Total synthesis of dictyodendrins A-E

Article abstract of DOI:10.1002/asia.201000544

A highly efficient total synthesis of dictyodendrins A-E was accomplished. The synthesis features a novel benzyne-mediated one-pot indoline formation/cross-coupling sequence for the construction of a highly substituted key indoline intermediate. Peripheral substituents were introduced onto this intermediate in a modular fashion to complete the total synthesis of dictyodendrins A-E. A benzyne-mediated one-pot indoline formation/cross-coupling sequence is used for the construction of a highly substituted common indole intermediate. The peripheral substituents were introduced using a Friedel-Crafts reaction on the indole intermediate in a modular fashion to complete the total synthesis. Copyright

Full text of DOI:10.1002/asia.201000544

FULL PAPERS
DOI: 10.1002/asia.201000544
Total Synthesis of Dictyodendrins A–E
Hidetoshi Tokuyama,*[a, b] Kentaro Okano,[a, b] Hideto Fujiwara,[a] Toshiharu Noji,[a] and
Tohru Fukuyama[b]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Abstract: A highly efficient total synthesis of dictyodendrins A–E was accom-
plished. The synthesis features a novel benzyne-mediated one-pot indoline forma-
tion/cross-coupling sequence for the construction of a highly substituted key indo-
line intermediate. Peripheral substituents were introduced onto this intermediate
in a modular fashion to complete the total synthesis of dictyodendrins A–E.
Keywords: arynes · cross-coupling ·
cyclization · natural products · total
synthesis
Introduction
Dictyodendrins (1–5) were isolated in 2003 by Fusetani and
Matsunaga from the extracts of a Japanese marine inverte-
brate, the marine sponge Dictyodendrilla verongiformis,
which was collected off Nagashima Island in Kagoshima,
Japan (Scheme 1).[1] These compounds were the first marine
alkaloids which possess inhibitory activity against telomer-
ase[2] (100% inhibition at a concentration of 50 mgmLÀ1).
Telomerase is an enzyme that adds the DNA sequence
(TTAGGG) repeats to the 3’ terminus.[3] As this enzyme is
expressed in most tumor cell lines[4] and its activity is associ-
ated with cell proliferation, telomerase inhibition represents
a potential target for cancer chemotherapy.[5] These com-
pounds have attracted considerable attention as synthetic
targets not only due to their important biological activity,[6]
but also to the unique structure consisting of the highly sub-
stituted pyrroloACHTUNGTRENNUNG[2,3-c]carbazole core.
Whilst a number of synthetic studies toward dictyoden-
drins[7] have so far been reported, only three groups includ-
ing ours have their achieved total synthesis. Fꢀrstner et al.[8]
Scheme 1. Structure of dictyodendrins A–E (1–5).
[a] Prof. Dr. H. Tokuyama, Dr. K. Okano, H. Fujiwara, T. Noji
Graduate School of Pharmaceutical Sciences
Tohoku University, Aramaki, Aoba-ku
Sendai 980-8578 (Japan)
accomplished the first total synthesis of dictyodendrin B (2),
C (3), and E (5). They constructed the characteristic tetracy-
clic pyrroloACTHNUGTRNEUNG[2,3-c]carbazole core using a combination of
three key reactions including cycloaddition of para-toluene-
sulfonylmethyl isocyanide (TosMIC) for the formation of
the pyrrole ring, their original titanium-induced reductive
oxoamide coupling reaction[9] to form the adjacent indole
nucleus, and a photochemical 6p-electrocyclization/aromati-
Fax : (+81)22-795-6877
E-mail: tokuyama@mail.pharm.tohoku.ac.jp
[b] Prof. Dr. H. Tokuyama, Dr. K. Okano, Prof. Dr. T. Fukuyama
Graduate School of Pharmaceutical Sciences
University of Tokyo, Hongo, Bunkyo-ku
Tokyo 113-0033 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000544.
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Chem. Asian J. 2011, 6, 560 – 572

Scheme 2. Retrosynthetic analysis of dictyodendrins A–E (1–5). PG=protecting group.
À
zation. Iwao, Ishibashi and co-workers disclosed the second
total synthesis of dictyodendrin B,[10] which featured the
Suzuki–Miyaura cross-coupling[11] of pyrrole triflate with
indole boronate, and pinacol coupling followed by dehydra-
tion. We recently communicated the total synthesis of dic-
tyodendrin A (1) and B (2) which featured the unprecedent-
ed benzyne-mediated one-pot cyclization/cross-coupling se-
quence as a key process.[12] Herein, we report a full account
of the development of benzyne-mediated indoline forma-
tion/cross-coupling sequence and its application to the total
synthesis of dictyodendrins A–E (1–5).
to 4-bromoindole derivative 8 and intramolecular C H in-
sertion via a nitrene intermediate[13] generated by thermoly-
sis of azide 9. We planned to prepare 4-bromoindole deriva-
tive 8, the substrate for the cross-coupling reaction, by re-
gioselective Friedel–Crafts reaction with the appropriate
electrophile at the 2-position of indole 10, which would be
derived from the key indole intermediate 6 by a convention-
al N-alkylation with a para-anisylethyl halide. Dictyoden-
drin E (5) would be obtained by oxidation of 11, which
should be derived from 6 in the same manner. On the other
hand, dictyodendrin C (3) and D (4) would be synthesized
by construction of the pyrroloACTHNUTRGNEUGN[2,3-c]carbazole skeleton by
À
the coupling of indole 6 with aryl azide 7, followed by C H
insertion of a nitrene intermediate and oxidation of the
Results and Discussion
pyrroloACHTNUTRGNE[UNG 2,3-c]carbazole skeleton. One of the key issues in
the above synthetic plan is therefore the construction of the
Retrosynthetic Analysis
In planning the synthesis of dictyodendrins, we designed a
versatile route, which would be amenable to the synthesis of
all the congeners by the introduction of peripheral subunits
onto the pivotal indole intermediate 6 in a modular fashion
pivotal indole intermediate 6.
Initial Approach using Copper-Mediated Amination
(Scheme 2). The pyrrolo
common framework of dictyodendrin A (1) and B (2),
would be formed by the installation of aryl azide segment 7
[2,3-c]carbazole skeleton,
a
For the synthesis of the key 7-anisyl-4-bromoindole 6,
through the corresponding indoline 12, we first examined a
strategy utilizing our copper-mediated aryl amination[14]
(Scheme 3). We planned to synthesize 4-bromoindoline 13
using the amination reaction of 2,3-dibromophenylethyla-
mine derivative 14, thereby keeping the other bromo group
intact. Installation of the anisyl group at the 7-position
would be possible by regioselective iodination and subse-
quent iodine-selective cross-coupling reaction. Finally, the
key indole intermediate 6 would be formed by oxidation.
Compound 15, the substrate for the amination reaction,
was prepared based on the protocol developed for our total
synthesis of duocarmycins[14d] (Scheme 4). 2,6-Dibromoiodo-
benzene derivative 16, prepared from para-nitrophenol (17)
Abstract in Japanese:
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fortunately, however, we isolated only undesired product 22,
which was iodinated at the 5-position.[16]
For the regioselective iodination at the 7-position, we ex-
amined a directed lithiation (Scheme 5). After switching the
nosyl group to a Boc group, the substrate was treated under
Scheme 5. Directed lithiation approach. Reagents and conditions:
a) Boc2O (1.2 equiv), 1008C, 15 min, 98%; b) sBuLi (1.2 equiv), TMEDA
(1.3 equiv), Et2O, À788C, 1 h; I2 (1.2 equiv), À788C, 30 min; RT, 1 h,
39%. Boc=tert-butoxycarbonyl, TMEDA=N,N,N’N’-tetramethylethyl-
enediamine.
Scheme 3. Retrosynthetic analysis of key 7-anisyl-4-bromoindole 6. PG=
protecting group.
typical directed lithiation conditions using, for example,
sBuLi and TMEDA.[17] However, the reaction was messy
and several unidentifiable mixtures were observed. We iso-
lated debrominated product 24 in 39% yield, thus indicating
that lithium–bromine exchange proceeded faster than lithia-
tion at the 7-position and also that the second lithiation did
not take place at all.
Development of the Benzyne-Mediated Cyclization/
Functionalization Sequence
From an initial unsuccessful investigation, we found that re-
gioselective introduction of the substituent at the 7-position
after the construction of the indoline skeleton would be a
difficult task owing to its sterically congested environment.
Therefore, we decided to develop a straightforward and re-
giochemically secured methodology based on benzyne
chemistry. Our working hypothesis is depicted in Scheme 6.
We envisioned that dianion 27, generated from 2,6-dibromo-
Scheme 4. First approach to 7-iodoindoline. Reagents and conditions:
a) nBuLi (1 equiv), toluene, À788C, 10 min; 18 (1 equiv), À788C, 2.5 h,
78%; b) Fe (30 equiv), FeCl2 (3 equiv), EtOH/1m HCl (10:1), reflux, 8 h;
c) o-NsCl (1 equiv), NaHCO3 (1.1 equiv), CH2Cl2/H2O (1:1), RT, 15 h,
85% (2 steps); d) CuI (1 equiv), CsOAc (5 equiv), DMSO, RT, 21 h,
94%; e) PhSH (1.1 equiv), Cs2CO3 (1.5 equiv), MeCN, RT, 3 h, 97%;
f) NIS (1 equiv), DMF, 08C, 1 h, 86%. Ns=nitrobenzenesulfonyl, Ac=
acetyl, Bn=benzyl, DMSO=dimethylsulfoxide, NIS=N-iodosuccini-
mide, DMF=N,N-dimethylformamide.
in six steps,[14d] was subjected to the iodine-selective halo-
gen–lithium exchange reaction with nBuLi in toluene at
À788C, followed by addition to nitroolefin 18 to give Mi-
chael adduct 19 in excellent yield.[14d,g] The nitro group was
then chemoselectively reduced and the resultant primary
amine was protected as a nosyl-amide[15] to give the desired
substrate 15. The key amination reaction proceeded smooth-
ly using a combination of CuI and CsOAc to give bromoin-
doline 20 in excellent yield. After deprotection of the nosyl
group,[15] we examined the iodination at the 7-position. Un-
Scheme 6. Working hypothesis of the benzyne-mediated one-pot indoline
formation/cross-coupling reaction.
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Total Synthesis of Dictyodendrins A–E
phenylethylamine 26 with more than two equivalents of
base at low temperature, would undergo benzyne formation
and subsequent cyclization upon elevating the reaction tem-
perature to give 7-metalated indoline 29, which would serve
as a suitable substrate for the cross-coupling reaction to pro-
vide 30. A literature survey found several examples of ben-
zyne-mediated cyclizations to form the indoline or the tetra-
hydroquinoline skeleton, but few examples of a one-pot cyc-
lization/functionalization sequence was reported.[18,19] Sie-
lecki and Meyers reported the one-pot benzyne-mediated
cyclization of an amidine derivative and the trapping of the
anion intermediate with simple electrophiles.[18a] However,
the scope was limited owing to the need for strong bases,
such as tBuLi or sBuLi. Therefore, we began an investiga-
tion to develop a benzyne-mediated cyclization/cross-cou-
pling sequence in which a milder base was used to afford
better functional group compatibility.
Scheme 7. Plausible mechanism for the formation of TMP-adduct 33.
First, we explored a suitable base to promote the benzyne
generation/cyclization cascade. Substrate 26, which was pre-
pared from 17 in a manner similar to 15 (see the Supporting
Information), was treated with various bases and the reac-
tion was quenched by CD3OD or DCl/D2O (Table 1). We
observed that the yield of the cyclization product and the D/
and the subsequent addition of TMP or LiTMP should give
the by-product 33. We were able to suppress the formation
of 33 by using a higher-order cuprate[22] or zincate,[23] pre-
sumably owing to the robust stability of the sp2 carbon
À
2
À
copper or sp carbon zinc bond compared to the protona-
tion by TMP (Table 1, entries 2 and 3). Whilst the yield of
the cyclization was improved by using higher-order cuprate
or zincate anions, the ratios of deuterated product were not
satisfactory. To our delight, we eventually found that Mg-
Table 1. Exploration of bases for benzyne generation-cyclization casca-
de.[a]
AHCTUNGTRENNUNG
(TMP)2·2 LiBr[24] quite effectively promoted the benzyne
formation/cyclization/deuteration sequence to provide
a
mixture of the 7-deuterated indoline 31 and protio com-
pound 32 (Table 1, entry 4) quantitatively in a ratio of 87:13.
Diminished amounts of MgACTHNUTRGNE(UNG TMP)2·2 LiBr resulted in lower
yield and D/H ratio (Table 1, entry 5).
Entry
Base
Yield [%][b]
R=D/H[c]
Encouraged by these promising results, we next investi-
gated an expansion of the benzyne-mediated indoline for-
mation reaction into a one-pot benzyne formation/cycliza-
tion/cross-coupling sequence (Table 2). First, the direct cou-
pling of 37 was examined under Kumada–Tamao coupling
conditions[25] (Table 2, entry 1). After indoline formation by
elevating the reaction temperature to 08C, the reaction mix-
ture was re-cooled to À788C. para-Iodoanisole (38) and [Pd-
1[d]
2
3
LiTMP
A
30
52
80
30:–[e]
43:9
66:14
87:13
65:30
ACHTUNGTRENNUNG
N
A
4
Mg
Mg
U
quant.
95
5[f]
[a] Reaction conditions: base (5 equiv), THF, À788C; then 08C; DCl/
D2O, À78 to 08C. [b] Yield of isolated product. [c] The ratio was deter-
mined by 1H NMR spectroscopy. [d] The reaction was quenched with
CD3OD. [e] Not observed. [f] Mg
2,2,6,6-tetramethylpiperidine.
ACHTUNGRTEN(NUNG TMP)2·2 LiBr: three equivalents. TMP:
AHCTUNTGRENGUN(N PPh3)4] were then added to the mixture. The desired cross-
coupling product 30 was isolated in very small amounts
along with protio indoline 32 as the major by-product, sug-
gesting that the rate of protonation is faster than that of the
cross-coupling reaction. A screen of phosphorus ligands did
not have the effect of improving the yield of 30. Finally, we
found that transmetalation to copper species 39 was crucial
for affording high-yielding coupling.[26] Thus, after the for-
mation of 7-magnesioindoline 37, the reaction mixture was
H ratio depended dramatically on the choice of base. When
26 was treated with LiTMP[20] at À788C for an hour and the
reaction was quenched at 08C,[21] the expected deuterated
indoline 31 was obtained, but the yield was as low as 30%
(Table 1, entry 1). A careful analysis of the by-products re-
vealed the generation of a significant amount (ca. 10%) of
the TMP adduct 33. A plausible pathway for the formation
of 33 is shown in Scheme 7. 7-Lithioindoline 35, generated
by cyclization, was protonated by raising the reaction tem-
perature to give 32 and LiTMP. Then, the generation of ben-
zyne 36 by deprotonation of the relatively acidic C-5 proton
re-cooled at À788C, and CuI, 38, and [Pd
ACHTUNGTRNEN(UNG PPh3)4] were
added. The desired product 30 was obtained in 76% yield
after stirring the mixture for two hours at room temperature
(Table 2, entry 2). Furthermore, the yield of 30 was im-
proved to 93% when 20 mol% of [Pd
ACHTUNGTREN(UNNG PPh3)4] was used
(Table 2, entry 3).[27] We also confirmed that this one-pot
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Table 2. Key one-pot indoline formation/cross-coupling sequence.[a]
2-Acylindole derivative 42a, an intermediate for the syn-
thesis of dictyodendrin B (2), was obtained in almost quanti-
tative yield by Friedel–Crafts acylation according to the pro-
cedure reported by Duval and Cuny[29] using para-methoxy-
benzoyl chloride (43) and zinc chloride as a promoter
(Table 3, entry 1). In contrast, installation of the para-anisy-
lacetate group,[30] which was required for synthesis of dictyo-
dendrin A (1), failed under the same reaction conditions
Table 3. Effect of Lewis acid in the regioselective Friedel–Crafts reac-
tion.[a,b]
Entry
CuI [equiv]
[Pd(PPh3)4] [mol%]
30 [%][b]
32 [%][b]
1
2
3
none
10
10
10
10
20
trace
76
77
13
93 (89[c]
)
5 (–[c,d]
)
[a] Reaction conditions: MgACHTGNUTRENNUNG
15 min; À78 to 08C, 1 h; CuI, À788C, 1 h; 38 (5 equiv), [Pd
ACHTUNGTRENNUNG
À788C; RT, 1.5 h. [b] Yield of isolated product. [c] Performed on a gram
scale. [d] Not isolated.
process could be scaled-up by running the reaction on a
gram scale to obtain 30 in 89% yield.
Introduction of Side-Chains using a Friedel–Crafts Reaction
Having successfully constructed the desired indoline with an
anisyl group at the 7-position by the efficient benzyne-medi-
ated cyclization/cross-coupling sequence, we then converted
it into the pivotal indole 41 by removal of the Boc group,
DDQ oxidation to the indole,[28] and attachment of a para-
anisylethyl group onto the nitrogen atom (Scheme 8). The
stage was then set for the installation of subunits on the
indole 2-position for the synthesis of dictyodendrin A (1), B
(2), and E (5).
Entry
RX
Lewis acid
Product
Yield [%][c]
99
1[a]
2[a]
3[b]
4[a]
5[b]
43
44
44
ZnCl2
ZnCl2
AgOTf
ZnCl2
42a
42b
42b
42c
42c
[d]
–
81
45
trace[e]
45[f]
AgOTf
–
[d]
[a] Reaction conditions: ZnCl2 (10 equiv), RX (2 equiv), Et2O, 0 8C.
[b] Reaction conditions: AgOTf (4 equiv), RX (3 equiv), THF, À788C.
[c] Yield of isolated product. [d] Complex mixture. [e] Recovery of
almost all the starting material. [f] 45: two equivalents. Reaction temper-
ature: À78 to 08C.
(Table 3, entry 2). For this transformation, we found that a
much milder activation with silver triflate[31] was effective
and the reaction proceeded at À788C to give the desired
product 42b in high yield (Table 3, entry 3). To obtain the
intermediate to dictyodendrin E (5), it was necessary to in-
troduce the para-methoxybenzyl group onto the indole 2-po-
sition. Unfortunately, reaction with zinc chloride or silver
triflate did not give the desired product at all (Table 3, en-
tries 4 and 5). It was assumed that the difficulty of para-me-
thoxybenzylation was due to the high reactivity of para-me-
thoxybenzyl chloride (45) and the presence of electron-rich
Scheme 8. Preparation of the substrate for the Friedel–Crafts reaction.
Reagents and conditions: a) TMSOTf (2 equiv), 2,6-lutidine (10 equiv),
CH2Cl2, 08C, 2 h, 95%; b) DDQ (1 equiv), toluene, RT, 1 h, 98%;
c) para-methoxyphenylethyl bromide (5 equiv), KOH (20 equiv), DMF,
RT, 2 h, 97%. TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl,
DDQ=2,3-dichloro-5,6-dicyanoquinone,
DMF=N,N-dimethylforma-
mide.
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Total Synthesis of Dictyodendrins A–E
aromatic rings in the substrate, which induce nonselective
benzylation. As a mild and catalytic generation of reactive
species, we examined combinations of para-methoxybenzyl
trichloroacetoimidate (46) and an acid catalyst (Table 4).
tention to the construction of the pyrroloACTHUNGTERNNU[G 2,3-c]carbazole
skeleton to complete the total synthesis of dictyodendrin A
(1), B (2), and E (5; Scheme 9).
After palladium-catalyzed pinacolborylation at the bromo
group of 42, the azidephenyl group[33] was introduced by
Suzuki–Miyaura coupling to give 49.[13,34] The azide group
remained untouched under the coupling conditions. The
Table 4. Successful introduction of the para-methoxybenzyl group with
imidate 46.[a]
pyrroloACHTNUTRGNE[NUG 2,3-c]carbazole skeleton was formed at this stage by
thermolysis of azide 49 at 1808C, and subsequent insertion
of the resultant nitrene into the adjacent sp2 C H bond
À
gave tetracyclic compound 51.[13] The endgame strategy was
established by the modification of the procedure by Fꢀrstner
et al.[8] The tert-butyl group was removed using boron tri-
chloride in the presence of pentamethylbenzene as a non-
Lewis basic cation scavenger.[35] We observed a substantial
decrease in the yield of this process without the addition of
pentamethylbenzene. The resultant phenol was converted
into trichloroethylsulfamate 53. Finally, five methyl
groups[36] and a trichloroethyl group were removed to pro-
vide dictyodendrin A (1; 8.2% overall yield from para-nitro-
phenol (17) over 21 steps). The total synthesis of dictyoden-
drin B (2) was also completed in the same manner by trans-
formation of 42a (12% overall yield from 17 over 21 steps).
According to the report by Fꢀrstner et al.,[8] the synthesis of
dictyodendrin E (5) was also achieved from 54c by removal
of the trichloroethyl group followed by DDQ oxidation
(7.4% overall yield from 17 over 22 steps).
Entry Acid
Ratio[b]
42c:47
Total yield[c]
(42c+47) [%] SM 41 [%]
Recovery of Conversion
G
Yield [%]
1[d,e]
2
TfOH[f]
Sc(OTf)3
La
TMSOTf 2.1:1
Yb(OTf)3 2.1:1
–
0
53
64
78
73
78
44
33
16
24
–
[g]
[g]
G
2.2:1
95
82
93
96
3[d]
4[h]
5
ACHTUNGTRENNUNG(OTf)3 1.9:1
ACHTUNGTRENNUNG
[a] Reaction conditions: imidate 46 (1.5 equiv), acid (20 mol%), CH2Cl2,
08C. [b] Determined by H NMR. [c] Yield of the isolated mixture of 42c
and 47. [d] Reaction temperature: 08C to RT. [e] Solvent: diethyl ether.
1
Dictyodendrin E (5) was also synthesized by structural
modification of the advanced intermediate of dictyoden-
drin B (2; Scheme 10). Thus, full reduction of the carbonyl
group in 51a to the methylene was executed with DIBAL.
As partial removal of the tert-butyl group was observed
during the reduction process, the remaining tert-butyl group
was deprotected in one pot to provide 52c, which was iden-
tical to the intermediate of 5 synthesized by direct Friedel–
Crafts para-methoxybenzylation (Scheme 9).
[f] Acid: 10 mol%. [g] Not determined. [h] Reaction temperature: RT.
When indole 41 was treated with 46 in the presence of
10 mol% of triflic acid,[32a] the desired product 42c was not
isolated at all with recovery of the starting material
(Table 4, entry 1). Gratifyingly, the use of scandium trifla-
te[32b] provided a mixture of the desired 2-benzylated prod-
uct 42c and the 5-benzylated product 47 in a combined yield
of 53% (Table 4, entry 2). In order to improve the yield and
the regioselectivity, we surveyed a variety of Lewis acids;
whilst the yield was improved to 64% using lanthanum tri-
flate,[32b] the regioselectivity remained at the same level
(Table 4, entry 3). Further investigation with trimethylsilyl
triflate[32c] and ytterbium triflate[32b] did not improve the re-
giochemistry (Table 4, entries 4 and 5). Of those tested, yt-
terbium triflate gave the para-methoxybenzylated products
in highest conversion yield. These regioisomers were separa-
ble by gel permeation chromatography. A large-scale reac-
tion (ca. 50 mg) using ytterbium triflate provided 56% of
the desired 2-benzylated product 42c. To the best of our
knowledge, this is the first use of benzyl trichloroacetoimi-
date for the mild benzylation of indole.
Total Synthesis of Dictyodendrin C and D
In accordance with the synthetic routes to dictyodendrin A
(1), B (2), and E (5), we also completed the total synthesis
of dictyodendrin C (3; Scheme 11). The pyrroloACTHNURTGNEU[GN 2,3-c]carba-
zole skeleton was constructed from a sequence involving
palladium-catalyzed pinacolborylation of indole 41, Suzuki–
À
Miyaura coupling, and intramolecular C H insertion of a ni-
trene intermediate generated by thermolysis of azide 55 to
give the tetracyclic compound 56. After switching the tert-
butyl group on the phenolic hydroxyl group to the mixed
sulfate, dictyodendrin C (3) was obtained, according to the
procedure reported by Fꢀrstner et al.,[8a,b] by demethylation,
oxidation of the pyrroloACTHNUGRTENUNG[2,3-c]carbazole framework, and the
deprotection of the mixed sulfate (5.9% overall yield from
17 over 21 steps).
Finally, the utility of this synthetic route was further dem-
onstrated by its application in the synthesis of dictyoden-
drin D (4) in the same manner (Scheme 12). Taking advant-
age of the synthetic route that enabled us to install a periph-
Total Synthesis of Dictyodendrin A, B, and E
Having successfully installed the requisite subunit on the 2-
position of the pivotal indole intermediate 41 by carefully
controlled Friedel–Crafts reactions, we then turned our at-
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H. Tokuyama et al.
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Scheme 9. Total synthesis of dictyodendrin A (1), B (2), and E (5). Reagents and conditions: a) pinB-Bpin (3–5 equiv), [PdCl
2ACHTUNGTRENN(NUG dppf)]·CH2Cl2 (5–
10 mol%), KOAc (9–18 equiv), 1,4-dioxane, reflux, 1.5–3 h; b) 50 (1.5–3 equiv), [PdCl2A(dppf)]·CH2Cl2 (5 mol%), 3m aqueous NaOH (3–5 equiv), 1,4-di-
CTHUNGTRENNUNG
oxane, RT–reflux, 20 min–3 h; c) o-C6H4Cl2, reflux, 20–40 min; d) BCl3 (2.5 equiv), C6HMe5 (3 equiv), CH2Cl2, À788C, 5–25 min; e) Cl3CCH2OSO2Cl
(1.5–3 equiv), DABCO (1.5–4 equiv), CH2Cl2, RT, 2 h; f) BCl3 (24–25 equiv), nBu4NI (24–25 equiv), CH2Cl2, 08C to RT, 30 min–1.5 h; g) Zn dust (4–
6 equiv), HCO2NH4 (6–9 equiv), MeOH, RT–508C, 1–5 h; h) Zn dust (8.4 equiv), HCO2NH4 (9 equiv), MeOH, RT, 2 h; concentration; i) DDQ (1 equiv),
THF, RT, 15 min, 95% (2 steps). DDQ=2,3-dichloro-5,6-dicyanobenzoquinone, dppf=1,1’-bis(diphenylphosphino)ferrocene, pin=pinacol, Ac=acetyl,
DABCO=1,4-diazabicycloACHTUNTRGNEUNG[2.2.2]octane.
eral subunit in a modular fashion, dictyodendrin D (4) was
easily synthesized (as it contains disulfate ions) through in-
troduction of the para-benzyloxyphenylethyl group onto the
key indole intermediate 40 (4.4% overall yield from 17 over
21 steps).
Conclusions
In conclusion, we have developed the unprecedented one-
pot benzyne-mediated indoline formation/cross-coupling se-
quence via transmetalation to a copper species. This meth-
odology provides direct access to a highly substituted indo-
line, which is applicable to the synthesis of various nitrogen-
containing heterocyclic compounds. By utilization of our
566
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Chem. Asian J. 2011, 6, 560 – 572

Total Synthesis of Dictyodendrins A–E
Scheme 10. Alternative approach to dictyodendrin E (5). Reagents and
conditions: DIBAL (20 equiv), C6HMe5 (5 equiv), toluene, RT; BCl3
(7 equiv), À788C. DIBAL=diisobutylalminum hydride.
newly developed methodology, we have accomplished a
highly efficient total synthesis of all of the members of the
dictyodendrin family. We have established a highly flexible
synthetic route by the introduction of the peripheral seg-
ments on the pivotal indole intermediate in a modular fash-
ion, which enabled us to synthesize dictyodendrins A–E (1–
5) systematically. The other key element of these successful
total syntheses is the establishment of Friedel–Crafts reac-
tion conditions for the each of the reaction partners.
Scheme 11. Total synthesis of dictyodendrin C (3). Reagents and condi-
tions: a) pinB-Bpin (3 equiv), [PdCl2A(dppf)]·CH2Cl2 (5 mol%), KOAc
(9 equiv), 1,4-dioxane, reflux, 1.5 h; b) 50 (1.5 equiv), [PdCl2
AHCTUNGTREGUN(NN dppf)]·CH2Cl2 (5 mol%), 3m aqueous NaOH (5 equiv), 1,4-dioxane, RT,
1.5 h; c) o-C6H4Cl2, reflux, 30 min, 67% (3 steps); d) BCl3 (2.5 equiv),
C6HMe5 (3 equiv), CH2Cl2, À788C, 30 min, 90%; e) Cl3CCH2OSO2Cl
(2 equiv), DABCO (2 equiv), CH2Cl2, RT, 1 h, 89%; f) BCl3 (24 equiv),
nBu4NI (24 equiv), CH2Cl2, 08C to RT, 35 min, 92%; g) aqueous H2O2,
MeCN, 08C to RT, 1 h, 59%; h) Zn dust (5 equiv), HCO2NH4 (15 equiv),
MeOH, RT, 45 min, O2, RT, 4 h, 53%. pin=pinacol, dppf=1,1’-bis(di-
phenylphosphino)ferrocene, Ac=acetyl, DABCO=1,4-diazabicyclo-
CTHUNGTRENNUNG
Experimental Section
General Remarks
Materials were obtained from commercial suppliers and used without fur-
ther purification unless otherwise mentioned. Anhydrous THF, Et2O, and
CH2Cl2 were purchased from Kanto Chemical Co. Inc. Anhydrous tolu-
ene, DMF, and MeCN were purchased from Wako Pure Chemical Indus-
tries. Anhydrous MeOH was dried and distilled according to the standard
procedures. Column chromatography was performed on silica gel 60N
(Kanto, spherical neutral, 63–210 mm), and flash column chromatography
was performed on silica gel 60N (Kanto, spherical neutral, 40–50 mm).
Preparative TLC was performed on Merck 60 F254 glass plates precoated
with a 0.50 mm thickness of silica gel. Analytical TLC was performed on
Merck 60 F254 glass plates precoated with a 0.25 mm thickness of silica
gel. Purification by medium-pressure liquid chromatography (MPLC)
was carried out using a Yamazen Co. No. 560. Gel permeation chromato-
graphic separations (GPC) were carried out using a Japan Analytical In-
dustry Co., Ltd. LC-9201. All melting points were determined on a
Yanaco micro melting point apparatus and uncorrected. NMR spectra
were recorded on a JNM-AL400 spectrometer, a GX500 spectrometer,
AHCTUNGTREG[NNUN 2.2.2]octane.
(Hz). The following abbreviations are used for spin multiplicity: s=sin-
glet, d=doublet, t=triplet, q=quartet, m=multiplet, and br=broad.
Chemical shifts for 13C NMR are reported in ppm, relative to the central
line of a triplet at 77.0 ppm for [D]chloroform. IR spectra were measured
on a SHIMADZU FTIR-8300 spectrometer. Mass spectra were recorded
on a JEOL JMS-DX-303 or a JMS-AX-500 spectrometers. Elemental
analyses were performed by a Yanaco CHN CORDER MT-5.
Total Synthesis of Dictyodendrin A
1-(1-(2,6-Dibromo-4-methoxyphenyl)-2-nitroethyl)-4-methoxybenzene:
An oven-dried 100 mL two-necked round-bottomed flask equipped with
a Teflon-coated magnetic stirring bar, a rubber septum, and an inlet
adapter with a three-way stopcock was charged with 2,6-dibromo-4-me-
thoxyiodobenzene (1.00 g, 2.55 mmol) and toluene (27 mL). To the solu-
tion, nBuLi (1.52m in n-hexane, 1.67 mL, 2.55 mmol) was added dropwise
at a rate that the inner temperature was maintained under À758C. The
1
and a JEOL ECA600 spectrometer. Chemical shifts for H NMR spectro-
scopic data are reported in parts per million (ppm) downfield from tetra-
methylsilane as the internal standard and coupling constants are in Hertz
Chem. Asian J. 2011, 6, 560 – 572
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www.chemasianj.org
567

H. Tokuyama et al.
FULL PAPERS
CDCl3): d=7.25 (br s, 2H), 7.05–7.03 (m, 2H), 6.83 (d, 2H, J=8.5 Hz),
5.93 (dd, 1H, J=7.5, 7.0 Hz), 5.43 (dd, 1H, J=13.0, 7.5 Hz), 5.22 (dd,
1H, J=13.0, 7.0 Hz), 3.779 (s, 3H), 3.775 ppm (s, 3H); 13C NMR
(150 MHz, CDCl3): d=159.2, 158.4, 129.9, 129.6, 127.93, 127.85, 123.9,
120.5, 118.6, 113.9, 76.7, 55.8, 55.2, 46.3 ppm; HRMS (EI): m/z calcd for
C16H15Br2NO4: 444.9347 [M]+; found: 444.9348.
tert-Butyl 2-(2,6-Dibromo-4-methoxyphenyl)-2-(4-methoxyphenyl)ethyl-
carbamate (26): A 100 mL round-bottomed flask equipped with a reflux
condenser and a Teflon-coated magnetic stirring bar was charged with ni-
troalkane (1.00 g, 2.24 mmol), Fe (1.25 g, 22.4 mmol), FeCl2 (283 mg,
2.24 mmol), 1m aqueous HCl (2.24 mL), and EtOH (22.4 mL). The re-
sulting mixture was heated at reflux for 3.5 h, after which time TLC (hex-
anes/ethyl acetate=3:1) indicated complete consumption of the starting
material. The resulting solid was removed by filtration through a pad of
Celite and washed thoroughly with EtOH, and the filtrate was concen-
trated under reduced pressure. The residue was basified with 4m aqueous
NaOH to pH 14, and the mixture was filtered through a pad of Celite.
The filtrate was concentrated under reduced pressure to give a crude
amine. Et3N was added to the residue (342 mL, 2.46 mmol) and MeCN
(10 mL) at room temperature. Boc2O was added to the mixture (488 mg,
2.24 mmol). The resulting suspension was stirred at room temperature
for 20 min, after which time TLC (CHCl3/MeOH=9:1) indicated com-
plete consumption of the crude amine. The reaction mixture was diluted
with ethyl acetate, and the aqueous layer was extracted three times with
ethyl acetate. The combined organic extracts were washed with 1m aque-
ous HCl and brine, dried over anhydrous sodium sulfate, and filtered.
The organic solvents were removed under reduced pressure to give the
crude material, which was purified by flash column chromatography on
silica gel (hexanes/ethyl acetate=3:1) followed by recrystallization to
afford the desired carbamate 26 (0.98 g, 1.9 mmol, 85% over 2 steps from
nitroalkane) as a white powder. Rf =0.36 (hexanes/ethyl acetate=3:1);
m.p.: 122–1248C (hexanes/ethyl acetate); IR (KBr disk): n˜ =1713, 1597,
1545, 1512, 1460, 1263, 1248, 1165, 1043 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d=7.18 (br s, 2H), 7.08 (d, 2H, J=8.0 Hz), 6.80 (d, 2H, J=
8.0 Hz), 5.23–5.08 (m, 1H), 4.51 (br s, 1H), 4.32–4.14 (m, 1H), 4.12–3.92
(m, 1H), 3.778 (s, 3H), 3.774 (s, 3H), 1.41 ppm (s, 9H); 13C NMR
(125 MHz, CDCl3): d=158.6, 157.8, 155.7, 132.0, 131.8, 128.7, 128.5,
124.1, 120.6, 118.2, 113.5, 79.2, 55.7, 55.2, 48.7, 41.2, 28.4 ppm; elemental
analysis: calcd (%) for C21H25Br2NO4: C 48.95, H 4.89, N 2.72; found:
C 48.91, H 4.87, N 2.73.
Scheme 12. Total synthesis of dictyodendrin D (4). Reagents and condi-
tions: a) para-benzyloxyphenylethyl bromide (5 equiv), KOH (20 equiv),
4-Bromo-6-methoxy-3,7-bis-(4-methoxy-phenyl)-2,3-dihydro-indole-1-car-
boxylic acid tert-butyl ester (30): A flame-dried 200 mL two-necked
round-bottomed flask equipped with a Teflon-coated magnetic stirring
bar, a rubber septum, and an inlet adapter with a three-way stopcock was
charged with 26 (1.03 g, 2.00 mmol). The flask was cooled to À788C. To
DMF, RT, 2 h, 82%; b) pinB-Bpin (5 equiv), [PdCl
(10 mol%), KOAc (18 equiv), 1,4-dioxane, reflux, 3 h, 85%; c) 50
(3 equiv), PdCl2A(dppf)·CH2Cl2 (5 mol%), 3m aqueous NaOH (5 equiv),
1,4-dioxane, reflux, 1 h, 88%; d) o-C6H4Cl2, reflux, 30 min, 67%; e) BCl3
(10 equiv), C6HMe5 (12 equiv), CH2Cl2, 50 min;
2ACHTUNGTRNEN(UNG dppf)]·CH2Cl2
CHTUNGTRENNUNG
the solution was added MgACTHNUTRGNE(UGN TMP)2·2 LiBr (0.27m in THF, 37.6 mL,
À788C,
10 mmol) prepared by the reported procedure[16c] dropwise at À788C.
The resulting mixture was stirred at À788C for 15 min, then warmed to
08C for 1 h, after which time TLC (hexanes/ethyl acetate=3:1) indicated
complete consumption of 26. The solution was cooled to À788C for
20 min, and to the reaction mixture was added a suspension of CuI
(3.89 g, 20.0 mmol) in THF (80 mL) at À788C dropwise over 10 min. The
resulting suspension was stirred at À788C for 1 h. To the reaction mixture
f) Cl3CCH2OSO2Cl (4 equiv), DABCO (4 equiv), CH2Cl2, RT, 45 min,
77% (2 steps); g) BCl3 (24 equiv), nBu4NI (24 equiv), CH2Cl2, 08C to RT,
1 h, 97%; h) aqueous H2O2, MeCN, 08C to RT, 1 h, 44%; i) Zn dust
(10 equiv), HCO2NH4 (20 equiv), MeOH, RT, 1 h, O2, RT, 4 h, 83%.
DMF=N,N-dimethylformamide, pin=pinacol, dppf=1,1’-bis(diphenyl-
phosphino)ferrocene,
[2.2.2]octane.
Ac=acetyl,
DABCO=1,4-diazabicyclo-
ACHTUNGTRENNUNG
was added [PdACHTNUGTRNEUNG(PPh3)4] (462 mg, 400 mmol) and para-iodoanisole (38)
(2.34 g, 10.0 mmol). The resulting suspension was warmed to room tem-
perature for 1.5 h, after which time TLC (hexanes/ethyl acetate=5:1) in-
dicated complete consumption of the protonated 39. The reaction was
quenched with 7% aqueous sodium chloride in 10% aqueous ammonium
hydroxide and the aqueous layer was extracted twice with ethyl acetate.
The combined organic extracts were washed with 1m aqueous HCl and
brine, dried over anhydrous sodium sulfate and filtered. The organic sol-
vents were removed under reduced pressure to give crude material
(3.60 g), which was purified by flash column chromatography on silica gel
(toluene/ethyl acetate=20:1) to afford 30 (0.96 g, 1.8 mmol, 89%) as a
colorless amorphous solid. Rf =0.30 (hexanes/ethyl acetate=5:1); IR
resulting suspension was stirred for 20 min. To the mixture was added a
solution of 18 (457 mg, 2.55 mmol) in toluene (9.0 mL) dropwise at
À788C. The reaction mixture was stirred for 25 min, after which time
TLC (hexanes/ethyl acetate=3:1) indicated complete consumption of the
starting trihalobenzene had occurred. The reaction was quenched with
1m aqueous HCl, and the aqueous layer was extracted twice with ethyl
acetate. The combined organic extracts were washed with saturated aque-
ous NaHCO3, dried over anhydrous sodium sulfate, and filtered. The or-
ganic solvents were removed under reduced pressure to give crude mate-
rial (1.40 g), which was purified by flash column chromatography on
silica gel (hexanes/ethyl acetate=6:1) to afford the title compound
(1.05 g, 2.30 mmol, 90%) as a colorless oil. Rf =0.37 (hexanes/ethyl ace-
tate=3:1); IR (KBr disk): n˜ =2937, 2837, 1593, 1556, 1514, 1464, 1429,
(neat): n˜ =3005, 2936, 1697, 1597, 1580, 1315, 1290, 802, 756 cmÀ1
;
1H NMR (600 MHz, CDCl3): d=7.44 (d, 2H, J=8.4 Hz), 7.01 (d, 2H, J=
9.0 Hz), 6.92 (d, 2H, J=8.4 Hz), 6.81 (s, 1H), 6.79 (d, 2H, J=9.0 Hz),
4.30 (dd, 1H, J=10.8, 7.8 Hz), 4.18 (d, 1H, J=7.8 Hz), 4.08 (d, 1H, J=
1373, 1296, 1252, 1184, 1032, 843, 827, 735 cmÀ1 1H NMR (500 MHz,
;
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Chem. Asian J. 2011, 6, 560 – 572

Total Synthesis of Dictyodendrins A–E
10.8 Hz), 3.818 (s, 3H), 3.816 (s, 3H), 3.76 (s, 3H), 1.08 ppm (s, 9H);
13C NMR (150 MHz, CDCl3): d=158.4, 158.3, 157.3, 153.0, 143.4, 133.8,
130.7, 128.1, 127.8, 120.2, 117.7, 113.9, 113.3, 111.0, 80.7, 60.0, 56.2, 55.2,
55.1, 47.5, 27.6 ppm (one signal is missing due to overlap); HRMS (EI):
m/z calcd for C28H30BrNO5: 539.1307 [M]+; found: 539.1246.
4.58 mmol, 97%) as a white powder. Rf =0.28 (hexanes/ethyl acetate=
3:1 developed twice); m.p.: 161–1638C (hexanes/CH2Cl2); IR (KBr disk):
n˜ =2359, 1611, 1562, 1512, 1462, 1302, 1285, 1246, 1175, 1034, 835,
756 cmÀ1 1H NMR (500 MHz, CDCl3): d=7.36–7.34 (m, 4H), 7.09 (s,
;
1H), 7.01 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 6.73 (s, 1H), 6.71
(d, 2H, J=8.5 Hz), 6.61 (d, 1H, J=8.5 Hz), 3.89 (s, 3H), 3.86 (s, 3H),
3.75 (s, 3H), 3.74 (s, 3H), 3.71–3.68 (m, 2H), 2.56–2.53 ppm (m, 2H);
13C NMR (125 MHz, CDCl3): d=159.2, 158.5, 158.2, 153.3, 135.3, 132.4,
132.0, 130.3, 130.1, 129.6, 127.3, 127.1, 121.9, 117.4, 113.9, 113.73, 113.69,
113.3, 112.6, 111.4, 57.4, 55.3, 55.2, 49.7, 36.6 ppm (one signal is missing
due to overlap); elemental analysis: calcd (%) for C32H30BrNO4: C 67.14,
H 5.28, N 2.45; found: C 67.05, H 5.40, N 2.43.
4-Bromo-6-methoxy-3,7-bis-(4-methoxy-phenyl)-2,3-dihydro-1H-indole:
A flame-dried 100 mL two-necked round-bottomed flask equipped with a
Teflon-coated magnetic stirring bar, a rubber septum, and an inlet adapt-
er with a three-way stopcock was charged with 30 (1.17 g, 2.16 mmol),
2,6-lutidine (2.56 mL, 21.6 mmol), and dry CH2Cl2 (21.6 mL). The result-
ing suspension was stirred at 08C for 20 min. To the solution was added
TMSOTf (782 mL, 4.32 mmol) dropwise at 08C. The resulting suspension
was stirred at 08C for 2 h, after which time TLC (hexanes/ethyl acetate=
5:1) indicated complete consumption of 30. The reaction was quenched
with saturated aqueous NaHCO3, and the aqueous layer was extracted
with CH2Cl2 three times. The combined organic extracts were dried over
anhydrous sodium sulfate and filtered. The organic solvents were re-
moved under reduced pressure to give the crude material, which was pu-
rified by flash column chromatography on silica gel (hexanes/ethyl ace-
tate/CH2Cl2 =6:1:1) to afford the title compound (909 mg, 2.06 mmol,
95%) as a colorless amorphous solid. Rf =0.31 (hexanes/ethyl acetate=
5:1); IR (neat): n˜ =3385, 3001, 1601, 1583, 1479, 1373, 1204, 1121, 835,
Methyl 2-(4-bromo-6-methoxy-1-(4-methoxyphenethyl)-3,7-bis(4-methoxy-
phenyl)-1H-indol-2-yl)-2-(4-methoxyphenyl)acetate (42b): A flame-dried
200 mL two-necked round-bottomed flask equipped with a Teflon-coated
magnetic stirring bar, a rubber septum, and an inlet adapter with a
three-way stopcock was charged with 41 (600 mg, 1.05 mmol), AgOTf
(1.08 g, 4.19 mmol), and dry THF (52 mL). The solution was cooled to
À788C. To the solution was added a-bromo ester 44 (816 mg,
3.15 mmol). The reaction mixture was stirred at À788C for 2 h, after
which time TLC (hexanes/ethyl acetate/CH2Cl2 =5:1:2) indicated com-
plete consumption of 41. The reaction mixture was quenched with satu-
rated aqueous NaHCO3. The resulting mixture was filtered through a
pad of Celite and extracted twice with ethyl acetate. The combined or-
ganic extracts were washed with brine, dried over anhydrous sodium sul-
fate, and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (hex-
anes/ethyl acetate/CH2Cl2 =5:1:1) to afford 42b (638 mg, 850 mmol, 81%)
as a gray amorphous solid. Rf =0.22 (hexanes/ethyl acetate=2:1); IR
(neat): n˜ =1740, 1611, 1562, 1512, 1462, 1302, 1285, 1246, 1175, 1090,
789 cmÀ1 1H NMR (600 MHz, CDCl3): d=7.37 (d, 2H, J=9.0 Hz), 7.19
;
(d, 2H, J=9.0 Hz), 6.97 (d, 2H, J=9.0 Hz), 6.84 (d, 2H, J=9.0 Hz), 6.44
(s, 1H), 4.42 (dd, 1H, J=8.7, 3.6 Hz), 3.94 (dd, 1H, J=9.0, 8.7 Hz), 3.87
(br s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H), 3.44 ppm (dd, 1H, J=
9.0, 3.6 Hz); 13C NMR (150 MHz, CDCl3): d=158.5, 158.2, 157.4, 151.8,
135.8, 131.0, 128.6, 126.5, 124.8, 118.6, 113.9, 113.7, 110.8, 104.7, 56.3,
56.0, 55.2, 55.1, 48.0 ppm; HRMS (EI): m/z calcd for C23H22BrNO3:
439.0783 [M]+; found: 439.0792.
1034, 733 cmÀ1 1H NMR (500 MHz, CDCl3): d=7.42–7.28 (m, 4H), 7.08
;
4-Bromo-6-methoxy-3,7-bis-(4-methoxy-phenyl)-1H-indole
(40):
A
(s, 1H), 7.07 (d, 2H, J=9.0 Hz), 7.00 (dd, 1H, J=8.3, 2.8 Hz), 6.96 (dd,
1H, J=8.3, 2.8 Hz), 6.90 (d, 2H, J=8.5 Hz), 6.79 (d, 2H, J=8.5 Hz), 6.59
(d, 2H, J=8.0 Hz), 6.25 (d, 2H, J=8.5 Hz), 5.25 (s, 1H), 3.85 (s, 3H),
3.84 (s, 3H), 3.79–3.65 (m, 2H), 3.76 (s, 3H), 3.71 (s, 3Hx2), 3.60 (s, 3H),
2.25–2.19 (m, 1H), 2.16–2.11 ppm (m, 1H); 13C NMR (125 MHz, CDCl3):
d=171.5, 159.1, 159.0, 158.6, 157.9, 153.8, 135.4, 135.0, 133.8, 133.3, 132.6,
132.5, 129.8, 129.5, 129.3, 128.4, 127.0, 126.6, 122.4, 118.3, 113.95, 113.87,
113.6, 113.5, 113.4, 113.3, 112.9, 112.7, 111.8, 57.5, 55.3, 55.24, 55.16, 52.3,
47.1, 46.8, 35.0 ppm; HRMS (EI): m/z calcd for C42H40BrNO7: 749.1988
[M]+; found: 749.1992.
100 mL round-bottomed flask equipped with a Teflon-coated magnetic
stirring bar, a rubber septum and an inlet adapter with a three-way stop-
cock was charged with indoline (909 mg, 2.06 mmol), DDQ (468 mg,
2.06 mmol), and dry toluene (21 mL). The mixture was stirred at room
temperature for 1 h, after which time TLC (hexanes/ethyl acetate=4:1)
indicated complete consumption of the starting indoline. The reaction
mixture was quenched with 1m aqueous NaOH. The reaction mixture
was extracted three times with ethyl acetate. The combined organic ex-
tracts were washed with 1m aqueous NaOH three times, water, and
brine, dried over anhydrous sodium sulfate, and filtered. The organic sol-
vents were removed under reduced pressure to give 40 (884 mg,
2.02 mmol, 98%) as analytically pure pale brown solid. Rf =0.43 (hex-
anes/CH2Cl2 =1:3); m.p.: 153–1548C (hexanes/CH2Cl2); IR (KBr disk):
Methyl 2-(6-methoxy-1-(4-methoxyphenethyl)-3,7-bis(4-methoxyphenyl)-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-2-(4-me-
thoxyphenyl)acetate (48b): A 20 mL two-necked round-bottomed flask
equipped with a reflux condenser, a Teflon-coated magnetic stirring bar,
a rubber septum, and an inlet adapter with a three-way stopcock was
charged with 42b (600 mg, 799 mmol), bis(pinacolato)diboron (607 mg,
n˜ =3412, 1570, 1504, 1491, 1286, 1238, 1175 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d=8.06 (br s, 1H), 7.45 (d, 2H, J=8.5 Hz), 7.42 (d, 2H, J=
8.5 Hz), 7.11 (s, 1H), 7.05 (d, 2H, J=9.0 Hz), 7.03 (d, 1H, J=2.5 Hz),
6.93 (d, 2H, J=9.0 Hz), 3.88 (s, 3H), 3.86 (s, 3H) 3.80 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=159.0, 158.6, 152.2, 136.8, 132.3, 131.0,
127.0, 126.0, 123.9, 120.2, 119.1, 114.4, 112.8, 112.7, 112.6, 111.8, 57.1,
55.3, 55.2 ppm; elemental analysis: calcd (%) for C23H20BrNO3: C 63.02,
H 4.60, N 3.20; found: C 62.75, H 4.61, N 3.16.
2.40 mmol), KOAc (706 mg, 7.19 mmol), [PdCl2ACHTNUTRGNE(UGN dppf)·CH2Cl2] (33 mg,
39 mmol), and 1,4-dioxane (8.0 mL). The resulting mixture was heated at
reflux for 3 h, after which time TLC (hexanes/ethyl acetate/CH2Cl2 =
5:1:2) indicated complete consumption of 42b. The reaction mixture was
quenched with water. The resulting mixture was extracted twice with
ethyl acetate. The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, and filtered through a pad of
Celite. The filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (hexanes/ethyl ace-
tate/CH2Cl2 =5:1:2) to afford 48b (515 mg, containing bis(pinacolato)di-
boron) as a white amorphous solid, which was used to the next reaction
without further purification. Rf =0.33 (hexanes/ethyl acetate/CH2Cl2 =
4:1:2). The physical data of purified 48b is the following; IR (neat): n˜ =
1740, 1611, 1514, 1464, 1391, 1358, 1339, 1302, 1285, 1246, 1202, 1175,
Methyl 2-(4-bromo-6-methoxy-1-(4-methoxyphenethyl)-3,7-bis(4-methoxy-
phenyl)-1H-indol-2-yl)-2-(4-methoxyphenyl)acetate (41): A flame-dried
100 mL two-necked round-bottomed flask equipped with a Teflon-coated
magnetic stirring bar, a rubber septum, and an inlet adapter with a three-
way stopcock was charged with 40 (2.07 g, 4.72 mmol), KOH (5.30 g,
94.4 mmol), and dry DMF (20 mL). The resulting suspension was stirred
at room temperature for 10 min. To the solution was added phenylethyl
bromide (5.08 g, 23.6 mmol). The reaction mixture was stirred for 2 h,
after which time TLC (hexanes/ethyl acetate=1:1) indicated complete
consumption of 40. The reaction mixture was quenched with saturated
aqueous NH4Cl. The reaction mixture was diluted with water. The result-
ing mixture was extracted with Et2O three times. The combined organic
extracts were washed with 7% aqueous NaCl four times, brine, dried
over anhydrous sodium sulfate, and filtered. The filtrate was concentrat-
ed under reduced pressure. The residue was purified by column chroma-
tography on silica gel (hexanes/CH2Cl2 =2:3) to afford 41 (2.62 g,
1144, 1096, 1036, 910, 733 cmÀ1 1H NMR (500 MHz, CDCl3): d=7.43–
;
7.38 (m, 3H), 7.26 (d, 1H, J=8.0 Hz), 7.23 (s, 1H), 7.09 (d, 2H, J=
8.5 Hz), 7.00 (dd, 1H, J=8.5, 2.5 Hz), 6.96 (dd, 1H, J=8.5, 2.5 Hz), 6.93–
6.87 (m, 2H), 6.77 (d, 2H, J=8.5 Hz), 6.58 (d, 2H, J=8.5 Hz), 6.25 (d,
2H, J=8.0 Hz), 5.24 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.77–3.66 (m,
2H), 3.75 (s, 3Hx2), 3.70 (s, 3H), 3.58 (s, 3H), 2.24–2.05 (m, 2H), 1.09 (s,
6H), 1.04 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=171.8, 158,9,
158.7, 158.5, 157.8, 153.3, 134.5, 134.0, 132.7, 132.5, 132.4, 130.1, 129.5,
Chem. Asian J. 2011, 6, 560 – 572
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
569

H. Tokuyama et al.
FULL PAPERS
129.3, 129.0, 128.8, 127.9, 127.8, 119.5, 116.9, 113.9, 113.7, 113.5, 113.41,
113.36, 113.2, 83.1, 57.7, 55.3, 55.21, 55.20, 55.1, 52.1, 47.0, 46.7, 35.1, 24.9,
24.6 ppm; HRMS (EI): m/z calcd for C48H52BNO9: 797.3735 [M]+; found
797.3737.
flask equipped with a Teflon-coated magnetic stirring bar, a rubber
septum, and an inlet adapter with three-way stopcock was charged with
51b (150 mg, 180 mmol), pentamethylbenzene (80.0 mg, 540 mmol), and
dry CH2Cl2 (1.8 mL). The solution was cooled to À788C. To the solution
was added BCl3 (1.0m in CH2Cl2, 450 mL, 0.45 mmol) dropwise at À788C.
The reaction mixture was stirred at À788C for 25 min, after which time
TLC (hexanes/ethyl acetate/CH2Cl2 =1:1:1) indicated complete consump-
tion of 51b. The excess BCl3 was quenched with 10% MeOH/CHCl3 at
À788C. The resulting mixture was concentrated under reduced pressure.
The residue was purified by recrystallization from CH2Cl2/hexanes to
afford 52b (129 mg, 166 mmol, 92%) as a gray powder. Rf =0.24 (hex-
anes/ethyl acetate/CH2Cl2 =1:1:1); m.p.: 239–2408C (CH2Cl2/hexanes/
THF); IR (KBr disk): n˜ =1740, 1611, 1576, 1541, 1512, 1474, 1468, 1437,
Methyl 2-(4-(2-azido-3-tert-butoxyphenyl)-6-methoxy-1-(4-methoxyphen-
ethyl)-3,7-bis(4-methoxyphenyl)-1H-indol-2-yl)-2-(4-methoxyphenyl)ace-
tate (49b): A 30 mL two-necked round-bottomed flask equipped with a
Teflon-coated magnetic stirring bar, a rubber septum, and an inlet adapt-
er with a three-way stopcock was charged with crude 48b (515 mg), 50
(614 mg, 1.94 mmol), 3m aqueous NaOH (1.07 mL, 3.23 mmol), [PdCl2
ACHTUNGTRENNUNG(dppf)·CH2Cl2] (26 mg, 32 mmol), and 1,4-dioxane (6.5 mL). The resulting
mixture was stirred at reflux for 20 min, after which time TLC (hexanes/
ethyl acetate/CH2Cl2 =5:1:2) indicated complete consumption of 48b.
The reaction mixture was quenched with water. The resulting mixture
was extracted twice with ethyl acetate. The combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate, and fil-
tered through a pad of Celite. The filtrate was concentrated under re-
duced pressure. The residue was purified by column chromatography on
silica gel (hexanes/ethyl acetate/CH2Cl2 =5:1:2) to afford 49b (431 mg,
500 mmol, 63% over 2 steps from 42) as an off-white amorphous solid.
Rf =0.30 (hexanes/ethyl acetate/CH2Cl2 =5:1:2); IR (neat): n˜ =2112,
1740, 1611, 1574, 1512, 1464, 1441, 1367, 1302, 1285, 1246, 1202, 1175,
1
1367, 1302, 1286, 1246, 1175, 1034 cmÀ1; H NMR (500 MHz, CDCl3): d=
8.47 (br s, 1H), 7.63–7.54 (m, 3H), 7.41 (dd, 1H, J=8.5, 2.5 Hz), 7.14 (d,
2H, J=8.5 Hz), 7.08–6.99 (m, 4H), 6.80 (d, 2H, J=9.0 Hz), 6.66 (d, 1H,
J=7.5 Hz), 6.61–6.58 (m, 3H), 6.28 (d, 2H, J=8.5 Hz), 5.71 (d, 1H, J=
8.0 Hz), 5.35 (s, 1H), 4.93 (s, 1H), 3.92 (s, 3H), 3.93–3.82 (m, 2H), 3.90
(s, 3H), 3.76 (s, 3H), 3.72 (s, 3H), 3.61 (s, 3H), 3.55 (s, 3H), 2.31–
2.20 ppm (m, 2H); 13C NMR (125 MHz, CDCl3): d=172.0, 159.3, 159.2,
158.5, 157.8, 140.7, 140.6, 133.7, 133.4, 133.0, 132.7, 132.6, 130.2, 129.6,
129.5, 129.4, 129.0, 128.9, 128.6, 127.4, 125.5, 120.4, 118.7, 118.0, 117.9,
117.0, 115.2, 113.8, 113.63, 113.57, 113.3, 108.9, 60.9, 55.5, 55.4, 55.3, 55.2,
52.3, 47.4, 47.1, 35.4 ppm; HRMS (FAB+): m/z calcd for C48H44N2O8:
776.3098 [M]+; found 776.3085.
1034, 1003, 910, 733 cmÀ1 1H NMR (600 MHz, CDCl3): d=7.56–7.44 (m,
;
2H), 7.23–7.21 (m, 0.5H), 7.10–6.59 (m, 15H), 6.34–6.26 (m, 2.5H), 5.29
(s, 0.5H), 5.27 (s, 0.5H), 3.87 (s, 3H), 3.79–3.71 (m, 14H), 3.57 (s, 1.5H),
3.51 (s, 1.5H), 2.29–3.17 (m, 2H), 1.43 (s, 3H), 1.38 ppm (s, 6H);
13C NMR (150 MHz, CDCl3): d=171.84, 171.76, 159.0, 158.55, 158.53,
157.88, 157.85, 157.76, 153.3, 153.2, 149.2, 134.9, 134.7, 134.6, 134.2, 133.6.
133.3, 132.83, 132.81, 132.7, 132.2, 132.0, 131.6, 131.5, 131.3, 130.3, 130.19,
130.17, 130.15, 129.54, 129.52, 129.46, 129.37, 128.82, 128.78, 127.8, 127.7,
127.4, 126.9, 125.9, 125.1, 123.4, 123.1, 122.14, 122.12, 112.2, 111.7, 109.2,
108.6, 80.4, 80.1, 57.4, 57.3, 55.3, 55.23, 55.16, 55.13, 55.09, 52.2, 47.1,
46.92, 46.86, 46.7, 35.4, 35.3, 28.43, 28.40 ppm (complexity due to atrop-
isomers); HRMS (FAB+): m/z calcd for C52H52N4O8: 860.3785 [M]+;
found: 860.3789.
Methyl 2-(5-methoxy-3-(4-methoxyphenethyl)-1,4-bis(4-methoxyphenyl)-
7-(2,2,2-trichloroethoxysulfonyloxy)-3,6-dihydropyrroloACTHNUTRGNEU[GN 2,3-c]carbazol-2-
yl)-2-(4-methoxy-phenyl)acetate (53b): A flame-dried screw-top test tube
equipped with a Teflon-coated magnetic stirring bar was charged with
52b (128 mg, 165 mmol), DABCO (55.0 mg, 495 mmol), and dry CH2Cl2
(0.90 mL). To the solution was added 2,2,2-trichloroethyl chlorosulfate
(80.0 mg, 333 mmol) at room temperature. The reaction mixture was
stirred at room temperature for 2 h, after which time TLC (hexanes/ethyl
acetate=1:1) indicated complete consumption of 52b. The reaction mix-
ture was quenched with saturated aqueous NH4Cl. The resulting mixture
was extracted twice with CH2Cl2. The combined organic extracts were
dried over anhydrous sodium sulfate, and filtered. The filtrate was con-
centrated under reduced pressure. The residue was purified by column
chromatography on silica gel (hexanes/ethyl acetate=3:1) to afford 53b
(151 mg, 153 mmol, 93%) as a gray amorphous solid. Rf =0.35 (hexanes/
ethyl acetate=1:1); IR (neat): n˜ =1738, 1611, 1514, 1464, 1443, 1416,
Methyl 2-(7-tert-butoxy-5-methoxy-3-(4-methoxyphenethyl)-1,4-bis(4-me-
thoxy-phenyl)-3,6-dihydropyrroloACTHNUTRGNE[NUG 2,3-c]carbazol-2-yl)-2-(4-methoxyphe-
nyl)acetate (51b): A 200 mL round-bottomed flask equipped with a
reflux condenser, a Teflon-coated magnetic stirring bar, and an inlet
adapter with
a three-way stopcock was charged with 49b (412 mg,
1402, 1310, 1286, 1246, 1196, 1175, 1161, 1034, 908, 731 cmÀ1 1H NMR
;
489 mmol) and ortho-dichlorobenzene (50 mL). The system was evacuat-
ed and backfilled with argon. The resulting mixture was heated at reflux
for 20 min, after which time TLC (hexanes/ethyl acetate/CH2Cl2 =5:1:2)
indicated complete consumption of 49b. After the flask was cooled to
room temperature, the resulting mixture was passed through a pad of
silica gel (hexanes to elute ortho-dichlorobenzene then ethyl acetate to
elute 51b). The organic solvents were removed under reduced pressure
to give crude material, which was purified by column chromatography on
silica gel (hexanes/ethyl acetate/CH2Cl2 =5:1:2) to afford 51b (322 mg,
(500 MHz, CDCl3): d=8.65 (br s, 1H), 7.68–7.52 (m, 3H), 7.41 (dd, 1H,
J=8.5, 2.0 Hz), 7.27–7.26 (m, 1H), 7.13 (d, 2H, J=9.0 Hz), 7.09–7.00 (m,
4H), 6.80 (d, 2H, J=8.5 Hz), 6.75 (dd, 1H, J=8.5, 7.5 Hz), 6.60 (d, 2H,
J=8.5 Hz), 6.28 (d, 2H, J=8.5 Hz), 6.01 (d, 1H, J=8.0 Hz), 5.35 (s, 1H),
4.74 (s, 2H), 3.94–3.85 (m, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.77 (s, 3H),
3.72 (s, 3H), 3.61 (s, 3H), 3.53 (s, 3H), 2.31–2.20 ppm (m, 2H); 13C NMR
(125 MHz, CDCl3): d=171.1, 159.4, 158.6, 157.9, 140.5, 134.6, 133.70,
133.67, 133.5, 132.61, 132.57, 130.7, 130.0, 129.9, 129.5, 129.4, 129.2, 129.0,
128.8, 127.5, 126.9, 123.7, 120.2, 119.1, 118.7, 117.9, 115.8, 114.5, 113.9,
113.86, 113.74, 113.73, 113.6, 113.3, 92.3, 80.8, 60.9, 55.5, 55.4, 55.24,
55.16, 52.3, 47.4, 47.1, 35.4 ppm; HRMS (FAB+): m/z calcd for
C50H45Cl3N2O11S: 986.1810 [M]+; found 986.1813.
387 mmol, 79%) as
a gray powder. Rf =0.23 (hexanes/ethyl acetate/
CH2Cl2 =5:1:2); m.p.: 224–2268C (hexanes/ethyl acetate/CH2Cl2); IR
(KBr disk): n˜ =3460, 1727, 1611, 1582, 1551, 1512, 1470, 1458, 1447, 1437,
1404, 1367, 1356, 1286, 1246, 1202, 1175, 1107, 1032, 1001, 833, 820,
770 cmÀ1 1H NMR (600 MHz, CDCl3): d=8.33 (br s, 1H), 7.62–7.55 (m,
;
Methyl 2-(5-hydroxy-3-(4-hydroxyphenethyl)-1,4-bis(4-hydroxyphenyl)-7-
3H), 7.43 (dd, 1H, J=8.4, 2.4 Hz), 7.14 (d, 2H, J=9.0 Hz), 7.08–7.00 (m,
4H), 6.92 (d, 1H, J=7.2 Hz), 6.80 (d, 2H, J=9.0 Hz), 6.65 (dd, 1H, J=
8.4, 7.8 Hz), 6.59 (d, 2H, J=8.4 Hz), 6.27 (d, 2H, J=8.4 Hz), 5.80 (d, 1H,
J=7.8 Hz), 5.34 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.88–3.84 (m, 2H),
3.76 (s, 3H), 3.72 (s, 3H), 3.61 (s, 3H), 3.54 (s, 3H), 2.29–2.20 (m, 2H),
1.45 ppm (s, 9H); 13C NMR (150 MHz, CDCl3): d=171.8, 159.34, 159.27,
158.5, 157.9, 140.5, 140.3, 134.6, 133.7, 133.5, 133.2, 132.7, 132.6, 130.1,
129.6, 129.5, 129.4, 129.0, 128.5, 127.4, 125.2, 120.4, 119.1, 118.4, 118.0,
117.8, 117.4, 115.2, 113.8, 113.7, 113.6, 113.5, 113.3, 79.9, 60.8, 55.5, 55.4,
55.2, 55.1, 52.2, 47.3, 47.1, 35.3, 29.1 ppm; HRMS (FAB+): m/z calcd for
C52H52N2O8: 832.3724 [M]+; found 832.3732.
(2,2,2-tri-chloroethoxysulfonyloxy)-3,6-dihydropyrroloACTHNUTRGNEU[GN 2,3-c]carbazol-2-
yl)-2-(4-hydroxy-phenyl)acetate (54b): A flame-dried 100 mL two-necked
round-bottomed flask equipped with a Teflon-coated magnetic stirring
bar, a rubber septum, and an inlet adapter with a three-way stopcock was
charged with 53b (126 mg, 127 mmol), TBAI (1.13 g, 3.05 mmol), and dry
CH2Cl2 (13 mL). The suspension was cooled to 08C. BCl3 (1.0m in
CH2Cl2, 3.05 mL, 3.05 mmol) was added dropwise to the solution at 08C
over 5 min. The reaction mixture was stirred at 08C for 10 min and was
warmed at room temperature. The reaction mixture was stirred for 1.5 h,
after which time TLC (CH2Cl2/MeOH=10:1) indicated complete con-
sumption of 53b. The reaction mixture was quenched with water, and the
resulting mixture stirred for 1 h. The resulting mixture was extracted with
ethyl acetate three times. The combined organic extracts were washed
with saturated aqueous Na2S2O3, brine, dried over anhydrous sodium sul-
Methyl
2-(7-hydroxy-5-methoxy-3-(4-methoxyphenethyl)-1,4-bis(4-me-
[2,3-c]carbazol-2-yl)-2-(4-methoxyphe-
flame-dried 20 mL two-necked round-bottomed
thoxy-phenyl)-3,6-dihydropyrrolo
AHCTUNGTRENNUNG
nyl)acetate (52b):
A
570
www.chemasianj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 560 – 572

Total Synthesis of Dictyodendrins A–E
fate, and filtered. The filtrate was concentrated under reduced pressure.
126.8, 125.5, 121.3, 120.9, 114.8, 114.1, 113.8, 113.5, 113.2, 112.6, 112.3,
57.3, 55.34, 55.28, 55.09, 55.05, 47.1, 36.3 ppm; HRMS (EI): m/z calcd for
C40H36BrNO6 705.1726 [M]+; found 705.1719.
The residue was purified by MPLC (CH2Cl2/MeOH=10:1, flow rate:
2.5 mLminÀ1
, ULTRA PACK: DIOL-A) to afford 54b (78.0 mg,
84.9 mmol, 67%) as a dark red amorphous solid. Rf =0.28 (CH2Cl2/
MeOH=10:1); IR (neat): n˜ =3331, 3022, 2951, 2839, 1722, 1612, 1597,
1556, 1514, 1479, 1461, 1445, 1404, 1371, 1323, 1261, 1219, 1196, 1171,
4-Bromo-6-methoxy-2-(4-methoxybenzyl)-1-(4-methoxyphenethyl)-3,7-
bis(4-methoxyphenyl)-1H-indole (42c):
A flame-dried screw-top test
tube equipped with a Teflon-coated magnetic stirring bar, a rubber
septum was charged with 41 (50.0 mg, 87.3 mmol), 46 (27.0 mL, 131 mmol),
and dry CH2Cl2 (1.0 mL). The solution was cooled to 08C. To the solu-
1159, 1099, 1009, 995, 899, 860, 841, 800, 727 cmÀ1 1H NMR (600 MHz,
;
CD3OD): d=7.45–7.34 (m, 3H), 7.31–7.18 (m, 2H), 7.04 (d, 2H, J=
8.4 Hz), 7.00–6.98 (m, 2H), 6.93–6.91 (m, 2H), 6.72 (d, 2H, J=9.0 Hz),
6.66 (dd, 1H, J=8.4, 8.4 Hz), 6.50 (d, 2H, J=7.8 Hz), 6.26 (d, 2H, J=
7.2 Hz), 6.09 (d, 1H, J=7.8 Hz), 5.30 (s, 1H), 5.05 (s, 2H), 3.81–3.71 (m,
2H), 3.54 (s, 3H), 2.23–2.22 ppm (m, 2H); 13C NMR (150 MHz,
CD3OD): d=174.0, 158.5, 158.2, 157.5, 156.4, 138.3, 136.2, 135.1, 134.7,
134.13, 134.09, 132.8, 132.1, 130.7, 130.6, 130.5, 130.3, 129.9, 129.4, 128.8,
128.3, 128.0, 127.1, 124.8, 119.0, 118.9, 118.6, 116.6, 116.5, 116.2, 116.15,
116.06, 116.0, 115.7, 115.6, 115.2, 113.7, 94.0, 81.9, 52.7, 47.9, 36.4 ppm;
HRMS (FAB+): m/z calcd for C45H35Cl3N2O11S: 916.1027 [M]+; found
916.1046.
tion was added YbACHTNUTRGNEUNG(OTf)3 (10.8 mg, 17.5 mmol). The reaction mixture was
stirred at 08C for 2.5 h. The reaction mixture was quenched with saturat-
ed aqueous NaHCO3. The resulting mixture was extracted with ethyl ace-
tate three times. The combined organic extracts were dried over anhy-
drous sodium sulfate, and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by GPC to afford 41
(13.2 mg, 23.1 mmol, 26%) and 42c (33.7 mg, 48.7 mmol, 56%, 76%
brsm) as a white amorphous solid. Rf =0.38 (hexanes/ethyl acetate=3:1);
IR (neat): n˜ =1611, 1564, 1512, 1462, 1302, 1246, 1175, 1090, 1034, 826,
756 cmÀ1 1H NMR (600 MHz, CDCl3): d=7.36 (d, 2H, J=8.4 Hz), 7.30
;
Dictyodendrin A (1): A 30 mL round-bottomed flask equipped with a
Teflon-coated magnetic stirring bar, a rubber septum, and an inlet adapt-
er with a three-way stopcock was charged with 54b (64.0 mg, 69.7 mmol),
HCO2NH4 (26.4 mg, 418 mmol), and dry MeOH (7 mL). To the solution
was added zinc dust (18.2 mg, 279 mmol) at room temperature. The reac-
tion mixture was stirred at room temperature for 2 h, after which time
TLC (CH2Cl2/MeOH=3:1) indicated complete consumption of 54b. The
reaction mixture was filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure. The residue was purified by MPLC
(CH2Cl2/MeOH=3:1, flow rate: 2.5 mLminÀ1, ULTRA PACK: DIOL-A)
to afford 1 (55.0 mg, 68.4 mmol, 98%) as a dark red amorphous solid.
Rf =0.13 (CH2Cl2/MeOH=3:1); IR (neat): n˜ =3385, 1719, 1611, 1570,
(d, 2H, J=7.8 Hz), 7.08 (s, 1H), 6.98 (d, 2H, J=7.8 Hz), 6.93 (d, 2H, J=
7.8 Hz), 6.90 (d, 2H, J=7.8 Hz), 6.75 (d, 2H, J=7.2 Hz), 6.64 (d, 2H, J=
7.2 Hz), 6.34 (d, 2H, J=8.4 Hz), 3.86 (s, 3H), 3.84 (s, 3H), 3.744 (s, 3H),
3.73 (s, 3H), 3.72 (s, 3H), 3.70 (s, 2H), 3.61–3.57 (m, 2H), 2.29–2.26 ppm
(m, 2H); 13C NMR (150 MHz, CDCl3): d=159.0, 158.7, 158.09, 158.06,
153.3, 138.2, 135.2, 133.1, 132.3, 130.9, 130.2, 129.5, 128.8, 127.5, 127.3,
122.3, 116.7, 113.9, 113.8, 113.6, 113.5, 112.9, 112.8, 111.2, 57.5, 55.3,
55.18, 55.14, 55.1, 46.2, 35.9, 30.1 ppm; HRMS (EI): m/z calcd for
C40H38BrNO5: 691.1933 [M]+; found: 691.1919.
Formal Synthesis of Dictyodendrin E from the Intermediate of
Dictyodendrin B
1558, 1514, 1474, 1458, 1437, 1356, 1223, 1171, 1057, 1005, 835, 800 cmÀ1
;
5-Methoxy-2-(4-methoxybenzyl)-3-(4-methoxyphenethyl)-1,4-bis(4-me-
1H NMR (600 MHz, CD3OD): d=7.44–7.35 (m, 3H), 7.24 (d, 1H, J=
7.8 Hz), 7.17 (d, 1H, J=7.8 Hz), 7.04 (d, 2H, J=8.4 Hz), 7.00–6.94 (m,
2H), 6.94–6.88 (m, 2H), 6.72 (d, 2H, J=8.4 Hz), 6.58 (dd, 1H, J=8.4,
7.2 Hz), 6.49 (d, 2H, J=8.4 Hz), 6.25 (d, 2H, J=8.4 Hz), 5.95 (d, 1H, J=
7.8 Hz), 5.29 (s, 1H), 3.78–3.71 (m, 2H), 3.55 (s, 3H), 2.24–2.17 ppm (m,
2H); 13C NMR (150 MHz, CD3OD): d=171.4, 158.4, 158.1, 157.5, 156.4,
138.4, 138.3, 135.0, 134.6, 134.2, 134.1, 133.7, 132.5, 130.7, 130.61, 130.58,
130.4, 130.1, 129.6, 128.6, 127.5, 127.2, 122.4, 119.12, 119.07, 118.7, 117.0,
116.5, 116.2, 116.0, 115.9, 115.7, 115.6, 115.5, 113.2, 52.6, 49.1, 48.0,
36.4 ppm; HRMS (FAB+): m/z calcd for C43H34N2O11S: 786.1883
[MÀNH3]+; found 786.1876.
thoxy-phenyl)-3,6-dihydropyrroloACHTUNGRTNE[NUG 2,3-c]carbazol-7-ol (52c): A flame-
dried 20 mL one-necked round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar, a rubber septum, and an inlet adapter with
a three-way stopcock was charged with 51a (100 mg, 127 mmol), pentam-
ethylbenzene (94.0 mg, 634 mmol) and toluene (200 mL). To the solution
was added DIBAL (1.0m in toluene, 2.5 mL, 2.5 mmol) at room tempera-
ture. The reaction mixture was stirred at room temperature for 2 h, after
which time TLC (hexanes/ethyl acetate=1:1) indicated complete con-
sumption of 51a. To the solution was added BCl3 (1.0m in CH2Cl2,
0.89 mL, 0.89 mmol) dropwised at À788C. The reaction mixture was
stirred at À788C for 30 min, after which time TLC (hexanes/ethyl ace-
tate=1:1) indicated complete consumption of 51c. The reaction mixture
was quenched with 1m aqueous HCl. The resulting mixture was extracted
with ethyl acetate four times. The combined organic extracts were dried
over anhydrous sodium sulfate, and filtered. The filtrate was concentrat-
ed under reduced pressure. The residue was purified by column chroma-
tography on silica gel (hexanes/ethyl acetate=3:2) to afford 52c
(65.1 mg, 90.6 mmol, 71%) as a brown amorphous solid. Rf =0.33 (hex-
anes/ethyl acetate=1:1); IR (neat): n˜ =3360, 2961, 2909, 2835, 1611,
1580, 1512, 1464, 1443, 1404, 1371, 1356, 1286, 1244, 1175, 1034, 908, 833,
Friedel–Crafts Reaction
(4-Bromo-6-methoxy-1-(4-methoxyphenethyl)-3,7-bis(4-methoxyphenyl)-
1H-indo-2-yl)(4-methoxyphenyl)methanone (42a):
A
flame-dried
100 mL two-necked round-bottomed flask equipped with a Teflon-coated
magnetic stirring bar, a rubber septum, and an inlet adapter with a three-
way stopcock was charged with anhydrous ZnCl2 (2.38 g, 17.5 mmol) and
dry Et2O (17 mL). To the mixture was added 41 (1.00 g, 1.75 mmol) at
08C to give a black solution. To the solution was added para-methoxy-
benzoyl chloride (43; 894 mg, 5.24 mmol) dropwise at 08C. The reaction
mixture was stirred at 08C for 1 h, after which time TLC (hexanes/ethyl
acetate/CH2Cl2 =5:1:2) indicated complete consumption of 41. The reac-
tion mixture was quenched with 1m aqueous HCl. The resulting mixture
was extracted twice with ethyl acetate. The combined organic extracts
were washed with 4m aqueous NaOH four times, brine, dried over anhy-
drous sodium sulfate, and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel (hexanes/ethyl acetate/CH2Cl2 =5:1:2) to afford the desired
product 42a (1.21 g, 1.73 mmol, 99%) as a yellow amorphous solid. Rf =
0.30 (hexanes/ethyl acetate/CH2Cl2 =5:1:2); IR (neat): n˜ =1597, 1572,
1
773, 732 cmÀ1; H NMR (500 MHz, CDCl3): d=8.55 (s, 1H), 7.56 (d, 2H,
J=9.0 Hz), 7.45 (d, 2H, J=9.0 Hz), 7.06–6.98 (m, 6H), 6.76 (d, 2H, J=
8.5 Hz), 6.69–6.60 (m, 4H), 6.34 (d, 2H, J=9.0 Hz), 5.91 (d, 1H, J=
7.5 Hz), 5.22 (br s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.82 (s, 2H), 3.77–3.72
(m, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 3.60 (s, 3H), 2.37–2.32 ppm (m, 2H);
13C NMR (125 MHz, CDCl3): d=159.2, 158.9, 158.00, 157.97, 140.8, 139.9,
136.5, 133.0, 132.4, 131.7, 130.6, 130.5, 129.6, 129.2, 129.0, 128.9, 128.3,
127.8, 125.7, 120.0, 118.6, 117.8, 117.1, 116.6, 115.0, 113.9, 113.7, 113.6,
113.5, 108.9, 61.1, 55.5, 55.4, 55.3, 55.2, 46.5, 36.2, 30.3 ppm; HRMS
(FAB+): m/z calcd for C46H42N2O6: 718.3043 [M]+; found: 776.3040.
1560, 1541, 1512, 1462, 1302, 1246, 1175, 1153, 1090, 1032, 837, 758 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.55 (d, 2H, J=9.0 Hz), 7.39 (d, 2H, J=
8.5 Hz), 7.18–7.15 (m, 3H), 7.02 (d, 2H, J=9.0 Hz), 6.68–6.64 (m, 4H),
6.59 (d, 2H, J=8.0 Hz), 6.49 (d, 2H, J=9.0 Hz), 3.87 (s, 3H), 3.84–3.81
(m, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 3.67 (s, 3H), 2.48–
2.44 ppm (m, 2H); 13C NMR (125 MHz, CDCl3): d=189.6, 163.3, 159.2,
158.6, 158.0, 154.9, 137.3, 136.9, 133.4, 132.2, 132.0, 131.0, 130.0, 129.5,
Acknowledgements
The authors thank Professors S. Matsunaga and N. Fusetani (University
of Tokyo) for providing valuable information and their spectral data.
Chem. Asian J. 2011, 6, 560 – 572
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
571

H. Tokuyama et al.
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This work was financially supported by the KAKENHI, Grant-in-Aid for
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Received: August 6, 2010
Published online: October 8, 2010
572
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Chem. Asian J. 2011, 6, 560 – 572