Total synthesis of dictyodendrins B and e

Article abstract of DOI:10.1021/jo400841d

The concise synthesis of the novel telomerase inhibitors dictyodendrins B and E was completed in only 9 and 11 steps (longest linear sequence). The highly convergent strategy employed a palladium-catalyzed Larock indole synthesis and a palladium-mediated one-pot consecutive Buchwald-Hartwig amination/C-H activation reaction as key steps. The present synthesis exhibits respectable levels of atom-, redox-, and step-economy.

Full text of DOI:10.1021/jo400841d

Note
pubs.acs.org/joc
Total Synthesis of Dictyodendrins B and E
Jingjing Liang,§,† Weimin Hu,§,† Pengyu Tao,† and Yanxing Jia*,†,‡
†State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road,
Beijing 100191, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: The concise synthesis of the novel telomerase
inhibitors dictyodendrins B and E was completed in only 9 and
11 steps (longest linear sequence). The highly convergent
strategy employed a palladium-catalyzed Larock indole
synthesis and a palladium-mediated one-pot consecutive
Buchwald−Hartwig amination/C−H activation reaction as
key steps. The present synthesis exhibits respectable levels of
atom-, redox-, and step-economy.
he development of shorter synthetic sequences for the
Tsynthesis of complex natural products is currently pursued
actively by organic chemists.1−4 Cascade reactions offer an
attractive strategy for the ideal synthesis of complex natural
products.5 Meanwhile, transition-metal-mediated direct C−H
activation has garnered increasing attention in the synthetic
community as the “ideal” method for carbon−carbon bond
formation, and some successful applications of C−H activation
for the total synthesis of complex natural products are
emerging.6 With our ongoing study on the efficient synthesis
of indole and pyrrole alkaloids, we report herein a concise and
efficient total synthesis of dictyodendrins B and E using a
palladium-mediated C−H activation strategy.
Dictyodendrins A−E (1−5) were isolated by Fusetani and
Matsunaga from the sponge of Dictyodendrilla verongiformis that
was collected off the south Japanese coast (Figure 1).7 These
compounds belong to a new family of alkaloids that feature a
characteristic and unique pyrrolo[2,3-c]carbazole moiety and
carry at least one sulfate group in the periphery. These scarce
alkaloids were claimed to be the first marine natural products
with telomerase inhibitory properties (100% inhibition at 50
μg/mL concentration). Since the telomerase enzyme is
overexpressed in >85% tumor cells but not in normal cells,8
telomerase inhibition represents a promising target for cancer
chemotherapy.9
Figure 1. Structures of dictyodendrins A−E.
total synthesis of dictyodendrin B by mainly using palladium-
catalyzed cross-coupling reactions.12
Because of their unique chemical structures and promising
From our point of view, dictyodendrins have a common fully
substituted indole moiety but differ in their respective
substituents at the 2-position. We performed retrosynthetic
analysis of 2 and 5 as shown in Scheme 1. We envisioned that
both 2 and 5 could be prepared from the same advanced
biological activity, the total synthesis of dectyodendrins has
been investigated by many chemists.10−13 Furstner and co-
̈
workers reported the first total synthesis of dictyodendrins B,
C, and E using their original titanium-induced reductive
coupling reaction.10 Tokuyama et al. reported the total
synthesis of dectyodendrins A−E (1−5) by using an elegant
cascade of indoline formation/cross-coupling sequence.11 In
addition, Iwao, Ishibashi, and co-workers disclosed the formal
Received: April 18, 2013
© XXXX American Chemical Society
A
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Scheme 1. Retrosynthetic Analysis of Dictyodendrins B and
E
Scheme 2. Synthesis of 2-Acylindole Derivative 7
position of indole 14 with NBS provided 7 in 98% yield. The
short synthesis of this key intermediate 7 could be carried out
on a multigram scale.
After the synthesis of the key intermediate 7, we investigated
the synthesis of the key carbazole by palladium-catalyzed one-
pot consecutive Buchwald−Hartwig amination/C−H activation
reaction (Table 1). Once again, an extensive literature search
did not show any use of this one-pot methodology for the
synthesis of complex carbazole natural products. To our
disappointment, treatment of 7 and 8 under Bedford’s reaction
conditions did not afford the desired product 6.15 Instead, only
the debrominated product 14, resulting from a reductive
process, was obtained in 50% yield (Table 1, entry 1). Of the
other catalyzed conditions examined, carbazole 6 was not
obtained. Subsequently, a variety of conditions (base, solvent,
and temperature) were examined in the presence of Pd(OAc)2
and (t-Bu3P)HBF4, and some of the representative results are
shown in Table 1. After the amount of Pd(OAc)2 and ligand
was increased, the desired 6 was obtained, albeit in very low
yield (Table 1, entries 2 and 3). When the reaction was
conducted with 1.0 equiv of Pd(OAc)2, the desired 6 was
obtained in 30% yield. Therefore, further optimization of
reaction conditions was carried out in the presence of 1.0 equiv
of Pd(OAc)2. Among the bases tested, t-BuONa was the best
one (entries 4 and 5). Of the solvents examined, although
toluene was the best one (entries 4 and 6−8), the polar solvent
DMSO also produced good result (entry 8). Since it was
reported that the higher temperature facilitates the one-pot
reaction, we then performed the reaction at 160 °C in DMSO
and found that the desired product carbazole 6 was obtained in
71% yield (entry 9). Surprisingly, when the nonpolar solvent
mesitylene was used as the solvent at 160 °C, only a trace
amount of 6 was obtained (entry 10). In all cases, the major
intermediate 6. The carbazole skeleton of 6 could be produced
from bromide 7 and 2-chloroaniline 8 via a palladium-catalyzed
one-pot consecutive Buchwald−Hartwig amination/C−H
activation reaction.14,15 The brominated indole 7 should be
easily obtained by a sequence of N-alkylation followed by
bromination from indole 9. In turn, the indole 9 could be
prepared by the palladium-catalyzed Larock indole synthesis16
from o-iodoaniline 10 and the known alkyne ketone 11.17
The synthesis of indole 14 commenced with the known
compound 12 (Scheme 2).18 Iodination of aniline 12 using ICl
gave o-iodoaniline 10 in 83% yield. Surprisingly, an extensive
literature search did not show any report on the use of such
alkynyl ketone compounds for the Larock indole annulation.
Although an alkynyl ester compound for the Larock indole
annulation has been reported in the literature,19 the
regioselectivity of this annulation reaction was not clear. The
reaction of o-iodoaniline 10 with alkynyl ketone 11 under the
standard Larock reaction conditions (Pd(OAc)2, PPh3,
Na2CO3, LiCl, DMF, 100 °C) was carried out.16 Gratifyingly,
the reaction was highly regioselective and yielded the desired
indole 9 as the only regioisomer, albeit in lower yield (44%).
Subsequently, a variety of conditions (palladium source, base,
solvent, and concentration) were further optimized to increase
the yield. We eventually found that the optimal condition was
10% Pd(PPh3)4 in the presence of 2.0 equiv of K2CO3 in THF
(c = 0.50 M), which provided the desired indole 9 in 95% yield.
N-Alkylation of 9 with 13 afforded the desired indole 14 in 95%
yield. The structure of 14 was unequivocally confirmed by X-
ray crystallographic analysis. Chemoselective bromination of 5-
B
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Note
a
was readily converted to dictyodendrin B in a three-step
sequence. Thus, our total synthesis of dictyodendrin B was
achieved in only nine steps and 27% overall yield from the
known compound 12.
Table 1. Optimization of the Reaction Conditions
After completion of the synthesis of dictyodendrin B, we
turned our attention to the synthesis of dictyodendrin E from
the advanced intermediate 6 (Scheme 4). Gratefully, reduction
Scheme 4. Total Synthesis of Dictyodendrin E (5)
b
yield (%)
entry
Pd(OAc)2 (equiv)
solvent
toluene
temp (°C)
6
14
1
2
3
4
0.1
0.2
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
110
110
110
110
110
110
110
110
160
160
0
50
91
86
61
95
83
86
58
19
88
toluene
toluene
toluene
toluene
1,4-dioxane
DMF
5
6
30
0
c
5
6
0
7
0
8
DMSO
DMSO
mesitylene
23
71
5
9
10
a
Reaction conditions: 7 (0.1 mmol), 8 (0.3 mmol), Pd(OAc)2, (t-
Bu3P)HBF4 (2 equiv of Pd(OAc)2), t-BuONa (0.5 mmol) in solvent
b
c
(4.0 mL). Isolated yields. Cs2CO3 was used as the base.
side product frequently observed was the debrominated starting
material 14. Moreover, the structure of 6 was unequivocally
confirmed by X-ray crystallographic analysis.
With the advanced intermediate 6 in hand, we proceeded
with the total synthesis of dictyodendrin B (2) (Scheme 3).
Removal of the benzyl ether by hydrogenolysis afforded 15 in
90% yield, and its characterization data were in agreement with
those reported in the literatures.10,11 Finally, according to the
of the carbonyl group in 6 using LiAlH4 in the presence of
AlCl3 provided the desired product 16 in 81% yield. Removal of
the benzyl ether by hydrogenolysis afforded the known
compound 17, which was then transformed to dictyodendrin
E in four steps.10,11 Our total synthesis of dictyodendrin E was
achieved in only 11 steps and 29% overall yield from the known
compound 12.
protocol reported by Furstner and Tokuyama, compound 15
̈
Scheme 3. Total Synthesis of Dictyodendrin B (2)
In summary, we have accomplished the robust, scalable, and
highly efficient total synthesis of dictyodendrins B and E from
the known compound 12. Our route delivered dictyodendrin B
in only nine steps with 27% overall yield and dictyodendrin E in
11 steps with 29% overall yield. The highly convergent strategy
employed was made possible by a palladium-mediated one-pot
consecutive Buchwald−Hartwig amination/C−H activation
reaction and a palladium-catalyzed Larock indole synthesis.
The present syntheses represent the shortest pathway for the
total synthesis of dictyodendrins B and E to date. The synthesis
represented another example of C−H activation strategy for the
rapid synthesis of biologically active natural products. The
synthesis and biological studies of the other members of the
dictyodendrin family and analogues are currently under
investigation.
EXPERIMENTAL SECTION
■
General Remarks. All reagents were obtained from commercial
suppliers unless otherwise stated. Tetrahydrofuran (THF) and ether
(Et2O) were distilled from potassium sodium alloys; dichloromethane
was distilled from calcium hydride; N,N-dimethylformamide (DMF)
was distilled from magnesium sulfate under vacuum. Dimethyl
sulfoxide (DMSO) was distilled from calcium hydride under vacuum.
Flasks were flame-dried under vacuum and cooled under a stream of
1
nitrogen or argon. H NMR were recorded on a 400 MHz NMR
C
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Note
spectrometer and 13C NMR on a 100 MHz NMR spectrometer unless
otherwise stated. The following abbreviations are used for the
multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet,
m: multiplet, br s: broad singlet for proton spectra and carbon spectra.
Coupling constants (J) are reported in hertz (Hz). High-resolution
mass spectra (HRMS) were acquired on an FT-MS (7.0 T) equipped
with an ESI source in positive mode. Infrared spectra were recorded
with a thin layer of the product on a KBr disk. Flash column
chromatography was performed using silica gel (200−300 mesh) with
solvents distilled prior to use.
°C. The resulting mixture was warmed to room temperature and
stirred for 12 h. The resulting mixture was concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (PE/EtOAc = 5:1) to afford 7 (3.46 g, 98%) as a yellow
1
amorphous solid: H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.60
(d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H),
7.06 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.8 Hz,
2H), 6.59 (d, J = 8.6 Hz, 2H), 6.52 (d, J = 8.6 Hz, 2H), 4.02−3.98 (m,
2H), 3.90 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H), 3.53 (s,
3H), 2.49−2.46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 189.0,
163.3, 159.5, 158.4, 158.0, 152.1, 135.2, 135.2, 132.4, 131.8, 131.0,
130.5, 129.8, 129.5, 126.6, 125.6, 125.4, 124.0, 121.7, 121.2, 113.8,
113.7, 113.5, 113.2, 110.9, 61.2, 55.3, 55.1, 55.0, 46.6, 36.6; IR (KBr)
3705, 3680, 2969, 2931, 1598, 1540, 1511, 1457, 1247, 1174, 1055,
1033, 836 cm−1; HRMS (ESI) m/z calcd for C40H37NO6Br (M + H)+
706.1799, found 706.1787.
Compound 10. To a stirred solution of 12 (2.29 g, 10 mmol) in
Et2O (50 mL) were added saturated aqueous Na2CO3 solution (11
mL) and iodine monochloride (1.78 g, 11 mmol) dissolved in Et2O
(45 mL) in the dark. The reaction mixture was stirred for 6 h. After
completion of the reaction, the mixture was diluted with Et2O and
quenched with saturated aqueous Na2S2O3. The aqueous layer was
extracted with EtOAc, and the combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was
evaporated under reduced pressure, and the resulting residue was
purified by flash column chromatography (PE/EtOAc = 12:1) afforded
Compound 6. To a stirred solution of compound 7 (159.3 mg, 0.2
mmol) in dry DMSO (9 mL) were added 8 (158.1 mg, 0.6 mmol) and
t-BuONa (108.4 mg, 1.0 mmol) successively under argon atmosphere,
After oxygen was discharged with argon for 0.5 h, Pd(OAc)2 (50.5 mg,
0.2 mmol) and (t-Bu3P)HBF4 (116.0 mg, 0.4 mmol) were added
under argon, and then the solution was heated at 160 °C for 6 h. The
mixture was then filtered through a pad of Celite, extracted with
EtOAc, washed with brine, dried over anhydrous Na2SO4, and filtered.
The filtrate was evaporated under reduced pressure, and the resulting
residue was purified by flash column chromatography (PE/EtOAc =
1
compound 10 as a white solid (2.95 g, 83%): H NMR (400 MHz,
CDCl3) δ 7.54 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.97 (d, J
= 8.8 Hz, 2H), 6.20 (d, J = 8.8 Hz, 1H), 3.96 (br s, 2H), 3.81 (s, 3H),
3.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 157.8, 145.3,
137.6, 131.3, 127.0, 115.8, 114.3, 103.2, 74.5, 55.7, 55.1; IR (KBr)
3447, 3359, 2965, 2932, 2836, 1608, 1576, 1510, 1294, 1239, 1033,
830, 777, 579 cm−1; HRMS (ESI) m/z calcd for C14H15INO2 (M +
H)+ 356.0142, found 356.0136.
1
3:1) to afford 6 (130.5 mg, 71%) as a yellow amorphous solid: H
NMR (400 MHz, CD2Cl2) δ 8.74 (s, 1H), 7.59−7.55 (m, 6H),7.44−
7.35 (m, 3H), 7.26 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.83
(d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H),
6.66 (t, J = 8.4 Hz, 1H), 6.61 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.8 Hz,
2H), 5.83 (d, J = 8.4 Hz, 1H), 5.26 (s, 2H), 3.95 (t, J = 8.0 Hz, 2H),
3.91 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.69 (s, 3H), 3.63 (s, 3H),
2.55−2.51 (m, 2H); 13C NMR (100 MHz, CD2Cl2) δ 189.9, 163.5,
159.9, 159.4, 158.5, 145.0, 143.2, 137.6, 136.5, 133.4, 132.6, 132.5,
132.0, 131.5, 130.7, 130.1, 130.0, 129.8, 128.9, 128.5, 128.3, 127.6,
124.9, 122.1, 119.7, 119.1, 118.6, 117.7, 115.8, 114.1, 113.8, 113.5,
113.5, 106,1, 70.8, 61.6, 55.8, 55.7, 55.7, 55.4, 54.3, 54.1, 53.5, 53.3,
47.9, 36.9; IR (KBr) 3357, 1632, 1595, 1573, 1536, 1513, 1461, 1441,
1423, 1286, 1246, 1174, 1157, 1030 cm−1; HRMS (ESI) m/z calcd for
C53H47N2O7 (M + H)+ 823.3378, found 823.3369.
Compound 9. To a stirred solution of 10 (356 mg, 1 mmol) in
anhydrous THF (2 mL) was added K2CO3 (276 mg, 2 mmol) under
argon atmosphere. After oxygen was discharged with argon for 0.5 h,
compound 11 (798 mg, 3 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol)
were added under argon, and then the solution was heated at 65 °C for
24 h. The mixture was cooled to room temperature, extracted with
EtOAc, washed with brine, dried over anhydrous Na2SO4, and filtered.
The filtrate was evaporated under reduced pressure, and the resulting
residue was purified by flash column chromatography (PE/EtOAc =
5:1) to afford 9 (467 mg, 95%) as a yellow solid: 1H NMR (400 MHz,
CDCl3) δ 8.89 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.54−7.50 (m, 4H),
7.15 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 9.0 Hz,
1H), 6.73 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H),
3.86 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 187.6, 162.3, 159.0, 158.5, 155.1, 136.6, 131.8, 131.8, 131.0, 130.9,
130.2, 126.4, 126.0, 124.7, 122.9, 121.5, 114.5, 113.6, 113.0, 112.8,
108.5, 56.9, 55.3, 55.3, 55.2; HRMS (ESI) m/z calcd for C31H28NO5
(M + H)+ 494.1962, found 494.1973.
Compound 15. Compound 6 (50.3 mg, 0.06 mmol) was
hydrogenated over 10% Pd/C (64.0 mg, 0.06 mmol) in EtOAc (6
mL) at 50 °C for 1 h. The mixture was then filtered through a pad of
Celite, and the insoluble material was washed well with hot EtOAc.
The filtrate was evaporated under reduced pressure, and the resulting
residue was purified by flash column chromatography (PE/EtOAc =
Compound 14. To a stirred solution of 9 (316 mg, 0.64 mmol) in
dry DMF (22 mL) was added KOH (714 mg, 12.8 mmol). The
resulting suspension was stirred at room temperature for 30 min. To
the solution was added 13 (860 mg, 2.56 mmol). The reaction mixture
was stirred at 50 °C for 24 h. The reaction mixture was quenched with
saturated aqueous NH4Cl. The reaction mixture was diluted with
water. The resulting mixture was extracted with EtOAc three times.
The combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (PE/EtOAc = 3:1) to afford 14 (385 mg, 95%) as a
1
3:1) to afford 15 (40.3 mg, 90%) as a yellow amorphous solid: H
NMR (400 MHz, CD2Cl2) δ 8.91 (s, 1H), 7.56−7.54 (m, 4H), 7.24
(d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H),
6.69 (m, 3H), 6.59 (m, 3H), 6.51 (d, J = 8.8 Hz, 2H), 6.07 (br s, 1H),
5.78 (d, J = 8.4 Hz, 1H), 3.94 (t, J = 8.0 Hz, 2H), 3.88 (s, 3H), 3.79 (s,
3H), 3.78 (s, 3H), 3.67 (s, 3H), 3.61 (s, 3H), 2.53−2.50 (m, 2H); 13C
NMR (100 MHz, CD2Cl2) δ 190.2, 163.6, 159.8, 159.4, 158.5, 143.3,
141.6, 136.5, 133.4, 132.7, 132.6, 131.8, 131.6, 130.7, 130.3, 129.9,
129.2, 128.9, 127.5, 125.5, 122.4, 119.8, 119.2, 118.7, 117.5, 115.9,
114.1, 113.8, 113.5, 109.3, 61.5, 55.8, 55.7, 55.7, 55.4, 47.9, 36.9; IR
(KBr) 3399, 2933, 1606, 1513, 1460, 1295, 1245, 1172, 1107, 1067,
1032, 966, 838, 772 cm−1; HRMS (ESI) m/z calcd for C46H41N2O7
(M + H)+ 733.2908, found 733.2879.
Dictyodendrin B (2). Dictyodendrin B (2) was prepared from
compound 15 followed the procedure as described in refs 11 and 12:
1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 8.4 Hz, 2H), 7.34 (d, J =
8.8 Hz, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.06−7.02 (m, 4H), 6.65 (d, J =
8.4 Hz, 2H), 6.59−6.55 (m, 3H), 6.48 (d, J = 8.8 Hz, 2H), 6.41 (d, J =
8.4 Hz, 2H), 6.01 (d, J = 8.0 Hz, 1H), 3.98−3.94 (m, 2H), 2.49−2.45
(m, 2H); 13C NMR (100 MHz, CD3OD) δ 191.9, 163.1, 158.7, 157.7,
156.8, 141.7, 138.7, 136.1, 134.2, 134.0, 134.0, 133.8, 131.9, 130.6,
130.6, 129.3, 129.2, 127.0, 126.8, 125.7, 122.7, 118.8, 118.2, 117.2,
1
yellow amorphous solid: H NMR (400 MHz, CDCl3) δ 7.68 (d, J =
8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.20
(d, J = 8.8 Hz, 2H), 7.05−7.00 (m, 3H), 6.73 (d, J = 8.8 Hz, 2H),
6.62−6.53 (m, 6H), 4.00−3.96 (m, 2H), 3.88 (s, 3H), 3.79 (s, 3H),
3.75 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H), 2.50−2.46 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 189.2, 163.1, 159.1, 158.2, 157.9, 155.7, 136.8,
134.2, 132.4, 132.1, 131.2, 131.1, 130.3, 129.6, 127.6, 126.5, 122.8,
121.0, 114.8, 113.7, 113.6, 113.5, 113.1, 107.7, 57.3, 55.3, 55.3, 55.2,
55.1, 46.6, 36.6; IR (KBr) 3433, 2936, 2837, 1594, 1511, 1462, 1248,
1175, 1083, 1033, 833, 732, 607, 533 cm−1; HRMS (ESI) m/z calcd
for C40H38NO6 (M + H)+ 628.2694, found 628.2702.
Compound 7. To a stirred solution of 14 (3.14 g, 5 mmol) in dry
CH2Cl2 (500 mL) was added NBS (0.98 g, 5.5 mmol) in the dark at 0
D
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Note
116.8, 116.0, 116.0, 115.5, 115.5, 112.6, 40.4, 37.7; HRMS (ESI) m/z
calcd for C41H29N2O10S (M − NH4)− 741.1548, found 741.1540.
Compound 16. To a stirred solution of compound 6 (41.4 mg,
0.05 mmol) in dry THF were added AlCl3 (100.0 mg, 0.75 mmol) and
LiAlH4 (60 mg, 1.5 mmol) successively under argon atmosphere. The
solution was refluxed for 0.5 h. The mixture was quenched with H2O,
extracted with EtOAc, washed with brine, dried over anhydrous
Na2SO4, and filtered. The filtrate was evaporated under reduced
pressure, and the resulting residue was purified by flash column
chromatography (PE/EtOAc = 4:1) to afford 16 (33.0 mg, 81%) as an
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (Nos. 21290180, 20972007), the National
Basic Research Program of China (973 Program, NO.
2010CB833200), and the Ph.D. Programs Foundation of
Ministry of Education of China (No. 20120001110100).
REFERENCES
■
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T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40−49. (b) Wender, P. A.;
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Hoffmann, R. W. Angew. Chem., Int. Ed. 2009, 48, 2854−2867.
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1
amorphous solid: H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.58
(d, J = 8.5 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H),
7.45−7.41 (m, 2H), 7.39−7.36 (m, 1H), 7.07−7.02 (m, 6H), 6.84 (d, J
= 7.8 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.72 (t, J = 8.0 Hz, 1H), 6.66
(d, J = 8.4 Hz, 2H), 6.36 (d, J = 8.4 Hz, 2H), 5.95 (d, J = 8.0 Hz, 1H),
5.27 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.85 (s, 2H), 3.81−3.77 (m,
2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.59 (s, 3H), 2.37 (t, J = 8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 159.2, 158.9, 158.0, 158.0, 144.5,
140.0, 137.2, 136.4, 133.0, 132.5, 131.7, 130.5, 130.5, 129.7, 129.6,
128.9, 128.6, 128.2, 128.1, 127.9, 127.8, 125.0, 119.9, 118.5, 117.7,
117.2, 116.5, 115.0, 113.9, 113.7, 113.5, 113.4, 105.6, 70.5, 61.1, 55.4,
55.4, 55.2, 55.2, 46.6, 36.2, 30.4; HRMS (ESI) m/z calcd for
C53H49N2O6 (M + H)+ 809.3585, found 809.3565.
Compound 17. Compound 16 (46.3 mg, 0.06 mmol) was
hydrogenated over 10% Pd/C (60.9 mg, 0.06 mmol) in EtOAc (6 mL)
at 50 °C for 1 h. The mixture was then filtered through a pad of Celite,
and the insoluble material was washed well with hot EtOAc. The
filtrate was evaporated under reduced pressure, and the resulting
residue was purified by flash column chromatography (PE/EtOAc =
3:1) to afford 1711,12 (37.0 mg, 90%) as an amorphous solid: 1H NMR
(400 MHz, CDCl3) δ 8.64 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.46 (d, J
= 8.4 Hz, 2H), 7.06−7.00 (m, 6H), 6.78 (d, J = 8.6 Hz, 2H), 6.68−
6.61 (m, 4H), 6.35 (d, J = 8.6 Hz, 2H), 5.91 (d, J = 7.6 Hz, 1H), 5.53
(br s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.83 (s, 2H), 3.80−3.75 (m,
2H), 3.76 (s, 3H), 3.75 (s, 3H), 3.60 (s, 3H), 2.38−2.34 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 159.2, 158.9, 158.0, 158.0, 140.7, 140.0,
136.5, 133.0, 132.4, 131.7, 130.5, 130.4, 129.6, 129.2, 129.0, 128.9,
128.2, 127.8, 125.7, 119.9, 118.6, 117.9, 117.2, 116.5, 115.0, 113.9,
113.7, 113.5, 113.4, 108.8, 61.1, 55.5, 55.4, 55.4, 55.3, 55.2, 46.5, 36.2;
HRMS (ESI) m/z calcd for C46H43N2O6 (M + H)+ 719.3116, found
719.3116.
(5) For recent reviews on cascade reactions in total synthesis, see:
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Hematol. 2000, 34, 111−126. (b) Neidle, S.; Parkinson, G. Nature
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Soc. 2005, 127, 11620−11621. (b) Furstner, A.; Domostoj, M. M.;
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Scheiper, B. J. Am. Chem. Soc. 2006, 128, 8087−8094. For
derivatization of dictyodendrins (c) Buchgraber, P.; Domostoj, M.
M.; Scheiper, B.; Wirtz, C.; Mynott, R.; Rust, J.; Furstner, A.
̈
Dictyodendrin E (5). Dictyodendrin E (5) was prepared from
compound 17 following the same procedure as described in refs 10b
Tetrahedron 2009, 65, 6519−6534.
1
(11) (a) Okano, K.; Fujiwara, H.; Noji, T.; Fukuyama, T.; Tokuyama,
H. Angew. Chem., Int. Ed. 2010, 49, 5925−5929. (b) Tokuyama, H.;
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and 11b: H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 8.4 Hz, 2H),
7.23−7.14 (m, 5H), 6.98−6.96 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 6.64
(m, 1H), 6.00 (s, 1H), 6.43 (br s, 4H), 5.77 (d, J = 8.4 Hz, 1H), 3.50−
3.47 (m, 2H), 2.31−2.28 (m, 2H); HRMS (ESI) m/z calcd for
C41H31N2O9S (M − NH3 + H)+ 727.1745, found 727.1758.
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ASSOCIATED CONTENT
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■
S
* Supporting Information
Copies of spectra for compounds 10, 9, 14, 7, 6, 15,
dictyodendrin B (2), 16, 17, and dictyodendrin E (5). X-ray
crystal structures of 14 and 6 and crystallographic data in CIF
format. This material is available free of charge via the Internet
at http://pubs.acs.org.
Reddy, K. R.; Knolker, H.-J. Chem. Rev. 2012, 112, 3193−3328.
̈
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of commercially available benzoyl chloride and terminal alkyne; see:
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Vasilevsky, S. F.; Alabugin, I. V. J. Org. Chem. 2011, 76, 7482−7490.
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7330−7335. (b) Hwu, J. R.; Hsu, Y. C.; Josephrajan, T.; Tsay, S.-C. J.
Mater. Chem. 2009, 19, 3084−3090. (c) Watterson, S. H.; Dhar, T. G.
M.; Ballentine, S. K.; Shen, Z.; Barrish, J. C.; Cheney, D.; Fleener, C.
A.; Rouleau, K. A.; Townsend, R.; Hollenbaugh, D. L.; Iwanowicz, E. J.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yxjia@bjmu.edu.cn.
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
E
dx.doi.org/10.1021/jo400841d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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F
dx.doi.org/10.1021/jo400841d | J. Org. Chem. XXXX, XXX, XXX−XXX