Synthetic studies of the zoanthamine alkaloids: The total syntheses of norzoanthamine and zoanthamine

Article abstract of DOI:10.1002/chem.200900310

The zoanthamine alkaloids, a type of heptacyclic marine alkaloid isolated from colonial zoanthids of the genus Zoanthus sp., have distinctive biological and pharmacological properties in addition to their unique chemical structures with stereochemical com

Full text of DOI:10.1002/chem.200900310

DOI: 10.1002/chem.200900310
Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of
Norzoanthamine and Zoanthamine
Fumihiko Yoshimura,[a] Minoru Sasaki,[a] Izumi Hattori,[a] Kei Komatsu,[a] Mio Sakai,[a]
Keiji Tanino,[a] and Masaaki Miyashita*[a, b]
Abstract: The zoanthamine alkaloids, a
type of heptacyclic marine alkaloid iso-
lated from colonial zoanthids of the
genus Zoanthus sp., have distinctive
biological and pharmacological proper-
ties in addition to their unique chemi-
cal structures with stereochemical com-
plexity. Namely, norzoanthamine (1)
can suppress the loss of bone weight
and strength in ovariectomized mice
and has been expected as a promising
candidate for a new type of antiosteo-
porotic drug, while zoanthamine (2)
has exhibited potent inhibitory activity
toward phorbol myristate-induced in-
flammation in addition to powerful an-
algesic effects. Recently, norzoantha-
mine derivatives were demonstrated to
inhibit strongly the growth of P-388
murine leukemia cell lines, in addition
to their potent antiplatelet activities on
human platelet aggregation. Their dis-
tinctive biological properties, combined
with novel chemical structures, make
this family of alkaloids extremely at-
tractive targets for chemical synthesis.
However, the chemical synthesis of the
zoanthamine alkaloids has been imped-
ed owing to their densely functional-
ized complex stereostructures. In this
paper, we report the first and highly ef-
ficient total syntheses of norzoantha-
mine (1) and zoanthamine (2) in full
detail, which involve stereoselective
synthesis of the requisite triene (18) for
an intramolecular Diels–Alder reaction
via the sequential three-component
coupling reactions, the key intramolec-
ular Diels–Alder reaction, and subse-
quent crucial bis-aminoacetalization as
the key steps. Ultimately, we achieved
the total synthesis of norzoanthamine
(1) in 41 steps with an overall yield of
3.5% (an average of 92% yield each
step) and that of zoanthamine (2) in
43 steps with an overall yield of 2.2%
(an average of 91% yield each step)
starting from (R)-5-methylcyclohexe-
none (3), respectively.
Keywords: antiosteoporotic drugs ·
cycloaddition · natural products ·
total
synthesis
·
zoanthamine alkaloids
Introduction
of key substances for drug discovery have been discov-
ered.[1]
Background: Marine species are a vast treasure trove of nat-
ural products and a wide variety of marine natural products
with novel chemical structures and distinctive biological
properties have been isolated so far, from which a number
The zoanthamine alkaloids, isolated from the genus Zoan-
thus sp., are of particular interest to both the medicinal and
synthetic communities because of their distinctive biological
and pharmaceutical properties as well as their novel molecu-
lar structures with stereochemical complexity.[2–9] Namely,
norzoanthamine (1) isolated by Uemura et al. in 1995,[2] can
suppress the loss of bone weight and strength in ovariectom-
ized mice and has been expected as a promising candidate
for an antiosteoporotic drug.[2c,10] On the other hand,
zoanthamine (2), isolated by Rao and Faulkner in 1984,[3]
has exhibited potent inhibitory activity toward phorbol myr-
istate-induced inflammation in addition to powerful analge-
sic effects.[3b,4] Recently, norzoanthamine derivatives were
demonstrated to strongly inhibit the growth of P-388 murine
leukemia cell lines in addition to their potent antiplatelet ac-
tivities on human platelet aggregation.[11] Thus, norzoantha-
mine (1) has been studied with keen interest, particularly, in
[a] Dr. F. Yoshimura, Dr. M. Sasaki, I. Hattori, Dr. K. Komatsu,
M. Sakai, 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
[b] Prof. Dr. M. Miyashita
Present address: Department of Applied Chemistry
Faculty of Engineering
Kogakuin University, Hachioji 192-0085 (Japan)
Fax : (+81)42-628-4870
E-mail: bt13149@ns.kogakuin.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900310.
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FULL PAPER
relation to the development of a new type of antiosteoporot-
ic drug for use in those advanced in age.[2c,10]
The key issues are stereoselective synthesis of the ABC
carbon framework bearing three quaternary asymmetric
carbon atoms and construction of the two aminoacetal struc-
tures in overcoming severe steric repulsion between the
methyl group at the C12 position, the bridged lactone (D
ring), and the G ring. In this article, we describe the highly
efficient total syntheses of norzoanthamine (1) and zoantha-
mine (2), the representative zoanthamine alkaloids, in full
details.
Norzoanthamine (1) and zoanthamine (2) have the same
chemical structure with the exception of the methyl group at
the C19 position as shown in Figure 1 and, therefore, it is
very interesting how the absence or presence of the C19
methyl group affects the unique biological properties of 1
and 2, respectively. Since their discovery from the metabo-
lites of the Zoanthus sp., the zoanthamine alkaloids, inter
alia, norzoanthamine (1) and zoanthamine (2) have attract-
ed much attention from a wide area of science, including
medicinal chemistry, pharmacology, natural product chemis-
try, and synthetic organic chemistry because of their remark-
able biological properties in addition to their novel molecu-
lar architectures.[12]
Results and Discussion
Synthetic strategy for norzoanthamine (1): First, we set
about synthetic studies of norzoanthamine (1) that aimed at
developing an efficient synthetic route flexible enough to
provide access to several members of the zoanthamine alka-
loids. Toward this end, we elaborated the synthetic route of
norzoanthamine (1) keeping the key issues in mind and fi-
nally reached the synthetic strategy in Scheme 1.
Namely, the DEFG-ring system including the distinctive
amino acetal structures would be constructed from the pre-
cursor keto acid (A) bearing an amino alcohol side chain by
bis-aminoacetalization. To construct the ABC-carbon frame-
work (B) stereoselectively, we designed a synthetic route via
an intramolecular Diels–Alder reaction of triene (C) based
on our preliminary synthetic studies of the ABC-ring
system.[20] We should note here that the key intramolecular
Diels–Alder reaction of triene (C) involves the construction
of two quaternary asymmetric carbon atoms, for which ex-
tremely high reaction temperature might be necessary and,
therefore, in order to lower the LUMO of the dienophile as
low as possible, two electron-withdrawing groups were in-
stalled to the dienophile moiety in the triene (C). If the key
intramolecular Diels–Alder reaction were to occur via the
exo-transition state the same as our model compound,[20] the
ABC-carbon framework (B) bearing two quaternary asym-
metric carbon atoms at the C12 and C22 positions would be
constructed in one step.
Figure 1. Molecular structures of norzoanthamine (1) and zoanthamine
(2).
The key issues in the synthesis of the zoanthamine alkaloids:
The remarkable biological properties of norzoanthamine (1)
and zoanthamine (2), combined with their novel molecular
structures make this family of alkaloids extremely attractive
targets for chemical synthesis. Indeed, great synthetic efforts
have been devoted to the total synthesis of these alka-
loids,[13–19] which Stoltz recently described in his excellent
review.[12] Synthetic studies of the zoanthamine alkaloids
had seriously been impeded, however, owing to their dense-
ly functionalized complex stereostructures, until we reached
the first total synthesis of norzoanthamine (1) in 2004.[20,21]
Very recently, Kobayashi and co-workers succeeded in the
second total synthesis of norzoanthamine (1) which involved
an elegant intramolecular Diels–Alder reaction strategy for
the construction of the AB ring system as the key step.[15d,e]
Synthetic challenges posed by norzoanthamine (1) and
zoanthamine (2) are as follows.
To synthesize the requisite triene (C) stereoselectively, we
also designed a synthetic route via sequential three-compo-
nent coupling reactions, which involves a conjugate addition
of a vinylcuprate reagent to (R)-5-methyl-2-cyclohexenone
(3),[22] followed by an aldol reaction of the resulting silyl
enol ether (E) with a furaldehyde, and subsequent photo-
sensitized oxidation of the furan derivative (D).
Synthetic studies of norzoanthamine (1): Our first objective
focused on the stereoselective synthesis of the crucial pre-
cursor triene (C) via three-component coupling reactions.
For this purpose, the preparation of lithium bis[(E)-1-
methyl-3-(triisopropylsilyl)oxy-1-propenyl]cuprate (6) and
the synthesis of 5-(tert-butyldimethylsilyl)-4-methylfurfural
(11), an aldol counterpart, were initially required, because
both compounds were unknown contrary to our expectation.
The requisite organocuprate 6 could be successfully pre-
pared by the four-step reaction sequence shown in
1) Stereoselective synthesis of the ABC carbon framework
consisting of the trans-anti-trans-fused perhydrophe-
nanthren skeleton.
2) Construction of the stereochemically dense C ring bear-
ing three adjacent quaternary asymmetric carbon atoms
at the C9, C12, and C22 positions.
3) Stereoselective construction of the two novel amino
acetal structures including a bridged d lactone (D ring)
and a spiro tetrahydropyran ring (G ring).
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M. Miyashita et al.
ed compound 11 in 88% overall
yield from 9. Although various
reagents including MnO2, PDC,
and Dess–Martin periodinane
were examined for this particu-
lar oxidation, only BaMnO4 af-
forded the furfural 11 in high
yield. Thus, 5-(tert-butyldime-
thylsilyl)-4-methylfurfural (11),
the aldol counterpart, was syn-
thesized in five steps in 78%
overall yield from acetoxy ace-
tone (7).
Synthesis of the triene 18 by
the sequential three-component
coupling reactions: With the
requisite reagents 6 and 11 in
hand, we carried out the three-
component coupling reactions.
Since the conjugate addition of
the vinylcuprate
methyl-2-cyclohexenone
6
to (R)-5-
(3)
Scheme 1. Retrosynthetic analysis of norzoanthamine (1).
was of critical importance in
Scheme 2, which involved conjugate addition of lithium
thiophenylACHTUNGTRENNUNG(tributyl)stannylcuprate to ethyl 2-butynoate (4)
in THF at À100 to À788C according to the Piers protocol,[23]
reduction of the ester with DIBAL in CH2Cl2 (94%, over
two steps), protection of the resulting alcohol with TIPSOTf
(100%), and subsequent treatment with nBuLi in THF at
À408C followed by an addition of CuBr·Me2S.
Scheme 3. Synthesis of 5-(tert-butyldimethylsilyl)-4-methylfurfural (11).
ꢀ
a) TIPSOCH2C CLi, THF, À788C, then K2CO3, MeOH, 08C; b) AgNO3,
hexane, RT, 89% (2 steps); c) nBuLi, THF, À45 to À308C, then TBSCl,
HMPA, RT; d) TBAF, THF, 08C to RT, 94% (2 steps); e) BaMnO4, ben-
zene, 708C, 94%.
Scheme 2. Preparation of (E)-di-[4-triisopropylsilyloxy]-2-butenylcuprate
(6). a) PhS
G
the present synthesis, we investigated the reaction condi-
tions in detail, particularly, focusing on the requisite but the
least quantity of nBuLi for the preparation of the cuprate,
the optimum reaction temperature for the preparation of 6
and that for the conjugate addition as well as their reaction
times. After many trials, we could eventually find the opti-
mum conditions for this particular reaction (Scheme 4).
Thus, conjugate addition of lithium (E)-di-[(4-triisopropylsi-
lyl)oxy]-2-butenylcuprate (6), which was prepared with
nBuLi (3 equiv) and CuBr·SMe2 (1.5 equiv) at À788C, to
(R)-5-methyl-2-cyclohexenone (3)[22] in the presence of
TMSCl (2 equiv)[25] in THF at À408C produced silyl enol
ether 12 in more than 90% yield, which was then subjected
to the aldol reaction with the furaldehyde 11 by means of
zinc enolate at À788C to furnish aldol 13 as a mixture of
four diastereomers in 84% yield. It should be noted that the
Michael reaction of the cuprate prepared by a combination
of nBuLi and CuI gave an approximately 2:1 mixture of 1,4-
CH2Cl2, À788C, 94% (2 steps); c) TIPSOTf, 2,6-lutidine, CH2Cl2, RT,
100%; d) nBuLi, THF, À40 to À308C, then CuBr·SMe2, À408C.
We also designed the efficient synthetic route for the
aldol counterpart 5-(tert-butyldimethylsilyl)-4-methylfurfural
(11), starting from commercially available acetoxy acetone
(7) (Scheme 3). Thus, addition of TIPSOCH2C CLi to 7 in
THF at À788C, followed by treatment with K2CO3 in
MeOH in a one-pot operation, afforded diol 8 quantitative-
ly. Upon treatment of the diol 8 with a catalytic amount of
AgNO3 in hexane at room temperature, the desired furan 9
was obtained in 89% yield.[24] Introduction of a TBS group
at the C2 position was efficiently performed by lithiation of
9 with nBuLi in THF at À45 to À308C followed by an addi-
tion of TBSCl and HMPA. Removal of the TIPS group in
10 with TBAF and subsequent oxidation of the primary al-
cohol with BaMnO4 in benzene at 708C afforded the target-
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Zoanthamine Alkaloids
FULL PAPER
and 1,2-addition products and the subsequent aldol reaction
of 12 with 11 in the absence of ZnBr2 resulted in the forma-
tion of a complex mixture. Under the optimum conditions,
the conjugate addition of 6 to 3 exclusively occurred from
the opposite side of the secondary methyl group on the cy-
clohexene ring as we expected.
steps). The requisite triene 18 was synthesized by treatment
of 17 with TBSOTf and Me2NEt in CH2Cl2 quantitatively.
Thus, the crucial precursor triene 18 including the doubly
activated dienophile moiety was synthesized efficiently and
highly stereoselectively via the sequential three-component
coupling reactions and subsequent photosensitized oxidation
of the furan 16.
The key intramolecular Diels–
Alder reaction: The next step is
the intramolecular Diels–Alder
reaction,[30] the key issue in the
present synthesis. Prior to the
Diels–Alder reaction, we ana-
lyzed feasible transition states
of the triene 18 and assumed
that the Diels–Alder reaction
of 18 would occur via the chair
conformation on the B-ring
from the result of our model
experiment.[20] Although two
transition states are feasible,
the exo and the endo transition
states as shown in Figure 2, the
exo transition state was thought
to be preferable to the endo
one, because the steric repul-
sion between the two 1,3-diaxial
methyl groups in the endo tran-
sition state was estimated larger
than that between the axial
methyl group and the ester
Scheme 4. Synthesis of the triene 18 by the three-component coupling reactions. a) TMSCl, THF, À408C;
b) nBuLi, THF, À308C, ZnBr2, À788C, then 11, À788C, 84% from 3; c) Im2C=O, toluene, 70 to 908C, 92%;
d) Et3SiH, [(C6H5)3P]3RhCl, THF, 508C; e) K2CO3, MeOH, RT, 86% (2 steps); f) LiBEt3H, THF, À788C,
98%; g) Ac2O, pyridine, 4-DMAP, CH2Cl2, RT; h) TBAF, THF, RT, 96% (2 steps); i) MnO2, CH2Cl2, RT;
j) MeLi, Et2O, À1008C; k) TPAP, NMO, MS4A, CH2Cl2, RT, 95% (3 steps); l) halogen lamp, rose bengal, O2,
CH2Cl2, 08C; m) TBAF, MeI, THF, RT, 97% (2 steps); n) TBSOTf, Me2NEt, CH2Cl2, 08C, 100%.
After dehydration of the aldols 13 by treatment with 1,1’-
thiocarbonyldiimidazole (Im2C=S) in heated toluene, the re-
sulting enones (E/Z 96:4) were subjected to the hydrosilyla-
tion reaction using Et3SiH and the Wilkinsonꢁs catalyst
([{(C6H5)3P}3RhCl])[26] in THF. Subsequent treatment of the
silyl enol ether with K2CO3 in MeOH furnished the trisub-
stituted cyclohexanone 14 with the desired stereochemistry
in 79% overall yield from 13. Reduction of the ketone 14
with LiBEt3H in THF at À788C afforded the single b-alco-
hol 15 quantitatively, which was further converted to methyl
ketone 16 by a routine five-step reaction sequence: 1) Ace-
tylation, 2) removal of the TIPS group, 3) oxidation with
MnO2, 4) addition of MeLi to aldehyde, and 5) oxidation of
the resulting secondary alcohol with TPAP[27] in 91% overall
yield.
group in the exo transition state. If the Diels–Alder reaction
occurred as we expected, the ABC carbon framework bear-
ing two quaternary asymmetric carbon atoms at the C12 and
C22 positions would be constructed in one step.
The next step involves the crucial photosensitized oxida-
tion of the furan 16 to (Z)-g-keto unsaturated silyl ester,
which is one of the key issues in the present synthesis. Fortu-
nately, photosensitized oxidation of 16 was successfully per-
formed according to the Katsumura protocol[28] with a halo-
gen lamp and rose bengal, to give (Z)-g-keto unsaturated
silyl ester quantitatively. Since the silyl ester was unstable
and prone to cyclize to butenolide hemiacetal, the crude
product was immediately converted to the stable methyl
ester 17 using TBAF and MeI[29] (97% yield, over two
Figure 2. Feasible transition states in the intramolecular Diels–Aler reac-
tion of 18.
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M. Miyashita et al.
Since the Diels–Alder reaction of 18 was the key step in
the present synthesis, we explored the optimum reaction
conditions in detail, focusing on the use of a sealed tube or
an open apparatus, with solvent or without solvent, and sol-
vent effects as well as the reaction temperature. Conse-
quently, we found that the Diels–Alder reaction of 18 did
occur at 2408C and, eventually, the key reaction was per-
formed with high efficiency by adding dropwise a solution
of 18 in 1,2,4-trichlorobenzene into the same solvent heated
at 2408C, which produced a 72:28 mixture of the exo and
the endo adducts, respectively, in 98% combined yield.
When adducts 19 were treated with HF·pyridine, the major
product 20 was readily obtainable by recrystallization in
51% isolated yield (Scheme 5), while the minor product 21
ternary asymmetric carbon center at the C9 position. To
construct this particular stereogenic center stereoselectively,
we designed the synthetic route shown in Scheme 6, which
involved an intramolecular acylation reaction of keto alco-
hol 29, followed by successive O-methylation and C-methyl-
ation reactions of the resulting b-keto lactone as the key
steps. First, the diketo ester 20 was converted to hydroxy
lactone 23 in a highly stereoselective manner by treatment
with K-selectride in THF, wherein the C10 ketone was re-
gioselectively reduced at À788C to form keto lactone 22 in
situ and, on raising the reaction temperature to 08C, another
ketone at the C20 position was stereoselectively reduced
from the b-side to afford 23. After protection of the hydrox-
yl group in 23 with a TBS group (86% yield from 20), the
acetate 24 was replaced with
TES ether in two steps, which
involved removal of the acetyl
group by treatment of 24 with
TiACTHNURTGENNUG(OEt)4 in refluxed toluene
and protection of the resulting
alcohol with a TES group, in
94% yield for the two steps. In
turn, the lactone 25 was rou-
tinely converted to diol 28 in
Scheme 5. Key Diels–Alder reaction. a) 1,2,4-trichlorobenzene, 2408C; b) HF·pyridine, THF, RT, 51%
(2 steps).
was obtained by recrystallization of the residue. The stereo-
structures of the major and the minor products were unam-
biguously confirmed by X-ray crystallographic analyses
(Figure 3) and determined to be those of the exo and the
endo adducts, 20 and 21, respectively. Thus, the intramolecu-
lar Diels–Alder reaction of the triene 18 occurred predomi-
nantly via the exo transition state as expected and the ABC
carbon framework bearing two quaternary asymmetric
carbon centers at the C12 and C22 positions could be con-
structed efficiently and stereoselectively. We should describe
here that the total yield of the ABC carbon framework 20
from 5-methylcyclohexenone (3) was remarkably high, 29%
in 16 steps.
three steps: 1) reduction of the lactone with DIBAL in tolu-
ene; 2) the Wittig reaction of lactol 26 with Ph3PCH3Br and
KOtBu in THF; 3) hydroboration of the resulting olefin 27
with 9-BBN followed by oxidative workup, in 78% overall
yield. Chemoselective oxidation of the secondary hydroxyl
group in 28 was successfully performed by the Trost proto-
col[31] using ammonium molybdate in THF, in high yield.
With the precursor keto alcohol 29 in hand, we focused
on the stereoselective construction of the quaternary asym-
metric carbon center at the C9 position (Scheme 6). The key
conversion was realized as follows. Upon treatment of 29
with (MeO)2C=O and LiOtBu in THF and HMPA at 758C,
formation of carbonate and subsequent intramolecular acy-
lation reaction smoothly occurred to generate the lithium
enolate of b-keto lactone 30 which was reacted with MeI to
give methyl enol ether 31 as a single product in 90% yield.
Although O-methylation occurred selectively in the reaction
of 30 with MeI, this unexpected result was very lucky for us,
because the more reactive ketone function in the keto lac-
tone could be unexpectedly protected as the methyl enol
ether. Further treatment of 31 with LiHMDS in THF and
DMPU, followed by an addition of MeI, produced the tar-
geted compound 33 as a single stereoisomer in 71% yield.
The second methylation reaction exclusively occurred from
the b-side of the lactone enolate, probably, via the confor-
mation shown in 32. Indeed, the stereostructure of the tetra-
cyclic lactone 33 was unambiguously determined by its NOE
measurement as shown in Figure 4. Thus, the quaternary
asymmetric carbon center of the C9 position could be nicely
constructed by the intramolecular acylation reaction of the
keto alcohol 29 followed by successive O-methylation and
C-methylation reactions with complete stereoselectivity.
Figure 3. X-ray crystallographic analyses of the major and the minor ad-
ducts.
Construction of the C9 quaternary asymmetric carbon
center: We next focused on the construction of another qua-
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Zoanthamine Alkaloids
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34 (84%, over two steps), for-
mation of enol triflate with
Tf2O in (CH2Cl)2 and subse-
quent elimination with DBU.
Although the desired product
35 was obtained in 65% yield
by this reaction sequence, the
unexpected vinyl ether 36 was
also formed in 24% yield. The
stereostructure of the vinyl
ether 36 was unambiguously de-
termined by NOE measure-
ment (Figure 4).
We rationalized the reaction
mechanism for the formation of
36 as shown in Scheme 8.
Namely, treatment of the
methyl ketone 34 with Tf2O
produces the corresponding
enol triflate 37, which was con-
verted to the alkyne 35 upon
treatment with DBU. An alter-
native route involving a 1,5-hy-
dride shift from the methylene
adjacent to the TBS ether to
the carbonyl group is also con-
ceivable. In this case, aldehyde
38 generated in situ probably
undergoes a smooth cyclization
via an enolate to give the vinyl
ether 36. This mechanistic anal-
ysis led us to use a deuterium
kinetic isotope effect. Namely,
we anticipated that a deuterium
isotope effect[32] would probably
suppress the problem 1,5-hy-
dride shift, consequently, for-
mation of 36. Based on this hy-
pothesis, the deuterium-incor-
porated methyl ketone 44 was
newly synthesized from the pre-
Scheme 6. Construction of the C9 quaternary asymmetric carbon center. a) K-selectride, THF, CH2Cl2, À78 to
08C; b) TBSOTf, 2,6-lutidine, CH2Cl2, RT, 86% (2 steps); c) TiACTHUNTRGNE(UGN OEt)4, toluene, 1008C; d) TESOTf, 2,6-luti-
dine, CH2Cl2, 08C, 94% (2 steps); e) DIBAL-H, toluene, À788C, 85% (repeated 3ꢂ); f) Ph3PCH3Br, KOtBu,
THF, 458C, 99%; g) 9-BBN, THF, 808C, then H2O2, NaOH (aq.), RT, 93%; h) (NH4)6Mo7O24·4H2O, Bu4NCl,
K2CO3, H2O2, THF, 508C, 96%; i) (MeO)2C=O, LiOtBu, HMPA, THF, 758C, then MeI, RT, 90%; j) LiHMDS,
DMPU, THF, À15 to À118C, then MeI, À118C to RT, 71%.
vious lactol 26 using a commercially available deuterated
Wittig reagent and a similar reaction sequence to that de-
scribed in the synthesis 33, in seven steps in 60% overall
yield (Scheme 9). When the deuterium-incorporated methyl
ketone 44 was subjected to the particular alkynylation reac-
tion, the alkyne 45 was obtainable in 81% yield and the for-
mation of by-product 46 was suppressed down to 9%. Thus,
the requisite alkyne segment 45 was efficiently synthesized
by exploiting a deuterium kinetic isotope effect.
Figure 4. Key NOE correlations of the methyl ketone 33 and the vinyl
ether 36.
A deuterium kinetic isotope effect in the synthesis of the
alkyne segment: Consideration of a coupling reaction with
the amino-alcohol segment led us to target synthesis of the
key alkyne segment 35 (Scheme 7). The alkyne 35 could be
derived from the lactone 33 in three steps, which involved
an addition of MeLi to the lactone 33 in Et2O, protection of
the resulting primary alcohol with a TBS group leading to
On the other hand, the amino-alcohol segment 52 was
synthesized from (R)-citroneral (47) according to
Scheme 10. First, 47 was transformed into epoxides 48 by
treatment with iodomethyllithium[33] in THF and the result-
ing 1:1 diastereomeric mixture of epoxides was subjected to
the asymmetric azide substitution reaction with (S,S)-N,N’-
bis-((3,5)-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-
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M. Miyashita et al.
stereomer in a 93:7 ratio in
39% yield. Then, 49 was con-
verted to amino acetal 50 by a
three-step reaction sequence:
1) oxidation with mCPBA in
CH2Cl2; 2) hydrogenation of
the azido group over PtO2 in
MeOH in the presence of
Boc2O; 3) protection of the hy-
droxyl and the amino groups by
treatment with 2-methoxypro-
pene and pyridinium m-nitro-
benzenesulfonate in DMF, in
91% overall yield. Treatment
of the epoxides 50 with Na-
Scheme 7. Synthesis of the alkyne segment 35. a) MeLi, Et2O, 0 8C; b) TBSCl, Et3N, 4-DMAP, CH2Cl2, RT,
84% (2 steps); c) Tf2O, 2,6-di-tert-butylpyridine, (CH2Cl)2, RT; DBU, (CH2Cl)2, 808C, 89%.
(OEt)3][35,36] in EtOH at
ACHUTNGREN[NUG PhSeACHTUNGTRENNUGN
808C, followed by oxidation of
the resulting hydroxy selenides
with H2O2 in a one-pot opera-
tion, furnished allyl alcohol 51
in 93% yield. Finally, ozonoly-
sis of 51 in MeOH-CH2Cl2 in
the presence of NaHCO3 pro-
duced the amino-alcohol seg-
ment 52 in 92% yield. Thus, the
amino alcohol counterpart 52
was synthesized in seven steps
from (R)-citroneral (47) in
29% overall yield.
Scheme 8. Mechanism of the formation of 35 and 36.
Total synthesis of norzoantha-
mine (1): With the key alkyne
segment 45 and the amino alco-
hol segment 52 in hand, we
then needed to couple the two
segments, installation of
a
double bond into the A ring,
and perform the final bis-ami-
noacetalizaton to form the
DEFG-ring framework. Since
the coupling reaction of 45 and
52 (Scheme 11) was of critical
importance for the synthesis of
the zoanthamine alkaloids, we
examined the reaction condi-
tions in detail and consequently
found that the coupling reac-
tion of the alkyne 45 and
2 equiv of 52 with 2 equiv of
nBuLi in THF at À308C gave
the best result, although ca.
40% of the alkyne 45 was re-
covered under the conditions.
Scheme 9. Synthesis of the deuterium-incorporated methyl ketone 44 and deuterium kinetic isotope effect in
the synthesis of the alkyne segment 45. a) Ph3PCD3Br, KHMDS, THF, 08C; b) 9-BBN, THF, 808C, then H2O2,
NaOH (aq.); c) (NH4)6Mo7O24·4H2O, Bu4NCl, K2CO3, H2O2, THF, RT to 508C, 90% (3 steps); d) (MeO)2C=
O, LiOtBu, HMPA, THF, 758C, then MeI, RT, 92%; e) LiHMDS, DMPU, THF, À18 to À118C, then MeI,
À118C to RT, 82%; f) MeLi, Et2O, 0 8C; g) TBSCl, Et3N, 4-DMAP, DMF, RT, 88% (2 steps); h) Tf2O, 2,6-di-
tert-butylpyridine, (CH2Cl)2, RT, then DBU, 808C, 90%.
chromium azide and TMSN3 in tBuOMe, according to the
Jacobsen kinetic resolution protocol.[34] The kinetic azide
substitution reaction of 48 nicely occurred under the condi-
tions giving rise to the desired azido alcohol 49 and its dia-
This result is probably due to the sterically bulky alkynyl-
lithium, which partly acted as a base to form an enolate
anion of the aldehyde 52. The crude adducts obtained by re-
peating the coupling reaction twice were oxidized with
6632
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Chem. Eur. J. 2009, 15, 6626 – 6644

Zoanthamine Alkaloids
FULL PAPER
Regioselective introduction of a double bond into the A-
ring was successfully performed by the Ito–Saegusa
method.[40] Thus, the treatment of 56 with LiHMDS and
TMSCl in THF at À658C solely produced trimethylsilyl enol
ether of the ketone in the A-ring. Reaction of the enol ether
with PdACHTNUTGRNEUNG(OAc)2 in CH3CN furnished the desired enone 57 in
remarkably high yield (96%, over three steps).
The final critical bis-aminoacetalization, that is, the con-
struction of the DEFG rings culminating in the total synthe-
sis of norzoanthamine (1), was achieved by initial treatment
of 57 with aqueous AcOH at 1008C, followed by treatment
of the resulting iminium salt 58 with aqueous trifluoroacetic
acid (TFA) at 1108C, to produce the ammonium salts of
norzoanthamine 59. Since these transformations were the
key issues in the total synthesis of the zoanthamine alka-
loids, we followed them carefully by performing the reac-
tions in NMR tubes and analyzing the NMR spectra of the
products rapidly. Finally, desalination of the ammonium
salts with basic alumina furnished norzoanthamine (1) in
81% yield for the three steps. The synthetic compound was
identical in all respects to naturally occurring norzoantha-
mine, including optical rotation ([a]2D4 = À6.0 (c=0.23,
Scheme 10. Synthesis of the chiral aminoalcohol segment 52. a) CH2I2,
MeLi, THF, 08C to RT, 95%; b) (S,S)-salen-CrN3, TMSN3, iPrOH,
tBuOMe, 08C to RT, 39%; c) mCPBA, CH2Cl2, 08C, 100%; d) H2
(1 atm), Pt2O, Boc2O, MeOH, RT, 99%; e) 2-methoxypropene, pyridini-
um m-nitrobenzenesulfonate, DMF, RT, 92%; f) NaACTHNUTRGNENUG[PhSeBACHTUTGNREN(NUNG OEt)3],
EtOH, 808C, then H2O2, THF, RT; 93% g) O3, NaHCO3, CH2Cl2,
MeOH, À508C, then Me2S, À508C to RT, 92%.
Dess–Martin periodinane[37] in
pyridine and CH2Cl2 to afford
alkynyl ketone 53 in 82% yield
from 45. Hydrogenation of the
triple bond in 53 over PtO2 in
EtOH containing AcOH, fol-
lowed by treatment of the prod-
ucts with aqueous AcOH at
508C, furnished amino acetal 54
in high yield, wherein the fol-
lowing four concomitant trans-
formations were involved in the
latter reaction: removal of the
acetonide and the TES group,
intramolecular amino-acetaliza-
tion leading to the FG-ring, and
hydrolysis of the methyl enol
ether. After removal of the two
TBS groups in 54 with TBAF,
oxidation of the resulting triol
with ammonium molybdate and
[31]
H2O2 in THF allowed chemo-
selective oxidation of the two
sterically crowded secondary
hydroxyl groups leading to 55,
which was further transformed
into the keto ester 56 by a
three-step reaction sequence: 1)
oxidation of the primary alco-
hol to aldehyde with TPAP[27]
in CH2Cl2; 2) sodium chlorite
(NaClO2) oxidation[38] of the al-
dehyde to a carboxylic acid; 3)
esterification with TMSCHN2
in CH2Cl2 and MeOH, in 61%
overall yield from 53.
Scheme 11. Total synthesis of norzoanthamine (1). a) nBuLi, THF, À308C, then 52, À788C; b) Dess–Martin
periodinane, pyridine, CH2Cl2, RT, 82% (2 steps); c) H2 (1 atm), PtO2, AcOH, EtOH, RT; d) AcOH, H2O,
508C; e) TBAF, THF, 708C, then (NH4)6Mo7O24·4H2O, K2CO3, H2O2, 508C; f) TPAP, MS4A, CH2Cl2, RT;
g) NaClO2, NaH2PO4, Me2C=CHMe, H2O, tBuOH, RT, 61% from 53; h) TMSCHN2, CH2Cl2, MeOH, RT;
[39]
i) TMSCl, LiHMDS, THF, À658C; j) Pd
ACHTUGNTRNE(UNNG OAc)2, CH3CN, 508C, 96% (3 steps); k) AcOH, H2O, 1008C; l) TFA,
H2O, 1108C; m) basic Al2O3, MeOH, RT, 81% from 57.
Chem. Eur. J. 2009, 15, 6626 – 6644
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6633

M. Miyashita et al.
CHCl3); natural norzoanthamine: [a]2D4 = À6.2 (c=0.23,
Total synthesis of zoanthamine (2): We next focused on the
second route utilizing the intermediate 56 in the synthesis
norzoanthamine (1) (Scheme 13). Since the compound 56
contains three ketone functions and an ester group, the re-
gioselective formation of a ketone enolate at the C19 posi-
tion in the B ring was the key issue. To solve this problem,
the triketone 56 was first transformed into enol TES ether
62 by treatment with LiHMDS and TESCl at À608C, and
the resulting silyl ether was subjected to the crucial methyla-
tion reaction. Thus, when 62 was conducted with LiHMDS
in THF and DMPU at À258C and then with MeI, an insepa-
rable 8:1 mixture of the desired product 63 and the starting
material was obtained. Subsequent treatment of the mixture
1
CHCl3),[41] circular dichroism, H and 13C NMR spectra, IR
and mass spectra. The total yield of synthetic norzoantha-
mine was 3.5% in 41 steps, an average of 92% yield each
step, starting from 5-methylcyclohexenone (3).
Synthetic studies of zoanthamine (2): Achievement of the
total synthesis of norzoanthamine (1) prompted us to pursue
the total synthesis of zoanthamine (2) as a matter of course.
Initially, we were optimistic about the total synthesis of
zoanthamine (2), since the synthetic task for its achievement
was only stereoselective introduction of a methyl group at
the C19 position. However, contrary to our expectation, this
issue was extremely difficult and needed almost two years
for its solution.
Toward the total synthesis of zoanthamine (2), we de-
signed the following three synthetic routes. One is the syn-
thesis of zoanthamine (2) from norzoanthamine (1) by way
of a stereoselective introduction of a methyl group at the
C19 position and the others are that by the use of an appro-
priate synthetic intermediate in the total synthesis of nor-
zoanthamine (1).
First, we set about the synthetic route via norzoanthamine
(1) (Scheme 12). For the purpose, the regioselective forma-
tion of an enolate anion at the C19 position in 1 was of criti-
cal importance. To solve this problem, the carbonyl group in
the A-ring was selectively protected as enol TES ether by
treatment of 1 with TESOTf and Et3N in CH2Cl2 at À708C
(72%). The resulting TES ether 60 was subjected to the key
methylation reaction. Thus, when 60 was treated with
LiHMDS in THF at À258C, followed by an addition of MeI,
an inseparable mixture of the methylated compound 61 and
the substrate was obtained. Further treatment of the mix-
ture with aqueous TFA and then with Et3N in MeOH fur-
nished a 1:3 mixture of norzoanthamine (1) and zoantha-
mine (2) in 40% yield. Although the 1H NMR spectra of
the products proved that the key methylation reaction did
occur at the C19 position in a stereoselective manner, this
route was non-reproducible, presumably due to instability of
the enol silyl ether 60 to basic conditions. Therefore, we de-
cided to withdraw from this synthetic route.
with PdACTHNURTGENNG(U OAc)2 in NMP furnished an 8:1 mixture of enones
64 and 57 in 37% overall yield. The products were finally
subjected to the bis-aminoacetalization reaction sequence:
1) aqueous AcOH at 1058C; 2) aqueous TFA at 1108C;
3) desalination with Et3N, which gave rise to zoanthamine
(2) and norzoanthamine (1) in a ratio of 8:1 in 62% yield.
To our delight, NMR spectra of the synthetic compound
were in agreement with those of natural zoanthamine (2).
Although we fulfilled a total synthesis of zoanthamine (2)
by the second approach, this route still involved a serious
synthetic problem. Namely, the yield of the Ito–Saegusa re-
action[40] of the enol TES ether 63 remained moderate, in
spite of many trials. Therefore, we decided to examine the
third approach toward the efficient total synthesis of zoanth-
amine (2).
The third route aimed at synthesizing zoanthamine (2) by
the use of the key precursor 57 for the bis-aminoacetaliza-
tion culminated in the total synthesis of norzoanthamine (1)
(Scheme 14). Initially, the enone moiety in the A ring was
protected by treatment of 57 with TBSOTf and Et3N in
CH2Cl2 at À708C, similarly to the first synthetic route
(Scheme 12), wherein a TBS group was employed instead of
a TES group in expectation to stability of the former in the
basic methylation reaction. The enol TBS ether 66 was ob-
tained in 98% combined yield by repeating the reaction
three times. Since the subsequent methylation reaction at
the C19 position was the key step in the synthesis of zoanth-
amine (2), we explored the reaction conditions in detail, par-
ticularly, focusing on a kind of base, an additive, the reaction
temperature, and the optimal
quantities of base and MeI.
After many trials and experi-
ments for as long as one year,
we eventually found the follow-
ing optimum conditions. Thus,
treatment of the enol TBS
ether 66 with LDA (5 equiv) in
THF at À558C for one hour,
followed by an addition of MeI
(20 equiv) at À508C, produced
the desired product 67 in 83%
yield. Although the product
contained less than 7% of the
72%; b) LiHMDS, THF, À258C, then MeI, À208C; c) TFA, H2O, RT; d) Et3N, MeOH, RT, 0–40% (3 steps). starting material 66, the mix-
Scheme 12. Attempts to convert norzoanthamine (1) to zoanthamine (2). a) TESOTf, Et3N, CH2Cl2, À708C,
6634
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Chem. Eur. J. 2009, 15, 6626 – 6644

Zoanthamine Alkaloids
FULL PAPER
Et3N in MeOH. Purification of
the product by PTLC (CH3CN/
MeOH 100:8) furnished the
pure zoanthamine (2) in 63%
overall yield from 67.
The synthetic compound was
identical in all respects to natu-
rally occurring zoanthamine, in-
cluding optical rotation ([a]D28
=
+21.1 (c=0.23, CHCl3); natural
zoanthamine: [a]D = +18 (c=
0.4,
CHCl3),[3a]
1H
and
13C NMR spectra, IR and mass
spectra. The total yield of syn-
thetic zoanthamine was 2.2%
in 43 steps, an average of 91%
yield each step, starting from 5-
methylcyclohexenone (3).
Conclusions
In summary, we achieved the
highly efficient total syntheses
of norzoanthamine (1) and
zoanthamine (2) and rigorously
verified their absolute struc-
tures by the present syntheses.
The chemistry described here
not only offers a solution to for-
midable synthetic challenges
but also opens a completely
chemical avenue to norzoantha-
mine (1), zoanthamine (2),
Scheme 13. Synthetic studies of zoanthamine (2) by use of the intermediate 56. a) TESCl, LiHMDS, THF,
À608C; b) LiHMDS, THF, DMPU, À258C, then MeI, À208C; c) Pd
ACHTUNGERTN(NUNG OAc)2, NMP, 558C, 37% (3 steps);
d) AcOH, H2O, 1058C; e) TFA, H2O, 1108C; f) Et3N, MeOH, RT, 62% from 64.
other
naturally
occurring
zoanthamine alkaloids, and
their synthetic derivatives.
Experimental Section
Materials and methods: All the reac-
tions were carried out in
a round-
bottom flask with an appropriate
number of necks and side arms con-
nected to a three-way stopcock 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. Solu-
tions and solvents were introduced by
Scheme 14. Total synthesis of zoanthamine (2). a) TBSOTf, Et3N, CH2Cl2, À708C, 98% (repeated 3ꢂ);
b) LDA, THF, À558C, then MeI, À508C, 83%; c) AcOH, H2O, RT to 1058C; d) TFA, H2O, 1108C; e) Et3N,
MeOH, RT, 63% from 67.
a
hypodermic syringe through
a
rubber septum. During the reaction,
the vessel was kept under a positive
pressure of argon. Dry diethyl ether
and THF were freshly prepared by distillation from benzophenone/ketyl
before use. Pyridine and triethylamine were distilled over CaH2 under
argon and stored over KOH pellets. Anhydrous hexane, toluene, CH2Cl2,
CH3CN, DMF, methanol and ethanol were purchased from Kanto Chem-
ical Co. Inc.
ture was successfully converted to zoanthamine (2) by the
bis-aminoacetalization reaction sequence: 1) aqueous AcOH
at 1058C; 2) aqueous TFA at 1108C; 3) desalination by
Chem. Eur. J. 2009, 15, 6626 – 6644
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6635

M. Miyashita et al.
Infrared (IR) spectra were recorded on a SHIMADZU FT-IR 8200A or
a JASCO FT/IR-4100 spectrophotometer using 5 mm NaCl plates. Wave-
J=6.8 Hz, 3H), 1.02–1.10 (m, 21H, involving a singlet at 1.07), 1.50–1.65
(m, 4H, involving a singlet at 1.57), 1.90 (ddd, J=4.6, 11.7, 13.7 Hz, 1H),
2.05 (s, 3H), 2.16–2.38 (m, 2H), 2.46 (dd, J=4.5, 13.7 Hz, 1H), 2.59 (dt,
J=4.6, 11.2 Hz, 1H), 2.83 (dd, J=4.3, 11.2 Hz, 1H), 4.12–4.30 (m, 3H, in-
volving a doublet at 4.15, J=10.2 Hz), 4.66 (dd, J=4.5, 10.2 Hz, 1H),
5.36 (brt, J=5.6 Hz, 1H), 6.08 ppm (s, 1H); 13C NMR (67.8 MHz,
CDCl3): d = À5.56, À5.53, 11.59, 12.10 (3C), 13.15, 17.89, 18.12 (6C),
20.18, 26.54 (3C), 28.45, 35.73, 43.14, 48.21, 55.29, 60.25, 67.77, 111.55,
127.99, 131.96, 135.11, 152.15, 158.14, 214.20 ppm; IR (neat): n˜ = 3450,
2866, 1703, 1464, 1250, 883, 775 cmÀ1; HRMS: m/z: calcd for C32H58O4Si2:
562.3874; found: 562.3877 [M]+.
length of maximum absorbance are quoted in cmÀ1 1H NMR spectra
.
were recorded on a JEOL Al-270 (270 MHz) or a JEOL ECA-500
(500 MHz) in CDCl3 with (CH3)4Si as an internal standard. Chemical
shifts are reported in part per million (ppm), and signal are expressed as
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br).
13C NMR spectra were recorded on a JEOL Al-270 (67.8 MHz) or a
JEOL ECA-500 (125 MHz) in CDCl3 with (CH3)4Si as an internal stan-
dard. Chemical shifts are reported in part per million (ppm). Electron
ionization mass (EI-MS) spectra, field desorption mass (FD-MS) spectra,
and high resolution mass (HR-MS) spectra were recorded on a JEOL
JMS AX-500 or a JEOL JMS-SX102 A at the GC-MS & NMR Laborato-
ry, 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) or E. Merck silica gel (60, particle size 0.040–0.063 mm)
was used for flash column chromatography.
Minor aldol product 13: [a]2D8 =+80.68 (c
=
0.64, CHCl3); 1H NMR
(CDCl3, 270 MHz): d = 0.22 (s, 6H), 0.86 (s, 9H), 1.00–1.12 (m, 24H, in-
volving a singlet at 1.06 and a doublet at 1.00, J=6.9 Hz), 1.60–1.68 (m,
4H, involving a singlet at 1.62), 1.95–2.15 (m, 5H, involving a singlet at
2.05), 1.95–2.15 (m, 5H, involving a singlet at 2.05), 2.35–2.48 (m, 1H),
2.57 (dd, J=5.6, 12.9 Hz, 1H), 2.89 (dt, J=4.0, 10.9 Hz, 1H), 2.98 (dd,
J=2.5, 10.9 Hz, 1H), 3.77 (d, J=10.9 Hz, 1H), 4.27 (brd, J=5.8 Hz, 2H),
4.63 (dd, J=2.0, 10.9 Hz, 1H), 5.57 (brt, J=5.8 Hz, 1H), 6.10 ppm (s,
1H); 13C NMR (67.8 MHz, CDCl3): d = À5.67, À5.63, 11.54, 12.12 (3C),
13.25, 17.80, 18.10 (6C), 19.21, 26.40 (3C), 30.80, 36.15, 45.75, 48.89,
55.42, 60.28, 67.25, 109.16, 128.32, 132,26, 135.56, 151.54, 159.74,
213.94 ppm; IR (neat): n˜ = 3500, 2866, 1705, 1464, 1250, 1103, 1061,
883 cmÀ1; HRMS: m/z: calcd for C32H58O4Si2: 562.3874; found: 562.3849
[M]+.
Numbered compounds which are suffixed with A, B, C, or D refer to in-
termediates obtained by manipulation of the appropriate compounds,
which have been omitted from certain schemes for reasons of clarity.
Each intermediate was isolated after one (A), two (B), three (C), or four
(D) transformations from the numbered compound. Additional experi-
AHCTUNGTRENGN(UN 3S,5R,E)-2-((5-(tert-Butyldimethylsilyl)-4-methylfuran-2-yl)methylene)-
5-methyl-3-((E)-4-(triisopropylsilyloxy)but-2-en-2-yl)cyclohexanone
(13A): A mixture of the aldols 13 (47.0 g, 83.5 mmol), 1,1’-thiocarbonyl
diimidazole (22.3 g, 125.3 mmol), and anhydrous toluene (170 mL) was
stirred at 708C for 1 h and then at 908C for 5.5 h. After the reaction mix-
ture was cooled to room temperature, water was added and the organic
layer was separated, and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with water and saturated
brine, dried over MgSO4, and concentrated. Purification of the residue by
silica gel column chromatography (EtOAc/hexane 1:24, 1:19) afforded
enone 13A (42.0 g, 92%) as a 96:4 E/Z mixture. [a]3D0 =À237.28 (c =
1.75, CHCl3); 1H NMR (CDCl3, 270 MHz): d = 0.25 (s, 3H), 0.27 (s,
3H), 0.89 (s, 9H), 0.94–1.04 (m, 24H, involving a singlet at 0.98), 1.45–
1.66 (m, 2H), 1.75 (s, 3H), 1.88–2.11 (m, 5H, involving a singlet at 2.08),
2.59–2.66 (m, 1H), 3.93–3.98 (m, 1H), 4.15–4.28 (m, 2H), 5.14–5.20 (m,
1H), 6.35 (m, 1H), 7.37 ppm (m, 1H); 13C NMR (67.8 MHz, CDCl3): d =
À5.81, 5.70, 11.43, 12.09 (3C), 16.54, 18.00 (6C), 22.28, 25.05, 26.39 (3C),
35.25, 45.24, 48.36, 60.75, 119.54, 124.24, 127.34, 133.31, 133.71, 135.63,
154.55, 157.21, 200.77 ppm; IR (neat): n˜ = 2866, 1678, 1601, 1464, 1252,
1111, 1063, 883, 758 cmÀ1; HRMS: m/z: calcd for C32H56O3Si2: 544.3768;
found: 544.3807 [M]+.
1
mental procedures and H and 13C NMR spectra of synthetic norzoantha-
mine (1) and zoanthamine (2) are available in the Supporting Informa-
tion.
Triisopropyl-((E)-3-((1R,5R)-5-methyl-3-(trimethylsilyloxy)cyclohex-2-
enyl)but-2-enyloxy)silane (12): A 2.64m solution of nBuLi in hexane
(42 mL, 110 mmol) was added dropwise to a solution of (E)-3-tributyl-
stannyl-2-butenyl triisopropyl silyl ether 5A[42] (54.3 g, 105 mmol) in an-
hydrous THF (150 mL) at À408C and the mixture was stirred at À308C
for 3 h. To the resultant solution of butenyllithium was added CuBr·Me2S
complex (10.8 g, 52.5 mmol) and the mixture was stirred at À408C for
30 min. Then, a solution of (R)-5-methyl-2-cyclohexenone (3)[22] (5.5 g,
50 mmol) and TMSCl (12.7 mL, 100 mmol) in THF (50 mL) was added
dropwise at À408C and stirring was continued at À408C for 1 h. The re-
action mixture was treated with a 10% aqueous solution of NH4OH and
NH4Cl and filtered through a pad of Celite by the aid of EtOAc. The or-
ganic layer of the filtrate was separated and the aqueous layer was ex-
tracted with EtOAc. The combined organic layers were washed with
water and saturated brine, dried over MgSO4, and concentrated under re-
duced pressure. The residue was passed through a short silica gel column
with EtOAc/hexane (1:50, 1:30). The eluate was concentrated under re-
duced pressure and the residue was used for the next step without purifi-
cation.
tert-Butyldimethyl(3-methyl-5-(((4R,6S)-4-methyl-2-(triethylsilyloxy)-6-
((E)-4-(triisopropylsilyloxy)but-2-en-2-yl)cyclohex-1-enyl)methyl)furan-2-
yl)silane (13B):
A mixture of the enone 13A (40.7 g, 74.6 mmol),
A
[(C6H5)3P]3RhCl (3.45 g, 3.73 mmol), Et3SiH (23.8 mL, 149.2 mmol), and
anhydrous THF (150 mL) was stirred at 508C for 2 h. To the cooled reac-
tion mixture were added Et3N and water, and the mixture was extracted
with EtOAc. The extracts were washed with water and saturated brine,
dried over MgSO4, and concentrated under reduced pressure. The residue
was passed through a short silica gel column with EtOAc. After evapora-
tion of the solvent, the crude product 13B was used for the next step
without purification.
ACHTUNGTRENNUNG
cyclohexanone (13): To a solution of the crude trimethylsilyl enol ether
12 (100 mmol) in anhydrous THF (135 mL) was added a 2.64m solution
of nBuLi in hexane (34 mL, 88.9 mmol) at À508C and stirring was con-
tinued at À308C for 2 h. Then, a solution of ZnBr2 (21.6 g, 95.8 mmol) in
anhydrous THF (80 mL) was added at À788C and the mixture was fur-
ther stirred for 2 h at the same temperature. A solution of the aldehyde
11[42] (21.5 g, 95.8 mmol) in THF (50 mL) was added at À788C, and the
mixture was stirred at À788C for an additional 3 h. After a saturated
aqueous solution of NH4Cl was added, the mixture was filtered through a
pad of celite by the aid of EtOAc. The organic layer was separated and
the aqueous layer was extracted with EtOAc. The combined organic
layers were washed with water and saturated brine, dried over MgSO4,
and concentrated. Purification of the residue by silica gel column chro-
matography (EtOAc/hexane 1:19, 1:9) afforded aldol 13 as a 66:34 ste-
reoisomeric mixture (47.5 g, 84% for the two steps).
AHCTUNGTRENGN(UN 2S,3R,5R)-2-((5-(tert-Butyldimethylsilyl)-4-methylfuran-2-yl)methyl)-5-
methyl-3-((E)-4-(triisopropylsilyloxy)but-2-en-2-yl)cyclohexanone (14):
To a solution of the crude silyl enol ether 13B (74.6 mmol) in THF
(140 mL) was added a methanolic saturated solution of K2CO3 (70 mL)
and the mixture was stirred at room temperature for 1 h. Water was
added to the reaction mixture, the organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined organic layers
were washed with water and saturated brine, dried over MgSO4, and con-
centrated. Purification of the residue by silica gel column chromatogra-
phy (EtOAc/hexane 1:19) furnished trisubstituted cyclohexanone 14
Major aldol product 13: [a]2D8 =À6.68 (c
=
1.50, CHCl3); 1H NMR
(CDCl3, 270 MHz): d = 0.23 (s, 3H), 0.24 (s, 3H), 0.88 (s, 9H), 0.91 (d,
(35.1 g, 86% from 13A). [a]3D0 =+23.08 (c 4.00, CHCl3); 1H NMR
=
6636
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6626 – 6644

Zoanthamine Alkaloids
FULL PAPER
(CDCl3, 270 MHz): d = 0.21 (s, 6H), 0.87 (s, 9H), 0.95 (d, J=7.1 Hz,
3H), 1.02–1.14 (m, 21H, involving a singlet at 1.07), 1.52–1.62 (m, 4H, in-
volving a broad singlet at 1.57), 1.93–2.04 (m, 4H, involving a singlet at
2.01), 2.13–2.19 (m, 1H), 2,33–2,57 (m, 4H), 2.68–2.77 (m, 1H), 2.97 (dd,
J=8.2, 15.0 Hz, 1H), 4.27 (brd, J=5.8 Hz, 2H), 5.42 (brt, J=5.8 Hz,
1H), 5.82 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d = À5.58, À5.55,
11.54, 12.12 (3C), 12.67, 17.81, 18.10 (6C), 19.42, 25.64, 26.47 (3C), 30.37,
36.22, 48.03, 48.63, 51.93, 60.32, 109.61, 127.93, 132.15, 135.98, 150.72,
157.82, 210.77 ppm; IR (neat): n˜ = 2866, 1713, 1464, 1389, 1250, 1111,
1061, 883, 758 cmÀ1; HRMS: m/z: calcd for C32H58O3Si2: 546.3924; found:
546.3934 [M]+.
837, 758 cmÀ1
434.2848 [M]+.
;
HRMS: m/z: calcd for C25H42O4Si: 434.2852; found:
(1R,2S,3R,5R)-2-((5-(tert-Butyldimethylsilyl)-4-methylfuran-2-yl)meth-
yl)-5-methyl-3-((E)-4-oxobut-2-en-2-yl)cyclohexyl acetate (15C): To a so-
lution of the allyl alcohol 15B (18.2 g, 41.9 mmol) in anhydrous CH2Cl2
(84 mL) was added MnO2 (62 g, 712.3 mmol) and the mixture was stirred
for 13 h at room temperature. The reaction mixture was filtered through
a pad of celite by the aid of EtOAc and the eluate was concentrated. The
crude aldehyde 15C was used for the next step without purification.
(1R,2S,3R,5R)-2-((5-(tert-Butyldimethylsilyl)-4-methylfuran-2-yl)meth-
yl)-3-((E)-4-hydroxypent-2-en-2-yl)-5-methylcyclohexyl acetate (15D):
To a solution of the crude aldehyde 15C (41.9 mmol) in dry Et2O
(1R,2S,3R,5R)-2-((5-(tert-Butyldimethylsilyl)-4-methylfuran-2-yl)meth-
yl)-5-methyl-3-((E)-4-(triisopropylsilyloxy)but-2-en-2-yl)cyclohexanol
(15): To a solution of the ketone 14 (29.1 g, 53.2 mmol) in anhydrous
THF (160 mL) was added a 1.05m solution of LiEt3BH in THF (76 mL,
79.8 mmol) at À788C and the mixture was stirred at the same tempera-
ture for 30 min. Then, water, a 1m aqueous solution of NaOH, and a
35% H2O2 solution (30 mL) were added and the mixture was vigorously
stirred at room temperature for 12 h. The organic layer was separated
and the aqueous layer was extracted with Et2O. The combined organic
layers were washed with water and saturated brine, dried over MgSO4,
and concentrated under reduced pressure. Purification of the residue by
silica gel column chromatography (EtOAc/hexane 1:19) afforded b-alco-
hol 15 as a single product (28.6 g, 98%). [a]3D0 =+6.78 (c = 1.50, CHCl3);
1H NMR (CDCl3, 270 MHz): d = 0.23 (s, 3H), 0.23 (s, 3H), 0.88 (s, 9H),
1.02–1.11 (m, 21H, involving a singlet at 1.07), 1.13 (d, J=7.3 Hz, 3H),
1.35–1.43 (m, 1H), 1.51–1.72 (m, 8H, involving a singlet at 1.54), 1.80–
2.00 (m, 2H), 2.04 (s, 3H), 2.37 (bdt, J=3.6, 9.6 Hz, 1H), 2.59 (dd, J=
2.0, 7.8 Hz, 1H), 3.76–3.82 (m, 1H), 4.29 (brd, J=5.8 Hz, 2H), 5.45 (brt,
J=5.8 Hz, 1H), 5.83 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d =
À5.61, À5.56, 11.57, 12.17 (3C), 13.70, 17.84, 18.12 (6C), 21.56, 26.47
(3C), 27.07, 27.56, 35.98, 37.95, 41.44, 43.07, 60.58, 68.29, 109.59, 126.29,
132.13, 137.65, 151.39, 158.52 ppm; IR (neat): n˜ = 3450, 2866, 1603, 1464,
1389, 1250, 1101, 1059, 883, 835 cmÀ1; HRMS: m/z: calcd for C32H60O3Si2:
548.4081; found: 548.4113 [M]+.
(210 mL) was added
a 1.20m solution of CH3Li in Et2O (38 mL,
46.1 mmol) at À1008C and the mixture was stirred at the same tempera-
ture for 3 h. A saturated aqueous solution of NH4Cl was added to the re-
action mixture, the organic layer was separated and the aqueous layer
was extracted with Et2O. The combined organic layers were washed with
water and saturated brine, dried over MgSO4, and concentrated under re-
duced pressure. The crude allyl alcohol 15D was used for the next step
without purification.
(1R,2S,3R,5R)-2-((5-(tert-Butyldimethylsilyl)-4-methylfuran-2-yl)meth-
yl)-5-methyl-3-((E)-4-oxopent-2-en-2-yl)cyclohexyl acetate (16): To
a
mixture of the crude allyl alcohol 15D (41.9 mmol), 4-methylmorphorine
N-oxide (9.8 g, 83.8 mmol), powdered MS-4ꢃ (1.26 g), and anhydrous
CH2Cl2 (84 mL) was added tetrapropylammonium perruthenate (TPAP)
(368 mg, 1.05 mmol) and the mixture was stirred at room temperature for
1.5 h. After removal of the solvent under reduced pressure, the residue
was purified by silica gel column chromatography (EtOAc/hexane 1:9) to
yield enone 16 (17.8 g, 95% from 15B). [a]3D0 =À26.28 (c = 1.63, CHCl3);
1H NMR (CDCl3, 270 MHz): d = 0.22 (s, 3H), 0.22 (s, 3H), 0.87 (s„
9H), 1.06 (d, J=7.1 Hz, 3H), 1.82 (m, 4H), 1.92–2.21 (m, 14H, involving
singlets at 2.02, 2.07, 2.21 and a doublet at 2.09, J=1.2 Hz), 2.41–2.53 (m,
3H), 4.92 (dt, J=3.3, 5.1 Hz, 1H), 5.76 (s, 1H), 6.26 ppm (s, 1H);
13C NMR (67.8 MHz, CDCl3): d
=
À5.63, À5.60, 11.51, 16.46, 17.80,
21.03, 21.39, 26.45 (3 C), 26.65, 27.53, 32.04, 34.50, 35.53, 40.64, 43.89,
70.94, 109.91, 124.45, 132.03, 151.67, 156.73, 159.91, 170.06, 198.55 ppm;
IR (neat): n˜ = 2928, 2856, 1740, 1688, 1611, 1244, 775 cmÀ1; HRMS: m/z:
calcd for C22H33O4Si: 389.2148; found: 389.2176 [MÀtBu]+.
(Z)-tert-Butyldimethylsilyl 5-((1S,2R,4R,6R)-2-acetoxy-4-methyl-6-((E)-
4-oxopent-2-en-2-yl)cyclohexyl)-2-methyl-4-oxopent-2-enoate (16A):
solution of the furan 16 (11.9 g, 26.6 mmol) and rose bengal (1.35 g,
1.33 mmol) in anhydrous CH2Cl2 (40 mL) was irradiated with a Riko-
HGA-300A halogen lamp under an oxygen atmosphere at 08C for 12 h.
After activated charcoal (10 g) was added to the reaction mixture, inor-
ganic materials were filtered off through a pad of Celite by the aid of
EtOAc and the eluate was concentrated under reduced pressure. The
crude product 16A was used for the next step without purification.
(1R,2S,3R,5R)-2-((5-(tert-Butyldimethylsilyl)-4-methylfuran-2-yl)meth-
yl)-5-methyl-3-((E)-4-(triisopropylsilyloxy)but-2-en-2-yl)cyclohexyl ace-
tate (15A): To a mixture of the alcohol 15 (28.0 g, 51.0 mmol), pyridine
(12.4 mL, 153.0 mmol), 4-dimethylaminopyridine (1.87 g, 15.3 mmol), and
anhydrous CH2Cl2 (100 mL) was added dropwise Ac2O (14.4 mL,
153 mmol) and the mixture was stirred at room temperature for 1.5 h.
After water was added to the reaction mixture, the organic layer was sep-
arated and the aqueous layer was extracted with EtOAc. The combined
organic layers were washed with water and saturated brine, dried over
MgSO4, and concentrated under reduced pressure. The crude acetate
15A was used for the next step without purification.
A
(1R,2S,3R,5R)-2-((5-(tert-Butyldimethylsilyl)-4-methylfuran-2-yl)meth-
yl)-3-((E)-4-hydroxy-but-2-en-2-yl)-5-methylcyclohexyl acetate (15B): To
a solution of the crude acetate 15A (51.0 mmol) in anhydrous THF
(Z)-Methyl 5-((1S,2R,4R,6R)-2-acetoxy-4-methyl-6-((E)-4-oxopent-2-en-
2-yl)cyclohexyl)-2-methyl-4-oxopent-2-enoate (17): To a solution of the
crude product 16 A (26.6 mmol) in anhydrous THF (75 mL) was added a
1.0m solution of TBAF in THF (40 mL, 40 mmol) and the mixture was
stirred at room temperature for 10 min. Then, CH3I (3.3 mL, 53.1 mmol)
was added and the mixture was stirred at room temperature for 1 h.
Water was added to the reaction mixture and the product was thoroughly
extracted with Et2O. The organic extracts were washed with water and
saturated brine, dried over MgSO4, and concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(EtOAc/hexane 1:4, 3:7) to afford methyl ester 17 (9.8 g, 97% from 16).
[a]2D8 =À30.08 (c = 1.35, CHCl3); 1H NMR (CDCl3, 270 MHz): d = 1.05
(d, J=7.1 Hz, 3H), 1.43 (dt, J=4.5, 13.4 Hz, 1H), 1.63–1.82 (m, 3H),
1.92–2.58 (m, 17H, involving singlets at 2.04, 2.21 and doublets at 2.00,
J=1.6 Hz, 2.06, J=1.2 Hz), 3.77 (s, 3H), 5.04–5.08 (m, 1H), 6.08 (q, J=
1.6 Hz, 1H), 6.22 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d = 16.96,
20.28, 21.02, 21.37, 26.52, 32.00, 34.62, 35.29, 36.12, 42.10, 43.97, 52.33,
71.47, 124.69, 129.89, 141.09, 159.13, 169.02, 170.10, 197.97, 198.54 ppm;
(100 mL) was added
a 1.0m solution of TBAF in THF (25.5 mL,
25.5 mmol) at 08C and the mixture was stirred at room temperature for
2 h. After a 1.0m solution of TBAF in THF (18 mL, 17.9 mmol) was
again added, the mixture was further stirred for 3 h at room temperature.
The reaction mixture was diluted with water and the product was extract-
ed with Et2O. The combined extracts were washed with water and satu-
rated brine, dried over MgSO4, and concentrated. The residue was puri-
fied by silica gel column chromatography (EtOAc/hexane 1:9, 1:3) to
afford allyl alcohol 15B (21.3 g, 96% from 15). [a]3D0 =À24.88 (c = 1.48,
1
CHCl3); H NMR (CDCl3, 270 MHz): d = 0.22 (s, 3H), 0.22 (s, 3H), 0.88
(s, 9H), 1.05 (d, J=7.1 Hz, 3H), 1.06 (d, J=7.1 Hz, 1H), 1.11–1.16 (m,
1H), 1.42 (bdt, J=3.8, 13.5 Hz, 1H), 1.52–1.79 (m, 5H, involving a singlet
at 1.55), 1.90–2.09 (m, 8H, including singlets at 2.02 and 2.05), 2.35–2.61
(m, 3H), 4.19 (brt, J=5.9 Hz, 2H), 4.88–4.93 (m, 1H), 5.58 (brt, J=
6.7 Hz, 1H), 5.76 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d = À5.61,
À5.58, 11.53, 13.36, 17.81, 21.13, 21.43, 26.47 (3C), 26.71, 27.46, 34.67,
35.32, 40.49, 42.24, 59.41, 71.39, 109.65, 125.02, 132.04, 140.78, 151.38,
157.47, 170.23 ppm; IR (neat): n˜ = 3450, 2928, 2856, 1736, 1603, 1250,
IR (neat): n˜ = 2953, 1736, 1688, 1612, 1371, 1246, 1138, 1028, 964 cmÀ1
HRMS: m/z: calcd for C21H30O6: 378.2042; found: 378.2060 [M]+.
;
Chem. Eur. J. 2009, 15, 6626 – 6644
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6637

M. Miyashita et al.
(Z)-Methyl 5-((1S,2R,4R,6R)-2-acetoxy-6-((E)-4-(tert-butyldimethylsilyl-
oxy)penta-2,4-dien-2-yl)-4-methylcyclohexyl)-2-methyl-4-oxopent-2-
enoate (18): To a solution of the methyl ester 17 (9.5 g, 25.0 mmol) and
Me2NEt (5.4 mL, 50 mmol) in anhydrous CH2Cl2 (50 mL) was added
TBSOTf (6.3 mL, 27.5 mmol) at 08C and the mixture was stirred at 08C
for 30 min. A saturated aqueous solution of NaHCO3 was added to the
reaction mixture and the product was thoroughly extracted with Et2O.
The organic extracts were washed with water and saturated brine, dried
over MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexane 1:9) to fur-
nish triene 18 (11.1 g, 100%). [a]2D8 =À9.78 (c = 1.13, CHCl3); 1H NMR
(CDCl3, 270 MHz): d = 0.17 (s, 6H), 0.94 (s, 9H), 1.05 (d, J=7.3 Hz,
3H), 1.37–1.46 (m, 1H), 1.67–1.80 (m, 5H, involving a doublet at 1.80,
J=1.2 Hz), 1.97–2.07 (m, 8H, involving a singlet at 2.04 and a doublet at
1.99, J=1.6 Hz), 2.27–2.44 (m, 4H), 3.76 (s, 3H), 4.21 (s, 1H), 4.35 (s,
1H), 5.02–5.06 (m, 1H), 5.68 (s, 1H), 6.08 ppm (q, J=1.6 Hz, 1H);
13C NMR (67.8 MHz, CDCl3): d = À4.27 (2C), 15.03, 18.35, 20.30, 20.95,
21.46, 25.91 (3C), 26.56, 34.69, 35.53, 36.98, 42.40, 43.09, 52.30, 72.13,
95.92, 124.72, 130.28, 140.62, 141.16, 155.14, 169.17, 170.21, 198.56 ppm;
IR (neat): n˜ = 2930, 2858, 1738, 1369, 1246, 1136, 837, 781 cmÀ1; HRMS:
m/z: calcd for C27H44O6Si: 492.2907; found: 492.2878 [M]+.
1724, 1366, 1240, 1097, 1022, 945 cmÀ1; HRMS: m/z: calcd for C21H30O6:
378.2042; found: 378.2044 [M]+.
CCDC 718877 (21) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(1R,3R,4aS,4bR,6R,8R,8aS,10S,10aS)-8-Acetoxy-10-hydroxy-1,4a,6-tri-
methyltetradecahydrophenanthrene-1,3-carbolactone (23): To a solution
of the diketone 20 (1.41 g, 3.73 mmol) in anhydrous THF (14.9 mL) con-
taining CH2Cl2 (3.7 mL) was added dropwise a 1.00m solution of K-selec-
tride in THF (14.9 mL, 14.9 mmol) at À788C and the mixture was stirred
at À788C for 1 h. Then, the mixture was warmed to 08C over 3 h and fur-
ther stirred at 08C for 4 h. To the reaction mixture were added water
(5 mL), a saturated aqueous solution of NaHCO3 (15 mL), and a 35%
H2O2 solution (15 mL) in order and the mixture was vigorously stirred at
room temperature for 16 h. The reaction mixture was extracted with
EtOAc (3ꢂ) and the extracts were washed with water and saturated
brine, and dried over MgSO4. The residue was azeotroped with methanol
(3ꢂ) and concentrated under reduced pressure. The crude hydroxy lac-
tone 23 was used for the next step without purification.
(1R,3R,4aS,4bR,6R,8R,8aS,10S,10aS)-8-Acetoxy-10-(tert-butyldimethylsi-
lyloxy)-1,4a,6-trimethyltetradecahydrophenanthrene-1,3-carbolactone
(24): To a solution of the crude hydroxy lactone 23 (3.73 mmol) and 2,6-
lutidine (1.1 mL, 9.32 mmol) in anhydrous CH2Cl2 (19 mL) was added
TBSOTf (1.28 mL, 5.59 mmol) at 08C and the mixture was stirred at
room temperature for 3 h. A saturated aqueous solution of NaHCO3 was
added to the reaction mixture, the organic layer was separated, and the
aqueous layer was extracted with Et2O. The combined organic layers
were successively washed with a 4% aqueous solution of KHSO4 (3ꢂ), a
saturated aqueous solution of NaHCO3, and saturated brine, dried over
MgSO4, and concentrated. The residue was purified by silica gel column
chromatography (EtOAc/hexane 1:9) to afford lactone 24 (1.48 g, 86%
from 20). [a]3D0 =À2.08 (c = 1.00, CHCl3); 1H NMR (CDCl3, 270 MHz): d
= 0.05 (s, 3H), 0.15 (s, 3H), 0.90 (s, 9H), 1.06 (d, J=7.4 Hz, 3H), 1.25 (s,
3H), 1.25 (s, 3H), 1.37–1.86 (m, 11H), 2.05–2.15 (m, 5H, involving a sin-
glet at 2.05 and a double double doublet at 2.11, J=1.6, 4.8, 13.8 Hz),
2.28 (ddd, J=1.6, 5.9, 11.0 Hz, 1H), 4.32–4.36 (m, 1H), 4.73 (brt, J=
5.1 Hz, 1H), 4.89 ppm (brq, J=2.9 Hz, 1H); 13C NMR (67.8 MHz,
CDCl3): d = À4.70, À3.80, 18.08, 18.67, 20.67, 21.22, 21.53, 25.85 (3C),
26.49, 30.44, 34.74, 35.05, 37.67, 37.78, 42.46, 44.41, 44.43, 49.26, 58.41,
Diels–Alder reaction of 18: A solution of triene 18 (10.7 g, 21.8 mmol) in
anhydrous 1,2,4-trichlorobenzene (22 mL) was added dropwise to
a
heated solution of 1,2,4-trichlorobenzene (22 mL) at 2408C over 1 h and
the mixture was further stirred at the same temperature for 30 min. After
cooling the reaction vessel to room temperature, the solution was passed
through a short silica gel column by the aid of EtOAc/hexane 1:9, 3:7.
The eluate was concentrated under reduced pressure and the crude ad-
ducts were used for the next step without purification. The ratio of the
adducts (19/19A) was determined to be 72:28 by a 1H NMR spectrum.
Deprotection of silyl enol ether of 19 and 19A: To a solution of the
Diels–Alder adducts 19 and 19A (21.8 mmol) in anhydrous THF (33 mL)
was added 70% pyridinium poly(hydrogenfluoride) (4.4 mL) at 08C and
the mixture was stirred at room temperature for 3 h. A saturated aqueous
solution of NaHCO3 was added to the reaction mixture and the product
was extracted with EtOAc (3ꢂ). The combined extracts were washed
with water and saturated brine, dried over MgSO4, and concentrated
under reduced pressure to leave crystals. Recrystallization of the crude
crystals from EtOAc/hexane afforded diketone 20 as colorless crystals
(4.4 g, 51% from 18). On the other hand, concentration of the mother
liquid, followed by recrystallization of the residue from EtOAc/hexane,
furnished an alternative diastereomer 21 as colorless crystals.
67.42, 74.00, 75.28, 170.46, 179.62 ppm; IR (CHCl3): n˜
= 2932, 2858,
1776, 1730, 1383, 1371, 1252, 1202, 1188, 1153, 1128, 1101, 1020, 966, 837
756 cmÀ1; HRMS: m/z: calcd for C22H35O5Si: 407.2254; found: 407.2287
[MÀtBu]+.
(1R,3R,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-Butyldimethylsilyloxy)-8-
hydroxy-1,4a,6-trimethyltetradecahydrophenanthrene-1,3-carbolactone
(1R,4aS,4bR,6R,8R,8aS,10aS)-Methyl 8-acetoxy-1,4a,6-trimethyl-3,10-di-
oxotetradecahydrophenanthrene-1-carboxylate (20): M.p. 203–2048C;
[a]3D0 =À73.18 (c = 1.70, CHCl3); 1H NMR (CDCl3, 270 MHz): d = 1.04
(s, 3H), 1.13 (d, J=7.4 Hz, 3H), 1.35–1.46 (m, 4H, involving a singlet at
1.39), 1.52–1.69 (m, 2H), 1.88–2.35 (m, 11H, involving a singlet at 2.11),
2.52 (dd, J=1.3, 14.7 Hz, 1H), 2.72 (dd, J=1.3, 14.7 Hz, 1H), 2.78 (s,
1H), 3.70 (s, 3H), 4.91 ppm (q, J=3.0 Hz, 1H); 13C NMR (67.8 MHz,
CDCl3): d = 16.09, 20.66, 21.44, 26.23, 28.63, 30.65, 34.45, 40.70, 43.33,
44.16, 45.11, 45.78, 50.54, 52.12, 52.52, 66.53, 72.47, 170.09, 174.97, 206.32,
206.76 ppm; IR (CHCl3): n˜ = 3022, 2951, 1732, 1466, 1435, 1312, 1244,
1170, 1126, 1097, 1051, 1024, 943, 754 cmÀ1; HRMS: m/z: calcd for
C21H30O6: 378.2042; found: 378.2076 [M]+.
(24A):
A mixture of the acetate 24 (1.48 g, 3.19 mmol), TiACHTUNGTRENNUNG(OEt)4
(2.0 mL, 7.32 mmol), and dry toluene (16 mL) was stirred at 1008C for
48 h. After the reaction mixture was cooled to room temperature, water
was added and the mixture was filtered through a pad of Celite by the
aid of EtOAc. The organic layer was separated and the aqueous layer
was extracted with EtOAc. The combined organic layer was washed with
water and saturated brine, dried over MgSO4, and concentrated. The
crude alcohol 24A was used for the next step without purification.
CCDC 718849 (20) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(1R,3R,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-Butyldimethylsilyloxy)-
1,4a,6-trimethyl-8-(triethylsilyloxy)tetradecahydrophenanthrene-1,3-car-
bolactone (25): To a solution of the crude alcohol 24A (3.19 mmol) and
2,6-lutidine (0.922 mL, 7.97 mmol) in anhydrous CH2Cl2 (11 mL) was
added TESOTf (0.94 mL, 4.14 mmol) at 08C and the mixture was stirred
at 08C for 1 h. A saturated aqueous solution of NaHCO3 was added to
the reaction mixture and the product was thoroughly extracted with
Et2O. The organic extracts were successively washed with a 3% aqueous
solution of KHSO4 twice, a saturated aqueous solution of NaHCO3, and
saturated brine, dried over MgSO4, and concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(1R,4aS,4bR,6R,8R,8aS,10aR)-Methyl 8-acetoxy-1,4a,6-trimethyl-3,10-di-
oxotetradecahydrophenanthrene-1-carboxylate (21): M.p. 230–2338C;
[a]3D0 =À82.78 (c = 1.00, CHCl3); 1H NMR (CDCl3, 270 MHz): d = 1.13
(d, J=7.4 Hz, 3H), 1.20 (dd, J=4.6, 12.7 Hz, 1H), 1.28 (s, 3H), 1.38 (s,
3H), 1.61–2.25 (m, 12H, involving a singlet at 2.11 and a double doublet
at 2.23, J=3.8, 11.7 Hz), 2.50 (d, J=14.7 Hz, 1H), 2.59 (brt, J=12.6 Hz,
1H), 3.18 (s, 1H), 3.24 (d, J=14.7 Hz, 1H), 3.65 (s, 3H), 4.94–4.95 ppm
(m, 1H); 13C NMR (67.8 MHz, CDCl3): d = 20.20, 21.41, 26.39, 26.82,
27.96, 31.53, 34.92, 39.49, 43.17, 44.02, 44.77, 46.19, 47.08, 47.29, 52.26,
62.70, 73.28, 170.05, 177.36, 209.63, 211.11 ppm; IR (CHCl3): n˜ = 2878,
(EtOAc/hexane 1:20) to give TBS ether 25 (1.62 g, 94% from 24). [a]D26
=
1
À9.68 (c = 1.25, CHCl3); H NMR (CDCl3, 270 MHz): d = 0.05 (s, 3H),
0.16 (s, 3H), 0.59 (brq, J=8.1 Hz, 6H), 0.91 (s, 9H), 0.97 (brt, J=8.1 Hz,
6638
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6626 – 6644

Zoanthamine Alkaloids
FULL PAPER
9H), 1.13 (d, J=7.4 Hz, 3H), 1.23 (s, 3H), 1.25 (s, 3H), 1.28–1.69 (m,
10H), 1.80 (d, J=11.2 Hz, 1H), 1.95–2.00 (m, 1H), 2.08 (ddd, J=1.6, 4.7,
13.9 Hz, 1H), 2.26 (ddd, J=1.6, 5.9, 11.0 Hz, 1H), 3.72–3.77 (m, 1H),
4.32–4.37 (m, 1H), 4.71 ppm (brt, J=5.1 Hz, 1H); 13C NMR (67.8 MHz,
(TBAC) (197 mg, 0.71 mmol), (NH4)6Mo7O24·4H2O (877 mg, 0.71 mmol),
and THF (7.1 mL) was added a 35% H2O2 solution at room temperature
and the mixture was stirred at 508C for 7 h. After the reaction mixture
was cooled to room temperature,
a saturated aqueous solution of
NaHCO3 was added and the mixture was extracted with Et2O. The or-
ganic extracts were washed with saturated brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (EtOAc/hexane 1:4) to afford keto alcohol
41 (710 mg, 90% from 26). [a]2D9 =À16.88 (c = 1.00, CHCl3); 1H NMR
(CDCl3, 270 MHz): d = 0.08 (s, 3H), 0.09 (s, 3H), 0.60 (brq, J=8.2 Hz,
6H), 0.89 (s, 9H), 0.94–1.02 (m, 10H, including a broad triplet at 0.98J=
8.2 Hz), 1.11–1.80 (m, 9H, including singlets at 1.15, 1.18, and a doublet
at 1.12, J=7.4 Hz), 1.80–2.20 (m, 3H), 2.34 (dd, J=2.3, 12.4 Hz, 1H),
2.40 (d, J=14.2 Hz, 1H), 2.50 (dd, J=2.4, 12.4 Hz, 1H), 3.75–3.80 (m,
1H), 4.54–4.58 ppm (m, 1H); 13C NMR (67.8 MHz, CDCl3): d = À4.40,
À3.55, 5.05 (3C), 7.16 (3C), 18.02, 18.37, 21.14, 26.01 (3C), 27.25, 28.36,
30.92, 36.39, 36.84, 38.43, 39.89, 42.35, 43.63, 43.68, 54.17, 56.49, 59.01,
68.14, 71.64, 212.27 ppm; IR (CHCl3): n˜ = 3420, 2953, 1701, 1464, 1381,
CDCl3): d
=
À4.65, À3.71, 5.12 (3C), 7.21 (3C), 18.11, 18.70, 21.40,
21.45, 25.89 (3C), 27.21, 31.17, 36.78, 37.75, 38.54, 38.58, 42.51, 43.66,
44.48, 49.34, 58.56, 67.88, 71.61, 75.49, 179.94 ppm; IR (CHCl3): n˜
=
2953, 1778, 1508, 1254, 1099 cmÀ1; HRMS: m/z: calcd for C26H47O4Si2:
479.3013; found: 479.3049 [MÀtBu]+.
(1R,3R,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-Butyldimethylsilyloxy)-
1,4a,6-trimethyl-8-(triethylsilyloxy)-3,1-((12-hydroxy)epoxymethano)te-
tradecahydrophenanthrene (26): To a solution of the lactone 25 (1.09 g,
2.03 mmol) in dry toluene (20 mL) was added dropwise a 1.01m solution
of DIBAL-H in toluene (2.0 mL, 2.03 mmol) at À788C and the mixture
was stirred at the same temperature for 2 h. A saturated aqueous solution
of sodium potassium tartrate was added to the reaction mixture and the
product was thoroughly extracted with EtOAc. The extracts were washed
with water and saturated brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane 1:19, 1:9, 1:4, 1:1) to give lactol 26
(711 mg, 65%) along with the starting material (327 mg). The recovered
starting material was again subjected to the above reduction. By repeat-
ing reduction of the recovered starting material (3ꢂ), an additional lactol
1256, 1057, 833, 756 cmÀ1
; HRMS: m/z: calcd for C27H49D2O4Si2:
497.3449; found: 497.3444 [MÀtBu]+.
(4aS,4bS,5S,6aS,7R,9R,10aR,10bS)-5-(tert-Butyldimethylsilyloxy)-3,3-di-
deuterio-12-methoxy-4a,9,10b-trimethyl-7-(triethylsilyloxy)-
3,4,4a,4b,5,6,6a,7,8,9,10,10a,10b,11-tetradecahydro-1H-naphtho
ACHTUNGTRENNUNG[2,1-f]iso-
26 was obtained (221 mg, 20%). [a]2D9 =+2.98 (c
= 1.40, CHCl3);
chromen-1-one (42): mixture of the keto alcohol 41 (556 mg,
A
1H NMR (CDCl3, 270 MHz): d = 0.07 (s, 3H), 0.09 (s, 3H), 0.59 (brq,
J=8.1 Hz, 6H), 0.88–2.11 (m, 42H, involving a singlet at 0.90 and broad
triplet at 0.97, J=8.1 Hz), 3.70–3.74 (m, 1H), 4.43–4.47 (m, 1H), 4.51
(brt, J=5.5 Hz, 1H), 5.59 (d, J=5.3 Hz, 1H) with peaks due to aldehyde
form at 2.33–2.40 (m, 1H), 3.74–3.78 (m, 1H), 4.05–4.12 (m, 1H), 4.64–
4.68 (m, 1H), 10.21 ppm (d, J=0.8 Hz, 1H); 13C NMR (67.8 MHz,
CDCl3): d = À4.54, À4.26, À3.80, À3.24, 5.12, 7.22, 18.04, 18.23, 18.84,
19.29, 20.38, 21.21, 21.42, 24.49, 25.96, 26.10, 27.40, 31.07, 31.41, 35.37,
36.55, 37.29, 37.48, 38.55, 38.68, 41.02, 42.35, 43.86, 44.86, 45.56, 46.55,
46.74, 49.82, 57.76, 59.50, 66.39, 68.25, 68.86, 71.61, 71.84, 76.53, 99.35,
1.00 mmol), (MeO)2CO (0.84 mL, 10.0 mmol), a 1.0m solution of LiOtBu
in THF (5.0 mL, 5.00 mmol), and HMPA (5.0 mL) was stirred at 758C
for 4 h. After the reaction mixture was cooled to room temperature, MeI
(1.25 mL, 20 mmol) was added and the mixture was stirred at room tem-
perature for 2 h. After the reaction was quenched with a saturated aque-
ous solution of NH4Cl, the mixture was extracted with Et2O. The organic
extracts were washed with saturated brine, dried over MgSO4, and con-
centrated under reduced pressure. The residue was purified by silica gel
column chromatography (EtOAc/hexane 1:9) to furnish methyl enol
ether 42 (543 mg, 92%). 1H NMR (CDCl3, 270 MHz): d = 0.07 (s, 3H),
0.08 (s, 3H), 0.59 (brq, J=8.2 Hz, 6H), 0.88 (s, 9H), 0.94–1.00 (m, 10H,
including a triplet at 0.97, J=8.2 Hz), 1.07 (s, 3H), 1.15–1.72 (m, 15H, in-
cluding a singlet at 1.22 and a doublet at 1.16, J=7.4 Hz), 1.91 (d, J=
16.7 Hz, 1H), 2.00–2.11 (m, 1H), 2.38 (d, J=16.7 Hz, 1H), 2.91 (d, J=
14.2 Hz, 1H), 3.69 (s, 3H), 3.78 (brq, J=2.6 Hz, 1H), 4.45–4.50 ppm (m,
1H); 13C NMR (67.8 MHz, CDCl3): d = À4.49, À3.05, 5.08 (3C), 7.19
(3C), 16.93, 18.25, 21.21, 26.21 (3C), 27.44, 31.82, 32.51, 32.55, 36.13,
36.78, 37.12, 38.54, 39.70, 41.46, 41.51, 54.09, 56.03, 68.07, 71.71, 110.86,
158.32, 168.20 ppm; IR (CHCl3): n˜ = 2953, 2878, 1746, 1462, 1254, 1221,
1128, 1096, 1042, 949 833 cmÀ1; HRMS: m/z: calcd for C33H58D2O5Si2:
594.4103.; found: 594.4105 [M]+.
210.89 ppm, involving peaks due to aldehyde form; IR (CHCl3): n˜
=
3402, 2953, 2361, 1705, 1464, 1414, 1254, 1059, 833 cmÀ1; HRMS: m/z:
calcd for C26H49O4Si2: 481.3169; found: 481.3179 [MÀtBu]+.
(1S,3S,4aS,4bR,6R,8R,8aS,10S,10aR)-10-(tert-Butyldimethylsilyloxy)-1-
(2,2-dideuteriovinyl-1,4a,6-trimethyl-8-(triethylsilyloxy)tetradecahydro-
phenanthren-3-ol
(39):
To
a
solution
of
methyl-
[D3]triphenylphosphonium bromide (3.07 g, 8.52 mmol) in anhydrous
THF was added at 08C a 0.50m solution of potassium bis(trimethylsilyl)a-
mide (KHMDS) in toluene (17.0 mL, 8.52 mmol) and the mixture was
stirred at 08C for 30 min. Then, a solution of the lactol 26 (765.9 mg,
1.42 mmol) in anhydrous THF (7.1 mL) was added to the above yellow-
colored solution of phosphorane and the mixture was stirred at 08C for
1.5 h. A saturated aqueous solution of NH4Cl was added to the reaction
mixture and the product was thoroughly extracted with Et2O. The ex-
tracts were washed with water and saturated brine, dried over MgSO4,
and concentrated. The residue was dissolved in Et2O and passed through
a short silica gel column to remove triphenylphosphine oxide. After
evaporation of the solvent, the crude product 39 was used for the next
step without purification.
(4aS,4bS,5S,6aS,7R,9R,10aR,10bS,12aS)-5-(tert-Butyldimethylsilyloxy)-
3,3-dideuterio-12-methoxy-4a,9,10b,12a-tetramethyl-7-(triethylsilyloxy)-
3,4,4a,4b,5,6,6a,7,8,9,10,10a,10b,12a-tetradecahydro-1H-naphthoACHTUNGTRENNUNG[2,1-f]iso-
chromen-1-one (43): To a solution of methyl enol ether 42 (499.2 mg,
0.839 mmol) in anhydrous THF (4.2 mL) and DMPU (4.2 mL) was added
a freshly prepared 1.0m solution of LiHMDS (3.36 mL, 3.36 mmol) in
THF at À188C and the mixture was stirred at À18 to À118C for 2 h.
Then, CH3I (784 mL, 12.6 mmol) was added and the mixture was stirred
at À118C for 20 min and then at room temperature for 3.6 h. After a sa-
turated aqueous solution of NH4Cl was added to the reaction mixture,
the product was extracted with Et2O (3ꢂ). The ether extracts were
washed with water and saturated brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by flash column
chromatography (SiO2, hexane/EtOAc 20:1, 15:1, 4:1) to give lactone 43
(418.4 mg, 82%, 97% based on the recovered starting material) along
with the starting material (79.5 mg, 16% recovery). [a]2D9 =+0.68 (c =
0.85, CHCl3); 1H NMR (CDCl3, 270 MHz): d = 0.09 (s, 3H), 0.10 (s,
3H), 0.59 (brq, J=7.9 Hz, 6H), 0.89–1.03 (m, 22H, including singlets at
0.89, 1.03 and a triplet at 0.96, J=7.9 Hz), 1.14 (d, J=7.4 Hz, 3H), 1.17
(s, 3H), 1.25–1.72 (m, 12H, including a singlet at 1.33), 2.00–2.13 (m,
1H), 3.07 (brd, J=15.5 Hz, 1H), 3.51 (s, 3H), 3.75–3.80 (m, 1H), 4.46–
(1R,3S,4aS,4bR,6R,8R,8aS,10S,10aR)-10-(tert-Butyldimethylsilyloxy)-1-
(2,2-dideuterio-2-hydroxyethyl)-1,4a,6-trimethyl-8-(triethylsilyloxy)tetra-
decahydrophenanthren-3-ol (40): A mixture of the crude deuterated-
alkene 39 (1.42 mmol), 9-BBN dimer (1.04 g, 4.26 mmol), and anhydrous
THF (7.1 mL) was stirred at 808C for 1 h. After the reaction mixture was
cooled to room temperature, water, a 3m aqueous solution of NaOH,
and a 35% H2O2 solution were added in order and the mixture was
stirred at room temperature for 12 h. The product was extracted with
EtOAc and the extracts were washed with water and saturated brine,
dried over MgSO4, and concentrated under reduced pressure. The crude
diol 40 was used for the next step without purification.
(1R,4aS,4bR,6R,8R,8aS,10S,10aR)-10-(tert-Butyldimethylsilyloxy)-1-(2,2-
dideuterio-2-hydroxyethyl)-1,4a,6-trimethyl-8-(triethylsilyloxy)dodecahy-
4.51 (m, 1H), 4.79 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d
=
drophenanthren-3
(4bH)-one (41): To a mixture of the crude diol 40
À4.11, À3.83, 5.12 (3C), 7.17 (3C), 18.02, 19.11, 19.87, 21.55, 25.99 (3C),
(1.42 mmol), K2CO3 (393 mg, 2.84 mmol), tetrabutylammonium chloride
27.56, 28.72, 31.22, 34.16, 37.21, 37.52, 38.68, 38.81, 39.54, 41.46, 49.22,
Chem. Eur. J. 2009, 15, 6626 – 6644
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6639

M. Miyashita et al.
52.92, 54.81, 68.44, 71.65, 104.00, 152.37, 174.61 ppm; IR (CHCl3): n˜
=
tert-Butyl((1R,4aS,4bS,5S,6aS,7R,9R,10aR,10bS,12aR)-1,3-dideuterio-12-
methoxy-1,4a,9,10b,12a-pentamethyl-7-(triethylsilyloxy)-
4a,4b,5,6,6a,7,8,9,10,10a,10b,12a-dodecahydro-1H-naphthoACTHNUGTRNEUNG[2,1-f]iso-
3018, 2953, 1746, 1666, 1462, 1217, 1142, 1094, 1005, 976, 943, 835 cmÀ1
;
HRMS: m/z: calcd for C34H60D2O5Si2: 608.4259; found: 608.4253 [M]+.
chromen-5-yloxy)dimethylsilane (46): [a]3D0 =+25.08 (c = 1.00, CHCl3);
1H NMR (CDCl3, 500 MHz): d = 0.06 (s, 3H), 0.09 (s, 3H), 0.55 (q, J=
8.0 Hz, 6H), 0.89 (s, 9H), 0.95 (t, J=8.0 Hz, 9H), 0.95 (s, 3H), 1.05 (s,
3H), 1.11 (d, J=7.5 Hz, 3H), 1.23 (s, 3H), 1.15–1.69 (m, 9H), 1.45 (s,
3H), 1.95–2.05 (m, 1H), 3.45 (s, 3H), 3.71–3.75 (m 1H), 4.44 (brs, 1H),
4.74 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d = À4.33, À3.79, 5.00
(3C), 7.09 (3C), 17.56, 17.68, 17.78, 18.05, 18.98, 21.41, 25.19, 25.99 (3C),
27.60, 29.70, 31.14, 36.83, 36.99, 38.79, 39.57, 40.38, 41.29, 44.91, 49.74,
54.10, 69.50, 71.93, 106.15, 111.96, 141.85, 155.79 ppm; IR (CHCl3): n˜ =
2953, 1665, 1472, 1379, 1254, 1140, 1055, 1067, 835, 760 cmÀ1; HRMS
(FD): m/z: calcd for C35H62D2O4Si2: 606.4467; found: 606.4473 [M]+.
1-((1S,2S,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-Butyldimethylsilyloxy)-1-
(2,2-dideuterio-2-hydroxyethyl)-3-methoxy-1,2,4a,6-tetramethyl-8-(tri-
ethylsilyloxy)-1,2,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydrophenanthren-2-yl)-
ethanone (43A): To a solution of the lactone 174 (256 mg, 0.42 mmol) in
dry Et2O (0.82 mL) was added a 1.02m solution of CH3Li in Et2O
(2.4 mL, 2.46 mmol) at À788C and the mixture was stirred at 08C for 1 h.
A saturated aqueous solution of NH4Cl was added to the reaction mix-
ture and the product was thoroughly extracted with Et2O. The organic
extract was washed with saturated brine, dried over MgSO4, and concen-
trated under reduced pressure to leave an oily residue. The crude keto al-
cohol 43A was used for the next step without purification.
(5R)-tert-Butyl 5-((2R)-6-((1S,2R,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-
butyldimethylsilyloxy)-1-(2-(tert-butyldimethylsilyloxy)-2,2-dideuterioeth-
yl)-3-methoxy-1,2,4a,6-tetramethyl-8-(triethylsilyloxy)-
1-((1S,2S,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-Butyldimethylsilyloxy)-1-
(2-(tert-butyldimethylsilyloxy)-2,2-dideuterioethyl)-3-methoxy-1,2,4a,6-
tetramethyl-8-(triethylsilyloxy)-1,2,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydro-
phenanthren-2-yl)ethanone (44): To a mixture of the crude lactol 43A
(0.42 mmol), Et3N (290 mL, 2.10 mmol), 4-dimethylaminopyridine
(154 mg, 1.26 mmol), and dry DMF (2.1 mL) was added TBSCl (189 mg,
1.26 mmol) at 08C and the mixture was stirred at room temperature for
3 h. A saturated aqueous solution of NaHCO3 was added to the reaction
mixture and the product was extracted with Et2O (3ꢂ). The organic ex-
tracts were washed with saturated brine, dried over MgSO4, and concen-
trated to leave an oil. Purification of the oily residue by silica gel column
chromatography (EtOAc/hexane 1:39) afforded methyl ketone 44
1,2,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydrophenanthren-2-yl)-4-hydroxy-2-
methylhex-5-ynyl)-2,2-dimethyloxazolidine-3-carboxylate (45A): To a so-
lution of the alkyne 45 (170.0 mg, 0.24 mmol) in anhydrous THF
(8.0 mL) was added a 1.58m solution of nBuLi in hexane (299 mL,
0.47 mmol) at À608C and the mixture was stirred at À308C for 30 min.
Then,
a
solution of the aminoalcohol segment 52[42] (134.7 mg,
0.47 mmol) in THF (0.25 mL) was added at À788C and the mixture was
stirred at the same temperature for 1 h. A saturated aqueous solution of
NH4Cl was added to the reaction mixture and the product was extracted
with Et2O. The organic extracts were washed with saturated brine, dried
over MgSO4, and concentrated under reduced pressure. Purification of
the oily residue by silica gel column chromatography (EtOAc/hexane
1:49, 1:19, 1:9) gave an inseparable mixture of the adduct 45A and the
amine segment 52, along with starting material 45 (74.8 mg, 44% recov-
ery). The recovered starting material was again subjected to the coupling
reaction with 52 and this manipulation was repeated two times. The com-
bined mixture was directly used for the next step.
(273 mg, 88% for the two steps). [a]2D9 =+18.58 (c
= 0.65, CHCl3);
1H NMR (CDCl3, 270 MHz): d = À0.03 (s, 3H), À0.02 (s, 3H), 0.07 (s,
3H), 0.09 (s, 3H), 0.57 (brq, J=8.1 Hz, 6H), 0.81–0.98 (m, 31H, includ-
ing singlets at 0.84, 0.89 and a triplet at 0.95, J=8.1 Hz), 1.10–1.72 (m,
17H, including singlets at 1.11, 1.13 and 1.31), 1.98–2.10 (m, 2H), 2.22 (s,
3H), 2.75 (d, J=14.2 Hz, 1H), 3.49 (s, 3H), 3.73–3.78 (m, 1H), 4.41–4.46
(m, 1H), 4.89 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d = À5.24,
À5.16, À4.31, À3.71, 5.12 (3C), 7.19 (3C), 18.05, 18.18, 19.32, 19.93,
20.20, 21.51, 25.96 (3C), 26.03, 26.08 (3C), 27.70, 30.62, 31.48, 36.29,
37.27, 37.39, 38.80, 40.29, 41.88, 42.15, 51.80, 53.94, 59.90, 68.75, 71.93,
5-((S)-6-((1S,2R,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-Butyldimethylsilyl-
oxy)-1-(2-(tert-butyldimethylsilyloxy)-2,2-deuterioethyl)-3-methoxy-
1,2,4a,6-tetramethyl-8-(triethylsilyloxy)-1,2,4a,4b,5,6,7,8,8a,9,10,10a-do-
decahydrophenanthren-2-yl)-2-methyl-4-oxohex-5-ynyl)-2,2-dimethyloxa-
zolidine-3-carboxylate (53): To a mixture of the crude adducts 45A
(0.24 mmol), pyridine (115 mL, 1.42 mmol), and CH2Cl2 (5 mL) was
added Dess–Martin periodinane (400.4 mg, 0.94 mmol) and the mixture
was stirred at room temperature for 2 h. A saturated aqueous solution of
NaHCO3 and that of Na2S2O3 were added to the reaction mixture and
the product was thoroughly extracted with Et2O. The organic extracts
were washed with water, a saturated aqueous solution of NaHCO3, and
saturated brine, dried over MgSO4, and concentrated. The residue was
purified by a silica gel column (EtOAc/hexane 1:19, 1:9) to give rise al-
kynyl ketone 53 (194.0 mg, 82% for the two steps). [a]3D0 =À2.08 (c =
1.00, CHCl3); 1H NMR (CDCl3, 270 MHz): d = À0.02 (s, 3H), À0.02 (s,
3H), 0.08 (s, 3H), 0.12 (s, 3H), 0.57 (brq, J=7.9 Hz, 6H), 0.84 (S, 9H),
0.90 (s, 9H), 0.95 (t, J=7.9 Hz, 9H), 1.03 (d, J=6.6 Hz, 3H), 1.08 (brs,
3H), 1.12 (d, J=7.4 Hz, 3H), 1.24 (s, 3H), 1.34 (s, 3H), 1.38–1.69 (m,
27H, including a broad singlet at 1.47), 1.93 (d, J=14.2 Hz, 1H), 1.96–
2.01 (m, 1H), 2.24–2.63 (m, 4H), 2.95–3.77 (m, 1H), 3.54 (s, 3H), 3.60–
3.78 (m, 2H, including a singlet at 3.78), 4.05–4.18 (m, 1H), 4.41 (brs,
1H), 4.67 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d = À5.21, À5.06,
À4.26, À3.93, 5.00, 7.06, 17.93, 18.12, 20.10, 20.49, 21.46, 24.28, 25.15,
26.01, 26.24, 27.12, 27.32, 27.51, 28.46, 31.34, 37.19, 37.29, 38.01, 38.62,
39.80, 40.01, 41.88, 41.90, 47.17, 49.96, 51.11, 52.74, 52.96, 54.76, 68.45,
71.75, 71.99, 79.27, 79.81, 83.72, 92.68, 93.19, 98.53, 103.43, 151.61, 151.97,
152.39, 186.83 ppm, including peaks due to tautomer; IR (CHCl3): n˜ =
2955, 2930, 2880, 2858, 2210, 1703, 1672, 1464, 1391, 1366, 1256, 1219,
105.28, 154.78, 213.04 ppm; IR (CHCl3): n˜
= 2953, 2856, 1699, 1668,
1472, 1387, 1254, 1219, 1142, 1057, 1007, 837 cmÀ1; HRMS: m/z: calcd for
C41H78D2O5Si3: 738.5437; found: 738.5441 [M]+.
Conversion of 44 to 45: To a mixture of the methyl ketone 44 (225 mg,
0.31 mmol), 2,6-di-tert-butylpyridine (620 mL, 2.75 mmol), and dry
(CH2Cl)2 (0.9 mL) was added trifluoromethanesulufonic anhydride
(155 mL, 0.915 mmol) at 08C and the mixture was stirred at room temper-
ature for 3 h. Then, DBU (460 mL, 3.05 mmol) was added and the mix-
ture was stirred at 808C for 3 h.
A saturated aqueous solution of
NaHCO3 was added to the reaction mixture and the product was extract-
ed with Et2O. The organic extracts were washed with saturated brine,
dried over MgSO4, and concentrated under reduced pressure. Purification
of the oily residue by silica gel column chromatography (EtOAc/hexane
1:49, 1:19) afforded alkyne 45 (178 mg, 81%) and vinyl ether 46
(16.6 mg, 9%).
tert-Butyl(1,1-dideuterio-2-((1S,2S,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-
butyldimethylsilyloxy)-2-ethynyl-3-methoxy-1,2,4a,6-tetramethyl-8-(tri-
ethylsilyloxy)-1,2,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydrophenanthren-1-
yl)ethoxy)dimethylsilane (45): [a]3D0 =+6.78 (c = 0.45, CHCl3); 1H NMR
(CDCl3, 270 MHz): d = 0.00 (s, 3H), 0.01 (s, 3H), 0.09 (s, 3H), 0.14 (s,
3H), 0.58 (brq, J=8.2 Hz, 6H), 0.87 (s, 9H), 0.92 (s, 9H), 0.96 (t, J=
7.7 Hz, 9H), 1.09 (s, 3H), 1.13 (d, J=7.4 Hz, 3H), 1.23–1.70 (m, 15H, in-
volving singlets at 1.26 and 1.32), 1.97 (d, J=13.8 Hz, 1H), 1.97–2.10 (m,
1H), 2.18 (s, 1H), 2.58 (brd, J=13.8 Hz, 1H), 3.58 (s, 3H), 3.74–3.79 (m,
1H), 4.41–4.45 (m, 1H), 4.68ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3):
d = À5.17, À5.04, À4.42, À3.85, 5.00 (3C), 7.05 (3C), 17.94, 18.22, 20.09,
21.44, 25.66, 26.00 (3C), 27.53, 31.32, 37.15, 37.29, 37.77, 38.65, 40.09,
41.59, 41.84, 46.40, 50.01, 55.04, 68.62, 70.69, 71.79, 88.74, 101,41,
1177, 1059, 1009, 837 cmÀ1
; HRMS: m/z: calcd for C56H101D2O8Si3:
1003.7115; found: 1003.7146 [M]+.
(R)-tert-Butyl 5-((S)-6-((1S,2S,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-bu-
tyldimethylsilyloxy)-1-(2-(tert-butyldimethylsilyloxy)-2,2-deuterioethyl)-3-
methoxy-1,2,4a,6-tetramethyl-8-(triethylsilyloxy)-
153.22 ppm (two peaks missing); IR (CHCl3): n˜
1668, 1254, 1217, 1057, 1007, 837 cmÀ1
HRMS: m/z: calcd for
C41H76D2O4Si3: 720.5331; found: 720.5319 [M]+.
= 3308, 2856, 2361,
;
1,2,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydrophenanthren-2-yl)-2-methyl-4-
6640
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6626 – 6644

Zoanthamine Alkaloids
FULL PAPER
oxohexyl)-2,2-dimethyloxazolidine-3-carboxylate (53A):
A
mixture of
(d, J=7.1 Hz, 3H), 1.08–1.33 (m, 9H, including a singlet at 1.17, and a
doublet at 1.28, J=8.2 Hz), 1.45 (s, 9H), 1.53–1.61 (m, 2H), 1.69–1.85 (m,
3H), 1.89–2.26 (m, 7H, including a doublet at 2.18, J=14.7), 2.44–2.68
(m, 6H), 2.30 (s, 1H), 3.14 (d, J=14.7 Hz, 1H), 3.34–3.55 (m, 2H), 3.62
(brd, J=2.1, 3H), 4.41 ppm (brs, 1H); 13C NMR (67.8 MHz, CDCl3): d
= 16.20, 18.98, 19.06, 19.20, 19.30, 19.56, 21.53, 21.58, 22.55, 23.06, 24.12,
28.42, 28.48, 29.73, 30.05, 30.18, 31.50, 36.46, 36.65, 37.56, 41.13, 41.57,
42.87, 46.39, 47.06, 47.14, 47.17, 49.28, 49.36, 50.28, 50.90, 50.99, 51.06,
51.17, 51.23, 51.27, 54.71, 54.75, 62.40, 62.43, 72.30, 72.41, 79.03, 79.61,
94.17, 94.26, 151.61, 152.36, 171.89, 172.01, 208.22, 208.50, 208.67, 208.73,
211.61, 211.77 ppm, containing peaks due to tautomer; IR (CHCl3): n˜ =
2956, 1703, 1396, 1290, 1244, 1176, 1120, 751 cmÀ1; HRMS: m/z: calcd for
C35H53NO8: 615.3771; found: 615.3777 [M]+.
PtO2 (purchased from Wako Pure Chemical Industries, Ltd., 6.0 mg,
26.4 mmol) and EtOH (0.54 mL) was stirred under H2 (1 atm) for 15 min.
To the mixture were added a solution of the alkynyl ketone 53 (40.0 mg,
39.9 mmol) in EtOH (1.06 mL) and AcOH (9.1 mL, 0.160 mmol) and the
mixture was vigorously stirred under a hydrogen atmosphere (1 atm) for
1 h. The reaction mixture was filtered through a pad of celite with EtOH.
The filtrate was concentrated in vacuo to give 43.0 mg of the ketone
53A, which was used for the next step without purification.
ACHTUNGTRENNUNG(1R,3S,5S)-tert-butyl 5-(2-((1S,2S,4aS,4bR,6R,8R,8aS,10S,10aS)-10-(tert-
butyldimethylsilyloxy)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxy-
1,2,4a,6-tetramethyl-3-oxotetradecahydrophenanthren-2-yl)ethyl)-3-
methyl-8-oxa-6-azabicycloACTHNUGTRNEUNG[3.2.1]octane-6-carboxylate (54): A solution of
the crude ketone 53A (39.9 mmol) in aqueous AcOH (AcOH/H2O 9:1,
0.40 mL) was stirred at room temperature for 2 h and then at 508C for
5 h. The cooled reaction mixture was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product 54 was used for
the next step without purification.
AHCTUNGTERG(NNUN 1R,3S,5S)-tert-butyl 5-(2-((1S,2S,4aS,4bR,6R,8aS,10aS)-1-(2-methoxy-2-
oxoethyl)-1,2,4a,6-tetramethyl-3,10-dioxo-8-(trimethylsilyloxy)-
1,2,3,4,4a,4b,5,6,8a,9,10,10a-dodecahydrophenanthren-2-yl)ethyl)-3-
methyl-8-oxa-6-azabicycloACTHNUTRGNE[NUG 3.2.1]octane-6-carboxylate (56A): To a solu-
tion of the crude methyl ester 56 (22.3 mmol) and TMSCl (28.3 mL,
0.22 mmol) in THF (0.45 mL) was added dropwise a 0.5m solution of
LiHMDS in THF (222.7 mL, 0.11 mmol) at À788C and the mixture was
stirred at À658C for 1 h. A saturated aqueous solution of NaHCO3 con-
taining Et3N was added to the reaction mixture and the product was ex-
tracted with Et2O. The organic extract was dried over Na2SO4 and con-
centrated under reduced pressure. The crude enol TMS ether 56A was
used for the next step without purification.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ate (55): To a solution of the crude aminoacetal 54 (39.9 mmol) in anhy-
drous THF (0.12 mL) was added a 1.0m solution of TBAF (0.22 mL,
0.22 mmol) in THF at room temperature and the mixture was stirred at
708C for 2 h. To the cooled reaction mixture were added
(NH4)6Mo7O24·4H2O (49.3 mg, 39.9 mmol), K2CO3 (5.5 mg, 39.8 mmol),
and a 30% H2O2 solution (150 mL) and the mixture was well agitated at
508C for 3 h. An aqueous solution of NaHCO3 was added to the reaction
mixture and the product was thoroughly extracted with Et2O. The organ-
ic extracts were washed with a saturated aqueous solution of NaHCO3
and saturated brine, dried over Na2SO4, and concentrated. The crude oil
was passed through a short silica gel column with hexane/EtOAc (3:2,
0:1) and the eluate was concentrated under reduced pressure. The crude
product 55 (19.4 mg) was used for the next step without purification.
AHCTUNGTERG(NNUN 1R,3S,5S)-tert-Butyl 5-(2-((1S,2S,4aS,4bR,8aS,10aS)-1-(2-methoxy-2-oxo-
ethyl)-1,2,4a,6-tetramethyl-3,8,10-trioxo-1,2,3,4,4a,4b,5,8,8a,9,10,10a-do-
decahydrophenanthren-2-yl)ethyl)-3-methyl-8-oxa-6-azabicyclo-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
was stirred at 508C for 2 h. Then, the mixture was passed through a short
silica gel column by the aid of EtOAc. After evaporation of the solvents
of the eluate, the residue was purified by preparative thin layer chroma-
tography (MeOH/CHCl3 6:94) to afford 12.8 mg (96% from 55B) of the
enone 57. [a]3D0 =+9.78 (c = 0.45, CHCl3); 1H NMR (CDCl3, 270 MHz):
d = 0.90 (d, J=1.1 Hz, 3H), 0.92 (s, 3H), 1.09–1.31 (m, 9H, including a
singlet at 1.17, and a doublet at 1.30, J=7.9 Hz), 1.45 (s, 9H), 1.52–1.83
(m, 3H), 2.00–2.24 (m, 10H, including a singlet at 2.00, and a doublet at
2.20, J=14.8), 2.30–2.58 (m, 3H), 2.76 (d, J=12.2 Hz, 1H), 2.80–2.88 (m,
1H), 3.01 (s, 1H), 3.16 (d, J=14.8 Hz, 1H), 3.34–3.55 (m, 2H), 3.63 (brd,
J=2.1 Hz, 3H), 4.42 ppm (brs, 1H), 5.92 (s, 1H); 13C NMR (67.8 MHz,
CDCl3): d = 16.73, 18.94, 19.35, 19.62, 21.54, 21.58, 22.57, 23.00, 24.12,
24.35, 28.42, 28.49, 30.09, 30.89, 31.55, 36.49, 36.70, 37.56, 41.09, 41.62,
43.14, 45.28, 45.42, 46.34, 46.37, 46.41, 48.43, 48.50, 50.90, 50.99, 51.09,
51.31, 51.82, 51.88, 54.73, 54.77, 62.07, 72.30, 72.42, 79.05, 79.61, 94.16,
94.22, 125.26, 151.63, 152.33, 159.86, 159.98, 171.84, 171.97, 197.69, 197.74,
207.49, 207.78, 211.37, 211.56 ppm, including peaks due to tautomer; IR
(CHCl3): n˜ = 3020, 1703, 1640, 1398, 1217, 1128, 756 cmÀ1; HRMS: m/z:
calcd for C35H51NO8: 613.3615; found: 613.3593 [M]+.
A
3-methyl-5-(2-((1S,2S,4aS,4bR,6R,8aS,10aS)-
AHCTUNGTRENNUNG
(55A): To a mixture of the crude triketone 55 (19.4 mg), powdered
MS4A (13.2 mg), and CH2Cl2 (0.26 mL) was added TPAP (13.9 mg,
39.6 mmol) and the mixture was stirred at room temperature for 1 h.
Then, the reaction mixture was passed through a short silica gel column
by the aid of hexane/EtOAc 1:1 to remove inorganic substances. After
evaporation of the solvent, the crude aldehyde 55A (14.9 mg, 64% from
53) was directly used for the next step.
2-((1S,2S,4aS,4bR,6R,8aS,10aS)-2-(2-((1R,3S,5S)-6-(tert-Butoxycarbon-
yl)-3-methyl-8-oxa-6-azabicycloACTHUNRTGNEUNG[3.2.1]octan-5-yl)ethyl)-1,2,4a,6-tetra-
methyl-3,8,10-trioxotetradecahydrophenanthren-1-yl)acetic acid (55B):
To a mixture of the crude aldehyde 55A (32.0 mg, 54.6 mmol), 2-methyl-
2-butene (45.9 mL, 0.55 mmol), NaH2PO4·2H2O (8.5 mg, 54.3 mmol), H2O
(0.08 mL), and tBuOH (0.19 mL) was added NaClO2 (14.8 mg,
0.16 mmol) and the mixture was stirred at room temperature for 1 h. A
saturated aqueous solution of NH4Cl was added to the reaction mixture
and the product was extracted with EtOAc. The extract was dried over
Na2SO4 and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (MeOH/CHCl3 0:1, 1:9) to
afford carboxylic acid 55B (31.4 mg, 61% for the six steps from the al-
kynyl ketone 53).
Norzoanthamine (1): A solution of the enone 57 (4.9 mg, 8.17 mmol) in
aqueous AcOH (AcOH/H2O 24:1, 0.50 mL) was heated at 1008C for
24 h. The reaction mixture was concentrated in vacuo and the residue
was dissolved in aqueous TFA (TFA/H2O 2:1, 0.3 mL) and the solution
was stirred at 1108C for 24 h. The reaction mixture was cooled to room
temperature and concentrated in vacuo. To a solution of the residue in
MeOH (2 mL) was added Al2O3 (490 mg) and the mixture was stirred at
room temperature for 1 h. Then Al2O3 was filtered off and the filtrate
was concentrated under reduced pressure. Purification of the residue by
preparative thin layer chromatography (MeOH/CHCl3 1:9) afforded
3.2 mg (81%) of norzoanthamine (1). M.p. 273–2768C; lit.[2a] m.p. 282–
2858C; [a]2D4 =À6.08 (c = 0.23, CHCl3); natural specimen. [a]2D4 =À6.28 (c
= 0.23, CHCl3);[41] CD (0.0001m, MeOH) 313.4 nm (+1.57), 240.1 nm
(À3.06), 227.2 nm (À2.07), and 202.0 nm (À24.53); lit.[2a] CD (0.0001m,
MeOH) 313.4 nm (+1.32), 240.1 nm (À2.91), 226.9 nm (À1.85), and
201.9 nm (À21.78); UV 233 nm (MeOH); lit.[2a] 234 nm (MeOH);
1H NMR (CDCl3, 270 MHz): d = 0.91 (d, J=6.7 Hz, 3H), 1.01 (s, 6H),
1.09 (dd, J=11.5, 12.7 Hz, 1H), 1.16 (s, 3H), 1.47 (dt, J=3.1, 12.5 Hz,
1H), 1.54–1.58 (m, 2H), 1.70 (bdt, J=3.7, 12.8 Hz, 1H), 1.77 (bdt, J=3.4,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
a solution of the carboxylic acid 55B (13.4 mg, 22.3 mmol) in CH2Cl2
(0.36 mL) containing MeOH (0.09 mL) was added a 2.0m solution of
TMSCHN2 in hexane (55.7 mL, 0.11 mmol) and the mixture was stirred at
room temperature for 1 h. After evaporation of the solvents, the crude
ester 56 was used for the next step without purification. A small quantity
of the product was purified by silica gel flash column chromatography
(hexane/EtOAc 1:1, 2:3) for characterization. [a]3D0 =+5.98 (c
CHCl3); H NMR (CDCl3, 270 MHz): d = 0.90 (s, 3H), 0.92 (s, 3H), 1.01
= 0.50,
1
Chem. Eur. J. 2009, 15, 6626 – 6644
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6641

M. Miyashita et al.
12.8 Hz, 1H), 1.89 (bdt, J=4.9, 13.4 Hz, 1H), 1.92 (d, J=14.0 Hz, 1H),
2.02 (s, 3H), 2.09 (dd, J=4.9, 12.7 Hz, 1H), 2.16 (d, J=14.0 Hz, 1H),
2.19–2.31 (m, 4H), 2.37 (d, J=20.8 Hz, 1H), 2.51 (dd, J=11.6, 14.6 Hz,
1H), 2.65 (dd, J=6.1, 14.6 Hz, 1H), 2.72 (bdt, J=6.1, 11.6 Hz, 1H), 2.84
(s, 1H), 3.23 (dd, J=6.1, 6.7 Hz, 1H), 3.28 (d, J=6.7, 1H), 3.67 (d, J=
20.8 Hz, 1H), 4.55–4.56 (m, 1H), 5.92 ppm (brs, 1H); 13C NMR
(67.8 MHz, CDCl3): d = 18.40, 18.47, 21.09, 21.82, 22.95, 23.66, 24.30,
29.93, 31.98, 35.88, 36.47, 38.87, 39.80, 39.89, 41.88, 42.42, 44.38, 46.44,
47.15, 53.15, 59.12, 74.22, 89.98, 101.52, 125.62, 159.82, 172.43, 198.46,
1H), 1.70–1.89 (m, 2H), 1.92–2.27 (m, 8H), 2.58–2.65 (m, 1H), 2.74 (d,
J=11.5 Hz, 1H), 2.82–2.90 (m, 1H), 3.17 (brd, J=14.9 Hz, 1H), 3.33 (s,
1H), 3.35 (d, J=9.8 Hz, 1/2H), 3.43–3.54 (m, 1H), 3.53 (d, J=9.7 Hz, 1/
2H), 3.63 (s, 9/2H), 3.63 (s, 9/2H), 4.39–4.45 (m, 1H), 4.59 (brs, 1H),
1
4.63 (brs, 1H), 5.51 (brs, 1H); H NMR (500 MHz, CD2Cl2): d = 0.19 (s,
3H), 0.23 (s, 3H), 0.78 (s, 3/2H), 0.79 (s, 3/2H), 0.90 (d, J=6.9 Hz, 3H),
0.94 (s, 9H), 0.90–1.25 (m, 2H), 1.14 (s, 3H), 1.15 (d, J=7.0 Hz, 3/2H),
1.16 (d, J=7.0 Hz, 3/2H), 1.19 (s, 3H), 1.23 (s, 3/2H), 1.43 (s, 9H), 1.53–
1.60 (m, 1H), 1.64–1.80 (m, 2H), 1.86–2.30 (m, 8H), 2.60–2.68 (m, 1H),
2.77 (d, J=12.0 Hz, 1H), 2.83 (quintet, J=6.9 Hz, 1/2H), 2.84 (quintet,
J=6.9 Hz, 1/2H), 3.22 (dd, J=14.9, 4.0 Hz, 1H), 3.32 (s, 1/2H), 3.32 (s, 1/
2H), 3.36 (d, J=9.8 Hz, 1H), 3.38–3.44 (m, 1H), 3.48 (d, J=9.8 Hz, 1H),
3.59 (s, 3/2H), 3.59 (s, 3/2H), 4.35–4.42 (m, 1H), 4.60 (s, 1H), 4.63 (s,
1H), 5.54 ppm (s, 1H), including peaks due to tautomer; 13C NMR
(125 MHz, CD2Cl2): d = À5.60, À4.96, 12.28, 15.82, 17.58, 18.35, 18.49,
18.54, 18.80, 20.99, 22.35, 22.51, 23.80, 23.82, 25.00, 27.83, 27.88, 29.46,
29.80, 31.00, 35.98, 36.10, 37.36, 40.74, 41.73, 42.54, 45.79, 45.82, 45.98,
46.26, 46.30, 47.21, 47.24, 48.83, 50.58, 50.69, 50.79, 50.82, 54.61, 54.63,
57.26, 72.06, 72.29, 78.50, 79.08, 93.90, 93.98, 106.28, 109.10, 141.82,
151.38, 152.00, 153.28, 153.31, 172.05, 212.19, 212.22, 212.37, 212.53 ppm,
including peaks due to tautomer; IR (film): n˜ = 2955, 2929, 2858, 1699,
1638, 1394, 1366, 1252, 1207, 1130, 999, 839 cmÀ1; HRMS (FD): m/z:
calcd for C42H67NO8Si: 741.4636; found: 741.4618 [M]+.
208.98 ppm; IR (CHCl3): n˜ = 3020, 2959, 1717, 1672, 1364, 1248 cmÀ1
HRMS: m/z: calcd for C29H39NO5: 481.2828; found: 481.2841 [M]+.
;
ACHTUNGTRENNUNG(1R,3S,5S)-tert-Butyl 5-(2-((1S,2S,4aS,4bR,8aS,10aS)-8-(tert-butyldime-
thylsilyloxy)-1-(2-methoxy-2-oxoethyl)-1,2,4a-trimethyl-6-methylene-3,10-
dioxo-1,2,3,4,4a,4b,5,6,8a,9,10,10a-dodecahydrophenanthren-2-yl)ethyl)-3-
methyl-8-oxa-6-azabicycloACTHNUGTRNEUNG[3.2.1]octane-6-carboxylate (66): To a solution
of the enone 57 (18.0 mg, 29.3 mmol) and Et3N (32.7 mL, 0.23 mmol) in
anhydrous CH2Cl2 (0.4 mL) was added TBSOTf (26.9 mL, 0.12 mmol) at
À758C and the mixture was stirred at the same temperature for 1 h. A
saturated aqueous solution of NaHCO3 was added to the reaction mix-
ture and the product was extracted with EtOAc. The extract was dried
over Na2SO4 and concentrated under reduced pressure. The residue was
purified by silica gel column flash chromatography (hexane/EtOAc 8:1,
2:1, 1:3) to give rise to 16.2 mg (76%) of the dienol silyl ether 66 and
4.0 mg (22% recovery) of the starting material 57. The recovered starting
material was subjected to the same reaction twice to afford an additional
Zoanthamine (2):
A solution of the enol TES ether 67 (3.3 mg,
4.45 mmol) in aqueous AcOH (AcOH/H2O 94:6, 0.32 mL) was stirred at
room temperature for 0.5 h and then at 1058C for 24 h. The cooled reac-
tion mixture was lyophilized to leave the crystalline residue. A solution
of the residue in aqueous TFA (TFA/H2O 2:1, 0.3 mL) was heated at
1108C for 16.5 h. The mixture was concentrated in vacuo and the residue
was dissolved in MeOH (0.25 mL) containing Et3N (31 mL, 0.22 mmol)
and the solution was stirred at room temperature for 1 h. Water was
added to the reaction mixture and the product was thoroughly extracted
with EtOAc. The extract was dried over Na2SO4 and concentrated under
reduced pressure. The crystalline residue was dissolved in CH2Cl2
(0.3 mL) and passed through a short basic aluminum column (Al2O3,
200 mg) by the aid of CH2Cl2/MeOH (5:1, 20 mL). After evaporation of
the solvents, the residue was purified by preparative thin layer chroma-
tography (Whatman LK6F silica gel 60 A TLC plate, CH3CN/MeOH
100:8) to afford pure zoanthamine (2) (1.4 mg, 63%). M.p. 300–3048C;
lit.[3a] m.p. 306–3088C; [a]D28 = +21.1 (c = 0.23, CHCl3); lit.:[3a] [a]D +18
(c = 0.48, CHCl3); 1H NMR (500 MHz, CDCl3): d = 0.91 (d, J=6.3 Hz,
3H), 0.97 (s, 3H), 1.00 (s, 3H), 1.10 (t, J=12.6 Hz, 1H), 1.17 (d, J=
6.9 Hz, 3H), 1.20 (s, 3H), 1.47 (brtd, J=13.8, 2.9 Hz, 1H), 1.54–1.60 (m,
2H), 1.70 (brtd, J=13.8, 4.0 Hz, 1H), 1.78 (brtd, J=12.6, 3.5 Hz, 1H),
1.90 (brtd, J=13.2, 4.6 Hz, 1H), 1.92 (d, J=13.8 Hz, 1H), 2.00 (s, 3H),
2.10 (dd, J=13.2, 5.2 Hz, 1H), 2.17 (d, J=14.3 Hz, 1H), 2.23 (m, 2H),
2.27 (m, 1H), 2.37 (d, J=19.5 Hz, 1H), 2.42 (m, 1H), 2.66 (dd, J=13.2,
5.2 Hz, 1H), 3.02 (qd, J=6.9, 5.8 Hz, 1H), 3.22 (s, 1H), 3.24 (t, J=
6.3 Hz, 1H), 3.29 (brd, J=6.3 Hz, 1H), 3.66 (d, J=20.0 Hz, 1H), 4.56
4.8 mg (22%) of 66. [a]D26
= 25.1 (c =
0.100, CH2Cl2); 1H NMR
(500 MHz, CDCl3): d = 0.18 (3H, s), 0.20 (3/2H, s), 0.20 (3/2H, s), 0.83
(d, J=6.3 Hz, 3H), 0.88 (3/2H, s), 0.90 (3/2H, s), 0.92 (9/2H, s), 0.92 (9/
2H, s), 1.02–1.35 (m, 3H), 1.15 (3/2H, s), 1.16 (3/2H, s), 1.26 (3/2H, s),
1.28 (3/2H, s), 1.45 (9/2H, s), 1.46 (9/2H, s), 1.50–1.88 (m, 3H), 1.95–2.30
(m, 9H), 2.55–2.63 (m, 1H), 2.74 (d, J=12.1 Hz, 1H), 2.80 (ddd, J=13.1,
8.6, 4.6 Hz, 1H), 3.08 (s, 1H), 3.13 (d, J=14.2 Hz, 1H), 3.35 (d, J=1/
2H), 3.44–3.50 (m, 1H), 3.52 (d, J=9.8 Hz, 1/2H), 3.63 (s, 9/2H), 3.63 (s,
9/2H), 4.38–4.45 (m, 1H), 4.59 (s, 1H), 4.64 (s, 1H), 5.41 (brs, 1H);
1H NMR (500 MHz, CD2Cl2): d = 0.19 (s, 3H), 0.21 (s, 3H), 0.78 (s, 3/
2H), 0.79 (s, 3/2H), 0.90 (d, J=6.3 Hz, 3H), 0.90–1.25 (m, 2H), 0.93 (s,
9H), 1.13 (s, 3/2H), 1.14 (s, 3/2H), 1.22 (s, 3/2H), 1.25 (s, 3/2H), 1.43 (s,
9H), 1.52–1.60 (m, 1H), 1.64–1.79 (m, 2H), 1.87–2.13 (m, 6H), 2.21 (d,
J=12.1 Hz, 1H), 2.17–2.30 (m, 2H), 2.55–2.63 (m, 1H), 2.73–2.78 (m,
1H), 2.77 (d, J=12.0 Hz, 1H), 3.08 (s, 1H), 3.17 (dd, J=14.9, 4.0 Hz,
1H), 3.35 (d, J=9.7 Hz, 1H), 3.38–3.43 (m, 1H), 3.48 (d, J=9.7 Hz, 1H),
3.59 (s, 3/2H), 3.59 (s, 3/2H), 4.35–4.41 (m, 1H), 4.59 (s, 1H), 4.64 (s,
1H), 5.44 (s, 1H), including peaks due to tautomer; 13C NMR (125 MHz,
CD2Cl2): d = À5.36, À4.99, 16.13, 17.68, 18.25, 18.35, 18.68, 18.94, 20.98,
22.21, 22.40, 23.80, 25.06, 27.81, 27.86, 29.67, 29.80, 30.99, 35.99, 36.10,
37.32, 39.99, 40.72, 41.70, 45.92, 46.07, 46.15, 48.63, 50.56, 50.70, 50.76,
50.82, 52.55, 52.58, 54.43, 62.45, 72.04, 72.26, 78.48, 79.04, 93.86, 93.94,
106.29, 106.95, 141.77, 151.36, 151.98, 154.85, 172.01, 208.43, 208.62,
212.22, 212.51, including peaks due to tautomer; IR (film): n˜ = 2953,
2930, 2858, 1701, 1638, 1396, 1363, 1251, 1176, 1001, 781 cmÀ1; HRMS
(FD): m/z: calcd for C41H65NO8Si: 727.4479; found: 727.4482 [M]+.
(m, 1H), 5.91 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d
= 13.77,
18.32, 18.38, 20.67, 21.80, 22.93, 23.69, 24.50, 29.92, 30.56, 35.93, 38.83,
39.52, 40.11, 41.90, 44.41, 45.79, 47.17, 47.99, 48.03, 53.76, 74.21, 89.99,
ACHTUNGTRENNUNG(1R,3S,5S)-tert-Butyl 5-(2-((1S,2S,4aS,4bR,8aR,9R,10aS)-8-(tert-butyldi-
methylsilyloxy)-1-(2-methoxy-2-oxoethyl)-1,2,4a,9-tetramethyl-6-methyl-
ene-3,10-dioxo-1,2,3,4,4a,4b,5,6,8a,9,10,10a-dodecahydrophenanthren-2-
101.61, 126.87, 159.91, 172.54, 197.26, 212.11ppm; IRACTHNUTRGNE(NUG film): n˜ = 2923,
2853, 1720 (br), 1664, 1460, 1261, 1124, 800 cmÀ1; HRMS (EI): m/z: calcd
for C30H41NO5: 495.2985; found: 495.3004 [M]+.
yl)ethyl)-3-methyl-8-oxa-6-azabicycloACTHNUGRTNEUNG[3.2.1]octane-6-carboxylate (67): To
a solution of the dienol TES ether 66 (15.3 mg, 21.0 mmol) in THF
(0.42 mL) was added dropwise a freshly prepared 1.0m solution of LDA
in THF (105 mL, 105 mmol) at À608C and the mixture was stirred at
À558C for 1 h. Then CH3I (26.2 mL, 0.42 mmol) was added and the mix-
ture was stirred at À508C for 2 h. Water was added to the reaction mix-
ture and the product was extracted with EtOAc. The extract was dried
over Na2SO4 and concentrated under reduced pressure. The residue was
dissolved in hexane/EtOAc 2.5:1 and passed through a short silica gel
column. Removal of the solvents gave methylation product 67 (12.9 mg,
Acknowledgements
We thank Professors Daisuke Uemura (Nagoya University) and Kazuo
Tachibana (The University of Tokyo) for providing us with natural nor-
zoanthamine and zoanthamine, respectively. We also acknowledge Dr.
Eri Fukushi and Mr. Kenji Watanabe (GC-MS and NMR Laboratory,
Graduate School of Agriculture, Hokkaido University) for their mass
spectrometric analyses. Financial support from the Ministry of Education,
Culture, Sports, Science and Technology, Japan (a Grant-in-Aid for Sci-
entific Research (A) (No. 12304042), a Grant-in-Aid for Scientific Re-
83%) as a 13:1 mixture with 66. [a]D29
= 39.8 (c = 0.150, CH2Cl2);
1H NMR (500 MHz, CDCl3): d = 0.17 (s, 3H), 0.22 (s, 3H), 0.82 (d, J=
7.5 Hz, 3H), 0.90 (s, 3/2H), 0.91 (s, 3/2H), 0.92 (s, 9H), 1.05–1.35 (m,
3H), 1.14 (d, J=6.9 Hz, 1/2H), 1.14 (d, J=7.5 Hz, 1/2H), 1.17 (s, 3H),
1.23 (s, 3/2H), 1.26 (s, 3/2H), 1.45 (s, 9/2H), 1.46 (s, 9/2H), 1.50–1.60 (m,
6642
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Chem. Eur. J. 2009, 15, 6626 – 6644

Zoanthamine Alkaloids
FULL PAPER
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.
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. Koi-
zumi, G. Hirai, H. Oguri, S. Kobayashi, S. Yamashita, M. Hirama,
Chem. Asian J. 2008, 3, 1549–1557.
[17] a) S. Ghosh, F. Rivas, D. Fischer, M. A. Gonzꢄlez, E. A. Theodora-
kis, Org. Lett. 2004, 6, 941–944; b) F. Rivas, S. Ghosh, E. A. Theo-
dorakis, Tetrahedron Lett. 2005, 46, 5281–5284.
[18] T. Irifune, T. Ohashi, T. Ichino, E. Sakai, K. Suenaga, D. Uemura,
Chem. Lett. 2005, 34, 1058–1059.
[19] 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. Behenna, B. M. Stoltz, Tetrahedron Lett.
2009, 50, 3182–3184.
[20] M. Sakai, M. Sasaki, K. Tanino, M. Miyashita, Tetrahedron Lett.
2002, 43, 1705–1708.
[21] a) M. Miyashita, M. Sasaki, I. Hattori, M. Sakai, K. Tanino, Science
2004, 305, 495–499; b) M. Miyashita, Pure Appl. Chem. 2007, 79,
651–665.
[22] S. Mutti, C. Daubiꢆ, F. Decalogne, R. Fournier, P. Rossi, Tetrahedron
Lett. 1996, 37, 3125–3128.
[23] a) E. Piers, H. E. Morton, J. Org. Chem. 1980, 45, 4263–4264; b) E.
Piers, J. M. Chong, H. E. Morton, Tetrahedron Lett. 1981, 22, 4905–
4908.
[24] For a similar annulation reaction catalyzed by cupurous chloride ni-
trate, see: F. Perveev, L. L. Shil’nikova, V. S. Gorchakov, Russ. J.
Org. Chem. 1972, 8, 2286–2288.
[25] E. Nakamura, S. Matsuzawa, Y. Horiguchi, I. Kuwajima, Tetrahe-
dron Lett. 1986, 27, 4029–4032.
[26] a) I. Ojima, T. Kogure, Y. Nagai, Tetrahedron Lett. 1972, 13, 5035–
5038; b) I. Ojima, T. Kogure, Organometallics 1982, 1, 1390–1399.
[27] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994,
639–666.
[28] a) W. Adam, A. Rodriguez, Tetrahedron Lett. 1981, 22, 3505–3508;
b) S. Katsumura, K. Hori, S. Fujiwara, S. Isoe, Tetrahedron Lett.
1985, 26, 4625–4628; c) M. R. Kernan, D. J. Faulkner, J. Org. Chem.
1988, 53, 2773–2776; d) T. Hata, K. Tanaka, S. Katsumura, Tetrahe-
dron Lett. 1999, 40, 1731–1734.
[29] T. Ooi, H. Sugimoto, K. Maruoka, Heterocycles 2001, 54, 593–596.
[30] For representative reviews of intramolecular Diels–Alder reactions,
see: a) E. Ciganek, Org. React. 1984, 32, 1–374; b) W. R. Roush in
Comprehensive Organic Synthesis Vol. 5 (Eds.: B. M. Trost, I. Flem-
ing, L. A. Paquette), Pergamon Press, Oxford, 1991, pp. 513–530;
c) K. Takao, R. Munakata, K. Tadano, Chem. Rev. 2005, 105, 4779–
4807.
[31] B. M. Trost, Y. Masuyama, Tetrahedron Lett. 1984, 25, 173–176.
[32] The use of deuterium isotope effects in natural product synthesis,
see: a) D. L. J. Clive, M. Cantin, A. Khodabocus, X. Kong, Y. Tao,
Tetrahedron 1993, 49, 7917–7930; b) D. L. J. Clive, Y. Tao, A. Kho-
dabocus, Y. Wu, A. G. Angoh, S. M. Benett, C. N. Boddy, L. Borde-
leau, D. Kellner, G. Kleiner, D. S. Middleton, C. J. Nicholas, S. R.
Richardson, P. G. Vernon, J. Am. Chem. Soc. 1994, 116, 11275–
11286; c) E. Vedejs, J. Little, J. Am. Chem. Soc. 2002, 124, 748–749.
[33] J. M. Concellꢇn, H. Cuervo, R. Fernꢄndez-Fano, Tetrahedron 2001,
57, 8983–8987.
[34] H. Lebel, E. N. Jacobsen, Tetrahedron Lett. 1999, 40, 7303–7306.
[35] M. Miyashita, T. Suzuki, M. Hoshino, A. Yoshikoshi, Tetrahedron
1997, 53, 12469–12486.
[36] K. B. Sharpless, R. F. Lauer, J. Am. Chem. Soc. 1973, 95, 2697–2699.
[37] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156;
b) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–7287.
[38] a) B. O. Lindgren, T. Nilsson, Acta Chem. Scand. 1973, 27, 888–890;
b) B. S. Bal, W. E. Childes, H. Pinnick, Tetrahedron 1981, 37, 2091–
2096.
[1] a) Macrolide Antibiotics: Chemistry, Biology, and Practice, 2nd ed.
(Ed.: S. Omura), Academic Press, San Diego, 2002; b) M. Kita, D.
Uemura, Top. Heterocycl. Chem. 2006, 6, 157–179.
[2] 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.
[3] a) C. B. Rao, A. S. R. Anjaneyula, N. S. Sarma, Y. Venkatateswarlu,
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. Anjaneyula,
N. S. Sarma, Y. Venkatateswarlu, R. M. Rosser, D. J. Faulkner, J.
Org. Chem. 1985, 50, 3757–3760.
[4] C. B. Rao, D. V. Rao, V. S. N. Raju, Heterocycles 1989, 28, 103–106.
[5] A.-u. Rahman, K. A. Alvi, S. A. Abbas, M. I. Choudhary, J. Clardy,
Tetrahedron Lett. 1989, 30, 6825–6828.
[6] a) A. H. Daranas, J. J. Fernꢄndez, J. A. Gavꢅn, M. Norte, Tetrahe-
dron 1998, 54, 7891–7896; b) A. H. Daranas, J. J. Fernꢄndez, J. A.
Gavꢅn, M. Norte, Tetrahedron 1999, 55, 5539–5546.
[7] H. Nakamura, Y. Kawase, K. Maruyama, A. Murai, Bull. Chem.
Soc. Jpn. 1998, 71, 781–787.
[8] Y. Venkateswarlu, N. S. Reddy, P. Ramesh, P. S. Reddy, K. Jamil,
Heterocycl. Commun. 1998, 4, 575–580.
[9] E. Fattorusso, A. Romano, O. Taglialatela-Scafati, M. J. Achmad, G.
Bavestrello, C. Cerrano, Tetrahedron Lett. 2008, 49, 2189–2192.
[10] K. Yamaguchi, M. Yada, T. Tsuji, M. Kuramoto, D. Uemura, Biol.
Pharm. Bull. 1999, 22, 920–924.
[11] R. M. Villar, J. Gil-Longo, A. H. Daranas, M. L. Souto, J. J. Fernꢄn-
dez, S. Peixinho, M. A. Barral, G. Santafꢆ, J. Rodriguez, C. Jimꢆnez,
Bioorg. Med. Chem. 2003, 11, 2301–2306.
[12] For an excellent review of the chemistry and biology of the zoantha-
mine 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.
[13] a) D. Tanner, P. G. Andersson, L. Tedenborg, P. Somfai, Tetrahedron
1994, 50, 9135–9144; b) T. E. Nielsen, S. Le Quement, M. Juhl, D.
Tanner, Tetrahedron 1995, 51, 8013–8024; c) D. Tanner, L. Teden-
borg, P. Somfai, Acta Chem. Scand. 1997, 51, 1217–1223; d) T. E.
Nielsen, D. Tanner, J. Org. Chem. 2002, 67, 6366–6371; e) M. Juhl,
T. E. Nielsen, S. Le Quement, D. Tanner, J. Org. Chem. 2006, 71,
265–280; f) M. Juhl, R. Monrad, I. Sotofte, D. Tanner, J. Org.
Chem. 2007, 72, 4644–4654.
[14] a) D. R. Williams, G. S. Cortez, Tetrahedron Lett. 1998, 39, 2675–
2678; b) D. R. Williams, T. A. Brugel, Org. Lett. 2000, 2, 1023–1026;
c) D. R. Williams, D. C. Ihle, T. A. Brugel, S. Patnaik, Heterocycles
2006, 70, 77–82; d) D. R. Williams, S. Patnaik, G. S. Cortez, Hetero-
cycles 2007, 72, 213–219.
[15] a) N. Hikage, H. Furukawa, K. Takao, S. Kobayashi, Tetrahedron
Lett. 1998, 39, 6237–6240; b) N. Hikage, H. Furukawa, K. Takao, S.
Kobayashi, Tetrahedron Lett. 1998, 39, 6241–6244; c) N. Hikage, H.
Furukawa, K. Takao, S. Kobayashi, Chem. Pharm. Bull. 2000, 48,
1370–1372; d) 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; e) D. Yamashita, Y.
Murata, N. Hinage, K. Takao, A. Nakazaki, S. Kobayashi, Angew.
Chem. 2009, 121, 1432–1434; Angew. Chem. Int. Ed. 2009, 48, 1404–
1406.
[16] a) G. Hirai, H. Oguri, M. Hirama, Chem. Lett. 1999, 141–142;
b) S. M. Moharram, G. Hirai, K. Koyama, H. Oguri, M. Hirama, Tet-
rahedron Lett. 2000, 41, 6669–6673; c) G. Hirai, H. Oguri, S. M. Mo-
harram, K. Koyama, M. Hirama, Tetrahedron Lett. 2001, 42, 5783–
5787; d) G. Hirai, Y. Koizumi, S. M. Moharram, H. Oguri, M.
[39] N. Hashimoto, T. Aoyama, T. Shioiri, Chem. Pharm. Bull. 1981, 29,
1475–1477.
[40] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011–1013.
Chem. Eur. J. 2009, 15, 6626 – 6644
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6643

M. Miyashita et al.
[41] The optical rotation of natural norzoanthamine provided by Prof.
Daisuke Uemura showed [a]D24 = À6.2 (c=0.23, CHCl3) contrary to
the reported value [a]D = +1.6 (c=0.42, CHCl3).[2]
[42] For the preparation of the compounds 5A, 11, and 52, see the Sup-
porting Information.
Received: February 5, 2009
Published online: May 28, 2009
6644
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Chem. Eur. J. 2009, 15, 6626 – 6644