategy for zoanthenol (3) based on isoaromatiza-
tion.
Scheme 7. Possible reaction mechanism of aromatization.
pointingly, all the reactions gave a complex mixture, which
is probably due to decomposition of the aminoacetal moiety
under the reaction conditions. Consequently, we employed
another synthetic approach toward the synthesis of zoanthe-
nol (3).
Synthetic approach by means of isoaromatization
At this stage, we remembered the aminoacetalization steps
(cf. 6!1, Scheme 1) in the total synthesis of norzoantha-
mine (1),[4] which involved the following reaction sequence:
1) removal of the tert-butoxycarbonyl (Boc) group and sub-
sequent formation of an iminium ion by treatment with
aqueous AcOH at 1008C; 2) hydrolysis of the methyl ester
followed by lactonization with aqueous trifluoroacetic acid
(TFA) at 1108C. These reactions suggest that the use of
Brønsted acids did not essentially affect the aminoacetal
moiety. Based on such assumption, we designed a new strat-
egy for construction of the aromatic ring (H) by means of a
Scheme 9. Model studies on isoaromatization. a) LDA, TMSCl, THF,
ꢀ708C; b) Pd
ACHTUNGTRNEN(UNG OAc)2, CH3CN, 508C; c) TFA, 508C, 42% (3 steps); d)
TBSNO3, pyridine, THF, RT, 82%; e) LiHMDS, THF, ꢀ788C, then MeI,
ꢀ788C; f) TASF, acetone, RT, 86% (3 steps).
Brønsted acid-mediated isoaromatization[22] of bis
(G) through double tautomerization, as shown in Scheme 8.
The requisite bis(enone) (G) may be derived from diketone
ACHTUNGTRNE(NUNG enone)
Although acetic acid induced isoaromatization of 24 at
1008C was not reproducible, the expected result was ob-
tained by treatment of 24 with TFA at 508C, thereby giving
rise to the aromatic compound 25 in 42% overall yield from
9. On the other hand, treatment of 24 with other Brønsted
acids such as TfOH at 08C, or SiO2 in EtOAc at 808C, did
not give satisfactory results.[23]
ACHTUNGTRENNUNG
(F) by a regioselective dehydrogenation reaction at the
C15–C16 and C18–C19 bonds. The new strategy for aromati-
zation, based on isoaromatization, followed by a stereoselec-
tive introduction of a methyl group at the C19 position
could direct us to the summit of zoanthenol (I).
We first synthesized the bis
(enone) 24 as a model sub-
Having discovered the new synthetic methodology for ar-
omatization, the remaining task for the synthesis of the tar-
geted compound 12, corresponding to the ABC ring system
of zoanthenol (3), was a stereoselective introduction of a
methyl group at the benzylic position. For this purpose, the
phenolic hydroxy group in 25 was initially protected as a
TBS ether by treatment with TBSNO3[24] in THF in the pres-
ence of pyridine (82% yield). It should be noted that when
strate (Scheme 9). Fortunately, 24 was readily derived from
the diketone 9 by means of the Ito–Saegusa method, which
involved regioselective formation of the bis(silyl enol ether)
by treatment with LDA and TMSCl at ꢀ708C followed by
oxidation with PdACHTUNGTRENNUNG(OAc)2 in CH3CN at 508C. Since the bis-
ACHTUNGTRENNUNG
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Zoanthamine Alkaloids
silylation was carried out under the generally used condi-
tions (e.g., TBSCl/Et3N or TBSCl/imidazole), the TBS enol
ether 26 was produced as the major product. In addition,
the silylation reaction of 25 with 1-(tert-butyldimethylsilyl)-
imidazole[25] in 1,2-dichloroethane resulted in formation of
the phenolic TBS ether of 25 in lower yield (58%), and a
substantial amount of the starting material was recovered.
Thus, the use of TBSNO3 was of critical importance for this
particular silylation reaction. The subsequent key methyla-
tion reaction at the benzylic position was successfully per-
formed by treatment of the phenolic TBS ether of 25 with
LiHMDS and MeI in THF at ꢀ788C. Finally, deprotection
of the TBS group with TASF (tris(dimethylamino)sulfonium
difluorotrimethylsilicate)[26] in acetone furnished the target-
ed compound 12 in 86% overall yield from 25. We should
point out that all other conditions examined to remove the
TBS group, such as aqueous AcOH, TFA, 1m HCl (aq.) in
THF, and tetrabutylammonium fluoride (TBAF) in THF, af-
forded lower yields of 12.
desired bisACTHNGUTERNNUG
(enone) 29 in good yield.[27] As the silyl enol
ether in the B ring was readily hydrolyzed by acetic acid
generated in situ, an addition of CaCO3 was of critical im-
portance for the latter reaction, while other acid scavengers,
such as MS4ꢁ, K2CO3, and 2,6-di-tert-butylpyridine, were
fruitless. The key aromatization was performed by treatment
of 29 with TFA at 508C for 1.5 h to provide the long-await-
ed aromatic compound 30,[28] that is, norzoanthenol. It
should be pointed out that norzoanthenol (30) was isolated
and characterized for the first time by the present synthesis;
isolation of norzoanthenol from natural sources has not
been reported yet.
The remaining task for the total synthesis of zoanthenol
(3) was the regio- and stereoselective introduction of a
methyl group onto the B ring. For this purpose, 30 was ini-
tially transformed into the TBS ether 31 by treatment with
TBSNO3 and pyridine in THF in 57% overall yield from 28.
The subsequent introduction of a methyl group at the C19
position was performed by treatment of 31 with LDA
(1.5 equiv) in THF at ꢀ788C followed by an addition of
MeI (20 equiv) to afford the methylated product 32 in a ste-
reoselective manner.[29] Finally, desilylation of the TBS ether
32 with TASF in acetone furnished the crude zoanthenol,
which was purified by reverse phase HPLC (Inertsil ODS-3,
MeOH/H2O=1:1), thereby giving rise to the pure zoanthe-
nol (3) in 53% yield over two steps. The spectral data of the
synthetic compound were in agreement with those of the
natural product, including optical rotation (½aꢁ2D8 =+7.0 (c=
0.18 in CHCl3); natural zoanthenol:[6] ½aꢁD25 =+7.1 (c=0.24 in
CHCl3), 1H and 13C NMR spectra, IR, and mass spectra.
Although the proposed structure of zoanthenol (3) was
verified by the present synthesis, we should point out that
all the aromatized compounds (30–32), as well as zoanthenol
(3), were highly sensitive to air, probably resulting in air oxi-
dation at the benzylic position and ultimately decomposi-
Total synthesis of zoanthenol
With the new synthetic methodology for construction of the
aromatic ring in hand, we focused on the total synthesis of
zoanthenol (3), starting from the key intermediate 27[4] in
the total synthesis of norzoanthamine (1) and zoanthamine
(2) (Scheme 10). First, 27 was converted into dihydronor-
zoanthamine (28) by treatment with aqueous AcOH at
1008C in 76% yield. The crucial precursor bisACHTNUTRGNE(NUG enone) 29 for
aromatization was derived from 28 by means of the Ito–Sae-
gusa method. Thus, treatment of 28 with an excess amount
of LDA (8 equiv) and TMSCl (6 equiv) in THF at ꢀ508C
furnished TMS enol ethers at the ketone functions in the
AB ring, and subsequent treatment of the bis(silyl enol
ether) with PdACHTUNGTRENNUNG(OAc)2 and CaCO3 in CH3CN produced the
Scheme 10. Total synthesis of zoanthenol (3). a) AcOH (aq.), 1008C, 76%; b) TMSCl, LDA, THF, ꢀ508C; c) Pd
ACHTUGNTREN(NUNG OAc)2, CaCO3, CH3CN, 558C; d) TFA,
508C; e) TBSNO3, pyridine, THF, RT, 57% (4 steps); f) LDA, THF, ꢀ788C, then MeI; g) TASF, acetone, RT, 53% (2 steps).
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M. Miyashita and K. Tanino et al.
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tion.[30] For example, approximately one third of zoanthenol
(3) was decomposed during the 36 hours 13C NMR acquisi-
tion time in CDCl3 (neutralized by basic Al2O3), and circa
30% of neat TBS ether 31 decomposed over several days of
refrigerated storage (ꢀ208C). Therefore, in order to mini-
mize decomposition in air, these compounds were handled
under an argon atmosphere with studious care taken in their
isolation and purification.
On the other hand, aiming at an alternative synthesis of
zoanthenol (3), one-pot manipulation including isoaromati-
zation, deprotection of the Boc group, and subsequent imi-
nium ion formation, was examined using bis
ACHTUNGTREN(NUNG enone) 34. The
bis
ACHTUNGTRENNUNG
steps as shown in Scheme 11. Contrary to our expectation,
however, treatment of 34 with aqueous AcOH at 1008C
caused decomposition and the cyclized iminium ion 35 was
not detected at all.
Scheme 12. Conversion of norzoanthamine hydrochloride to zoanthenol
(3). a) Pd/C, H2 (1 atm), MeOH, RT, then Et3N, 95%; b) TMSCl, LDA,
THF, ꢀ508C; c) Pd
ACHTNUGRTEN(NUGN OAc)2, CaCO3, CH3CN, 558C; d) TFA, 508C;
e) TBSNO3, pyridine, THF, RT, 54% (4 steps).
hydroxyl group with TBSNO3 in THF, in 54% overall yield.
All the spectral data of the synthetic compound 31 were
identical with those of the previously synthesized compound
from 28 (Scheme 10). Thus, we have established an alterna-
tive efficient synthetic route from commercially available
norzoanthamine hydrochloride to zoanthenol (3). The over-
all yield for this particular conversion was 27% in seven
steps.
Conclusions
Scheme 11. Unsuccessful synthetic route to zoanthenol through 34.
a) LDA, TMSCl, THF, ꢀ708C; b) Pd
ACHTUNGTREN(NGNU OAc)2, CH3CN, 508C, >99%
(2 steps); c) AcOH (aq.), 1008C.
In summary, we have achieved the first total synthesis of
zoanthenol (3), which involves the novel TFA-promoted iso-
aromatization of the bisACTHNUTRGNE(NUG enone) 29 to the aromatic com-
pound 30, norzoanthenol, as the key step. We have also es-
tablished another efficient synthetic route to zoanthenol (3),
starting from the commercially available norzoanthamine
hydrochloride (1·HCl), in seven steps. It is noteworthy that
three types of the representative zoanthamine alkaloids, nor-
zoanthamine (1), zoanthamine (2), and zoanthenol (3) were
efficiently synthesized through the common intermediate 27.
The chemistry described herein opens up a completely
new chemical avenue to zoanthenol (3), to the hitherto un-
known norzoanthenol (30), and to aromatic members of the
zoanthamine alkaloids and their synthetic derivatives.
Conversion of norzoanthamine hydrochloride into
zoanthenol
We next studied an alternative synthetic approach from
commercially available norzoanthamine hydrochloride
(1·HCl)[31] to zoanthenol (3), as Uemura and co-workers re-
ported the efficient conversion of the former into (15S)-
15,16-dihydronorzoanthamine (36),[1c] the C15 epimer of 28,
by simple catalytic hydrogenation (Scheme 12). Indeed, nor-
zoanthamine hydrochloride was efficiently converted into 36
by hydrogenation over Pd/C in MeOH and subsequent de-
salination with Et3N in 95% yield, which was then trans-
formed into the TBS ether 31 by a four-step reaction se-
quence similar to that from 28 to 31: 1) regioselective forma-
tion of bis-trimethylsilyl enol ethers at the ketone functions
in the AB ring; 2) oxidation of the resulting bis(silyl enol
Experimental Section
Materials and methods
ether) with Pd
ACHTUNGTRENNUNG(OAc)2 in the presence of CaCO3 in CH3CN;
All the reactions were carried out in a round-bottomed flask with an ap-
propriate number of necks and sidearms connected to a three-way stop-
3) isoaromatization with TFA; 4) protection of the phenolic
928
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 922 – 931

Zoanthamine Alkaloids
cock and/or a rubber septum cap under an argon atmosphere. All vessels
were first evacuated by a rotary pump and then flushed with argon prior
to use. Solutions and solvents were introduced by a hypodermic syringe
through a rubber septum. During the reaction, the vessel was kept under
a positive pressure of argon. Dry THF was freshly prepared by distilla-
tion from sodium benzophenone ketyl before use. Anhydrous acetone,
CH3CN, CH2Cl2, dioxane, MeOH, and pyridine were purchased from
Kanto Chemical Co. Inc. In order to minimize decomposition by air oxi-
dation, extreme care was taken in the handling and isolation of sensitive
compounds, especially for zoanthenol (3) and its aromatic precursors
(30–32). These compounds were always handled under an argon atmos-
phere.
A mixture of the crude TMS enol ether (11.8 mmol), CaCO3 (12 mg,
118 mmol), and CH3CN (0.3 mL) was stirred at room temperature for
5 min. Then, PdACHTNUGTRENUNG(OAc)2 (10.6 mg, 47.4 mmol), and the mixture was stirred
at 558C for 1.5 h. The reaction mixture was cooled to room temperature
and filtered through a pad of celite by the aid of EtOAc (0.5 mL). A sa-
turated aqueous solution of NaHCO3 (0.5 mL) and l-serine (15 mg,
143 mmol) was added to the filtrate and the mixture was vigorously
stirred at room temperature for 1 h. The organic layer was separated and
the aqueous layer was extracted with EtOAc. The combined organic ex-
tracts were dried over Na2SO4 and concentrated under reduced pressure
to give the bis
crude bis(enone) 29 was used for the next step without purification.
Norzoanthenol (30): A solution of the crude bis(enone) 29 (11.8 mmol, a
ACHTUNGTREN(NUGN enone) 29 as a 50:3 mixture with norzoanthamine (1). The
AHCTUNGTRENNUNG
Infrared (IR) spectra were recorded on a JASCO FT/IR-4100 spectro-
photometer using 5 mm NaCl plates. Wavelength of maximum absorb-
ACHTUNGTRENNUNG
50:3 mixture with 1) in TFA (0.5 mL) was heated at 508C for 1.5 h. After
the mixture was cooled to room temperature, phosphate buffer (pH 7.4,
0.5 mL) and EtOAc (0.5 mL) were added. After being stirred at room
temperature for 30 min, the product was throughly extracted with
EtOAc. The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to give norzoanthenol
(30) as a 50:3 mixture with norzoanthamine (1). The crude norzoanthenol
(30) was used for the next step without purification.
ance are quoted in cmꢀ1 1H NMR spectra were recorded on a JEOL
.
ECA-500 (500 MHz) in CDCl3 with (CH3)4Si as an internal standard.
Chemical shifts are reported in parts per million (ppm), and signals are
expressed as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m),
broad (br). 13C NMR spectra were recorded on
a JEOL ECA-500
(125 MHz) or JEOL ECA-600 (150 MHz) in CDCl3 with (CH3)4Si as an
internal standard. Chemical shifts are reported in ppm. High resolution
mass spectra (HRMS) were recorded on a JEOL JMS AX-500, JEOL
JMS-SX102A or JEOL JMS-T-100GCV at the GC-MS and NMR Labo-
ratory, Graduate School of Agriculture, Hokkaido University. Analytical
thin-layer chromatography (TLC) was performed using 0.25 mm E.
Merck Silica gel (60F-254) plates. Reaction components were visualized
by illumination with ultraviolet light (254 nm) and by staining with 6%
ethanolic p-anisaldehyde (includes 6% conc. sulfuric acid and 1% acetic
acid), 8% ethanolic phosphomolybdic acid, or ceric ammonium molyb-
date in 10% sulfuric acid. Kanto Chem. Co. Silica Gel 60N (particle size
0.040–0.050 mm) was used for column chromatography.
For characterization, further purification by reverse phase HPLC (Inertsil
ODS-3, 10 mm x 50 mm, MeOH/H2O=1:1) afforded the pure norzoane-
nol (30) as an amorphous solid. 1H NMR (CDCl3, 500 MHz): d=6.58 (s,
1H), 6.51 (s, 1H), 5.48–4.87 (br, 1H), 4.61–4.58 (m, 1H), 3.77 (d, J=
20.6 Hz, 1H), 3.64 (d, J=21.8 Hz, 2H), 3.43–3.38 (m, 2H), 3.38 (d, J=
20.6 Hz, 1H), 3.22 (s, 1H), 2.61 (d, J=13.7 Hz, 1H), 2.53 (d, J=13.7 Hz,
1H), 2.46 (d, J=20.6 Hz, 1H), 2.38–2.32 (m, 4H), 2.31 (s, 3H), 2.13 (dd,
J=12.9, 4.9 Hz, 1H), 1.91 (td, J=12.7, 3.8 Hz, 1H), 1.79 (dd, J=10.0,
3.7 Hz, 1H), 1.73 (dd, J=13.7, 4.0 Hz, 1H), 1.63–1.56 (m, 2H), 1.49 (td,
J=12.6, 2.7 Hz, 1H), 1.16 (s, 3H), 1.11 (s, 3H), 1.10 (s, 3H), 0.93 ppm (d,
J=6.9 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=208.17, 200.29, 153.47,
138.04, 115.62, 114.10, 112.79, 102.30, 90.21, 74.52, 57.41, 47.48, 44.61,
41.56, 40.81, 39.98, 39.15, 39.01, 36.88, 35.82, 30.20, 28.60, 23.97, 23.20,
22.90, 22.10, 21.70, 21.51, 18.73 ppm; IR (film): n˜ =3600–3000 (br), 2952,
Additional experimental procedures are available in the Supporting In-
formation.
Compound 28:
A
solution of the carboxylic acid 27[4] (16.8 mg,
27.9 mmol) in aqueous AcOH (AcOH/H2O=24:1, 0.5 mL) was heated at
1008C for 24 h. The reaction mixture was concentrated under reduced
pressure and the residue was dissolved in EtOAc (1 mL) containing Et3N
(100 mL). The solution was stirred at room temperature for 20 min. Water
was added to the mixture and the product was thoroughly extracted with
EtOAc (ꢂ5). The combined organic extracts were washed with brine,
dried over MgSO4, and concentrated under reduced pressure. Purification
by silica gel column chromatography (hexane/EtOAc=1:3) afforded
10.2 mg (76%) of dihydronorzoanthamine (28) as a colorless solid. M.p.
274–2768C; ½aꢁ3D2 =+33.6 (c=0.21 in CH2Cl2); 1H NMR (CDCl3,
500 MHz): d=4.55–4.53 (m, 1H), 3.62 (d, J=20.0 Hz, 1H), 3.25–3.19 (m,
2H), 2.83 (s, 1H), 2.79 (td, J=11.9, 5.5 Hz, 1H), 2.70 (dd, J=13.5,
11.7 Hz, 1H), 2.62–2.54 (m, 2H), 2.35 (d, J=20.0 Hz, 1H), 2.31 (dd, J=
14.3, 5.2 Hz, 1H), 2.28–2.21 (m, 1H), 2.14 (d, J=14.3 Hz, 1H), 2.08 (dd,
J=13.2, 4.6 Hz, 1H), 2.00 (td, J=12.5, 3.2 Hz, 1H), 1.89 (td, J=13.2,
4.6 Hz, 1H), 1.83–1.78 (m, 2H), 1.67 (td, J=13.6, 3.6 Hz, 1H), 1.55 (dd,
J=13.7, 4.6 Hz, 1H), 1.45 (td, J=12.7, 2.9 Hz, 1H), 1.17 (s, 3H), 1.09–
1.07 (m, 1H), 1.02 (d, J=7.4 Hz, 3H), 1.00 (s, 3H), 0.99 (s, 3H),
0.90 ppm (d, J=6.3 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=209.58,
209.21, 172.54, 101.69, 89.91, 74.16, 59.49, 52.05, 51.04, 47.26, 46.98, 44.39,
42.54, 42.14, 40.45, 39.83, 38.82, 36.44, 35.83, 30.89, 29.93, 29.80, 23.59,
22.91, 21.79, 21.03, 19.56, 18.42, 17.80 ppm; IR (film): n˜ =2959, 2927,
2871, 1713, 1383, 1363, 1341, 1320, 1308, 1287, 1277, 1246, 1237, 1186,
923, 910 cmꢀ1; HRMS (FD): m/z: calcd for C20H28O5: 483.2985; found:
483.2965 [M]+.
2925, 2870, 1713, 1684, 1591, 1454, 1361, 1269, 1247, 1191, 913, 732 cmꢀ1
;
HRMS (FD): m/z: calcd for C29H37NO5: 479.2672; found: 479.2682 [M]+.
Compound 31: Pyridine (29 mL, 354 mmol) was added to a mixture of nor-
zoanthenol (30; 11.8 mmol, a 50:3 mixture with 1) and AgNO3 (30 mg,
177 mmol) in THF (150 mL), and the resulting mixture was stirred at
room temperature for 0.5 h at which point most of silver complex was
dissolved. Then TBSCl (18 mg, 118 mmol) was added, and the resulting
mixture was stirred at room temperature for 1.5 h. After addition of
water, the resulting mixture was filtered through a cotton plug by the aid
of EtOAc. The organic layer was separated and the aqueous layer was
extracted with EtOAc. The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. Purification by silica
gel column chromatography (hexane/EtOAc=1:1) afforded 4.0 mg (57%
from 28) of the TBS ether 31 as a colorless amorphous solid. The TBS
29
ether 31 was used for next step immidiately due to its instability. ½aꢁD
=
1
ꢀ11.4 (c=0.34 in CH2Cl2); H NMR (CDCl3, 500 MHz): d=6.60 (s, 1H),
6.52 (s, 1H), 4.60–4.56 (m, 1H), 3.77 (d, J=20.0 Hz, 1H), 3.62 (d, J=
22.3 Hz, 1H), 3.40 (ddd, J=13.2, 7.4, 6.3 Hz, 2H), 3.34 (d, J=22.3 Hz,
1H), 3.20 (s, 1H), 2.60 (d, J=13.7 Hz, 1H), 2.52 (d, J=14.3 Hz, 1H),
2.45 (dd, J=20.0, 1.1 Hz, 1H), 2.37–2.34 (m, 1H), 2.32 (s, 3H), 2.14 (dd,
J=12.9, 4.9 Hz, 1H), 1.90 (dt, J=13.2, 6.9 Hz, 1H), 1.78–1.75 (m, 2H),
1.62–1.55 (m, 2H), 1.49 (td, J=12.6, 2.7 Hz, 1H), 1.16 (s, 3H), 1.11 (3H,
s), 1.10 (3H, s), 1.00 (s, 9H), 0.93 (d, J=6.3 Hz, 3H), 0.26 (s, 3H),
0.24 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=208.43, 190.08,
153.33, 150.83, 119.67, 116.77, 115.59, 101.91, 89.95, 74.27, 57.10, 47.22,
44.35, 41.65, 41.34, 39.73, 38.91, 38.81, 36.61, 35.60, 29.97, 29.69, 28.38,
25.73, 24.69, 23.74, 22.96, 21.85, 21.26, 18.48, 18.22, ꢀ40.4, ꢀ4.17 ppm; IR
Compound 29:
A solution of dihydronorzoanthamine (28) (5.7 mg,
11.8 mmol) and TMSCl (9.0 mL, 70.7 mmol) in THF (0.2 mL) was added
dropwise to a freshly prepared solution of LDA (1.0m) in THF (94 mL,
94 mmol) at ꢀ788C and the mixture was stirred at ꢀ508C for 1.5 h. A sa-
turated aqueous solution of NaHCO3 containing Et3N was added to the
reaction mixture and the product was extracted with EtOAc. The organic
extract was dried over Na2SO4 and concentrated under reduced pressure.
The crude TMS enol ether was used for the next step without purifica-
tion.
(film): n˜ =2953, 2927, 2857, 1716, 1542, 1457, 1362, 1251, 1189, 836 cmꢀ1
;
HRMS (FD): m/z: calcd for C35H51NO5Si: 593.3537; found: 593.3523
[M]+.
Compound 32: A freshly prepared solution of LDA (1.0m) in THF
(12.4 mL, 12.4 mmol) was added to a solution of the TBS ether 31 (4.9 mg,
8.3 mmol) in THF (100 mL) at ꢀ788C and the mixture was stirred at the
Chem. Asian J. 2011, 6, 922 – 931
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
929

M. Miyashita and K. Tanino et al.
FULL PAPERS
same temperature for 1 h. Then MeI (10.2 mL, 165 mmol) was added and
the mixture was stirred at ꢀ788C for 2 h. Water was added to the mixture
and the product was extracted with EtOAc. The combined organic ex-
tracts were dried over Na2SO4 and concentrated under reduced pressure
to give the methylation product 32 as a 3:1 mixture with 31. The crude
methylation product 32 was used for next step without purification.
2 min. Then PdACTHUGNTERNNU(G OAc)2 (13.7 mg, 61.2 mmol) was added and the mixture
was stirred at 558C for 1.5 h. The reaction mixture was cooled to room
temperature and filtered through a pad of celite by the aid of EtOAc
(0.5 mL). A saturated aqueous solution of NaHCO3 (0.5 mL) and l-
serine (15 mg, 143 mmol) was added to the filtrate, and the mixture was
vigorously stirred at room temperature for 1 h. The organic layer was
separated and the aqueous layer was extracted with EtOAc. The com-
bined organic extracts were dried over Na2SO4 and concentrated under
reduced pressure to give the bisACHTNUGTRENNUNG
zoanthamine (1). The crude bisACHTNUGTRENNUNG
without purification.
Zoanthenol (3): A solution of TASF (9.0 mg, 33.2 mmol) in acetone
(100 mL) was added to the crude methylation product 32 (8.3 mmol, a 3:1
mixture with 31), and the mixture was stirred at room temperature for
1 h. The reaction was quenched by addition of phosphate buffer solution
(pH 7.4, 0.5 mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated under reduced pressure.
Purification by reverse phase HPLC (Inertsil ODS-3, 10 mm x 50 mm,
MeOH/H2O=1:1) afforded 2.2 mg (53% from 31) of the pure zoanthe-
nol (3) as an amorphous solid. ½aꢁ2D8 =+7.0 (c=0.18 in CHCl3); lit.:[6]
½aꢁ2D5 =+7.1 (c=0.24 in CHCl3); 1H NMR (CDCl3, 500 MHz): d=6.55 (s,
1H), 6.48 (s, 1H), 4.62–4.57 (m, 1H), 3.91 (d, J=20.0 Hz, 1H), 3.56 (s,
1H), 3.55 (q, J=6.9 Hz, 1H), 3.42 (d, J=6.3 Hz, 1H), 3.37 (t, J=6.3 Hz,
1H), 2.64 (d, J=13.7 Hz, 1H), 2.50 (d, J=13.7 Hz, 1H), 2.44 (dd, J=
20.0, 1.1 Hz, 1H), 2.36–2.33 (m, 1H), 2.30 (s, 3H), 2.14 (dd, J=13.2,
5.2 Hz, 1H), 1.92 (td, J=13.6, 4.8 Hz, 1H), 1.82–1.73 (m, 1H), 1.54 (d,
J=6.9 Hz, 3H), 1.50–1.39 (m, 1H), 1.17 (s, 3H), 1.13 (dd, J=12.0,
10.3 Hz, 1H), 1.11 (s, 3H), 1.06 (s, 3H), 0.93 ppm (d, J=6.3 Hz, 3H);
13C NMR (CDCl3, 150 MHz): d=201.28, 150.74, 138.17, 116.05, 115.02,
102.28, 90.24, 74.50, 52.54, 47.46, 46.66, 44.68, 41.75, 40.61, 40.04, 39.14,
36.33, 36.01, 32.12, 30.06, 29.57, 23.93, 22.90, 22.06, 21.49, 21.19,
18.52 ppm; IR (film): n˜ =3700–3100 (br), 2955, 2922, 2850, 1716, 1457,
1362, 1259 cmꢀ1; HRMS (FD): m/z: calcd for C30H39NO5: 494.2866;
found: 494.2860 [M+H]+.
A solution of the bisACTHNUTRGNE(UNG enone) 29 (15.3 mmol, a 25:2 mixture with 1) in
TFA (0.5 mL) was heated at 508C for 1.5 h. After the mixture was
cooled to room temperature, phosphate buffer (pH 7.4, 0.5 mL) and
EtOAc (0.5 mL) were added. After being stirred for 30 min, the product
was throughly extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated under reduced
pressure to give norzoanthenol (30) as a 25:2 mixture with norzoantha-
mine (1). The crude norzoanthenol (30) was used for the next step with-
out purification.
Pyridine (29 mL, 354 mmol) was added to a mixture of norzoanthenol (30;
15.3 mmol, a 25:2 mixture with 1) and AgNO3 (30 mg, 177 mmol) in THF
(150 mL), and the resulting mixture was stirred at room temperature for
0.5 h at which point most of the silver complex was dissolved. Then
TBSCl (18 mg, 118 mmol) was added, and the resulting mixture was
stirred at room temperature for 1.5 h. After addition of water, the result-
ing mixture was filtered through a cotton plug by the aid of EtOAc. The
organic layer was separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were dried over Na2SO4 and con-
centrated under reduced pressure. Purification by silica gel column chro-
matography (hexane/EtOAc=1:1) afforded 4.9 mg (54% from 36) of the
TBS ether 31 as a colorless amorphous solid. The spectrospcopic data of
the synthetic compound 31 from norzoanthamine hydrochloride were all
identical with those of the previously synthesized compound from 28.
½aꢁ3D1 =ꢀ9.4 (c=0.25 in CH2Cl2); 1H NMR (CDCl3, 500 MHz): d=6.60
(1H, s), 6.52 (s, 1H), 4.62–4.57 (m, 1H), 3.76 (d, J=20.6 Hz, 1H), 3.62
(d, J=22.3 Hz, 1H), 3.43–3.38 (m, 1H), 3.34 (d, J=22.3 Hz, 1H), 3.20 (s,
1H), 2.60 (d, J=14.3 Hz, 1H), 2.52 (d, J=13.7 Hz, 1H), 2.45 (d, J=
20.0 Hz, 1H), 2.38–2.32 (m, 1H), 2.32 (s, 1H), 2.14 (dd, J=12.9, 4.9 Hz,
1H), 1.90 (td, J=13.6, 4.6 Hz, 1H), 1.79–1.70 (m, 1H), 1.78 (td, J=15.5,
3.4 Hz, 1H), 1.63–1.51 (m, 2H), 1.49–1.46 (m, 1H), 1.16 (s, 3H), 1.11 (s,
3H), 1.10 (s, 3H), 1.00 (s, 9H), 0.93 (d, J=6.3 Hz, 3H), 0.26 (s, 3H),
0.24 ppm (s, 3H); 13C NMR (CDCl3, 150 MHz): d=208.43, 190.08,
153.33, 150.83, 119.67, 116.77, 115.59, 101.91, 89.95, 74.27, 57.10, 47.22,
44.35, 41.65, 41.34, 39.73, 38.91, 38.81, 36.61, 35.60, 29.97, 29.69, 28.33,
25.73, 24.69, 23.73, 22.96, 21.85, 21.26, 18.48, 18.22, ꢀ4.04, ꢀ4.17 ppm; IR
(film): n˜ =2957, 2930, 2860, 1714, 1577, 1459, 1362, 1304, 1191, 1075,
1061, 836 cmꢀ1; HRMS (FD): m/z: calcd for C35H51NO5Si: 593.3537;
found: 593.3526 [M]+.
Compound 36: A mixture of the 5% Pd/C (purchased from Nacalai
Tesque, Inc., 4.0 mg) and MeOH (1 mL) was stirred under H2 (1 atm) at
room temperature for 15 min. A solution of norzoanthamine hydrochlo-
ride (1·HCl)[31] (11.2 mg, 21.7 mmol) in MeOH (1 mL) was added to the
mixture, and the mixture was vigorously stirred under H2 (1 atm) for 3 h.
The reaction mixture was filtered through a pad of celite with MeOH.
The filtrate was concentrated under reduced pressure and the residue
was dissolved in MeOH (1 mL) containing Et3N (15 mL, 108.5 mL) and
the solution was stirred at room temperature for 1 h. The mixture was
concentrated and the residue was purified by silica gel column chroma-
tography (hexane/EtOAc=1:3) to afford 10.0 mg (95%) of (15S)-15,16-
dihydronorzoanthamine (36) as an amorphous solid. ½aꢁ2D9 =+3.28 (c=
1
0.50 in CH2Cl2); H NMR (CDCl3, 500 MHz): d=4.56–4.52 (m, 1H), 3.62
(d, J=20.0 Hz, 1H), 3.28–3.22 (m, 2H), 2.80 (s, 1H), 2.74 (td, J=11.5,
4.6 Hz, 1H), 2.70 (q, J=12.0 Hz, 1H), 2.47 (ddd, J=13.2, 4.0, 1.7 Hz,
1H), 2.35 (dd, J=11.5, 4.6 Hz, 1H), 2.32 (dd, J=13.7, 5.2 Hz, 1H), 2.29–
2.24 (m, 1H), 2.17 (d, J=14.3 Hz, 1H), 2.08 (dd, J=13.2, 4.6 Hz, 1H),
2.05 (t, J=13.2 Hz, 1H), 1.93–1.83 (m, 2H), 1.76 (dt, J=13.0, 3.4 Hz,
1H), 1.67 (td, J=14.0, 4.0 Hz, 1H), 1.54 (td, J=8.7, 4.2 Hz, 1H), 1.46 (td,
J=12.6, 3.2 Hz, 1H), 1.27–1.25 (m, 1H), 1.15 (s, 2H), 1.12–1.05 (m, 1H),
1.11 (d, J=6.3 Hz, 3H), 0.99 (s, 3H), 0.98 (s, 3H), 0.91 ppm (d, J=
6.9 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=209.38, 208.42, 172.30,
101.48, 89.66, 73.93, 58.94, 56.16, 50.18, 49.09, 46.82, 44.14, 42.21, 41.88,
40.26, 39.55, 38.57, 36.15, 35.57, 33.53, 33.50, 29.64, 23.35, 22.65, 22.12,
21.54, 20.77, 18.07, 17.62 ppm; IR (film): n˜ =2955, 2926, 2869, 1714, 1683,
1652, 1455, 1361, 1245, 1187, 983, 912, 729 cmꢀ1; HRMS (FD): m/z: calcd
for C29H41NO5: 483.2985: found: 483.2991 [M]+.
Acknowledgements
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 Sci-
ence, Hokkaido University) are acknowledged for their mass spectral
and NMR measurements. Financial support from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan (a Grant-in-Aid for
Scientific Research (A) (No. 12304042), a Grant-in-Aid for Scientific Re-
search on Priority Areas (A) “Exploitation of Multi-Element Cyclic Mol-
ecules” (No. 13029003), and the Global COE Program (Project No. B01:
Catalysis as the Basis for Innovation in Materials Science)) is gratefully
acknowledged.
Conversion of 36 into 31: A solution of (15S)-15,16-dihydronorzoantha-
mine (36) (7.4 mg, 15.3 mmol) and TMSCl (12.0 mL, 91.8 mmol) in THF
(0.3 mL) was added dropwise to a freshly prepared solution of LDA
(1.0m) in THF (153 mL, 153 mL) at ꢀ788C, and the mixture was stirred at
ꢀ508C for 1.5 h. A saturated aqueous solution of NaHCO3 containing
Et3N was added to the reaction mixture and the product was extracted
with EtOAc. The organic layer was extracted, dried over Na2SO4, and
concentrated under reduced pressure. The crude TMS enol ether was
used for the next step without purification.
A mixture of the crude TMS enol ether (15.3 mmol), CaCO3 (15.3 mg,
153 mmol), and CH3CN (0.3 mL) was stirred at room temperature for
930
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 922 – 931

Zoanthamine Alkaloids
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Received: August 11, 2010
Published online: December 23, 2010
Chem. Asian J. 2011, 6, 922 – 931
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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