Total synthesis of the neuronal cell-protecting carbazole alkaloids carbazomadurin A and (S)-(+)-carbazomadurin B

Article abstract of DOI:10.1002/ejoc.201301059

The total syntheses of the neuronal cell-protecting carbazole alkaloids carbazomadurin A and (S)-(+)-carbazomadurin B were achieved. The key step of the synthesis of the polysubstituted carbazole rings included an allene-mediated electrocyclic reaction of the 6π-electron system that involved the indole 2,3-bond. The cleavage of the alkoxy groups of the resulting 3-ethoxy-8-isopropoxycarbazole successfully gave the 3,8-dihydroxycarbazole, which was converted into the 3,8-bis(OSEM)-carbazole (SEM = 2- trimethylsilylethoxymethyl). A Suzuki-Miyaura cross-coupling reaction of the 3,8-bis(OSEM)-carbazole with the corresponding alkenyl pinacol borates afforded the 1-alkenylcarbazoles, which were treated with tetra-n-butylammonium fluoride (TBAF) followed by reduction with NaBH₄ to provide carbazomadurin A and (S)-(+)-carbazomadurin B, respectively. The total syntheses of the neuronal cell-protecting carbazole alkaloids carbazomadurin A and (S)-(+)-carbazomadurin B were achieved. The key step of the synthesis of the polysubstituted carbazole rings included an allene-mediated electrocyclic reaction that involved the indole 2,3-bond. Copyright

Full text of DOI:10.1002/ejoc.201301059

FULL PAPER
DOI: 10.1002/ejoc.201301059
Total Synthesis of the Neuronal Cell-Protecting Carbazole Alkaloids
Carbazomadurin A and (S)-(+)-Carbazomadurin B
Yuhzo Hieda,[a] Tominari Choshi,*[a] Haruto Fujioka,[a] and Satoshi Hibino*[a]
Keywords: Total synthesis / Alkaloids / Nitrogen heterocycles / Electrocyclic reactions / Cross-coupling / Configuration
determination
The total syntheses of the neuronal cell-protecting carbazole
alkaloids carbazomadurin A and (S)-(+)-carbazomadurin B
were achieved. The key step of the synthesis of the polysub-
stituted carbazole rings included an allene-mediated electro-
cyclic reaction of the 6π-electron system that involved the
indole 2,3-bond. The cleavage of the alkoxy groups of the
resulting 3-ethoxy-8-isopropoxycarbazole successfully gave
the 3,8-dihydroxycarbazole, which was converted into the
3,8-bis(OSEM)-carbazole (SEM = 2-trimethylsilylethoxy-
methyl). A Suzuki–Miyaura cross-coupling reaction of the
3,8-bis(OSEM)-carbazole with the corresponding alkenyl
pinacol borates afforded the 1-alkenylcarbazoles, which
were treated with tetra-n-butylammonium fluoride (TBAF)
followed by reduction with NaBH4 to provide carbazomadu-
rin A and (S)-(+)-carbazomadurin B, respectively.
Introduction
Carbazole alkaloids have attracted much interest among
synthetic organic chemists because of their broad range of
biological activities.[1,2] Since 1979, several groups have
found new types of highly substituted carbazole alkaloids
from different natural resources.[1,2] In 1997, the structurally
unique carbazole alkaloids carbazomadurin A (1a) and B
(1b, see Figure 1) were isolated by Seto and co-workers
from the microorganism Actinomadura madurae 2808-
SV1.[3] These alkaloids exhibit strong neuronal cell-protect-
ing activities against cell death, which is induced by l-glut-
amate.[3] On the basis of their spectroscopic data, the struc-
tures of both alkaloids were determined to have the new
3,8-dioxygenated and highly functionalized carbazole
framework. The absolute configuration of (+)-carbazomad-
urin B (1b), however, remained unknown.[3] In 2003, the
first total synthesis of carbazomadurin A (1a) was reported
by the Knölker group, which used a palladium-catalyzed
sequence of the Buchwald–Hartwig amination, an oxidative
cyclization, and a Stille coupling reaction.[4] A few years
later, the same group reported the first enantioselective to-
tal synthesis of (+)-carbazomadurin B (1b), and the ste-
reogenic center at the C-11 position was assigned as having
the S configuration.[5]
Figure 1. Carbazomadurins A (1a) and B (1b).
We are interested in the syntheses of bioactive nitrogen-
containing fused heteroaromatic compounds, which in-
cludes natural products, through the employment of a ther-
mal electrocyclic reaction that uses either a 6π- or an aza
6π-electron system and in principle involves an aromatic or
heteroaromatic double bond.[6] Among these, we have re-
ported the total syntheses of the hyellazoles, carazostatin,
the carbazoquinocins,[7] murrayaquinone, furocarbazole,
carbazomycin G,[8] the calothrixins,[9] mukonine,[10] and the
carquinostatins[11] by using an allene-mediated thermal
electrocyclic reaction that involves the indole 2,3-bond. Re-
cently, we reported a new total synthesis of carbazomadu-
rin A (1a) by using our methodology through the construc-
tion of a highly substituted carbazole framework.[12]
Herein, we describe the detailed total synthesis of carbazo-
madurin A (1a) and a new asymmetric total synthesis of
(S)-(+)-carbazomadurin B (1b). Our synthetic strategy for
1a and 1b is illustrated by the retrosynthetic analysis in
Scheme 1, in which the 1,3,8-trioxygenated carbazole
framework 2 is obtained from 2-allenylindole intermediate
4 that is generated from 2-propargylindole 5. Furthermore,
we plan to introduce an alkenyl side chain with the E con-
[a] Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama
University,
Fukuyama, Hiroshima 729-0292, Japan
E-mail: choshi@fupharm.fukuyama-u.ac.jp
hibino@fupharm.fukuyama-u.ac.jp
Homepage: www.fukuyama-u.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301059.
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Y. Hieda, T. Choshi, H. Fujioka, S. Hibino
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figuration at the C-1 position of 1 through a Suzuki–Mi-
yaura reaction[13] with alkenyl pinacol borates 3.
Scheme 2. Reagents and conditions: (a) Cl2CHOCH3, TiCl4 (1 m),
CH2Cl2, –10 °C, 4 h, 8a (89%), 8b (86%); (b) NaBH4, EtOH, 0 °C,
3 h, 9a (99%), 9b (99%); (c) MOMCl, iPr2NEt, CH2Cl2, 0 °C to
room temp., 5 h, 10a (97%), 10b (86%); (d) 65% Red-Al, toluene,
0 °C, 3 h, 11a (99%), 11b (99%); (e) MnO2, CH2Cl2, room temp.,
12 h, 12a (87%), 12b (84%); (f) KOH, I2, N,N-dimethylformamide
(DMF), 0 °C, 12 h, 6a (91%), 6b (94%).
We then synthesized 1,3,8-trioxygenated 1,2,3,5,8-penta-
substituted carbazoles 19a and 19b from 2,3,4,7-tetrasubsti-
tuted indoles 6a and 6b (see Scheme 3). The Stille coupling
reaction of 3-iodoindoles 6a and 6b with tributyl(2-ethoxy-
vinyl)stannane[16] in the presence of PdCl2(PPh3)2 gave 3-
alkenylindoles 13a (E/Z, 1:3) and 13b (E/Z, 1:3), respec-
tively. The Grignard reaction of 13a and 13b with ethynyl-
magnesium bromide followed by treatment of the resulting
Scheme 1. Retrosynthetic analysis of carbazomadurines A and B
(MOM = methoxymethyl).
Results and Discussion
To synthesize the initially required 7-oxygenated 2,3,4,7- alcohols 14a and 14b with MOMCl and iPr2NEt produced
tetrasubstituted indoles 6a and 6b, we chose known ethyl MOM propargyl ethers 15a (E/Z, 1:3) and 15b (E/Z, 1:3)
7-alkoxyindole-2-carboxylates 7a and 7b[14] as the starting corresponding to 5. We subjected 15a and 15b to an allene-
materials (see Scheme 2). The treatment of 7a or 7b with mediated thermal electrocyclic reaction[6–12] using tetra-n-
[15]
α,α-dichloromethyl methyl ether in the presence of TiCl4
butylammonium fluoride (TBAF) in tetrahydrofuran
gave 4-formylindoles 8a and 8b, respectively. The formyl (THF) according to our reported method[8b] to provide the
groups of 8a and 8b were subsequently reduced with desired carbazoles 16a and 16b corresponding to 2, respec-
NaBH4 to give the hydroxymethyl groups of 9a and 9b, tively, in somewhat low yields. The oxidation of 16a
which were treated with chloromethyl methyl ether and 16b with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(MOMCl) in the presence of N,N-diisopropylethylamine (DDQ) afforded 5-formylcarbazoles 17a and 17b, which
(iPr2NEt) to yield MOM ethers 10a and 10b. The reduction were treated with 4 m HCl in THF to yield the 1-hydroxy-
of the ester groups of 10a and 10b by treatment with Red- carbazoles 18a and 18b. The sequential treatment of 18a
Al in toluene followed by oxidation of the resulting alcohols and 18b with N-phenyl-bis(trifluoromethanesulfonimide)
11a and 11b with MnO2 afforded indole-2-carbaldehydes (PhNTf2) and NaH gave the corresponding triflates 19a
12a and 12b. Further treatment of 12a or 12b with I2 gave (10.4% yield from 7a in 13 steps) and 19b (8.5% from 7b
the two required 7-oxygenated-2,3,4,7-tetrasubstituted in- in 13 steps). To prepare the 3,8-dihydroxycarbazole at the
doles 6a (67% yield from 7a) and 6b (57% yield from 7b), next stage, we attempted a cleavage of the 3,8-dialkoxy
respectively.
groups of 19a and 19b. Although treatment of 19a with
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Total Synthesis of Carbazomadurins A and B
BBr3 in CH2Cl2 gave only 3-hydroxycarbazole 20a (60%), catalyzed carboalumination of 22a and 22b by treatment
the treatment of 19b with BBr3 successfully gave 3,8-di- with trimethylaluminum in the presence of zirconocene di-
hydroxycarbazole 20b. The hydroxy groups of compound chloride, according to the reported procedure by Negishi,[18]
20b were immediately protected by using 2-(trimethylsilyl)- followed by the addition of I2 afforded (E)-alkenyl iodides
ethoxymethyl chloride (SEMCl) and iPr2NEt to produce 23a (78%) and 23b (58%).[4,5] A subsequent Suzuki–
3,8-bis(OSEM)-carbazole 21 (97% from 19b).
Miyaura reaction[13] of 23a and 23b with bis(pinacolato)-
diboron in the presence of PdCl2(dppf) afforded pinacol
borates 3a (48%) and 3b (53%, [α]D = +26.5), respectively.
Scheme 4. Reagents and conditions: (a) (1) Me3Al, Cp2ZrCl2 (Cp
= cyclopentadienyl), 1,2-dichloroethane, room temp., 12 h; (2) I2,
THF, 0 °C to room temp., 1 h, 23a (79%), 23b (58%); (b) bis-
(pinacolato)diboron, KOAc, PdCl2(dppf), dimethyl sulfoxide
(DMSO), 80 °C, 2 h, 3a (48%), 3b (53%).
As shown in Scheme 5, triflates 19a and 19b were sub-
jected to a Suzuki–Miyaura cross-coupling reaction[13] with
alkenyl pinacol borates 3a in the presence of Pd(PPh3)4 and
Na2CO3 to give 1-alkenylcarbazoles 24a (96%) and 24b
(99%), respectively, in excellent yields. The treatment of 24a
or 24b with BBr3 to cleave the two ether bonds, however,
did not provide the expected 3,8-dihydroxycarbazole 27a.
On the other hand, the cross-coupling reaction of the trifl-
ate 21 with 3a or 3b in the presence of Na2CO3 and
Pd(PPh3)4 gave the corresponding 1-alkenylcarbazoles 25a
(86%) and 25b (83%, [α]D = +7.1), respectively. Although
reduction of the formyl group of 25a afforded alcohol 26,
the sequential treatment with TBAF did not provide carba-
zomadurin A (1a) as had been previously reported.[12] As a
result, the cleavage of both SEM groups of 25a and 25b by
using TBAF in hexamethylphosphoramide (HMPA) pro-
duced the expected 3,8-dihydroxycarbazole 27a (71%) and
27b (67%, [α]D = +20.0), respectively. Finally, the reduction
of 27a and 27b with NaBH4 in MeOH provided the corre-
sponding carbazomadurin A (1a, 70%) and (S)-(+)-carb-
azomadurin B (1b, 78%). The spectral and physical data of
synthetic carbazomadurin A (1a) and (+)-carbazomadu-
rin B (1b) were identical with those of the reported data.[3–5]
The value for the specific rotation of our synthetic (+)-car-
bazomadurin B (1b) was [α]D = +13.1 (c = 0.05, MeOH),
which is consistent with the value [α]D = +13.0 (c = 0.05,
MeOH) that was reported by the Knölker group.[5] This
Scheme 3. Reagents and conditions: (a) tributyl(2-ethoxyvinyl)-
stannane, PdCl2(PPh3)2, Et4NCl, DMF, 80 °C, 2 h, 13a (77%), 13b
(86%); (b) ethynylmagnesium bromide, THF, 0 °C or –30 °C, 1 h,
14a (97%), 14b (81%); (c) MOMCl, iPr2NEt, CH2Cl2, 50 °C, 12 h,
15a (80%), 15b (81%); (d) TBAF, THF, 80 °C, 6 h, 16a (40%),
16b (40%); (e) DDQ, CH2Cl2, room temp., 20 min, 17a (95%), 17b
(73%); (f) HCl (4 m), ethylene glycol, THF, 50 °C, 30 min, 18a
(89%), 18b (91%); (g) PhNTf2, NaH, THF, 0 °C, 30 min, 19a
(77%), 19b (99%); (h) BBr3, CH2Cl2, –78 °C to room temp., 3 h,
20a (60%), 20b (99%); (i) SEMCl, iPr2NEt, CH2Cl2, 0 °C to room
temp., 12 h, 98%.
However, to introduce the (E)-alkenyl side chain, which value of specific rotation was higher than that of natural
is found at the C-1 position of carbazomadurins A (1a) and (+)-carbazomadurin B {1b, [α]D = +4 (c = 0.05, MeOH)}.[3]
B (1b), pinacol borates 3a and 3b were prepared from com- The absolute configuration of 1b was S, as it was derived
mercially available 5-methyl-1-hexyne (22a) and known (S)- from known (S)-(+)-5-methyl-1-heptyne (22b).[17] The
(+)-5-methyl-1-heptyne (22b), respectively, {[α]D = +15.3 Knölker group[5] also assigned the S configuration to the
(CHCl3)}[5,17] in two steps (see Scheme 4). The zirconium- stereogenic center of 1b.
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Experimental Section
General Methods: All nonaqueous reactions were carried out under
nitrogen in dried glassware, unless otherwise noted. Solvents were
dried and distilled according to standard protocols. Analytical thin
layer chromatography was performed with silica gel 60PF254
(Merck). Silica gel column chromatography was performed with
silica gel 60N (63-210 μm, Kanto Chemical Co. Ltd.). All melting
points were determined with a Yanagimoto micro melting point
apparatus. The proton nuclear magnetic resonance (1H NMR)
spectroscopic data were recorded with a JEOL AL-300 at 300 MHz
and a JEOL JMN-LA500 at 500 MHz. Chemical shifts are re-
ported relative to Me4Si (δ = 0.00 ppm). The NMR spectroscopic
data were recorded using CDCl3, unless otherwise noted. Multi-
plicities are indicated by s (singlet), d (doublet), t (triplet), q (quar-
tet), m (multiplet), and br. (broad). The carbon nuclear magnetic
resonance (13C NMR) spectroscopic data were recorded with a
JEOL AL-300 at 75 MHz and JEOL JMN-LA500 at 125 MHz.
Chemical shifts are reported relative to CDCl3 (δ = 77.0 ppm) and
[D6]DMSO (δ = 39.7 ppm). Infrared spectra were recorded using
the attenuated total reflectance (ATR) method with a Shimadzu
FTIR-8000 spectrophotometer and Technologies DuraScop. Low
and high resolution mass spectra were recorded with JEOL JMS-
700 spectrometers by using a direct inlet system. Optical rotations
were measured with a JASCO P-2200 polarimeter.
Ethyl 4-Formyl-7-methoxyindole-2-carboxylate (8a): To a solution
of ethyl 7-methoxyindole-2-carboxylate (7a[14], 1.0 g, 4.54 mmol)
and α,α-dichloromethyl methyl ether (1.24 mL, 13.62 mmol) in dry
CH2Cl2 (30 mL) was added dropwise TiCl4 (1.5 mL, 13.62 mmol)
at –10 °C. The mixture was stirred at the same temperature for 4 h
and then was poured into ice water. The mixture was extracted with
CH2Cl2. The CH2Cl2 phase was washed with water and brine, dried
with Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by column chromatography (silica gel, 10 g;
EtOAc/hexane, 1:5 v/v) to give 4-formylindole 8a (1.0 g, 89%) as a
Scheme 5. Reagents and conditions: (a) 3a, Pd(PPh3)4, Na2CO3,
DMF, 80 °C, 5 h, 24a (96%), 24b (99%); (b) BBr3, CH2Cl2, –78 °C,
3 h; (c) 3a or 3b, Pd(PPh3)4, Na2CO3 (3 m aqueous solution), DMF,
70 °C, 2 h, 25a (86%), 25b (83%); (d) diisobutylaluminum hydride
(DIBAL-H), toluene, 0 °C, 1 h, 90%; (e) TBAF, THF, 80 °C, 1 h;
(f) TBAF, HMPA, 100 °C, 1 h, 27a (71%), 27b (67%); (g) NaBH4,
MeOH, room temp., 5 min, 1a (70%), 1b (78%).
pale yellow solid; m.p. 165–167 °C (acetone/hexane). IR (ATR): ν
˜
1
= 1710, 1650 cm–1. H NMR (300 MHz, CDCl3): δ = 1.42 (t, J =
7.2 Hz, 3 H), 4.07 (s, 3 H), 4.42 (q, J = 7.2 Hz, 2 H), 6.83 (d, J =
7.9 Hz, 1 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.94 (d, J = 2.2 Hz, 1 H),
9.29 (br. s, 1 H), 10.06 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.4, 55.9, 61.3, 103.5, 109.1, 124.2, 125.9, 127.9, 129.6, 132.1,
151.5, 161.7, 191.2 ppm. MS (EI): m/z = 247 [M]+. HRMS (EI):
calcd for C13H13NO4 247.0845; found 247.0849.
Conclusions
On the basis of these results, the known ethyl 7-isoprop-
oxyindole-2-carboxylate (7b)[14] was a convenient starting
material to realize our total syntheses of carbazomadur-
ins A (1a) and B (1b). The 2,3,4,7-tetrasubstituted indole 6b
was prepared from the indole 7b in six steps. The synthesis
of functionalized carbazole 19b was achieved in seven steps
from 6b through an allene-mediated electrocyclic reaction
of the 6π-electron system that involved the indole 2,3-bond.
Carbazole 19b was converted into 3,8-bis(OSEM)-carb-
azole 21, which was subjected to a Suzuki–Miyaura cross-
coupling reaction by treatment with alkenyl pinacol borates
3a or 3b to yield 1-alkenylcarbazoles 25a and (+)-25b,
respectively, The treatment of either 25a or (+)-25b with
TBAF gave the desired 3,8-dihydroxycarbazoles 27a and
(+)-27b, which were then reduced with NaBH4 to provide
carbazomadurin A (1a; 3.5% overall yields in 18 steps from
7b) and (S)-(+)-carbazomadurin B (1b; 3.3% overall yields
in same number of steps from 7b), respectively. The physical
and spectroscopic data of synthetic carbazomadurin A (1a)
and (S)-(+)-carbazomadurin B (1b) were consistent with
natural and synthetic carbazomadurins A (1a) and B (1b)
in all respects.[3–5]
Ethyl 4-Formyl-7-isopropoxyindole-2-carboxylate (8b): The same
procedure as above was carried out using ethyl 7-isopropoxyindole-
2-carboxylate (7b[14]
, 240 mg, 1.03 mmol), α,α-dichloromethyl
methyl ether (0.28 mL, 3.11 mmol), and TiCl4 (0.34 mL,
3.11 mmol) in dry CH2Cl2 (30 mL) to give 4-formylindole 8b
(230 mg, 86%) as a pale yellow solid; m.p. 134–137 °C (EtOAc).
1
IR (ATR): ν = 1706, 1654 cm–1. H NMR (300 MHz, CDCl ): δ =
˜
3
1.42 (t, J = 7.2 Hz, 3 H), 1.47 (d, J = 6.1 Hz, 6 H), 4.42 (q, J =
7.2 Hz, 2 H), 4.81–4.93 (m, 1 H), 6.80 (d, J = 8.1 Hz, 1 H), 7.60
(d, J = 8.1 Hz, 1 H), 7.92 (d, J = 2.4 Hz, 1 H), 9.31 (br. s, 1 H),
10.04 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4, 22.0
(2ϫ), 61.3, 71.2, 104.7, 109.1, 123.6, 126.0, 128.6, 129.4, 132.2,
150.0, 161.8, 191.1 ppm. MS (EI): m/z = 275 [M]+. HRMS (EI):
calcd. for C15H17NO4 275.1158; found 275.1159.
Ethyl 4-Hydroxymethyl-7-methoxyindole-2-carboxylate (9a): To a
solution of 4-formylindole 8a (100 mg, 0.40 mmol) in EtOH (4 mL)
was added NaBH4 (18.3 mg, 0.48 mmol) at 0 °C. The mixture was
stirred at room temperature for 3 h and then was concentrated un-
der reduced pressure. Water was added to the residue, and then the
mixture was extracted with EtOAc. The EtOAc phase was washed
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Total Synthesis of Carbazomadurins A and B
with water and brine, dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 10 g; EtOAc/hexane, 1:4 v/v) to give the 4-
hydroxymethylindole 9a (101 mg, 99%) as a white solid; m.p. 106–
filtrate was extracted with EtOAc. The EtOAc phase was washed
with water and brine, dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 30 g; EtOAc/hexane, 1:1 v/v) to give the oily
107 °C (EtOAc/hexane). IR (ATR): ν = 3320, 1700 cm–1. 1H NMR alcohol 11a (417 mg, 99%). IR (ATR): ν = 3290 cm–1. 1H NMR
˜
˜
(300 MHz, CDCl3): δ = 1.42 (t, J = 7.2 Hz, 3 H), 3.98 (s, 3 H), (CDCl3): δ = 3.44 (s, 3 H), 3.95 (s, 3 H), 4.71 (s, 2 H), 4.80 (br. s,
4.41 (q, J = 7.2 Hz, 2 H), 4.92 (s, 1 H), 6.68 (d, J = 7.7 Hz, 1 H), 2 H), 4.81 (br. s, 2 H), 6.50 (d, J = 2.2 Hz, 1 H), 6.59 (d, J = 7.7 Hz,
7.04 (d, J = 7.7 Hz, 1 H), 7.35 (d, J = 2.2 Hz, 1 H), 9.13 (br. s, 1 1 H), 7.00 (d, J = 7.7 Hz, 1 H), 8.69 (br. s, 1 H) ppm. 13C NMR
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4, 55.5, 61.1, 63.7,
(75 MHz, CDCl3): δ = 55.3, 55.4, 58.7, 67.5, 95.2, 99.4, 101.6,
120.8, 121.8, 126.8, 128.5, 137.4, 146.0 ppm. MS (EI): m/z = 251
103.7, 107.2, 120.1, 126.7, 127.2, 127.3, 128.1, 146.4, 161.8 ppm.
MS (EI): m/z = 249 [M]+. HRMS (EI): calcd. for C13H15NO4 [M]+. HRMS (EI): calcd. for C13H17NO4 251.1158; found
249.1001, found 249.1015.
251.1171.
Ethyl 4-Hydroxymethyl-7-isopropoxyindole-2-carboxylate (9b): The
same procedure as above was carried out using 4-formylindole 8b
2-Hydroxymethyl-7-isopropoxy-4-(methoxymethyloxy)methylindole
(11b): The same procedure as above was carried out using MOM
(224 mg, 0.81 mmol) and NaBH4 (37 mg, 0.98 mmol) in EtOH ether 10b (2.2 g, 6.69 mmol) and Red-Al (65% in toluene, 4.99 g,
(8 mL) to give 4-hydroxymethylindole 9b (224 mg, 99%) as a white 16.06 mmol) in dry toluene (50 mL) to give the oily alcohol 11b
solid; m.p. 132–134 °C (EtOAc). IR (ATR): ν = 3460, 1680 cm–1.
(2.2 g, 99 %). IR (ATR): ν = 3200 cm–1 1H NMR (300 MHz,
.
˜
˜
1H NMR (300 MHz, CDCl3): δ = 1.39–1.44 (m, 9 H), 4.40 (q, J = CDCl3): δ = 1.40 (d, J = 5.9 Hz, 6 H), 3.44 (s, 3 H), 4.66–4.81 (m,
7.2 Hz, 2 H), 4.66–4.79 (m, 1 H), 4.90 (s, 2 H), 6.66 (d, J = 7.7 Hz,
1 H), 7.01 (d, J = 7.7 Hz, 1 H), 7.33 (d, J = 2.5 Hz, 1 H), 9.16 (br.
7 H), 6.48 (d, J = 2.6 Hz, 1 H), 6.59 (d, J = 7.7 Hz, 1 H), 6.97 (d,
J = 7.7 Hz, 1 H), 8.72 (br. s, 1 H) ppm. 13C NMR (75 MHz,
s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4, 22.1 (2ϫ), 61.1, CDCl3): δ = 22.2 (2ϫ), 55.3, 58.7, 67.6, 70.2, 95.2, 99.4, 103.8,
63.6, 70.5, 105.7, 107.2, 120.1, 126.4, 127.2, 127.3, 129.1, 144.5,
161.9 ppm. MS (EI): m/z = 277 [M]+. HRMS (EI): calcd. for
C15H19NO4 277.1314; found 277.1284.
120.9, 121.4, 127.8, 128.7, 137.3, 144.1 ppm. MS (EI): m/z = 279
[M]+. HRMS (EI): calcd. for C15H21NO4 279.1471; found
249.1459.
Ethyl 7-Methoxy-4-(methoxymethyloxy)methylindole-2-carboxylate
7-Methoxy-4-(methoxymethyloxy)methylindole-2-carbaldehyde
(12a): A mixture of the alcohol 11a (400 mg, 1.69 mmol) and acti-
vated MnO2 (733 mg, 8.44 mmol) in dry CH2Cl2 (40 mL) was
stirred at room temperature for 12 h. The reaction mixture was
filtered through a pad of Celite, and then the filtrate was concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel, 40 g; EtOAc/hexane, 2:8 v/v) to give
(10a): To
a solution of 4-hydroxymethylindole 9a (94 mg,
0.377 mmol) and MOMCl (0.03 mL, 0.45 mmol) in dry CH2Cl2
(30 mL) was added dropwise iPr2NEt (0.33 mL, 1.89 mmol) with
cooling by an ice-water bath. The mixture was stirred at room tem-
perature for 5 h and then was quenched with aqueous NH4Cl. The
resulting mixture was extracted with CH2Cl2. The CH2Cl2 phase
was washed with water and brine, dried with Na2SO4, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel, 10 g; EtOAc/hexane, 1:4 v/v) to give
MOM ether 10a (127 mg, 97%) as a pale yellow solid; m.p. 82–
aldehyde 12a (344 mg, 87%) as a pale yellow solid; m.p. 94–96 °C
1
(Et O/hexane). IR (ATR): ν = 1660 cm–1. H NMR (CDCl ): δ =
˜
2
3
3.45 (s, 3 H), 3.97 (s, 3 H), 4.72 (s, 2 H), 4.84 (s, 2 H), 6.72 (d, J =
7.7 Hz, 1 H), 7.06 (d, J = 7.7 Hz, 1 H), 7.37 (d, J = 2.2 Hz, 1 H),
9.24 (br. s, 1 H), 9.84 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 55.5, 55.6, 67.2, 95.4, 105.3, 113.4, 121.8, 124.2, 127.7, 129.5,
83 °C (Et O). IR (ATR): ν = 1710 cm–1. 1H NMR (300 MHz,
˜
2
CDCl3): δ = 1.41 (t, J = 7.2 Hz, 3 H), 3.44 (s, 3 H), 3.97 (s, 3 H),
4.40 (q, J = 7.2 Hz, 2 H), 4.72 (s, 2 H), 4.82 (s, 2 H), 6.67 (d, J = 135.6, 146.8, 181.9 ppm. MS (EI): m/z = 249 [M]+. HRMS (EI):
7.7 Hz, 1 H), 7.04 (d, J = 7.7 Hz, 1 H), 7.32 (d, J = 2.2 Hz, 1 H), calcd. for C13H13NO4 249.1001; found 249.1014.
9.13 (br. s, 1 H) ppm. 13C NMR (300 MHz, CDCl3): δ = 14.4, 55.4,
7-Isopropoxy-4-(methoxymethyloxy)methylindole-2-carbaldehyde
55.5, 61.0, 67.3, 95.4, 103.7, 107.5, 121.4, 123.5, 127.3, 127.8, 128.1,
(12b): The same procedure as above was carried out using alcohol
146.5, 161.8 ppm. MS (EI): m/z = 293 [M]+. HRMS (EI): calcd.
11b (2.3 g, 8.23 mmol) and activated MnO2 (3.58 g, 41.13 mmol) in
for C15H19NO5 293.1263; found 293.1277.
dry CH2Cl2 (40 mL) to give aldehyde 12b (1.9 g, 84%) as a pale
1
Ethyl 7-Isopropoxy-4-(methoxymethyloxy)methylindole-2-carboxyl-
ate (10b): The same procedure as above was carried out using 4-
hydroxymethylindole 9b (750 mg, 2.70 mmol), MOMCl (0.25 mL,
yellow solid; m.p. 78–80 °C (Et O). IR (ATR): ν = 1670 cm–1. H
˜
2
NMR (300 MHz, CDCl3): δ = 1.40 (d, J = 6.1 Hz, 6 H), 3.45 (s, 3
H), 4.67–4.75 (m, 3 H), 4.83 (s, 2 H), 6.71 (d, J = 7.7 Hz, 1 H),
3.24 mmol), and iPr2NEt (2.34 mL, 13.52 mmol) in dry CH2Cl2 7.03 (d, J = 7.7 Hz, 1 H), 7.36 (d, J = 2.2 Hz, 1 H), 9.38 (br. s, 1
(30 mL) to give the oily MOM ether 10b (720 mg, 86%). IR (ATR):
H), 9.83 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.1 (2ϫ),
55.5, 67.2, 70.6, 95.4, 107.3, 113.4, 121.9, 123.8, 127.8, 130.5, 135.5,
144.9, 182.0 ppm. MS (EI): m/z = 277 [M]+. HRMS (EI): calcd for
C15H19NO4 277.1314; found 277.1291.
1
ν = 1700 cm–1. H NMR (300 MHz, CDCl ): δ = 1.39–1.44 (m, 9
˜
3
H), 3.45 (s, 3 H), 4.41 (q, J = 7.0 Hz, 2 H), 4.66–4.76 (m, 3 H),
4.82 (s, 2 H), 6.66 (d, J = 7.9 Hz, 1 H), 7.01 (d, J = 7.9 Hz, 1 H),
7.31 (d, J = 2.2 Hz, 1 H), 9.15 (br. s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.4, 22.1 (2ϫ), 55.4, 61.0, 67.3, 70.4, 95.4, 105.7,
107.4, 121.5, 123.1, 127.1, 128.0, 129.1, 144.6, 161.9 ppm. MS (EI):
m/z = 321 [M]+. HRMS (EI): calcd. for C17H23NO5 321.1576;
found 321.1570.
3-Iodo-7-methoxy-4-(methoxymethyloxy)methylindole-2-carbal-
dehyde (6a): To a mixture of aldehyde 12a (300 mg, 1.20 mmol) and
KOH powder (81 mg, 1.44 mmol) in DMF (10 mL) was added a
solution of I2 (229 mg, 1.81 mmol) in DMF (10 mL) with cooling
by an ice-water bath. The mixture was stirred at room temperature
2-Hydroxymethyl-7-methoxy-4-(methoxymethyloxy)methylindole for 12 h and then was poured into a solution of NaHSO3 (140 mg,
(11a): To a solution of MOM ether 10a (500 mg, 1.70 mmol) in dry 1.33 mmol), 28% NH3 (10 mL), and water (10 mL). The mixture
toluene (10 mL) was added dropwise Red-Al (65 % in toluene,
1.27 g, 4.09 mmol) with cooling by an ice-water bath. The mixture
was stirred at room temperature for 2 h and then was poured into
ice water. The mixture was filtered through a pad of Celite. The
was extracted with EtOAc. The EtOAc phase was washed with
water and brine, dried with Na2SO4, and concentrated under re-
duced pressure. The residue was purified by column chromatog-
raphy (silica gel, 10 g; EtOAc/hexane, 1:5 v/v) to give 3-iodoindole
Eur. J. Org. Chem. 2013, 7391–7401
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7395

Y. Hieda, T. Choshi, H. Fujioka, S. Hibino
FULL PAPER
6a (362 mg, 91%) as a pale yellow solid; m.p. 112–113 °C (EtOAc/
3-Ethoxyvinyl-2-(1-hydroxyprop-2-yn-1-yl)-7-methoxy-4-(methoxy-
hexane). IR (ATR): ν = 1660 cm–1. 1H NMR (CDCl ): δ = 3.45 (s, methyloxy)methylindole (14a): To a solution of 3-alkenylindole 13a
˜
3
3 H), 3.96 (s, 3 H), 4.81 (s, 2 H), 5.11 (s, 2 H), 6.72 (d, J = 7.9 Hz,
1 H), 7.13 (d, J = 7.9 Hz, 1 H), 9.48 (br. s, 1 H), 9.85 (s, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 55.7, 55.7, 65.1, 67.6, 95.5, 105.4,
124.2, 124.4, 127.5, 129.6, 133.4, 146.9, 183.5 ppm. MS (EI): m/z
= 375 [M]+. HRMS (EI): calcd. for C13H14NO4I 374.9968; found
374.9951.
(4.7 g, 14.6 mmol) in dry THF (30 mL) was gradually added ethyn-
ylmagnesium bromide (0.5 m in THF, 87.6 mL, 43.8 mmol) at 0 °C.
After stirring the reaction at 0 °C for 1 h, the mixture was quenched
with aqueous NH4Cl solution. The resulting mixture was extracted
with EtOAc. The EtOAc phase was washed with brine, dried with
Na2SO4, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, 20 g; EtOAc/hex-
3-Iodo-7-isopropoxy-4-(methoxymethyloxy)methylindole-2-carbal-
dehyde (6b): The same procedure as above was carried out using
aldehyde 12b (2.5 g, 8.83 mmol), KOH powder (594 mg,
10.60 mmol), and I2 (3.36 g, 13.25 mmol) to give 3-iodoindole 6b
(3.3 g, 94%) as a pale yellow solid; m.p. 88–89 °C (EtOAc). IR
ane, 3:17 v/v) to give the oily 2-propargyl alcohol 14a (4.9 g, 97%).
1
IR (ATR): ν = 3280 cm–1. H NMR (300 MHz, CDCl ): δ = 1.28
˜
3
(t, J = 7.0 Hz, 9/4 H), 1.36 (t, J = 7.0 Hz, 3/4 H), 2.65–2.67 (m, 1
H), 3.43 (s, 3 H), 3.85–4.01 (m, 5 H), 4.66–4.99 (m, 4 H), 5.69–5.73
(m, 1 H), 5.81 (d, J = 7.0 Hz, 3/4 H), 6.17 (d, J = 12.8 Hz, 1/4 H),
6.26 (d, J = 7.0 Hz, 3/4 H), 6.57–6.65 (m, 5/4 H), 6.97–7.05 (m, 1
H), 8.84 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.8,
14.9, 55.3, 55.3, 57.3, 65.1, 66.9, 67.0, 68.6, 74.4, 74.5, 81.3, 82.4,
94.5, 94.8, 97.5, 99.0, 101.9, 101.9, 108.3, 110.9, 122.3, 122.4, 122.6,
122.7, 126.3, 126.5, 126.9, 127.2, 133.4, 145.1, 146.2, 146.3 ppm.
MS (EI): m/z = 345 [M]+. HRMS (EI): calcd. for C19H23NO5
345.1576; found 345.1588.
1
(ATR): ν = 1670 cm–1. H NMR (300 MHz, CDCl ): δ = 1.40 (d,
˜
3
J = 6.2 Hz, 6 H), 3.46 (s, 3 H), 4.66–4.78 (m, 1 H), 4.81 (s, 2 H),
5.10 (s, 2 H), 6.71 (d, J = 7.7 Hz, 1 H), 7.10 (d, J = 7.7 Hz, 1 H),
9.47 (br. s, 1 H), 9.85 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 22.0 (2ϫ), 55.6, 65.1, 67.7, 70.8, 95.5, 107.3, 123.9, 124.3, 127.6,
130.5, 133.3, 145.0, 183.6 ppm. MS (EI): m/z = 403 [M]+. HRMS
(EI): calcd. for C15H18NO4I 403.0281; found 403.0266.
3-Ethoxyvinyl-7-methoxy-4-(methoxymethyloxy)methylindole-2-
carbaldehyde (13a): A solution of tributyl(2-ethoxyvinyl)stannane
(458 mg, 1.27 mmol) in dry DMF (20 mL) was added to a stirred
suspension of 3-iodoindole 6a (350 mg, 1.06 mmol), Et4NCl
(200 mg, 1.27 mmol), and PdCl2(PPh3)2 (6 mg, 0.0093 mmol) in dry
DMF (10 mL) at the room temperature, and then the mixture was
heated at 80 °C for 2 h. After cooling the reaction to an ambient
temperature, the mixture was quenched with aqueous 30% KF. The
mixture was stirred at the same temperature for 30 min and then
was filtered through a pad of Celite. The filtrate was extracted with
EtOAc. The EtOAc phase was washed with water and brine, dried
with Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by column chromatography (silica gel, 5 g; EtOAc/
3-Ethoxyvinyl-2-(1-hydroxyprop-2-yn-1-yl)-7-isopropoxy-4-(meth-
oxymethyloxy)methylindole (14b): The same procedure as above
was carried out using 3-alkenylindole 13b (1.1 g, 3.17 mmol) and
ethynylmagnesium bromide (0.5 m in THF, 18.9 mL, 9.49 mmol),
which was added at –30 °C. The reaction mixture was then stirred
at 0 °C for 1 h to give the oily 2-propargyl alcohol 14b (960 mg,
1
81%). IR (ATR): ν = 3280 cm–1. H NMR (300 MHz, CDCl ): δ
˜
3
= 1.28 (t, J = 7.0 Hz, 9/4 H), 1.36–1.42 (m, 27/4 H), 2.67 (d, J =
2.2 Hz, 3/4 H), 2.69 (d, J = 2.2 Hz, 1/4 H), 3.42 (s, 3 H), 3.84–3.97
(m, 2 H), 4.65–4.78 (m, 5 H), 5.72 (t, J = 2.6 Hz, 1 H), 5.81 (d, J
= 7.0 Hz, 3/4 H), 6.16 (d, J = 12.8 Hz, 1/4 H), 6.26 (d, J = 7.0 Hz,
3/4 H), 6.57–6.63 (m, 5/4 H), 6.95 (d, J = 7.0 Hz, 1 H), 8.71 (br. s,
1/4 H), 8.75 (br. s, 3/4 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.8, 14.9, 22.1 (2ϫ), 22.2 (2ϫ), 55.2, 55.4, 57.2, 66.9, 68.7, 70.2,
70.3, 74.4, 74.5, 81.2, 82.4, 94.6, 94.9, 97.5, 99.1, 104.0, 105.5,
108.3, 110.8, 121.9, 122.7, 126.9, 127.3, 127.4, 133.1, 144.3, 144.4,
144.9, 145.0 ppm. MS (EI): m/z = 373 [M]+. HRMS (EI): calcd.
for C21H27NO5 373.1889; found 373.1873.
hexane, 2:8 v/v) to give the oily 3-alkenylindole 13a (310 mg, 77%).
1
IR (ATR): ν = 1650 cm–1. H NMR (300 MHz, CDCl ): δ = 1.26
˜
3
(t, J = 7.0 Hz, 9/4 H), 1.39 (t, J = 7.0 Hz, 3/4 H), 3.43 (s, 3 H),
3.88–4.04 (m, 5 H), 4.70 (s, 6/4 H), 4.71 (s, 2/4 H), 4.87 (s, 2/4 H),
4.87 (s, 6/4 H), 5.89 (d, J = 7.0 Hz, 3/4 H), 6.36 (d, J = 12.5 Hz, 1/
4 H), 6.42 (d, J = 7.0 Hz, 3/4 H), 6.62–6.71 (m, 5/4 H), 6.98–7.03
(m, 1 H), 9.04 (br. s, 1 H), 9.81 (s, 1/4 H), 10.0 (s, 3/4 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.7, 15.1, 55.4, 65.8, 66.7, 66.7, 68.5,
94.6, 94.8, 96.3, 96.5, 104.5, 105.1, 121.2, 123.0, 123.0, 124.3, 124.6,
125.3, 126.1, 126.5, 129.1, 129.2, 130.9, 131.9, 146.6, 146.7, 147.2,
151.6, 181.7, 183.8 ppm. MS (EI): m/z = 319 [M]+. HRMS (EI):
calcd. for C17H21NO5 319.1420; found 319.1402.
3-Ethoxyvinyl-7-methoxy-2-{[1-(methoxymethyloxy)prop-2-yn-1-
yl]}-4-(methoxymethyloxy)methylindole (15a): To a mixture of pro-
pargyl alcohol 14a (546 mg, 1.56 mmol) and iPr2NEt (1.35 mL,
7.82 mmol) in dry CH2Cl2 (30 mL) was added chloromethyl methyl
ether (0.35 mL, 4.69 mmol) with cooling by an ice-water bath, and
then the mixture was heated at 50 °C for 12 h. After cooling the
reaction to an ambient temperature, the mixture was quenched with
aqueous NH4Cl. The resulting mixture was extracted with CH2Cl2.
The CH2Cl2 phase was washed with water and brine, dried with
3-Ethoxyvinyl-7-isopropoxy-4-(methoxymethyloxy)methylindole-2-
carbaldehyde (13b): The same procedure as above was carried out
using 3-iodoindole 6b (606 mg, 1.50 mmol), Et4NCl (373 mg,
2.25 mmol), and PdCl2(PPh3)2 (10 mg, 0.015 mmol) in dry DMF Na2SO4, and concentrated under reduced pressure. The residue was
(10 mL) along with tributyl(2-ethoxyvinyl)stannane (814 mg, purified by column chromatography (silica gel, 10 g; EtOAc/hex-
2.25 mmol) in dry DMF (20 mL) to give the oily 3-alkenylindole
ane, 3:17 v/v) to give the oily propargyl ether 15a (492 mg, 80%).
1
13b (451 mg, 86%). IR (ATR): ν = 1650 cm–1. 1H NMR (300 MHz,
IR (ATR): ν = 3274 cm–1. H NMR (300 MHz, CDCl ): δ = 1.30
˜
˜
3
CDCl3): δ = 1.25 (t, J = 7.0 Hz, 9/4 H), 1.36–1.42 (m, 27/4 H), 3.43 (t, J = 7.0 Hz, 9/4 H), 1.37 (t, J = 7.0 Hz, 3/4 H), 2.56 (d, J =
(s, 3 H), 3.91 (q, J = 7.0 Hz, 6/4 H), 4.01 (q, J = 7.0 Hz, 2/4 H),
4.65–4.73 (m, 3 H), 4.87 (s, 2 H), 5.89 (d, J = 7.2 Hz, 3/4 H), 6.36
(d, J = 12.5 Hz, 1/4 H), 6.41 (d, J = 7.2 Hz, 3/4 H), 6.62–6.70 (m,
5/4 H), 6.96–7.01 (m, 1 H), 9.09 (br. s, 1 H), 9.81 (s, 1/4 H), 10.04
(s, 3/4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.7, 15.0, 21.9
(2ϫ), 55.4, 65.8, 66.7, 66.7, 68.5, 70.3, 70.3, 94.6, 94.8, 96.4, 96.6,
106.5, 107.0, 121.3, 123.1, 123.1, 123.9, 124.1, 125.4, 126.3, 126.6,
2.2 Hz, 3/4 H), 2.63–2.66 (m, 1/4 H), 3.40 (s, 3 H), 3.43 (s, 3 H),
3.88–3.98 (m, 5 H), 4.63–5.03 (m, 6 H), 5.73 (d, J = 7.0 Hz, 3/4
H), 5.85 (d, J = 2.2 Hz, 3/4 H), 6.13 (d, J = 12.7 Hz, 1/4 H), 6.23
(d, J = 7.0 Hz, 3/4 H), 6.55–6.61 (m, 5/4 H), 6.95–7.02 (m, 1 H),
8.65 (br. s, 1/4 H), 8.69 (br. s, 3/4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.8, 15.2, 55.4, 55.8, 56.0, 56.4, 59.6, 60.3, 65.1, 66.9,
67.0, 68.3, 74.1, 75.4, 80.3, 80.7, 93.6, 93.6, 94.7, 95.0, 97.2, 97.7,
130.1, 130.2, 130.8, 131.8, 144.7, 144.8, 147.2, 151.5, 181.7, 101.7, 102.0, 109.6, 111.8, 122.3, 122.6, 122.8, 126.6, 126.8, 127.1,
183.9 ppm. MS (EI): m/z = 347 [M]+. HRMS (EI): calcd. for
129.8, 130.6, 145.1, 146.2, 149.3 ppm. MS (EI): m/z = 389 [M]+.
C19H25NO5 347.1733; found 347.1756.
HRMS (EI): calcd. for C21H27NO6 389.1838; found 389.1841.
7396
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7391–7401

Total Synthesis of Carbazomadurins A and B
3-Ethoxyvinyl-7-isopropoxy-2-{[1-(methoxymethyloxy)prop-2-yn-1-
yl]}-4-(methoxymethyloxy)methylindole (15b): The same procedure
as above was carried out using propargyl alcohol 14b (2.6 g,
6.88 mmol), iPr2NEt (5.96 mL, 34.41 mmol), and MOMCl
NMR (300 MHz, CDCl3): δ = 1.50 (t, J = 7.0 Hz, 3 H), 2.35 (s, 3
H), 3.76 (s, 3 H), 4.11 (s, 3 H), 4.25 (q, J = 7.0 Hz, 2 H), 5.23 (s,
2 H), 6.96 (d, J = 8.0 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 8.49 (s,
1 H), 9.55 (br. s, 1 H), 10.20 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 9.9, 15.0, 55.9, 57.1, 64.5, 98.7, 103.5, 104.1, 119.1,
121.9, 122.4, 125.7, 127.8, 130.1, 131.0, 141.7, 150.8, 151.7,
192.0 ppm. MS (EI): m/z = 343 [M]+. HRMS (EI): calcd. for
C19H21NO5 343.1420; found 343.1419.
(1.57 mL, 20.64 mmol) to give the oily propargyl ether 15b (2.4 g,
1
81%). IR (ATR): ν = 3280 cm–1. H NMR (300 MHz, CDCl ): δ
˜
3
= 1.31 (t, J = 7.0 Hz, 9/4 H), 1.38–1.46 (m, 27/4 H), 2.59 (d, J =
2.2 Hz, 3/4 H), 2.66 (d, J = 2.2 Hz, 1/4 H), 3.41–3.43 (m, 6 H),
3.88–3.98 (m, 2 H), 4.65–4.97 (m, 7 H), 5.72–5.75 (m, 1 H), 5.86
(d, J = 2.2 Hz, 3/4 H), 6.14 (d, J = 12.8 Hz, 1/4 H), 6.23 (d, J =
7.0 Hz, 3/4 H), 6.55–6.61 (m, 5/4 H), 6.94–7.00 (m, 1 H), 8.63 (s,
1/4 H), 8.67 (s, 3/4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.8,
15.2, 22.1 (2ϫ), 22.1 (2ϫ), 55.3, 55.7, 56.0, 59.6, 60.3, 65.0, 66.9,
67.0, 68.2, 70.0, 70.1, 74.1, 75.3, 80.4, 80.7, 93.6, 93.6, 94.7, 95.0,
97.3, 97.8, 103.8, 104.0, 109.5, 111.7, 122.1, 122.3, 122.3, 126.9,
127.2, 127.5, 127.8, 129.7, 130.5, 144.2, 144.3, 145.0 ppm. MS (EI):
m/z = 417 [M]+. HRMS (EI): calcd. for C23H31NO6 417.2151;
found 417.2140.
3-Ethoxy-8-isopropoxy-1-methoxymethyloxy-2-methylcarbazole-5-
carbaldehyde (17b): The same procedure as above was carried out
using carbazole 16b (2.3 g, 5.51 mmol) and DDQ (1.5 g,
6.61 mmol) to give carbazole-5-carbaldehyde 17b (1.5 g, 73%) as a
pale yellow solid; m.p. 130–131 °C (EtOAc). IR (ATR): ν =
˜
1
1670 cm–1. H NMR (300 MHz, CDCl3): δ = 1.48–1.53 (m, 9 H),
2.35 (s, 3 H), 3.75 (s, 3 H), 4.25 (q, J = 7.0 Hz, 2 H), 4.82–4.94 (m,
1 H), 5.22 (s, 2 H), 6.93 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 8.3 Hz,
1 H), 8.48 (s, 1 H), 9.55 (br. s, 1 H), 10.18 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 9.9, 15.1, 22.2 (2ϫ), 57.0, 64.5, 71.2, 98.9,
103.6, 105.9, 119.2, 121.9, 122.5, 125.3, 128.0, 131.0, 141.7, 149.3,
151.6, 191.9 ppm. MS (EI): m/z = 371 [M]+. HRMS (EI): calcd.
for C21H25NO5 371.1733; found 371.1720.
3-Ethoxy-8-methoxy-1-methoxymethyloxy-5-(methoxymethyloxy)-
methyl-2-methylcarbazole (16a): To a solution of propargyl ether
15a (120 mg, 0.31 mmol) in dry THF (1 mL) was added TBAF (1 m
in THF, 0.92 mL, 0.924 mmol) at room temperature, and then the
mixture was heated at 80 °C for 6 h. After cooling the reaction to
an ambient temperature, the mixture was quenched with water. The
resulting mixture was extracted with EtOAc. The EtOAc phase was
washed with water and brine, dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, 30 g; EtOAc/hexane, 1:9 v/v) to give
carbazole 16a (40 mg, 40 %) as a yellow solid; m.p. 105–106 °C
(EtOAc/hexane). 1H NMR (300 MHz, CDCl3): δ = 1.48 (t, J =
7.0 Hz, 3 H), 2.33 (s, 3 H), 3.44 (s, 3 H), 3.75 (s, 3 H), 4.01 (s, 3
H), 4.15 (q, J = 7.0 Hz, 2 H), 4.76 (s, 2 H), 5.08 (s, 2 H), 5.23 (s,
2 H), 6.79 (d, J = 7.9 Hz, 1 H), 7.06 (d, J = 7.9 Hz, 1 H), 7.50 (s,
1 H), 9.25 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 9.8,
15.1, 55.5, 55.6, 57.1, 64.9, 67.9, 95.1, 98.6, 101.4, 104.5, 117.5,
120.6, 122.0, 123.1, 123.7, 127.1, 130.2, 142.0, 146.0, 151.9 ppm.
MS (EI): m/z = 389 [M]+. HRMS (EI): calcd. for C21H27NO6
389.1838; found 389.1827.
3-Ethoxy-1-hydroxy-8-methoxy-2-methylcarbazole-5-carbaldehyde
(18a): To a mixture of 5-formylcarbazole 17a (940 mg, 2.74 mmol)
and ethylene glycol (2 mL) in THF (20 mL) was added HCl (4 m
solution, 2 mL) at room temperature. After stirring the reaction at
50 °C for 30 min, the mixture was cooled to an ambient tempera-
ture and then extracted with EtOAc. The EtOAc phase was washed
with water and brine, dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 10 g; EtOAc/hexane, 4:6 v/v) to give 1-hydroxycar-
bazole 18a (730 mg, 89%) as a pale yellow solid; m.p. 234–236 °C
(EtOAc/hexane). IR (ATR): ν = 3367, 1646 cm–1 1H NMR
.
˜
(300 MHz, [D6]DMSO): δ = 1.42 (t, J = 7.0 Hz, 3 H), 2.19 (s, 3
H), 4.06–4.11 (m, 5 H), 7.17 (d, J = 8.1 Hz, 1 H), 7.78 (d, J =
8.1 Hz, 1 H), 8.12 (s, 1 H), 8.99 (s, 1 H), 10.13 (s, 1 H), 10.85 (br.
s, 1 H) ppm. 13C NMR (300 MHz, [D6]DMSO): δ = 9.2, 14.9, 55.9,
63.6, 98.4, 104.6, 111.6, 120.2, 121.1, 125.0, 125.3, 129.3, 131.0,
140.0, 150.7, 151.1, 192.0 ppm. MS (EI): m/z = 299 [M]+. HRMS
(EI): calcd. for C17H17NO4 299.1158; found 299.1153.
3-Ethoxy-8-isopropoxy-1-methoxymethyloxy-5-(methoxymethyloxy)-
methyl-2-methylcarbazole (16b): The same procedure as above was
carried out using propargyl ether 15b (2.4 g, 5.63 mmol) and TBAF
(1 m in THF, 16.9 mL, 16.9 mmol) to give carbazole 16b (930 mg,
40 %) as a pale yellow solid; m.p. 69–71 °C (Et2O). 1H NMR
(300 MHz, CDCl3): δ = 1.44 (d, J = 6.1 Hz, 6 H), 1.49 (t, J =
7.0 Hz, 3 H), 2.34 (s, 3 H), 3.46 (s, 3 H), 3.75 (s, 3 H), 4.15 (q, J =
7.0 Hz, 2 H), 4.67–4.75 (m, 1 H), 4.78 (s, 2 H), 5.08 (s, 2 H), 5.23
(s, 2 H), 6.82 (d, J = 7.9 Hz, 1 H), 7.04 (d, J = 7.9 Hz, 1 H), 7.49
(s, 1 H), 9.28 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
9.8, 15.1, 22.3 (2ϫ), 55.6, 57.0, 64.9, 67.9, 71.2, 95.1, 98.7, 101.5,
108.0, 117.5, 120.6, 122.0, 123.3, 123.7, 127.2, 131.6, 141.9, 144.1,
151.8 ppm. MS (EI): m/z = 417 [M]+. HRMS (EI): calcd. for
C23H31NO6 417.2151; found 417.2151.
3-Ethoxy-1-hydroxy-8-isopropoxy-2-methylcarbazole-5-carbal-
dehyde (18b): The same procedure as above was carried out using
5-formylcarbazole 17b (411 mg, 1.11 mmol) and HCl (4 m solution,
2 mL) to give 1-hydroxycarbazole 18b (329 mg, 91%) as a pale yel-
low solid; m.p. 207–209 °C (EtOAc). IR (ATR): ν = 3320,
˜
1
1650 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 1.38–1.46 (m, 9
H), 2.18 (s, 3 H), 4.08 (q, J = 7.0 Hz, 2 H), 4.97–5.05 (m, 1 H),
7.16 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 8.12 (br. s, 1
H), 9.08 (br. s, 1 H), 10.10 (s, 1 H), 10.65 (s, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 9.6, 15.3, 22.2, 31.0, 64.1, 71.2, 99.0,
106.5, 112.1, 120.7, 121.6, 124.9, 125.4, 130.3, 131.8, 140.2, 149.4,
151.5, 192.5 ppm. MS (EI): m/z = 327 [M]+. HRMS (EI): calcd.
for C19H21NO4 327.1471; found 327.1484.
3-Ethoxy-8-methoxy-1-methoxymethyloxy-2-methylcarbazole-5-
carbaldehyde (17a): To a solution of carbazole 16a (1.2 g,
3.08 mmol) in CH2Cl2 (30 mL) was added DDQ (839 mg,
3.70 mmol) at room temperature, and the resulting mixture was
stirred at that temperature for 20 min. The reaction mixture was
filtered through a pad of Celite. The filtrate was concentrated under
reduced pressure, and the resulting residue was purified by column
chromatography (silica gel, 40 g; EtOAc/hexane, 2:8 v/v) to give
carbazole-5-carbaldehyde 17a (1.0 g, 95%) as a pale yellow solid;
3-Ethoxy-8-methoxy-2-methyl-1-(trifluoromethylsulfonyloxy)carb-
azole-5-carbaldehyde (19a): To a stirred mixture of NaH (60 %,
240 mg, 6.01 mmol) in THF (20 mL) was added 1-hydroxycarb-
azole 18a (720 mg, 2.41 mmol) in THF (5 mL) with cooling by an
ice-water bath. After stirring the resulting mixture at 0 °C for
10 min, Tf2NPh (992 mg, 2.65 mmol) was added to the reaction
mixture at the same temperature. The stirring was continued at the
same temperature for an additional 30 min, and then the mixture
was quenched with aqueous NH4Cl. The resulting soluton was ex-
m.p. 102–103 °C (EtOAc/hexane). IR (ATR): ν = 1650 cm–1. 1H tracted with EtOAc. The EtOAc phase was washed with water and
˜
Eur. J. Org. Chem. 2013, 7391–7401
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7397

Y. Hieda, T. Choshi, H. Fujioka, S. Hibino
FULL PAPER
brine, dried with Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by column chromatography (silica
gel, 10 g; EtOAc/hexane, 1:9 v/v) to give triflate 19a (800 mg, 77%)
dihydroxycarbazole 20b (115 mg, 0.30 mmol) in CH2Cl2 (10 mL)
was added SEMCl (157 μL, 0.89 mmol) and iPr2NEt (256 μL,
1.48 mmol) with cooling by an ice-water bath. After stirring at
room temperature for 12 h, the reaction mixture was quenched with
aqueous NH4Cl. The resulting mixture was extracted with CH2Cl2.
as a pale yellow solid; m.p. 165–167 °C (EtOAc/hexane). IR (ATR):
1
ν = 1680, 1400, 1210 cm–1. H NMR (300 MHz, CDCl ): δ = 1.52
˜
3
(t, J = 7.0 Hz, 3 H), 2.42 (s, 3 H), 4.13 (s, 3 H), 4.29 (q, J = 7.0 Hz, The organic layer was washed with water and brine, dried with
2 H), 7.02 (d, J = 8.3 Hz, 1 H), 7.73 (d, J = 8.3 Hz, 1 H), 8.59 (br. Na2SO4, and concentrated under reduced pressure. The residue was
s, 1 H), 8.82 (s, 1 H), 10.14 (s, 1 H) ppm. 13C NMR (75 MHz, purified by column chromatography (silica gel, 10 g; EtOAc/hex-
CDCl3): δ = 10.3, 14.9, 56.0, 64.9, 105.1, 108.1, 116.6, 121.4, 121.6,
ane, 1:19 v/v) to give the oily SEM ether 21 (187 mg, 97%). IR
123.4, 125.7, 127.0, 130.6, 131.4, 132.5, 150.9, 151.6, 191.9 ppm.
(ATR): ν = 1690, 1400, 1210, 1040 cm–1 1H NMR (300 MHz,
.
˜
MS (EI): m/z = 431 [M]+. HRMS (EI): calcd. for C18H16F3NO6S CDCl3): δ = 0.01 (s, 9 H), 0.01 (s, 9 H), 0.99–1.08 (m, 4 H), 2.44
431.0650; found 431.0658.
(s, 3 H), 3.88 (t, J = 8.3 Hz, 4 H), 5.43 (s, 2 H), 5.51 (s, 2 H), 7.29
(d, J = 8.1 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 8.77 (br. s, 1 H),
8.98 (s, 1 H), 10.18 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= –1.5 (3ϫ), –1.4 (3ϫ), 10.6, 18.1, 18.1, 66.7, 67.4, 93.6, 94.4, 109.3,
111.8, 116.5, 120.8, 122.2, 123.5, 126.3, 128.0, 131.0, 131.2, 131.6,
148.5, 149.6, 191.7 ppm. MS (EI): m/z = 649 [M]+. HRMS (EI):
calcd. for C27H38NO8SSi2 649.1809; found 649.1779.
3-Ethoxy-8-isopropoxy-2-methyl-1-(trifluoromethylsulfonyloxy)carb-
azole-5-carbaldehyde (19b): The same procedure as above was car-
ried out using NaH (60%, 37 mg, 0.92 mmol), 1-hydroxycarbazole
18b (200 mg, 0.68 mmol) in THF (5 mL), and Tf2NPh (254 mg,
0.68 mmol) to give triflate 19b (310 mg, 99%) as a pale yellow solid;
m.p. 131–133 °C (EtOAc). IR (ATR): ν = 1680, 1400, 1210 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 1.50–1.54 (m, 9 H), 2.42 (s, 3
H), 4.28 (q, J = 7.0 Hz, 2 H), 4.87–4.95 (m, 1 H), 7.01 (d, J =
8.3 Hz, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 8.59 (br. s, 1 H), 8.82 (s, 1
H), 10.12 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 10.4,
14.9, 22.1 (2ϫ), 64.8, 71.6, 106.6, 108.1, 121.2, 121.8, 123.4, 125.2,
126.9, 131.3, 131.5, 132.5, 149.4, 151.5, 191.9 ppm. MS (EI): m/z =
459 [M]+. HRMS (EI): calcd. for C20H20F3NO6S 459.0963; found
459.0966.
1-Iodo-2,5-dimethylhex-1-ene (23a): To a solution of Cp2ZrCl2
(608 mg, 2.08 mmol) in dry 1,2-dichloroethane (4 mL) was added
Me3Al (15% in hexane, 4.46 mL, 6.24 mmol) at room temperature,
and the resulting mixture was stirred at the same temperature for
20 min. A solution of 5-methyl-1-hexyne (22a, 0.274 mL,
2.08 mmol) in dry 1,2-dichloroethane (2 mL) was added, and the
mixture was stirred at the same temperature for 12 h and then co-
oled to 0 °C. A solution of I2 (633 mg, 2.50 mmol) in dry THF
(4 mL) was added dropwise. After stirring at room temperature for
1 h, the reaction was poured into ice water, and the resulting mix-
ture was filtered through a pad of Celite. The filtrate was extracted
with EtOAc. The organic layer was washed with water and brine,
dried with Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, 20 g;
hexane) to give the oily alkenyl iodide 23a (390 mg, 79 %). 1H
NMR (300 MHz, CDCl3): δ = 0.89 (d, J = 6.6 Hz, 6 H), 1.26–1.35
(m, 3 H), 1.45–1.55 (m, 1 H), 1.83 (d, J = 1.1 Hz, 3 H), 2.20 (dt, J
= 1.1, 7.7 Hz, 2 H), 5.86 (q, J = 1.1 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.4 (2ϫ), 23.9, 27.5, 36.9, 37.5, 74.2,
148.5 ppm. MS (EI): m/z = 238 [M]+. HRMS (EI): calcd. for
C8H15I 238.0218; found 238.0222.
3-Hydroxy-8-methoxy-2-methyl-1-(trifluoromethylsulfonyloxy)carb-
azole-5-carbaldehyde (20a): To a solution of triflate 19a (50 mg,
0.12 mmol) in CH2Cl2 (10 mL) was added BBr3 (57 μL, 0.58 mmol)
at –78 °C. After stirring at room temperature for 3 h, the reaction
mixture was poured into ice water. The mixture was extracted with
EtOAc. The EtOAc phase was washed with water and brine, dried
with Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by column chromatography (silica gel, 10 g;
EtOAc/hexane, 2:8 v/v) to give 3-hydroxycarbazole 20a (28 mg,
60%) as a pale yellow solid; m.p. 280–284 °C (EtOAc/hexane). IR
(ATR): ν = 3200, 1650 cm–1. 1H NMR (300 MHz, CDCl3): δ =
˜
2.29 (s, 3 H), 4.11 (s, 3 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.85 (d, J =
8.3 Hz, 1 H), 8.65 (s, 1 H), 9.78 (s, 1 H), 10.09 (s, 1 H), 11.61 (s, 1
H) ppm. 13C NMR (300 MHz, CDCl3): δ = 11.0, 56.3, 106.2, 110.0,
116.1, 118.9, 120.3, 123.3, 125.2, 126.9, 127.0, 131.0, 132.7, 148.9,
151.3, 192.4 ppm. MS (EI): m/z = 403 [M]+. HRMS (EI): calcd.
for C16H12F3NO6S 403.0337; found 403.0331.
1-Iodo-2,5-dimethylhept-1-ene (23b): The same procedure as above
was carried out using (S)-(+)-5-methyl-1-heptyne (22b,[5,17] 300 mg,
2.72 mmol), Cp2ZrCl2 (796 mg, 2.72 mmol), Me3Al (15% in hex-
ane, 5.8 mL, 8.17 mmol), and I2 (829 mg, 3.27 mmol) to give the
oily alkenyl iodide 23b (400 mg, 58%). [α]2D0 = +13.1 (c = 0.05,
MeOH). 1H NMR (300 MHz, CDCl3): δ = 0.84–0.88 (m, 6 H),
1.07–1.49 (m, 5 H), 1.83 (d, J = 1.1 Hz, 3 H), 2.14–2.23 (m, 2 H),
5.86 (q, J = 1.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
11.3, 19.0, 23.9, 29.3, 33.9, 34.5, 37.2, 74.2, 148.6 ppm. MS (EI):
m/z = 252 [M]+. HRMS (EI): calcd. for C9H17I 252.0375; found
252.0372.
3,8-Dihydroxy-2-methyl-1-(trifluoromethylsulfonyloxy)carbazole-5-
carbaldehyde (20b): To a solution of triflate 19b (64 mg, 0.14 mmol)
in CH2Cl2 (10 mL) was added BBr3 (136 μL, 1.39 mmol) at –78 °C.
After stirring at room temperature for 5 h, the reaction mixture
was poured into ice water. The mixture was extracted with EtOAc.
The EtOAc phase was washed with water and brine, dried with
Na2SO4, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, 10 g; EtOAc/hex-
ane, 4:6 v/v) to give 3-hydroxycarbazole 20b (54 mg, 99%) as a pale
Pinacol (2,5-Dimethylhex-1-en-1-yl)boronate (3a): A solution of
alkenyl iodide 23b (100 mg, 0.42 mmol) in dry DMSO (20 mL) was
added to a stirred suspension of bis(pinacolato)diboron (106 mg,
0.42 mmol), KOAc (124 mg, 1.26 mmol), and PdCl2(dppf) [3 mg,
0.0042 mmol, dppf = 1,1Ј-bis(diphenylphosphanyl)ferrocene] in dry
DMSO (20 mL) at room temperature, and then the mixture was
heated at 80 °C for 1 h. After cooling to an ambient temperature,
the reaction was quenched with aqueous NH4Cl, and the resulting
mixture was stirred at the same temperature for 30 min. After filter-
ing the mixture through a pad of Celite, the filtrate was extracted
with EtOAc. The EtOAc layer was washed with water and brine,
dried with Na2SO4, and concentrated under reduced pressure. The
yellow solid; m.p. 266–268 °C (EtOAc/hexane). IR (ATR): ν =
˜
1
3200, 1650 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 2.28 (s, 3
H), 7.02 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 8.65 (s, 1
H), 10.00 (s, 1 H), 11.35 (s, 1 H), 11.39 (br. s, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 11.1, 110.2, 110.4, 116.3, 119.0, 121.2,
123.6, 124.1, 127.1, 130.9, 132.7, 133.2, 149.0, 150.3, 192.1 ppm.
MS (EI): m/z = 389 [M]+. HRMS (EI): calcd. for C15H10F3NO6S
389.0181; found 389.0179.
2-Methyl-1-trifluoromethylsulfonyloxy-3,8-bis[(2-trimethylsilyl)eth-
oxymethyloxy]carbazole-5-carbaldehyde (21): To a solution of 3,8-
7398
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7391–7401

Total Synthesis of Carbazomadurins A and B
residue was purified by column chromatography (silica gel, 20 g;
EtOAc/hexane, 1:19 v/v) to give the oily pinacol 1-alkenylboronate
3a (48 mg, 48%). 1H NMR (300 MHz, CDCl3): δ = 0.87 (d, J =
as above was carried out using SEM ether 21 (75 mg, 0.12 mmol),
Na2CO3 (3 m solution, 115 μL, 0.35 mmol), Pd(PPh3)4 (1.39 mg,
0.0012 mmol), and pinacol 1-alkenylboronate 3a (72 mg,
6.6 Hz, 6 H), 1.19–1.36 (m, 14 H), 1.49–1.57 (m, 1 H), 1.97 (s, 1 0.35 mmol) to give the oily 3,8-bis(OSEM)-1-alkenylcarbazole 25a
H), 2.09 (t, J = 7.7 Hz, 2 H), 5.11 (s, 1 H) ppm. 13C NMR (61 mg, 86 %). IR (ATR): ν = 1680, 1060 cm–1 1H NMR
(75 MHz, CDCl3): δ = 21.2, 22.6 (2ϫ), 24.9 (4ϫ), 27.7, 36.9, 40.0, (300 MHz, CDCl3): δ = 0.01 (s, 9 H), 0.02 (s, 9 H), 0.88–0.94 (m,
.
˜
82.6 (2ϫ), 163.6 ppm. The carbon signal adjacent to boron was not
observed because of low intensity.[19] MS (EI): m/z = 238 [M]+.
HRMS (EI): calcd. for C14H27BO2 238.2104; found 238.2100.
1 H), 0.99–1.10 (m, 10 H), 1.53 (s, 3 H), 1.64–1.76 (m, 2 H), 2.32
(s, 3 H), 2.36 (t, J = 7.3 Hz, 1 H), 3.88 (q, J = 8.4 Hz, 4 H), 5.42
(s, 2 H), 5.49 (s, 2 H), 6.34 (s, 1 H), 7.19 (d, J = 7.2 Hz, 1 H), 7.66
(d, J = 7.2 Hz, 1 H), 8.33 (br. s, 1 H), 8.70 (s, 1 H), 10.28 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = –1.4 (6ϫ), 13.7, 17.8,
18.1, 18.1, 22.6 (2ϫ), 27.9, 37.2, 37.3, 66.3, 67.1, 93.5, 94.4, 108.2,
109.7, 118.9, 119.8, 121.5, 123.2, 126.3, 127.3, 129.5, 130.3, 134.4,
143.2, 148.0, 149.8, 191.7 ppm. MS (EI): m/z = 611 [M]+. HRMS
(EI): calcd. for C34H53NO5SSi2 611.3462; found 611.3470.
Pinacol (2,5-Dimethylhept-1-en-1-yl)boronate (3b): The same pro-
cedure as above was carried out using alkenyl iodide 23b (200 mg,
0.79 mmol), bis(pinacolato)diboron (201 mg, 0.79 mmol), KOAc
(234 mg, 2.38 mmol), and PdCl2(dppf) (6 mg, 0.0079 mmol) to give
the oily pinacol 1-alkenylboronate 3b (101 mg, 53%). [α]2D0 = +26.5
(c = 0.05, MeOH). 1H NMR (300 MHz, CDCl3): δ = 0.83–0.87 (m,
6 H), 1.05–1.52 (m, 17 H), 1.98 (d, J = 1.1 Hz, 1 H), 2.01–2.12 (m,
2 H), 5.12 (d, J = 1.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 11.3, 19.1, 21.2, 24.9 (4ϫ), 29.37, 34.1, 34.5, 39.7, 82.6 (2ϫ),
163.7 ppm. The carbon signal adjacent to boron was not observed
because of low intensity.[19] MS (EI): m/z = 252 [M]+. HRMS (EI):
calcd. for C15H29BO2 252.2261; found 252.2258.
1-(2,5-Dimethylhept-1-en-1-yl)-2-methyl-3,8-bis[(2-trimethylsilyl)-
ethoxymethyloxy]carbazole-5-carbaldehyde (25b): The same pro-
cedure as above was carried out using SEM ether 21 (75 mg,
0.12 mmol), Na2CO3 (3 m solution, 115 μL, 0.35 mmol),
Pd(PPh3)4 (1 mg, 0.0012 mmol), and pinacol 1-alkenylboronate 3b
(87 mg, 0.346 mmol) to give the oily 3,8-bis(OSEM)-1-alkenylcarb-
azole 25b (60 mg, 83%). [α]2D0 = +7.1 (c = 0.05, MeOH). IR
3-Ethoxy-1-(2,5-dimethylhex-1-en-1-yl)-8-methoxy-2-methylcarb-
azole-5-carbaldehyde (24a): To a stirred mixture of triflate 19a
(100 mg, 0.23 mmol), Na2CO3 (74 mg, 0.70 mmol), and Pd(PPh3)4
(3 mg, 0.0023 mmol) in dry DMF (5 mL) was added a solution
of pinacol 1-alkenylboronate 3a (166 mg, 0.70 mmol) in dry DMF
(15 mL) at room temperature. The mixture was heated at 80 °C for
3 h and then was cooled to an ambient temperature. The mixture
was quenched with aqueous NH4Cl, and the resulting mixture was
stirred at the same temperature for 30 min. After filtration through
a pad of Celite, the filtrate was extracted with EtOAc. The EtOAc
phase was washed with water and brine, dried with Na2SO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, 5 g; EtOAc/hexane, 1:14 v/v) to
(ATR): ν = 1680, 1080 cm–1. 1H NMR (300 MHz, CDCl3): δ =
˜
0.01 (s, 9 H), 0.02 (s, 9 H), 0.83–0.90 (m, 1 H), 0.94–1.09 (m, 10
H), 1.22–1.31 (m, 1 H), 1.41–1.51 (m, 2 H), 1.53 (d, J = 0.7 Hz, 3
H), 1.62–1.71 (m, 1 H), 2.31 (s, 3 H), 2.37 (t, J = 6.6 Hz, 1 H), 3.88
(q, J = 8.4 Hz, 4 H), 5.41 (s, 2 H), 5.49 (s, 2 H), 6.34 (s, 1 H), 7.20
(d, J = 8.1 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 8.29 (br. s, 1 H),
8.68 (s, 1 H), 10.29 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= –1.5 (3ϫ), –1.4 (3ϫ), 11.5, 13.7, 17.8, 18.1, 18.1, 19.2, 29.4, 34.2,
34.9, 36.9, 66.3, 67.1, 93.4, 94.4, 108.1, 109.7, 119.0, 119.9, 121.5,
123.2, 126.3, 127.3, 129.5, 130.3, 134.4, 143.1, 148.0, 149.8,
191.6 ppm. MS (EI): m/z = 625 [M]+. HRMS (EI): calcd. for
C35H55NO5SSi2 625.3619; found 625.3621.
give 1-alkenylcarbazole 24a (88 mg, 96%) as a pale yellow solid;
1
m.p. 130–132 °C (Et O/hexane). IR (ATR): ν = 1660 cm–1. H
1-(2,5-Dimethylhex-1-en-1-yl)-5-hydroxymethyl-2-methyl-3,8-bis[(2-
trimethylsilyl)ethoxymethyloxy]carbazole (26): To a solution of 3,8-
bis(OSEM)-1-alkenylcarbazole 25a (75 mg, 0.12 mmol) in dry tolu-
ene (1 mL) was added DIBAL-H (0.99 m in toluene, 247 μL,
0.25 mmol) with cooling by an ice-water bath. After stirring at
room temperature for 20 min, the reaction mixture was poured into
ice water. The mixture was filtered through a pad of Celite, and
then the filtrate was extracted with EtOAc. The EtOAc phase was
washed with water and brine, dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, 5 g; EtOAc/hexane, 3:7 v/v) to give the
˜
2
NMR (300 MHz, CDCl3): δ = 1.01 (d, J = 6.6 Hz, 6 H), 1.49–1.57
(m, 9 H), 1.64–1.75 (m, 1 H), 2.28 (s, 3 H), 2.35 (t, J = 7.0 Hz, 2
H), 4.11 (s, 3 H), 4.26 (q, J = 7.0 Hz, 2 H), 6.33 (s, 1 H), 6.95 (d,
J = 8.1 Hz, 1 H), 7.68 (d, J = 8.1 Hz, 1 H), 8.11 (br. s, 1 H), 8.58
(s, 1 H), 10.22 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.5,
15.1, 17.8, 22.6 (2ϫ), 27.9, 37.2, 37.4, 55.8, 64.3, 103.9, 106.0,
118.9, 119.8, 121.6, 125.7, 126.5, 129.8, 130.7, 130.7, 133.6, 143.2,
150.4, 151.7, 192.0 ppm. MS (EI): m/z = 393 [M]+. HRMS (EI):
calcd. for C25H31NO3 393.2304; found 393.2302.
3-Ethoxy-8-isopropoxy-1-(2,5-dimethylhex-1-en-1-yl)-2-methylcarb-
azole-5-carbaldehyde (24b): The same procedure as above was car-
ried out using triflate 19b (20 mg, 0.44 mmol), Na2CO3 (14 mg,
0.131 mmol), Pd(PPh3)4 (5 mg, 0.0044 mmol), and pinacol 1-alken-
ylboronate 3a (31 mg, 0.131 mmol) to give 1-alkenylcarbazole 24b
oily 5-hydroxymethylcarbazole 26 (68 mg, 90%). IR (ATR): ν =
˜
1
3460, 1060 cm–1. H NMR (300 MHz, CDCl3): δ = 0.02 (s, 9 H),
0.02 (s, 9 H), 1.00–1.06 (m, 10 H), 1.54 (t, J = 10.0 Hz, 5 H), 1.66–
1.75 (m, 1 H), 2.29 (s, 3 H), 2.34 (t, J = 7.7 Hz, 2 H), 3.86 (t, J =
8.1 Hz, 4 H), 5.18 (s, 2 H), 5.34 (s, 2 H), 5.38 (s, 2 H), 6.33 (s, 1
H), 7.01–7.07 (m, 2 H), 7.82 (s, 1 H), 8.36 (br. s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = –1.4 (3ϫ), –1.4 (3ϫ), 13.5, 17.9, 18.1,
18.2, 22.6, 27.9, 37.3, 37.4, 64.1, 66.1, 66.7, 94.1, 94.6, 107.1, 109.9,
118.7, 119.1, 119.7, 121.9, 123.0, 125.3, 128.6, 130.6, 133.7, 142.9,
143.2, 150.2 ppm. MS (EI): m/z = 613 [M]+. HRMS (EI): calcd.
for C34H53NO5SSi2 613.3619; found 613.3614.
(18 mg, 99%) as a pale yellow solid; m.p. 84–86 °C (EtOAc/hex-
1
ane). IR (ATR): ν = 1670 cm–1. H NMR (300 MHz, CDCl ): δ =
˜
3
1.02 (d, J = 6.6 Hz, 6 H), 1.49–1.55 (m, 9 H), 1.68–1.76 (m, 1 H),
2.29 (s, 3 H), 2.37 (t, J = 7.9 Hz, 1 H), 4.26 (q, J = 7.0 Hz, 2 H),
4.86–4.94 (m, 1 H), 6.35 (s, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 7.64
(d, J = 8.0 Hz, 1 H), 8.06 (br. s, 1 H), 8.58 (s, 1 H), 10.20 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.5, 15.1, 17.7, 22.2
(2ϫ), 22.7 (2ϫ), 27.8, 37.3, 37.4, 64.3, 71.1, 105.5, 106.1, 119.3,
119.9, 121.5, 122.8, 125.2, 126.5, 130.6, 130.7, 133.5, 143.0, 148.9,
151.7, 191.9 ppm. MS (EI): m/z = 421 [M]+. HRMS (EI): calcd.
for C27H35NO3 421.2617; found 421.2600.
3,8-Dihydroxy-2-methyl-1-(2,5-dimethylhex-1-en-1-yl)carbazole-5-
carbaldehyde (27a): To a solution of 3,8-bis(OSEM)-1-alkenyl-
carbazole 25a (83 mg, 0.14 mmol) in dry HMPA (2 mL) was added
TBAF (1 m in THF, 678 μL, 0.68 mmol) at room temperature. The
mixture was heated at 100 °C for 1 h and then was cooled to an
ambient temperature. The mixture was quenched with water, and
1-(2,5-Dimethylhex-1-en-1-yl)-2-methyl-3,8-bis[(2-trimethylsilyl)eth-
oxymethyloxy]carbazole-5-carbaldehyde (25a): The same procedure
Eur. J. Org. Chem. 2013, 7391–7401
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7399

Y. Hieda, T. Choshi, H. Fujioka, S. Hibino
FULL PAPER
the resulting mixture was extracted with EtOAc. The EtOAc phase
was washed with water and brine, dried with Na2SO4, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel, 5 g; EtOAc/hexane, 1:1 v/v) to give 3,8-
dihydroxycarbazole 27a (34 mg, 71%) as a pale yellow solid; m.p.
ture was extracted with EtOAc. The organic layer was washed with
water and brine, dried with Na2SO4, and concentrated under re-
duced pressure. The residue was recrystallized with CHCl3/hexane
to give carbazomadurin B (1b, 55 mg, 78%) as a pale yellow solid,
m.p. 166–167 °C (CHCl3/hexane); ref.[3] m.p. 108–110 °C; ref.[5]
248–250 °C (EtOAc/hexane). IR (ATR): ν = 3430, 1650 cm–1. 1H
m.p. 165 °C. [α]2D0 = +13.1 (c = 0.05, MeOH). IR (ATR): ν = 3480,
˜
˜
NMR (300 MHz, [D6]DMSO): δ = 0.97 (d, J = 6.2 Hz, 6 H), 1.44
(s, 3 H), 1.51 (t, J = 7.7 Hz, 2 H), 1.60–1.69 (m, 1 H), 2.13 (s, 3
H), 2.28–2.33 (m, 2 H), 6.38 (s, 1 H), 6.91 (d, J = 8.1 Hz, 1 H),
7.61 (d, J = 8.1 Hz, 1 H), 8.39 (s, 1 H), 8.99 (s, 1 H), 10.03 (s, 1
3430, 1630, 1580, 1430, 1370 cm–1. 1H NMR (500 MHz,
CD3COCD3): δ = 0.95 (t, J = 7.3 Hz, 3 H), 1.00 (d, J = 6.1 Hz, 3
H), 1.22–1.29 (m, 1 H), 1.44–1.52 (m, 3 H), 1.57 (d, J = 1.2 Hz, 3
H), 1.68–1.74 (m, 1 H), 2.27 (s, 3 H), 2.32–2.43 (m, 2 H), 3.90 (t,
H), 10.27 (s, 1 H), 10.78 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): J = 5.5 Hz, 1 H), 5.02 (d, J = 5.2 Hz, 2 H), 6.44 (s, 1 H), 6.74 (d,
δ = 13.7, 17.8, 22.6, 27.5 (2ϫ), 36.74 (2ϫ), 107.7, 109.0, 119.2,
119.6, 121.5, 121.8, 123.8, 123.8, 129.3, 131.3, 133.4, 141.5, 148.7,
149.3, 191.4 ppm. MS (EI): m/z = 351 [M]+. HRMS (EI): calcd.
for C22H25NO3 351.1834; found 351.1804.
J = 7.6 Hz, 1 H), 6.93 (d, J = 7.6 Hz, 1 H), 7.60 (s, 1 H), 7.78 (br.
s, 1 H), 8.37 (br. s, 1 H), 8.86 (br. s, 1 H) ppm. 13C NMR (125 MHz,
CD3COCD3): δ = 11.4, 13.2, 17.6, 19.1, 29.8, 34.7, 35.4, 37.2, 63.5,
106.8, 109.4, 118.6, 120.1, 121.2, 122.1, 122.2, 123.3, 128.2, 130.3,
133.4, 142.5, 142.6, 149.7 ppm. MS (EI): m/z = 367 [M]+. HRMS
(EI): calcd. for C23H29NO3 367.2147; found 367.2154.
3,8-Dihydroxy-2-methyl-1-(2,5-dimethylhept-1-en-1-yl)carbazole-5-
carbaldehyde (27b): To a solution of 3,8-bis(OSEM)-1-alkenylcarb-
azole 25b (50 mg, 0.08 mmol) in dry HMPA (2 mL) was added
TBAF (1 m in THF, 399 μL, 0.39 mmol) at room temperature. The
mixture was heated at 100 °C for 1 h and then was cooled to an
ambient temperature. The mixture was quenched with water, and
the resulting mixture was extracted with EtOAc. The EtOAc phase
was washed with water and brine, dried with Na2SO4, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel, 5 g; EtOAc/hexane, 1:4 v/v) to give 3,8-
dihydroxycarbazole 27b (20 mg, 67%) as a pale yellow solid; m.p.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of all compounds.
Acknowledgments
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) of the Japan Society for the Promotion of Science
(grant number 17590025 for S. H.).
222–224 °C (EtOAc/hexane). [α]2D0 = +20.0 (c = 0.05, MeOH). IR
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1
(ATR): ν = 3420, 1640 cm–1. H NMR (300 MHz, [D ]DMSO): δ
˜
6
= 0.91 (t, J = 7.2 Hz, 3 H), 0.96 (d, J = 6.1 Hz, 3 H), 1.18–1.27
(m, 1 H), 1.42–1.48 (m, 6 H), 1.61–1.68 (m, 1 H), 2.15 (s, 3 H),
2.27–2.35 (m, 2 H), 6.39 (s, 1 H), 6.92 (d, J = 7.9 Hz, 1 H), 7.62
(d, J = 7.9 Hz, 1 H), 8.39 (s, 1 H), 8.98 (s, 1 H), 10.04 (s, 1 H),
10.24 (s, 1 H), 10.77 (br. s, 1 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 11.3, 13.7, 17.8, 19.1, 28.9, 33.7, 34.3, 36.4, 107.7,
109.0, 119.3, 119.6, 121.5, 121.9, 123.8, 123.8, 129.3, 131.2, 133.3,
141.5, 148.7, 149.2, 191.4 ppm. MS (EI): m/z = 365 [M]+. HRMS
(EI): calcd. for C23H27NO3 365.1991; found 365.1989.
Carbazomadurin A (1a): To a solution of 3,8-dihydroxycarbazole
27a (62 mg, 0.18 mmol) in MeOH was added NaBH4 (8 mg,
0.22 mmol) at room temperature. After stirring at that temperature
for 5 min, the reaction mixture was concentrated under reduced
pressure. Water was added, and the resulting mixture was extracted
with EtOAc. The organic layer was washed with water and brine,
dried with Na2SO4, and concentrated under reduced pressure. The
residue was recrystallized with chloroform/hexane to give carbazo-
madurin A (1a, 44 mg, 70%) as a pale yellow solid; m.p. 167–
169 °C (CHCl /hexane). IR (ATR): ν = 3480, 3420, 1640, 1580,
˜
3
1430, 1370 cm–1. H NMR (300 MHz, CD3COCD3): δ = 0.99 (d,
1
J = 6.2 Hz, 6 H), 1.55 (s, 3 H), 1.63–1.73 (m, 1 H), 2.25 (s, 3 H),
2.34 (t, J = 7.7 Hz, 2 H), 3.89 (t, J = 5.5 Hz, 1 H), 5.00 (d, J =
5.9 Hz, 2 H), 6.42 (s, 1 H), 6.71 (d, J = 7.7 Hz, 1 H), 6.90 (d, J =
7.7 Hz, 1 H), 7.57 (s, 1 H), 7.78 (br. s, 1 H), 8.35 (br. s, 1 H), 8.88
(br. s, 1 H) ppm. 13C NMR (75 MHz, CD3COCD3): δ = 13.6, 18.0,
22.9, 28.6, 37.8, 38.0, 63.9, 107.1, 109.7, 118.9, 120.4, 121.5, 122.4,
122.5, 123.7, 128.5, 130.6, 133.6, 133.7, 142.8, 143.0, 150.0 ppm.
MS (EI): m/z = 353 [M]+. HRMS (EI): calcd. for C22H27NO3
353.1991; found 353.1975.
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7400
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Eur. J. Org. Chem. 2013, 7391–7401

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Received: July 17, 2013
Published Online: September 20, 2013
Eur. J. Org. Chem. 2013, 7391–7401
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7401