Total synthesis of carbazomycins A and B

Article abstract of DOI:10.1248/cpb.c17-00851

Total syntheses of carbazomycins A and B were demonstrated using a ytterbium-catalyzed Diels-Alder reaction with (silyloxyvinyl)indole as a diene. The densely substituted benzene ring of the target compound was successfully constructed by functionalization of a hydrocarbazolone intermediate and subsequent aromatization using N-bromosuccinimide.

Full text of DOI:10.1248/cpb.c17-00851

178
Chem. Pharm. Bull. 66, 178–183 (2018)
Vol. 66, No. 2
Regular Article
Total Synthesis of Carbazomycins A and B
,a,b
Siyuan Wu,a Shinji Harada,a,b Takahiro Morikawa,a and Atsushi Nishida*
a Graduate School of Pharmaceutical Sciences, Chiba University; 1–8–1 Inohana, Chuo-ku, Chiba 260–8675,
b
Japan: and Molecular Chirality Research Center, Chiba University; 1–33 Yayoi-cho, Inage-ku, Chiba 263–8522,
Japan.
Received October 20, 2017; accepted November 14, 2017
Total syntheses of carbazomycins A and B were demonstrated using a ytterbium-catalyzed Diels–Alder
reaction with (silyloxyvinyl)indole as a diene. The densely substituted benzene ring of the target compound
was successfully constructed by functionalization of a hydrocarbazolone intermediate and subsequent aroma-
tization using N-bromosuccinimide.
Key words total synthesis; carbazomycin; Diels–Alder reaction; ytterbium; carbazole
Carbazole is a tricyclic skeleton that is frequently seen as
Our group has been focusing on the stereo- and regi-
a core structure in biologically active compounds.1–6) Among oselective synthesis of the hydrocarbazole skeleton by the
them, carbazomycins have a simple structure, but attractive catalytic Diels–Alder reaction using highly acid-sensitive
biological activities. Especially, carbazomycins A and B, 3-(silyloxyvinyl)indole as a diene25,26) (Chart 2). An asymmet-
which were isolated from the extract of cultured mycelia of ric version of this reaction was promoted by a chiral holmium
Streptoverticillium ehimensis strain H1051-MY107–9) (Chart catalyst, and the optically active hydrocarbazole 6 with three
1), show inhibitory activity against 5-lipoxygenase, and have contiguous chiral centers was obtained in a single step. Con-
weak antibacterial and antiyeast activities. Carbazomycin B is cise total syntheses of (−)-minovincine27) and natural alkaloid
also active against malaria.10,11) Therefore, carbazomycins have (+)-828) demonstrated the synthetic utility of 6.
been receiving considerable attention, and there have been
During the synthesis of 8, stereoselective hydroxylation of
several reports on their total synthesis.12–23) In the synthesis hydrocarbazolone intermediate 9 derived from 6 was the key
of these compounds, the methods used to construct the fully step. We noticed that the aromatization of 8 would lead a total
substituted benzene ring in their structure have been the main synthesis of carbazomycins. However, aromatization of 8 itself
subject of synthetic strategies, because it is generally difficult was unsuccessful because of its instability. Therefore, we ex-
to construct a fully substituted benzene ring from benzene plored aromatization methods using the substrates 10 and 12,
derivatives by aromatic substitution and/or cross-coupling which were equivalent to compound 8, to obtain the carbazo-
strategies due to a shortage of reliable methods for installing a mycin skeleton (Chart 3).
functional group at the desired position.24)
Chart 1. Structures of Carbazomycins A and B, and Related Carbazole Alkaloid 3
Chart 2. Enantioselective Synthesis of Chiral Hydrocarbazole 6, and Its Application to the Asymmetric Total Syntheses of Natural Compounds 7
and 8
*To whom correspondence should be addressed. e-mail: anishida@faculty.chiba-u.jp
© 2018 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
179
Chart 3. Plan for the Synthesis of Carbazomycins
Chart 4. Catalytic Diels–Alder Reaction of Silyloxyvinylindole 4, and Derivatization to Hydrocarbazolone 9
Chart 5. Bromination of Hydrocarbazolone 9, and Attempts to Introduce a Methoxy Group at C3
sequent oxidative conversion of triisopropylsilyl (TIPS) enol
Results and Discussion
The synthesis began with our Diels–Alder reaction between ether to enone.
silyloxyvinylindole 4 and dienophile 5a.25) The racemic re-
Bromination of 9 with copper bromide33) gave dibrominated
action of 4 and 5a was promoted by ytterbium triflate,29–31) product 13 in 92% yield (Chart 5). Treatment with potassium
and the exo-adduct 6a was obtained in 84% yield as a single carbonate gave aryl bromide 11. We examined its aromatic
diastereomer on a 15-g scale32) (Chart 4). From 6a, hydrocar- substitution with a methoxy group.34) We tried several condi-
bazolone 9 was synthesized by following the synthetic route to tions using copper catalysis for the synthesis of 14, however,
(+)-8 in our previous report,28) via reductive cleavage of the only complex mixtures were obtained. Meanwhile, we isolated
acyl oxazolidinone moiety to a methyl group at C10 and sub- compound 15, which had a methoxy group at C10, under the

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Vol. 66, No. 2 (2018)
Chart 6. Introduction of a Methoxy Group via TMS Enol Ether 16
Chart 7. Key Correlations in NOESY Analyses of 17 and 18
Chart 9. Total Synthesis of Carbazomycins A and B
Therefore, we aromatized 17 with N-bromosuccinimide
(NBS) before deprotection to give carbazole 21 (Chart 9).
Next, Mbs was removed with Na/anthracene to finally ac-
complish the total synthesis of carbazomycin B, which was
converted to carbazomycin A by following Moody’s method.14)
Conclusion
Chart 8. Unexpected Synthesis of Hydrocarbazolone 20 with Exocyclic
We accomplished the total synthesis of carbazomycins A
Olefin
and B. The key point in our synthesis is that the hydrocarba-
conditions described in Chart 5. This type of benzylic oxida- zole skeleton was built in a single step by using our lantha-
tion of carbazole derivative has been reported using potassium noid catalysis, which gave three-fourths of the substituents
persulfate in the presence of copper sulfate.35) A mechanistic of carbazomycins A and B. Subsequent installation of a me-
study of our reaction is underway because compound 15 could thoxy group and aromatization achieved the construction of a
be a potential synthetic intermediate for carbazole alkaloids fully substituted benzene ring in the carbazomycin skeleton.
with an oxygen functionality at C10, like compound 3.
Moreover, the application of this new oxidation method at the
Next, we turned our attention to another synthetic route. benzylic position of carbazole derivatives as well as the intro-
We performed the methoxylation of hydrocarbazolone via duction of substituents to silyloxyvinylindole and the use of a
trimethylsilyl (TMS) enol ether.36) After the in situ generation variety of dienophiles opens the way to the construction of a
of TMS enol ether 16, we obtained the desired compound 17 library of carbazomycin derivatives. The biological activities
in 78% yield along with hydroxy derivative 18 in 20% yield of the synthetic intermediates will be screened in due course.
(Chart 6). The relative stereochemistries of 17 and 18 were
determined by the key correlations in a nuclear Overhauser
effect spectroscopy (NOESY) analysis (Chart 7).
Experimental
General Information NMR spectra were recorded at
1
Deprotection of the carbazole nitrogen was realized with 400 or 600MHz for H-NMR, and at 100 or 150MHz for
potassium carbonate in methanol. However, a subsequent at- 13C-NMR. Chemical shifts for proton are reported in parts per
tempt at aromatization gave unexpected hydrocarbazolone 20 million downfield from tetramethylsilane, and are referenced
with an exocyclic olefin (Chart 8). During this transformation, to residual protium in the NMR solvent (CDCl3 δ: 7.26ppm).
the stereochemistry of the methoxy group was epimerized. For 13C-NMR, chemical shifts are reported relative to the
To date, we have had no clear explanation on this epimeriza- NMR solvent (CDCl3 δ: 77.0ppm) as an internal reference. In-
tion,37) but the structure was unambiguously determined by frared spectra were recorded on an attenuated total reflectance
X-ray crystallographic analysis.38) Compound 20 as well as (ATR). Mass spectra were recorded using electrospray ioniza-
19 could not be converted to carbazomycin B under several tion (ESI) or atmospheric pressure chemical ionization (APCI)
conditions.
mode with a time of flight (TOF) analyzer. Reactions were

Vol. 66, No. 2 (2018)
Chem. Pharm. Bull.
181
carried out in dry solvents under an argon atmosphere, unless 0.05mmol) in N,N-dimethylformamide (DMF) (0.3mL) was
otherwise noted. Solvents and reagents were purified by gen- added K2CO3 (15mg, 0.10mmol, 2.0 equiv.) at room tempera-
eral methods. Flash column chromatography was performed ture. The mixture was stirred at room temperature for 8h. The
on silica gel 60µm particles, unless otherwise noted.
resulting mixture was diluted with CH2Cl2 and the organic
( )-3-(9-((4-Methoxyphenyl)sulfonyl)-2-methyl-4- phase was washed with water, dried over Na2SO4, filtered
((triisopropylsilyl)oxy)-2,3,9,9a-tetrahydro-1H-carbazole- with a plug of cotton, and concentrated under reduced pres-
1-carbonyl)oxazolidin-2-one (6a) Yb(OTf)3 (1.74g, 2.8mmol, sure. The residue was purified by flash column chromatogra-
10mol%) was placed in a 300mL flask with a stirring bar and phy (SiO2, 1/5=ethyl acetate/hexane) to give 11 as a yellow
1
heated at 120°C under reduced pressure (<0.01mmHg) for solid (19.2mg, 78%). H-NMR (CDCl3, 400MHz) δ: 2.54 (s,
30min. After being cooled to room temperature, the flask was 3H), 3.70 (s, 3H), 3.67 (s, 3H), 5.94 (s, 1H), 6.49 (d, J=8.8Hz,
charged with dry argon, and CH2Cl2 (23mL) were added. The 2H), 6.98 (d, J=8.8Hz, 2H), 7.25 (t, J=7.6Hz, 1H), 7.34 (t,
reaction mixture was cooled to 0°C. A solution of dienophile J=7.6Hz, 1H), 7.84 (d, J=7.6Hz, 1H), 8.09 (d, J=7.6Hz, 1H);
5a (4.34g, 28mmol) in CH2Cl2 (25+5mL to rinse) was added. 13C-NMR (CDCl3, 150MHz) δ: 19.8, 20.8, 55.4, 111.6, 113.1,
A solution of diene 4 (16.3g, 34mmol, 1.2 equiv.) in CH2Cl2 117.0, 119.4, 122.6, 123.4, 125.9, 126.3, 126.4, 129.1, 129.3,
(50+5mL to rinse) was then added, and the mixture was 136.3, 141.4, 141.5, 145.1, 163.2; HR-MS (APCI) m/z Calcd for
stirred for 2h under argon at room temperature. The reaction C21H17Br1N1O4S1 [M–H]− 458.0062. Found 458.0060; IR (neat):
was quenched by the addition of H2O and filtered through ν 2925, 1738, 1593, 1364, 1259, 1166cm−1.
a pad of Celite. The water layer was extracted three times
3-Bromo-1-(methoxymethyl)-9-((4-methoxyphenyl)-
with CH2Cl2, and the combined organic layers was dried over sulfonyl)-2-methyl-9H-carbazol-4-ol (15) To a solution of
Na2SO4, filtered with a plug of cotton, and concentrated under 11 (17mg, 0.036mmol) in MeOH (0.4mL) in sealed tube was
reduced pressure. The residue was purified by flash column added AcOEt/toluene (1/1, 0.2mL), CuBr (10mg, 0.07mmol,
chromatography (CHROMATOREX-NH, 1/4=ethyl acetate/ 2 equiv.), NaOMe (25mg, 0.36mmol, 10 equiv.) at room tem-
1
hexane) to give 6a as a colorless foam (15g, 84%). H-NMR perature. Then the resulting mixture was heated to 80°C and
(CDCl3, 400MHz) δ: 1.06 (d, J=7.6Hz, 9H), 1.07 (d, J=7.6Hz, stirred for 3d under argon. After being cooled to room tem-
9H), 1.09 (d, J=5.6Hz, 3H), 1.19 (qq, J=7.6, 7.6Hz, 3H), 2.11 perature, H2O was added to the reaction mixture. The organic
(ddd, J=2.0, 8.0, 16.8Hz, 1H), 2.28 (m, 1H), 2.46 (ddd, J=2.0, layer was washed with water, dried over Na2SO4, filtered with
5.6, 16.8Hz, 1H), 3.78 (s, 3H), 4.09 (ddd, J=8.8, 8.8, 8.8Hz, a plug of cotton, and concentrated under reduced pressure.
1H), 4.30 (ddd, J=8.8, 8.8, 8.8Hz, 1H), 4.34 (dd, J=8.0, The residue was purified by flash column chromatography
8.0Hz, 1H), 4.42 (ddd, J=6.0, 8.8, 8.8Hz, 1H), 4.49 (ddd, (SiO2, 1/3=ethyl acetate/hexane) to give 15 as a colorless
1
J=8.8, 8.8, 8.8Hz, 1H), 4.75 (td, J=2.0, 8.0Hz, 1H), 6.84 (d, solid (4.5mg, 27%). H-NMR (CDCl3, 400MHz) δ: 2.65 (s,
J=8.8Hz, 2H), 6.98 (dd, J=7.2, 8.0Hz, 1H), 7.10 (dd, J=8.0, 3H), 3.31 (s, 3H), 3.67 (s, 3H), 5.09 (s, 2H), 6.47 (d, J=8.8Hz,
8.0Hz, 1H), 7.56 (d, J=7.2Hz, 1H), 7.65 (d, J=8.8Hz, 2H), 2H), 6.91 (d, J=8.8Hz, 2H), 7.23 (t, J=7.6, 1H), 7.36 (t, J=7.6,
7.74 (d, J=8.0Hz, 1H); 13C-NMR (CDCl3, 100MHz) δ: 13.5, 1H), 7.84 (d, J=7.6Hz, 1H), 8.08 (d, J=7.6Hz, 1H); 13C-NMR
17.9, 19.9, 32.5, 37.8, 43.0, 48.6, 55.4, 62.0, 65.4, 111.0, 114.0, (CDCl3, 150MHz) δ: 21.1, 55.4, 57.8, 70.3, 112.7, 113.1,
115.9, 123.4, 124.0, 126.9, 127.3, 129.0, 130.1, 144.1, 144.7, 116.5, 119.4, 122.7, 123.5, 125.9, 126.0, 126.5, 128.6, 129.4,
153.7, 163.3, 175.0; high resolution (HR)-MS (ESI) m/z Calcd 138.5, 141.2, 141.3, 146.5, 163.4; HR-MS (ESI) m/z Calcd for
for C33H44N2Na1O7S1Si1 [M+Na]+ 663.2536. Found 663.2528; C21H20Br1N1Na1O5S1 [M+Na]+ 512.0143. Found 512.0137; IR
IR (neat): ν 2945, 2867, 1775, 1678, 1385, 1355, 1162, 1091, (neat): ν 2924, 1726, 1366, 1167, 1087cm−1.
1016 cm−1.
( )-3,3-Dibromo-9-((4-methoxyphenyl)sulfonyl)-1,2-di- methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (17), and
methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (13) To ( )-3-hydroxy-9-((4-methoxyphenyl)sulfonyl)-1,2-dimethyl-
( )-3-Methoxy-9-((4-methoxyphenyl)sulfonyl)-1,2-di-
a
solution of 9 (38mg, 0.1mmol) in AcOEt (0.3mL) was added 1,2,3,9-tetrahydro-4H-carbazol-4-one (18) Trimethylsilyl
CuBr2 (132.5mg, 0.6mmol) at room temperature. Then the re- trifluoromethanesulfonate (TMSOTf) (0.75mL, 4.2mmol, 2
sulting mixture was heated to reflux and stirred for 1d under equiv.) was added dropwise to a solution of 9 (800mg,
argon. After being cooled to room temperature, H2O was 2.1mmol) and N,N-diisopropylethylamine (DIEA) (1.4mL,
added to the reaction mixture. The organic layer was washed 8.4mmol, 4 equiv.) in CH2Cl2 (11mL) at 0°C under argon. The
with water, dried over Na2SO4, filtered with a plug of cotton, mixture was warmed up to room temperature and stirred for
and concentrated under reduced pressure. The residue was 6h. Then the mixture was concentrated under reduced pres-
purified by flash column chromatography (SiO2, 1/4=ethyl sure. Volatile materials were further removed under reduced
acetate/hexane) to give 13 as a colorless foam (49.7mg, 92%). pressure (ca. 5mmHg) for 6h. Then, the residue was dissolved
1H-NMR (CDCl3, 400MHz) δ: 1.75 (d, J=6.8Hz, 3H), 1.77 in MeOH and added PhI(O2CCF3)2 (1.4g, 3.2mmol, 1.5 equiv.)
(d, J=6.4Hz, 3H), 2.38–2.41 (m, 1H), 3.47–3.51 (m, 1H), at −50°C. The resulting mixture was stirred for 1d at the
3.74 (s, 3H), 6.72 (d, J=8.8Hz, 2H), 7.32–7.34 (m, 2H), 7.56 same temperature. The mixture was diluted with CH2Cl2 and
(d, J=8.8Hz, 2H), 8.00–8.02 (m, 1H), 8.11–8.13 (m, 1H); the organic layer was washed with water, dried over Na2SO4,
13C-NMR (CDCl3, 150MHz) δ: 18.1, 22.7, 38.6, 52.5, 55.6, filtered with a plug of cotton, and concentrated under reduced
75.9, 113.5, 114.3, 115.4, 122.0, 125.7, 126.1, 126.5, 128.2, pressure. The residue was purified by flash column chromatog-
129.1, 137.9, 154.7, 164.1, 181.8; HR-MS (APCI) m/z Calcd for raphy (CHROMATOREX-NH, 1/2=ethyl acetate/hexane) to
C21H19Br2N1O4S1 [M+H]+ 539.9480. Found 539.9465; IR (neat): give 17 as a colorless form (676.5mg, 78%) and 18 as a color-
1
ν 2970, 1688, 1591, 1396, 1266, 1180, 1087cm−1.
less foam (167.6mg, 20%). For 17, H-NMR (CDCl3, 600MHz)
3-Bromo-9-((4-methoxyphenyl)sulfonyl)-1,2-dimeth- δ: 0.91 (d, J=7.2Hz, 3H), 1.71 (d, J=6.6Hz, 3H), 2.46–2.79
yl-9H-carbazol-4-ol (11) To a solution of 13 (29mg, (m, 1H), 3.65 (s, 3H), 3.73–3.77 (m, 1H), 3.79 (s, 3H), 4.29

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(d, J=4.8Hz, 1H), 6.86 (d, J=9.0Hz, 2H), 7.33–7.37 (m, 2H), by flash column chromatography (SiO2, 1/2=ethyl acetate/
1
7.71 (d, J=9.0Hz, 2H), 8.12–8.14 (m, 1H), 8.18–8.20 (m, 1H); hexane) to give 21 as a yellow solid (135mg, 82%). H-NMR
13C-NMR (CDCl3, 150MHz) δ: 13.7, 20.8, 37.3, 41.5, 55.8, (CDCl3, 600MHz) δ: 2.37 (s, 3H), 2.62 (s, 3H), 3.67 (s, 3H),
59.1, 81.3, 114.5, 114.6, 116.3, 121.8, 125.2, 125.5, 125.8, 128.7, 3.81 (s, 3H), 5.85 (s, 1H), 6.47 (d, J=9.0Hz, 2H), 6.96 (d,
129.5, 136.8, 153.3, 164.2, 193.1; HR-MS (ESI) m/z Calcd J=9.0Hz, 2H), 7.24 (t, J=7.2Hz, 1H), 7.31 (t, J=7.8Hz, 1H),
for C22H23N1Na1O5S1 [M+Na]+ 436.1195. Found 436.1199; IR 7.81 (d, J=7.8Hz, 1H), 8.07 (d, J=7.2Hz, 1H); 13C-NMR
(neat): ν 2970, 2932, 1680, 1592, 1370, 1267, 1167, 1088cm−1. (CDCl3, 150MHz) δ: 13.4, 18.5, 55.3, 61.3, 112.9, 116.8,
1
For 18, H-NMR (CDCl3, 600MHz) δ: 0.84 (d, J=6.6Hz, 3H), 119.6, 122.3, 122.7, 125.7, 125.8, 126.3, 129.3, 129.8, 123.0,
1.71 (d, J=6.6Hz, 3H), 2.65–2.69 (m, 1H), 3.66 (brs, 1H), 137.9, 141.5, 141.5, 143.5, 163.1; HR-MS (ESI) m/z Calcd for
3.78–3.81 (m, 1H), 3.80 (s, 3H), 4.76 (d, J=4.8Hz, 1H), 6.87 C22H21N1Na1O5S1 [M+Na]+ 434.1038. Found 434.1035; IR
(d, J=8.4Hz, 2H), 7.33–7.39 (m, 2H), 7.72 (d, J=8.4Hz, 2H), (neat): ν 2970, 2858, 1366, 1170, 1065, 908cm−1.
8.13–8.17 (m, 2H); 13C-NMR (CDCl3, 150MHz) δ: 13.1, 20.5,
3-Methoxy-1,2-dimethyl-9H-carbazol-4-ol (2, Carbazomy-
37.1, 43.0, 55.8, 72.3, 114.7, 121.5, 125.3, 125.4, 125.6, 128.8, cin B) To a solution of anthracene (90mg, 0.5mmol, 5 equiv.)
129.6, 136.9, 155.0, 164.3, 194.6; HR-MS (ESI) m/z Calcd in THF (2mL) was added Na (excess) at room temperature,
for C21H21N1Na1O5S1 [M+Na]+ 422.1034. Found 422.1038; IR and the mixture was stirred for 0.5h. To this mixture, was
(neat): ν 3055, 2983, 1672, 1595, 1384, 1264, 1169, 731cm−1.
added 21 (41.3mg, 0.1mmol) in THF (0.2mL), and the whole
( )-3-Methoxy-1,2-dimethyl-1,2,3,9-tetrahydro-4H-car- mixture was stirred for 1h. The supernatant was diluted with
bazol-4-one (19) To a solution of 17 (41.3mg, 0.1mmol) in CH2Cl2, and to this mixture was added water. The organic
MeOH (0.2mL) was added K2CO3 (55mg, 0.4mmol, 4 equiv.) layer was washed with water, dried over Na2SO4, filtered with
at room temperature. The mixture was stirred for 4h at 50°C. a plug of cotton, and concentrated under reduced pressure.
The resulting mixture was cooled to room temperature and di- The residue was purified by flash column chromatography
luted with CH2Cl2. The organic layer was washed with water, (SiO2, 1/2=ethyl acetate/hexane) to give carbazomycin B (2)
1
dried over Na2SO4, filtered with a plug of cotton, and concen- as a yellow solid (15.9mg, 66%). H-NMR (CDCl3, 600MHz)
trated under reduced pressure. The residue was purified by δ: 2.38 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 6.02 (s, 1H), 7.22
flash column chromatography (SiO2, 2/1=ethyl acetate/hexane) (t, J=7.2Hz, 1H), 7.36 (t, J=7.2Hz, 1H), 7.40 (d, J=7.8Hz,
1
to give 19 as a white solid (20.7mg, 85%). H-NMR (CDCl3, 1H), 7.78 (brs, 1H), 8.24 (d, J=7.8Hz, 1H); 13C-NMR (CDCl3,
600MHz) δ: 1.27 (d, J=6.0Hz, 3H), 1.51 (d, J=6.6Hz, 3H), 150MHz) δ: 12.8, 13.2, 61.5, 109.3, 109.3, 110.0, 119.5, 122.6,
2.15–2.17 (m, 1H), 2.90–2.93 (m, 1H), 3.63 (d, J=10.2Hz, 1H), 123.2, 124.8, 127.0, 136.7, 138.4, 139.2, 140.0; HR-MS (ESI)
3.68 (s, 3H), 7.24–7.27 (m, 2H), 7.34 (d, J=7.8Hz, 1H), 8.22 m/z Calcd for C15H16N1O2 [M+H]+ 242.1183. Found 242.1181;
(d, J=6.6Hz, 1H), 8.35 (brs, 1H); 13C-NMR (CDCl3, 150MHz) IR (neat): ν 3426, 1454, 1411, 750cm−1.
δ : 16.0, 17.0, 35.6, 43.6, 59.6, 86.6, 110.8, 111.9, 121.8, 122.7,
3,4-Dimethoxy-1,2-dimethyl-9H-carbazole (1, Carbazo-
123.6, 125.0, 136.2, 152.5, 192.5; HR-MS (ESI) m/z caled for mycin A) To a solution of 2 (6mg, 0.025mmol) in acetone
C15H17N1Na1O2 [M+Na]+ 266.1157. Found 266.1163; IR (neat): (2mL) was added K2CO3 (50mg, 0.36mmol, 14 equiv.) and
ν 3217, 2970, 1737, 1634, 1471, 1373, 1229, 1217cm−1.
methyl iodide (MeI) (0.3mL) at room temperature. The mix-
( )-3-Methoxy-2-methyl-1-methylene-1,2,3,9-tetra- ture was heated under reflux for 5h. The resulting mixture
hydro-4H-carbazol-4-one (20) To a solution of 19 (8mg, was diluted with CH2Cl2 and the organic layer was washed
0.03mmol) in CH2Cl2 (0.2mL) was added 2,3-dichloro-5,6- with water, dried over Na2SO4, filtered with a plug of cotton,
dicyanobenzoquinone (DDQ) (30mg, 0.13mmol, 4 equiv.) at and concentrated under reduced pressure. The residue was
room temperature and the mixture was stirred for 1d. The purified by flash column chromatography (SiO2, 1/10=ethyl
resulting mixture was taken up in CH2Cl2, and the organic acetate/hexane) to give carbazomycin A (1) as a pale yellow
1
phase was washed with water, dried over Na2SO4, filtered with solid (6mg, 93%). H-NMR (CDCl3, 600MHz) δ: 2.38 (s, 3H),
a plug of cotton, and concentrated under reduced pressure. 2.40 (s, 3H), 3.83 (s, 3H), 6.02 (s, 1H), 7.22 (t, J=7.2Hz, 1H),
The residue was purified by flash column chromatography 7.36 (t, J=7.2Hz, 1H), 7.40 (d, J=7.8Hz, 1H), 7.78 (brs, 1H),
(SiO2, 2/1=ethyl acetate/hexane) to give 20 as a colorless solid 8.24 (d, J=7.8Hz, 1H); 13C-NMR (CDCl3, 150MHz) δ: 12.7,
1
(5mg, 62%). H-NMR (CDCl3, 600MHz) δ: 1.31 (d, J=7.2Hz, 13.7, 60.6, 61.2, 110.3, 113.6, 114.5, 119.6, 122.6, 123.0, 125.1,
3H), 3.16–3.19 (m, 1H), 3.55 (s, 3H), 3.62 (d, J=6.0Hz, 1H), 128.9, 136.5, 139.5, 144.6, 146.1; HR-MS (ESI) m/z Calcd for
5.47 (d, J=1.2Hz, 1H), 5.63 (s, 1H), 7.26–7.30 (m, 2H), 7.38 C16H18N1O2 [M+H]+ 256.1338. Found 256.1337; IR (neat): ν
(d, J=7.2Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.62 (brs, 1H); 3428, 2926, 1454, 1292, 1013cm−1.
13C-NMR (CDCl3, 150MHz) δ: 16.9, 43.0, 58.8, 86.6, 111.1,
111.5, 111.8, 122.2, 122.9, 124.8, 125.1, 136.7, 137.8, 144.1,
Acknowledgments This work was supported by Japan So-
191.6; HR-MS (ESI) m/z Calcd for C15H16N1Na1O2 [M+Na]+ ciety for the Promotion of Science (JSPS) KAKENHI [Grant
264.1001. Found 264.1002; IR (neat): ν 2970, 1738, 1726, 1367, Numbers 25460006, 16K08154 (SH), 14J03297 (TM), and
1228, 1217, 1029cm−1.
25293001, 17H03969 (AN)], the Takeda Science Foundation
3-Methoxy-9-((4-methoxyphenyl)sulfonyl)-1,2-dimeth- (SH), and the Tokyo Biochemical Research Foundation (SH).
yl-9H-carbazol-4-ol (21) To a solution of 17 (165mg,
0.4mmol) in tetrahydrofuran (THF) (4mL) was added NBS
Conflict of Interest The authors declare no conflict of
(267mg, 1.5mmol, 4 equiv.) at room temperature. The mix- interest.
ture was stirred for 12h. The resulting mixture was dissolved
in CH2Cl2, and the organic layer was washed with water,
Supplementary Materials The online version of this ar-
dried over Na2SO4, filtered with a plug of cotton, and con- ticle contains supplementary materials.
centrated under reduced pressure. The residue was purified

Vol. 66, No. 2 (2018)
Chem. Pharm. Bull.
183
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