Total syntheses of eudistomins Y1-Y7 by an efficient one-pot process of tandem benzylic oxidation and aromatization of 1-benzyl-3,4-dihydro-β-carbolines

Article abstract of DOI:10.1002/ejoc.201300080

The first total synthesis of eudistomin Y₇ (7) and total syntheses of eudistomins Y₁-Y₆ (1-6) are described. An efficient room-temperature conversion of 1-benzyl-3,4-dihydro-β-carbolines (11) into 1-benzoyl-β-carbolines (14) by a one-pot process of tandem benzylic oxidation and aromatization as the key step of these total syntheses was also studied in detail. The first total synthesis of eudistomin Y ₇ (7) and total syntheses of eudistomins Y₁-Y₆ (1-6) are described. An efficient room-temperature conversion of 1-benzyl-3,4-dihydro-β-carbolines (11) into 1-benzoyl-β-carbolines (14) by a one-pot process of tandem benzylic oxidation and aromatization as the key step of these total syntheses was also studied in detail. Copyright

Full text of DOI:10.1002/ejoc.201300080

FULL PAPER
DOI: 10.1002/ejoc.201300080
Total Syntheses of Eudistomins Y1–Y7 by an Efficient One-Pot Process of
Tandem Benzylic Oxidation and Aromatization of 1-Benzyl-3,4-dihydro-β-
Carbolines
Tien Ha Trieu,[a] Jing Dong,[a] Qiang Zhang,[a] Bo Zheng,[a] Tian-Zhuo Meng,[a] Xia Lu,[a]
and Xiao-Xin Shi*[a]
Keywords: Natural products / Alkaloids / Total synthesis / Nitrogen heterocycles / Aromatization
The first total synthesis of eudistomin Y7 (7) and total synthe-
ses of eudistomins Y1–Y6 (1–6) are described. An efficient
room-temperature conversion of 1-benzyl-3,4-dihydro-β-
carbolines (11) into 1-benzoyl-β-carbolines (14) by a one-pot
process of tandem benzylic oxidation and aromatization as
the key step of these total syntheses was also studied in de-
tail.
Table 1. Structures of Eudistomins Y1–Y7 (1–7).
Introduction
Eudistomins are a sub-class of prevalent and biologically
active β-carboline alkaloids, many of which have been iso-
lated from marine tunicates of the Eudistoma genus.[1–6]
Rinehart and co-workers first reported the isolation and de-
termined the structures of eudistomins A–Q.[1] Later, Ko-
bayashi and co-workers also reported the isolation of eudis-
tomins A–F,[2] Kinzer and Cardellina reported the isolation
of eudistomins R–T,[3] Fransisco and co-workers reported
the isolation of eudistomin U,[4] Quinn and co-workers re-
ported the isolation of eudistomin V,[5] and Proksch and co-
workers reported the isolation of eudistomins W and X.[6]
Eudistomins Y1–Y7 (Table 1, 1–7) are seven new mem-
bers of this class of β-carboline alkaloids. These com-
pounds were originally isolated from a tunicate of the
Eudistoma genus off the coast of Korea by Kang and co-
workers in 2008.[7] Recently, eudistomins Y2–Y7 (2–7) were
also isolated from the Korean ascidian Synoicum sp. by Oh,
Shin and co-workers in 2012.[8] Biological evaluation dem-
onstrated that eudistomins Y1–Y7 (1–7) and their deriva-
tives showed moderate to significant antimicrobial activity,
weak cytotoxic activity, and inhibitory activities towards
sortase A, isocitrate lyase, and Na+/K+-ATPase.[7,8]
Eudistomins
R1
R2
R3
R4
Y1 (1)
Y2 (2)
Y3 (3)
Y4 (4)
Y5 (5)
Y6 (6)
Y7 (7)
H
Br
H
Br
H
Br
H
H
H
H
H
H
H
Br
H
H
Br
Br
Br
Br
Br
H
H
H
H
Br
Br
Br
use of microwave radiation. Moreover, to the best of our
knowledge, the total synthesis of eudistomin Y7 (7) has not
been reported to date. Considering their wide-ranging bio-
logical activities, we are interested in developing efficient
and practical syntheses of eudistomins Y1–Y7 (1–7) and
their derivatives. In this paper, we report the first total syn-
thesis of eudistomin Y7 (7) and also total syntheses of eudi-
stomins Y1–Y6 (1–6).
Since the isolation of eudistomins Y1–Y7 (1–7) in 2008,
Lindsley and co-workers have reported the first total syn-
theses of eudistomins Y1–Y6 (1–6),[9] however, these total
syntheses suffered from low overall yields and required the
Results and Discussion
[a] Department of Pharmaceutical Engineering, School of
Pharmacy, East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237, P. R. China
Fax: +86-21-64252052
Our total syntheses of eudistomins Y1–Y7 (1–7) were
performed according to the synthetic route shown in
Scheme 1. 2-Arylacetyl chlorides were prepared prior to use
by the reaction of 2-arylacetic acids 8a–d with thionyl
chloride (SOCl2) in refluxing dichloromethane. They were
then exposed to tryptamine (9a) or 6-bromotryptamine (9b)
E-mail: xxshi@ecust.edu.cn
Homepage: http://www.ecust.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300080.
Eur. J. Org. Chem. 2013, 3271–3277
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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X.-X. Shi et al.
FULL PAPER
Scheme 1. Total syntheses of eudistomins Y1–Y7 (1–7).
under basic conditions in a biphasic mixed solvent of yields, respectively, over three steps from compounds
dichloromethane and water (CH2Cl2/H2O = 3:1), to give 10a–d.
the desired coupling products (i.e., 10a–d) in 90, 86, 88, and
Compounds 14a–d are the precursors to eudistomins Y1
90% yields, respectively. Subsequently, compounds 10a–d (1), Y3 (3), Y5 (5), and Y7 (7). When compounds 14a–d
were treated with phosphoryl trichloride (POCl3) in re- were treated with aqueous HBr in acetic acid at reflux
fluxing ethyl acetate to give a tautomeric mixture of com- (110 °C), the cleavage of the phenol methyl ethers took
pounds 11 and 12 by a Bischler–Napieralski cyclization.[10] place to give the desired eudistomins Y1 (1), Y3 (3), Y5 (5),
Because of the imine–enamine tautomerism, the mixture of and Y7 (7) in 92, 92, 95, and 93% yields, respectively. When
compounds 11 and 12 was hard to separate, and so it was compounds 14a–c were treated with N-bromosuccinimide
used as such for the next step. When the tautomeric mix- (NBS) in a mixed solvent of acetonitrile and acetic acid
tures of compounds 11/12a–d were treated with 1,8-diazabi- (CH3CN/AcOH = 3:1), a highly selective monobromination
cyclo[5.4.0]undec-7-ene (DBU) in dimethyl sulfoxide occurred smoothly at the C-6 position to give compounds
(DMSO) at room temperature under an atomosphere of air, 15a–c in almost quantitative yields. Compounds 15a–c are
benzylic oxidation of the imine–enamine tautomers oc- the precursors to eudistomins Y2 (2), Y4 (4), and Y6 (6),
curred smoothly to produce 1-benzoyl-3,4-dihydro-β- and they were then converted into the desired eudistomins
carbolines 13a–d, which then rapidly turned into 1-benzoyl- Y2 (2), Y4 (4), and Y6 (6) in 93, 95, and 94% yields, respec-
β-carbolines 14a–d by oxidative aromatization. The desired tively, after ether cleavage by treatment with aqueous HBr
compounds (i.e., 14a–d) were formed in 78, 75, 70, and 72% in acetic acid at reflux (110 °C).
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Total Synthesis of Eudistomins Y1–Y7
6-Bromotryptamine (9b) was prepared from 6-bromo- In contrast, when R was an alkyl or aryl group, the aroma-
1H-indole according to the synthetic route shown in tization was sluggish at room temperature, but it occurred
Scheme 2. First, (E)-6-bromo-3-(2-nitrovinyl)-1H-indole smoothly at 125 °C (Table 2, entries 5–9). These results im-
(16) was prepared in 96% yield following a known pro- ply that benzylic oxidation of 1-benzyl-3,4-dihydro-β-
cedure.,[11] Compound 16 was then treated with sodium carbolines 11 (or 12) should occur first to form 1-benzoyl-
borohydride and boric acid in a mixed solvent of 2-prop- 3,4-dihydro-β-carbolines 13, and then the aromatization of
anol and tetrahydrofuran to produce 6-bromo-3-(2-nitro- 1-benzoyl-3,4-dihydro-β-carbolines 13 would take place
ethyl)-1H-indole (17) in 94% yield. Reduction of the nitro rapidly to give 1-benzoyl-β-carbolines 14. Other solvents
group of compound 17 with zinc powder in the presence of such as ethyl acetate, tetrahydrofuran, acetonitrile, or 2-
HCl gave 6-bromotryptamine 9b in 91% yield. Because the propanol were also tested, but DMSO was the most appro-
yield (86%) of the modified two-step conversion from com- priate for this reaction (see also a previous report[13]). DBU
pound 16 into compound 9b is clearly better than the yield worked better than the other bases tested such as triethyl-
(73%) of the known one-step procedure,[11] it is recom- amine, pyridine, 4-(dimethylamino)pyridine, sodium car-
mended for the preparation of 6-bromotryptamine (9b).
bonate, potassium carbonate, potassium hydroxide, and so-
dium hydroxide.
Table 2. Aromatization of various 3,4-dihydro-β-carbolines 18.
Entry
R
Temp.
[°C]
Time Product
[h]
Yield
[%][a]
1
2
3
4
5
6
7
8
9
C6H5CO
CH3CO
COOCH3
COOC2H5
C6H5
3-(CH3O)C6H4
3,5-(CH3O)2C6H3
H
25[b]
25[b]
25[b]
25[b]
125
125
125
125
125
0.5
0.5
3
3
6
6
6
10
10
19a
19b
19c
19d
19e
19f
19g
19h
19i
93
88
85
86
92
95
96
72
76
Scheme 2. Preparation of 6-bromotryptamine (9b).
In the above-described total syntheses of eudistomins
Y1–Y7 (1–7), the key transformation was the conversion of
1-benzyl-3,4-dihydro-β-carbolines 11 into 1-benzoyl-β-
carbolines 14 by benzylic oxidation and aromatization. This
key conversion can be achieved in one pot by either of two
known methods.[9,12] In Lindsley’s method,[9] the one-pot
conversion was carried out at 160 °C by a microwave-as-
sisted MnO2-oxidation protocol, but only low yields were
obtained from this protocol. In Jenkins’ method,[12] a pho-
tochemical protocol was used for the one-pot conversion.
Although the yields of products were good, this photo-
chemical protocol is not practical and convenient due to
the use of a 500 W halogen lamp and the need for a short
distance between the lamp and the reaction flask. In con-
trast, our DBU-promoted room-temperature method is
much more efficient and practical than the two known pro-
tocols.[9,12]
To get more insight into the above-mentioned key con-
version, we prepared various 1-substituted 3,4-dihydro-β-
carbolines 18, and attempted the aromatization of these
compounds. When compounds 18 were treated with DBU
in DMSO at room temperature or 125 °C under air, the
corresponding 1-substituted-β-carbolines (i.e., 19a–i) were
obtained in 72–96% yields. The results are summarized in
Table 2. When R was an electron-deficient group such as
benzoyl, acetyl, or an ester group, the aromatization was
CH3
[a] Isolated yield. [b] Room temperature.
Conclusions
In conclusion, total syntheses of eudistomins Y1–Y6 (1–
6) and the first total synthesis of eudistomin Y7 (7) have
been performed. Our total syntheses of eudistomins Y1–
Y6 (1–6) are clearly more efficient and practical than the
previously reported syntheses.[9] The overall yield of eudis-
tomin Y1 (1) increased from 30[9] to 65%; the overall yield
of eudistomin Y2 (2) increased from 20[9] to 64%; the over-
all yield of eudistomin Y3 (3) increased from 15[9] to 59%;
the overall yield of eudistomin Y4 (4) increased from 15[9]
to 60%; the overall yield of eudistomin Y5 (5) increased
from 7[9] to 59%; and the overall yield of eudistomin Y6 (6)
increased from 6[9] to 57%. Eudistomin Y7 (7) was synthe-
sized in 60% overall yield in five steps from 6-bromo-trypt-
amine.
Experimental Section
General Methods: H and 13C NMR spectra were acquired with a
1
very fast, even at room temperature (Table 2, entries 1–4). Bruker AM-400 spectrometer at 400 and 100 MHz, respectively.
Eur. J. Org. Chem. 2013, 3271–3277
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X.-X. Shi et al.
FULL PAPER
Chemical shifts are given on the delta scale as parts per million
(ppm) with tetramethylsilane (TMS) as the internal standard. IR
spectra were recorded with a Nicolet Magna IR-550 instrument.
Mass spectra were recorded with a HP5989A instrument. Melting
points were determined with a Mel-TEMP II melting point appara-
tus. Column chromatography was performed on silica gel. All rea-
gents and solvents were analytically pure. Tryptamine and 6-
bromo-1H-indole were purchased from Aldrich.
General Procedure for the Preparation of Compounds 10a–d: Thio-
nyl chloride (7.140 g, 60.01 mmol) was added to a solution of com-
pound 8 (20.00 mmol) in dichloromethane (20 mL). The mixture
was stirred at reflux for 4 h. The solvent and excess thionyl chloride
were then removed by vacuum distillation. The residue was dis-
solved in dichloromethane (25 mL), and the resulting solution was
slowly added into the cooled (0–10 °C) two-phase system of NaOH
(2 m aq.; 25 mL) and a solution of compound 10 (20.0 mmol) in
dichloromethane (50 mL). After the addition was finished, the re-
action mixture was stirred for a further 1 h. The two phases were
then separated, and the organic phase was dried with anhydrous
MgSO4. The solvent was removed by vacuum evaporation to give
a solid crude product, which was purified by flash chromatography
(eluent: EtOAc/hexane = 1:3) to afford pure compounds 10a–d in
90, 86, 88, and 90% yields, respectively.
(E)-6-bromo-3-(2-nitrovinyl)-1H-indole (16): Compound 16 was pre-
pared from 6-bromo-1H-indole in 96% yield according to a known
procedure.[11]
6-Bromo-3-(2-nitroethyl)-1H-indole (17): H3BO3 powder (1.855 g,
30.00 mmol) was added to a solution of compound 16 (1.340 g,
5.017 mmol) in a mixed solvent of tetrahydrofuran (100 mL) and
isopropanol (300 mL), then NaBH4 (1.135 g, 30.00 mmol) was
added in portions. The reaction mixture was stirred at room tem-
perature for 2 h. Then HCl (2 m aq.; 15 mL) was slowly added. The
solvents were removed by vacuum distillation. Water (20 mL) was
added, and the aqueous solution was extracted with EtOAc (2ϫ
30 mL). The organic extracts were combined, washed with water
(10 mL), and then dried with anhydrous MgSO4. The organic solu-
tion was evaporated under reduced pressure, and the residue was
purified by flash chromatography (eluent: EtOAc/hexane = 1:6) to
give pure compound 17 (1.270 g, 4.720 mmol, 94%) as a pale yel-
low solid. m.p. 57.0–57.5 °C. 1H NMR (400 MHz, CDCl3): δ =
8.09 (br. s, 1 H, NH in indole ring), 7.51 (d, J = 1.6 Hz, 1 H, 7-
H), 7.42 (d, J = 8.5 Hz, 1 H, 4-H), 7.25 (dd, J = 8.5, J = 1.6 Hz,
1 H, 5-H), 7.02 (d, J = 2.4 Hz, 1 H, 2-H), 4.64 (t, J = 7.1 Hz, 2 H,
CH2NO2), 3.45 (t, J = 7.1 Hz, 2 H, CH2CH2NO2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 136.97 (Ar), 125.59 (Ar), 123.28 (Ar),
123.16 (Ar), 119.41 (Ar), 116.01 (Ar), 114.42 (Ar), 110.21 (Ar),
N-[2-(1H-Indol-3-yl)ethyl]-2-(4-methoxyphenyl)acetamide
(10a):
White crystals. m.p. 152.5–153.0 °C; NMR (400 MHz, [D6]-
DMSO): δ = 10.82 (br. s, 1 H, NH in indole ring), 8.08 (br. s, 1 H,
NHCO), 7.52 (d, J = 7.8 Hz, 1 H, 7-H in indole), 7.34 (d, J =
7.8 Hz, 1 H, 4-H in indole), 7.15 (d, J = 8.6 Hz, 2 H, both ortho-
H in Ph), 7.11 (d, J = 2.1 Hz, 1 H, 2-H in indole), 7.07 (t, J =
7.8 Hz, 1 H, 6-H in indole), 6.97 (t, J = 7.8 Hz, 1 H, 5-H in indole),
6.84 (d, J = 8.6 Hz, 2 H, both meta-H in Ph), 3.72 (s, 3 H, OCH3),
3.32 (s, 2 H, ArCH2CONH), 3.36–3.27 (m, 2 H, CH2NHCO), 2.81
(t, J = 7.3 Hz, 2 H, CH2CH2NHCO) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 170.35 (CONH), 157.81 (Ar), 136.21 (Ar), 129.95
(Ar), 128.39 (Ar), 127.19 (Ar), 122.65 (Ar), 120.88 (Ar), 118.25
(Ar), 118.19 (Ar), 113.56 (Ar), 111.75 (Ar), 111.33 (Ar), 54.93
(OCH3), 41.56 (CH2NHCO), 40.06 (CH2CONH) 25.17
(CH2CH2NHCO) ppm. MS (EI): m/z (%) = 308 [M]+ (7), 149 (6),
144 (10), 143 (100), 130 (28), 121 (9). HRMS (ESI): calcd. for
C19H21N2O2 [M + H]+ 309.1603; found 309.1600.
75.70 (CH NO ), 23.42 (CH CH NO ) ppm. IR (KBr film): ν =
˜
2
2
2
2
2
N-[2-(1H-Indol-3-yl)ethyl]-2-(3-bromo-4-methoxyphenyl)acetamide
(10b): White crystals. m.p. 94.5–95.0 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.19 (br. s, 1 H, NH in indole ring), 7.53 (d, J =
7.8 Hz, 1 H, 7-H in indole), 7.36 (d, J = 7.8 Hz, 1 H, 4-H in indole),
7.32 (d, J = 1.8 Hz, 1 H, 2-H in indole), 7.20 (t, J = 7.8 Hz, 1 H,
6-H in indole), 7.11 (t, J = 7.8 Hz, 1 H, 5-H in indole), 7.01 (dd, J
= 8.0, J = 1.6 Hz, 1 H, 6Ј-H in Ph), 6.85 (d, J = 1.6 Hz, 1 H, 2Ј-
H in Ph), 6.74 (d, J = 8.0 Hz, 1 H, 5Ј-H in Ph), 5.49 (br. s, 1 H,
NHCO), 3.86 (s, 3 H, OCH3), 3.56–3.50 (m, 2 H, CH2NHCO),
3 . 3 9 ( s, 2 H , C H 2 C O N H ) , 2 . 9 1 ( t , J = 6 . 5 H z , 2 H ,
CH2CH2NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.74
(CONH), 155.02 (Ar), 136.39 (Ar), 134.04 (Ar), 129.60 (Ar), 128.41
(Ar), 127.17 (Ar), 122.29 (Ar), 122.14 (Ar), 119.44 (Ar), 118.59
(Ar), 112.47 (Ar), 112.18 (Ar), 111.77 (Ar), 111.37 (Ar), 56.30
(OCH3 ), 42.45 (CH2 NHCO), 39.78 (CH2CONH), 25.02
(CH2CH2NHCO) ppm. HRMS (ESI): calcd. for C19H20BrN2O2
[M + H]+ 387.0708; found 387.0712.
3389 (N–H), 1613, 1546, 1455, 1424, 1382, 1104, 1086, 805, 772,
704 cm–1. HRMS (ESI): calcd. for C10H10BrN2O2 [M + H]+
268.9926; found 268.9924.
3-(2-Aminoethyl)-6-bromo-1H-indole (9b): Compound 17 (1.350 g,
5.017 mmol) was dissolved in methanol (100 mL) and aqueous HCl
(2 m aq.; 100 mL), and zinc powder (5.885 g, 90.01 mmol) was
added in portions over 15 min. After the addition was finished, the
suspension was stirred and heated at reflux for 3 h. After being
cooled down to room temperature, the reaction mixture was fil-
tered, and the residue was washed with methanol (3ϫ 15 mL). The
organic solution was concentrated under reduced pressure to re-
move the solvents. A cooled aqueous solution of NaOH (15%
w/w; 20 mL) was added, and the resulting aqueous solution was
then extracted with diethyl ether (3ϫ 40 mL). The organic extracts
were combined and dried with anhydrous MgSO4. Removal of the
solvent by vacuum distillation gave a crude product, which was
purified by flash chromatography (eluent: dichloromethane/meth-
N-[2-(1H-Indol-3-yl)ethyl]-2-(3,5-dibromo-4-methoxyphenyl)-
anol/triethylamine = 50:5:1) to give pure compound 9b (1.092 g, acetamide (10c): White crystals. m.p. 98.0–100.0 °C. 1H NMR
4.567 mmol, 91%) as a colourless oil. 1H NMR (400 MHz,
CDCl3): δ = 8.52 (br. s, 1 H, NH in indole ring), 7.49 (s, 1 H, 7-
H), 7.45 (d, J = 8.4 Hz, 1 H, 4-H), 7.20 (d, J = 8.4 Hz, 1 H, 5-H),
(400 MHz, [D6]DMSO): δ = 10.81 (br. s, 1 H, NH in indole ring),
8.19 (br. s, 1 H, NHCO), 7.52 (s, 2 H, 2Ј-H and 6Ј-H in Ph), 7.51
(d, J = 7.8 Hz, 1 H, 7-H in indole), 7.33 (d, J = 7.8 Hz, 1 H, 4-H
6.98 (s, 1 H, 2-H), 3.02 (t, J = 6.6 Hz, 2 H, CH2CH2NH2), 2.88 (t, in indole), 7.13 (d, J = 1.6 Hz, 1 H, 2-H in indole), 7.06 (t, J =
J = 6.6 Hz, 2 H, CH2NH2), 1.39 (br. s, 2 H, NH2) ppm. 13C NMR 7.8 Hz, 1 H, 6-H in indole), 6.97 (t, J = 7.8 Hz, 1 H, 5-H in indole),
(100 MHz, CDCl3): δ = 137.32 (Ar), 126.39 (Ar), 122.95 (Ar), 3.78 (s, 3 H, OCH3), 3.34 (s, 2 H, CH2CONH), 3.40–3.31 (m, 2 H,
122.35 (Ar), 120.04 (Ar), 115.36 (Ar), 114.17 (Ar), 113.41 (Ar),
42.13 (CH NH ), 29.06 (CH CH NH ) ppm. IR (KBr film): ν =
3419 (br., N–H), 3356 (N–H), 3148, 2930, 2889, 1613, 1586, 1454,
1339, 1232, 1049, 893, 802 cm–1. HRMS (ESI): calcd. for
C10H12BrN2 [M + H]+ 239.0184; found 239.0175.
CH2NHCO), 2.82 (t, J = 7.5 Hz, 2 H, CH2CH2NHCO) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 169.14 (CONH), 151.87 (Ar),
136.23 (Ar), 135.86 (Ar), 133.29 (Ar), 133.28 (Ar), 127.16 (Ar),
122.64 (Ar), 120.90 (Ar), 118.21 (Ar), 116.97 (Ar), 111.70 (Ar),
111.37 (Ar), 60.31 (OCH3 ), 40.54 (CH2 NHCO), 39.76
˜
2
2
2
2
2
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Eur. J. Org. Chem. 2013, 3271–3277

Total Synthesis of Eudistomins Y1–Y7
(CH CONH), 25.15 (CH CH NHCO) ppm. IR (KBr film): ν = (3-Bromo-4-methoxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone
˜
2
2
2
3356 (N–H), 3284 (N–H), 3082, 2940, 1649 (C=O), 1625, 1592, (14b): Pale yellow solid. m.p. 196.0–196.5 °C. 1H NMR (400 MHz,
1564, 1488, 1466, 1423, 1271, 1062, 1026, 748 cm–1. HRMS (ESI):
calcd. for C19H19Br2N2O2 [M + H]+ 464.9813; found 464.9816.
[D6]DMSO): δ = 12.04 (br. s, 1 H, NH in indole ring), 8.57 (d, J
= 2.1 Hz, 1 H, 2Ј-H in Ph), 8.55 (d, J = 4.9 Hz, 1 H, 3-H), 8.45 (d,
J = 4.9 Hz, 1 H, 4-H), 8.37 (dd, J = 8.7, J = 2.1 Hz, 1 H, 6Ј-H in
Ph), 8.32 (d, J = 8.0 Hz, 1 H, 5-H), 7.81 (d, J = 8.0 Hz, 1 H, 8-H),
7.62 (t, J = 8.0 Hz, 1 H, 7-H), 7.32 (t, J = 8.0 Hz, 1 H, 6-H), 7.31
(d, J = 8.7 Hz, 1 H, 5Ј-H in Ph), 3.98 (s, 3 H, OCH3) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 190.26 (C=O), 158.62 (Ar),
141.62 (Ar), 137.02 (Ar), 136.33 (Ar), 135.83 (Ar), 135.67 (Ar),
132.81 (Ar), 131.02 (Ar), 130.85 (Ar), 128.91 (Ar), 121.76 (Ar),
120.13 (Ar), 120.01 (Ar), 118.79 (Ar), 112.95 (Ar), 111.79 (Ar),
N-[2-(6-Bromo-1H-indol-3-yl)ethyl]-2-(3,5-dibromo-4-methoxy-
phenyl)acetamide (10d): White crystals. m.p. 95.0–96.0 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 10.98 (br. s, 1 H, NH in indole
ring), 8.18 (br. s, 1 H, NHCO), 7.51 (s, 1 H, 7-H in indole), 7.50
(s, 2 H, 2Ј-H and 6Ј-H in Ph), 7.47 (d, J = 8.4 Hz, 1 H, 4-H in
indole), 7.17 (s, 1 H, 2-H in indole), 7.09 (d, J = 8.4 Hz, 1 H, 5-H
in indole), 3.78 (s, 3 H, OCH3), 3.39 (s, 2 H, CH2CONH), 3.34–
3 . 2 8 ( m , 2 H , C H 2 N H C O ) , 2 . 8 0 ( t , J = 7 . 1 H z , 2 H ,
CH2CH2NHCO) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
169.11 (CONH), 151.85 (Ar), 137.04 (Ar), 135.83 (Ar), 133.27 (Ar),
126.24 (Ar), 123.79 (Ar), 121.05 (Ar), 120.02 (Ar), 116.93 (Ar),
113.88 (Ar), 113.69 (Ar), 112.15 (Ar), 60.33 (OCH3), 40.46
(CH2NHCO), 39.96 (CH2CONH) 24.87 (CH2CH2NHCO) ppm.
110.00 (Ar), 56.62 (OCH ) ppm. IR (KBr film): ν = 3396 (N–H),
˜
3
3053, 2922, 2841, 1711 (weak, C=O), 1623, 1591, 1494, 1468, 1318,
1275, 1208, 1053, 1013, 978, 730 cm–1. HRMS (EI): calcd. for
C19H13BrN2O2 [M]+ 380.0160; found 380.0155.
(3,5-Dibromo-4-methoxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)-
IR (KBr film): ν = 3294 (br., N–H), 3079, 2927, 2852, 1647 (C=O),
˜
1
1627, 1546, 1471, 1454, 1419, 1261, 996, 802, 738 cm–1. HRMS
(ESI): calcd. for C19H18Br3N2O2 [M + H]+ 542.8918; found
542.8921.
methanone (14c): Pale yellow solid. m.p. 199.5–200.5 °C. H NMR
(400 MHz, [D6]DMSO): δ = 12.11 (br. s, 1 H, NH in indole ring),
8.57 (d, J = 4.9 Hz, 1 H, 3-H), 8.49 (d, J = 4.9 Hz, 1 H, 4-H), 8.47
(s, 2 H, both ortho-H in Ph), 8.33 (d, J = 7.9 Hz, 1 H, 5-H), 7.83
(d, J = 7.9 Hz, 1 H, 8-H), 7.62 (t, J = 7.9 Hz, 1 H, 7-H), 7.33 (t, J
= 7.9 Hz, 1 H, 6-H), 3.92 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 189.67 (C=O), 156.27 (Ar), 141.72
(Ar), 137.26 (Ar), 135.91 (Ar), 135.82 (Ar), 135.31 (Ar), 135.19
(Ar), 131.25 (Ar), 129.05 (Ar), 121.82 (Ar), 120.31 (Ar), 119.94
(Ar), 119.35 (Ar), 116.99 (Ar), 113.03 (Ar), 60.58 (OCH3) ppm. IR
General Procedure for the Preparation of Compounds 14a–d: Com-
pound 10 (5.000 mmol) was dissolved in EtOAc (60 mL), and
freshly distilled POCl3 (3.835 g, 25.01 mmol) was added. The re-
sulting solution was stirred at reflux for 1.5 h. When the reaction
was complete (checked by TLC), the mixture was cooled down to
room temperature in an ice-bath, then potassium carbonate (20%
w/w aq.; 50 mL) was added. The mixture was vigorously stirred for
15 min, then the two phases were separated. The aqueous phase
was re-extracted with EtOAc (30 mL). The organic extracts were
combined, washed with brine (10 mL), and dried with anhydrous
MgSO4. The organic solution was concentrated to dryness under
vacuum to give a tautomeric mixture of compounds 11 and 12,
which was used as such in the next step.
(KBr film): ν = 3433 (N–H), 3085, 2923, 2852, 1714 (weak, C=O),
˜
1637, 1618, 1592, 1465, 1427, 1315, 1255, 1207, 1062, 1013, 987,
728 cm–1. HRMS (EI): calcd. for C19H12Br2N2O2 [M]+ 460.1188;
found 460.1181.
(3,5-Dibromo-4-methoxyphenyl)(7-bromo-9H-pyrido[3,4-b]indol-1-
yl)methanone (14d): Pale yellow solid. m.p. 217.0–217.5 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 12.20 (br. s, 1 H, NH in indole
ring), 8.59 (d, J = 4.9 Hz, 1 H, 3-H), 8.51 (d, J = 4.9 Hz, 1 H, 4-
H), 8.47 (s, 2 H, both ortho-H in Ph), 8.31 (d, J = 8.4 Hz, 1 H, 5-
H), 7.99 (d, J = 1.6 Hz, 1 H, 8-H), 7.49 (dd, J = 8.4, J = 1.7 Hz,
1 H, 6-H), 3.92 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 189.58 (C=O), 156.34 (Ar), 142.47 (Ar), 137.77 (Ar),
135.92 (Ar), 135.62 (Ar), 135.21 (Ar), 135.20 (Ar), 130.59 (Ar),
123.64 (Ar), 123.27 (Ar), 121.83 (Ar), 119.48 (Ar), 119.12 (Ar),
The above tautomeric mixture of compounds 11 and 12 was dis-
solved in DMSO (15 mL), and DBU (1.525 g, 10.02 mmol) was
added. The reaction mixture was then stirred at room temperature
for 24–48 h. When the reaction was complete (checked by TLC),
the reaction solution was poured into water (60 mL), then the mix-
ture was extracted with EtOAc (3ϫ 60 mL). The organic extracts
were combined, washed with brine (20 mL), and dried with anhy-
drous MgSO4. Evaporation of the solvent gave a residue, which
was purified by flash chromatography (eluent: CH2Cl2/EtOAc =
9:1) to give compounds 14a–d in 78, 75, 70, and 72% yields, respec-
tively.
117.00 (Ar), 115.57 (Ar), 60.60 (OCH ) ppm. IR (KBr film): ν =
˜
3
3418 (N–H), 3089, 2925, 2855, 1713 (weak, C=O), 1637, 1616,
1587, 1529, 1462, 1417, 1276, 1205, 1060, 989, 895, 803, 729 cm–1.
HRMS (ESI): calcd. for C19H12Br3N2O2 [M + H]+ 536.8449; found
536.8450.
(4-Methoxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone (14a):
Pale yellow solid. m.p. 184.0–185.0 °C. H NMR (400 MHz, [D6]-
1
DMSO): δ = 12.01 (br. s, 1 H, NH in indole ring), 8.53 (d, J =
5.0 Hz, 1 H, 3-H), 8.43 (d, J = 5.0 Hz, 1 H, 4-H), 8.37–8.29 (m, 3
H, both ortho-H in Ph and 5-H in indole), 7.80 (d, J = 8.2 Hz, 1
General Procedure for the Preparation of Compounds 15a–c: Com-
pound 14 (1.000 mmol) was dissolved in a mixed solvent of acetoni-
H, 8-H), 7.62 (t, J = 8.2 Hz, 1 H, 7-H), 7.33 (t, J = 8.2 Hz, 1 H, trile (15 mL) and glacial acetic acid (5 mL), and NBS (0.196 g,
6-H), 7.13 (d, J = 7.1 Hz, 2 H, both meta-H in Ph), 3.88 (s, 3 H,
OCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 191.61 (C=O),
162.74 (Ar), 141.56 (Ar), 136.97 (Ar), 136.90 (Ar), 135.73 (Ar),
133.38 (Ar), 130.82 (Ar), 129.73 (Ar), 128.82 (Ar), 121.72 (Ar),
120.05 (Ar), 120.03 (Ar), 118.41 (Ar), 113.35 (Ar), 112.89 (Ar),
55.42 (OCH3) ppm. MS: m/z (%) = 302 (71) [M]+, 301 (100), 287
1.101 mmol) was added. The mixture was warmed and stirred at
45 °C for 30 min. Evaporation of the solvent under vacuum gave a
solid residue, which was then partitioned between EtOAc (30 mL)
and potassium carbonate (20% w/w aq.; 20 mL). The two phases
were separated, and the aqueous phase was extracted with EtOAc
(2ϫ 20 mL). The organic extracts were combined, washed success-
(11), 274 (31), 273 (44), 259 (10), 258 (8), 244 (8), 243 (6), 135 (20). ively with sodium sulfite (saturated aq.; 10 mL) and brine (15 mL).
IR (KBr film): ν = 3423 (N–H), 3002, 2919, 2844, 1710 (weak, After being dried with anhydrous MgSO4, the organic solution was
˜
C=O), 1620, 1599, 1566, 1463, 1313, 1249, 1218, 1170, 1028, 968,
850, 796 cm–1. HRMS (EI): calcd. for C19H14N2O2 [M]+ 302.1055;
found 302.1050.
concentrated under vacuum. The solid crude residue was purified
by flash chromatography (eluent: CHCl3/EtOAc = 9:1) to give com-
pounds 15a–c in 98, 98, and 99% yields, respectively.
Eur. J. Org. Chem. 2013, 3271–3277
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3275

X.-X. Shi et al.
FULL PAPER
(4-Methoxyphenyl)(6-bromo-9H-pyrido[3,4-b]indol-1-yl)methanone Eudistomin Y3 (3): Pale yellow solid. m.p. 246 °C (dec.). Character-
(15a): Pale yellow solid. m.p. 199.1–200.0 °C. 1H NMR (400 MHz, ization data were identical with the reported data.[9]
[D6]DMSO): δ = 12.14 (br. s, 1 H, NH in indole ring), 8.60 (s, 1
Eudistomin Y4 (4): Pale yellow solid. m.p. 260 °C (dec.). Character-
H, 5-H), 8.55 (d, J = 4.9 Hz, 1 H, 3-H), 8.48 (d, J = 4.9 Hz, 1 H,
ization data were identical with the reported data.[9]
4-H), 8.32 (d, J = 8.9 Hz, 2 H, both meta-H in Ph), 7.76–7.70 (m,
2 H, 7-H and 8-H), 7.11 (d, J = 8.9 Hz, 2 H, both ortho-H in Ph),
3.88 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
191.44 (C=O), 162.88 (Ar), 140.27 (Ar), 137.37 (Ar), 137.24 (Ar),
135.90 (Ar), 133.45 (Ar), 131.32 (Ar), 129.84 (Ar), 129.59 (Ar),
124.43 (Ar), 122.05 (Ar), 118.94 (Ar), 114.92 (Ar), 113.44 (Ar),
Eudistomin Y5 (5): Pale yellow solid. m.p. 270 °C (dec.). Character-
ization data were identical with the reported data.[9]
Eudistomin Y6 (6): Pale yellow solid. m.p. 291 °C (dec.). Character-
ization data were identical with the reported data.[9]
1
112.13 (Ar), 55.52 (OCH ) ppm. IR (KBr film): ν = 3405 (N–H),
˜
3
Eudistomin Y7 (7): Pale yellow solid. m.p. 298 °C (dec.). H NMR
2926, 1709 (weak, C=O), 1616, 1597, 1471, 1252, 1215, 1167, 974,
849, 795 cm–1. HRMS (EI): calcd. for C19H13BrN2O2 [M]+
380.0160; found 380.0161.
(400 MHz, [D6]DMSO): δ = 11.98 (br. s, 1 H, NH in indole ring),
8.55 (d, J = 5.0 Hz, 1 H, 3-H), 8.50 (s, 2 H, 12-H and 16-H), 8.40
(d, J = 5.0 Hz, 1 H, 4-H), 8.28 (d, J = 8.4 Hz, 1 H, 5-H), 7.94 (d,
J = 1.5 Hz, 1 H, 8-H), 7.44 (dd, J = 8.4, J = 1.5 Hz, 1 H, 6-H)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 187.39 (C=O), 159.46
(Ar), 158.43 (Ar), 142.24 (Ar), 137.74 (Ar), 137.36 (Ar), 135.66
(Ar), 135.40 (Ar), 130.09 (Ar), 123.59 (Ar), 122.93 (Ar), 121.55
(Ar), 119.25 (Ar), 118.31 (Ar), 115.40 (Ar), 112.42 (Ar) ppm. IR
(3-Bromo-4-methoxyphenyl)(6-bromo-9H-pyrido[3,4-b]indol-1-yl)-
1
methanone (15b): Pale yellow solid. m.p. 189.2–190.0 °C. H NMR
(400 MHz, [D6]DMSO): δ = 12.17 (br. s, 1 H, NH in indole ring),
8.61 (s, 1 H, 5-H), 8.59–8.54 (m, 2 H, 3-H in indole and 2Ј-H in
Ph), 8.51 (d, J = 4.6 Hz, 1 H, 4-H), 8.36 (d, J = 8.6 Hz, 1 H, 6Ј-H
in Ph), 7.78–7.70 (m, 2 H, 7-H and 8-H), 7.31 (d, J = 8.6 Hz, 1 H,
5Ј-H in Ph), 3.98 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 190.04 (C=O), 158.67 (Ar), 140.26 (Ar), 137.27 (Ar),
136.65 (Ar), 135.93 (Ar), 135.66 (Ar), 132.83 (Ar), 131.34 (Ar),
130.65 (Ar), 129.96 (Ar), 124.38 (Ar), 121.94 (Ar), 119.24 (Ar),
114.91 (Ar), 112.18 (Ar), 111.79 (Ar), 110.00 (Ar), 56.64 (OCH3)
(KBr film): ν = 3395 (N–H, O–H), 3057, 2962, 2923, 2853, 1724
˜
(weak, C=O), 1652, 1618, 1585, 1462, 1422, 1388, 1282, 1262, 1235,
1205, 1095, 1048, 1022, 801, 723, 645 cm–1. HRMS (ESI): calcd.
for C18H10Br3N2O2 [M + H]+ 522.8292; found 522.8292.
Supporting Information (see footnote on the first page of this arti-
cle): Procedure for preparation of compounds 8b and 8c; Charac-
terization data for compounds 8b, 8c, 16, and 19a–i; 1H and 13C
NMR spectra for compounds 1–7, 8b, 8c, 9b, 10a–d, 14a–d, 15a–c,
16, 17, and 19a–i.
ppm. IR (KBr film): ν = 3399 (N–H), 3052, 2963, 2921, 2840, 1707
˜
(weak, C=O), 1621, 1589, 1493, 1469, 1317, 1273, 1208, 1051, 1013,
979, 731 cm–1. HRMS (EI): calcd. for C19H12Br2N2O2 [M]+
457.9265; found 457.9264.
(3,5-Dibromo-4-methoxyphenyl)(6-bromo-9H-pyrido[3,4-b]indol-1-
yl)methanone (15c): Pale yellow solid. m.p. 241.0–241.5 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 12.22 (br. s, 1 H, NH in indole
ring), 8.61 (s, 1 H, 5-H), 8.58 (d, J = 4.9 Hz, 1 H, 3-H), 8.52 (d, J
= 4.9 Hz, 1 H, 4-H), 8.45 (s, 2 H, both ortho-H in Ph), 7.80–7.72
(m, 2 H, 7-H and 8-H), 3.91 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 189.70 (C=O), 156.36 (Ar), 140.41
(Ar), 137.60 (Ar), 135.99 (Ar), 135.74 (Ar), 135.70 (Ar), 135.19
(Ar), 131.55 (Ar), 130.22 (Ar), 124.52 (Ar), 121.91 (Ar), 119.89
(Ar), 117.02 (Ar), 115.03 (Ar), 112.40 (Ar), 60.64 (OCH3) ppm. IR
Acknowledgments
The authors thank the National Natural Science Foundation of
China (NSFC) (grant number 20972048) and the Shanghai Educa-
tional Development Foundation (The Dawn Program, grant
number 03SG27) for financial support for this work. T. H. T.
thanks the Ministry of Education and Training, Vietnam for finan-
cial support.
(KBr film): ν = 3424 (N–H, O–H), 2924, 2854, 1710 (weak, C=O),
˜
1634, 1619, 1470, 1273, 1261, 1210, 995 cm–1. HRMS (EI): calcd.
for C19H11Br3N2O2 [M]+ 535.8371; found 535.8374.
[1] a) K. L. Rinehart Jr., J. Kobayashi, G. C. Harbour, R. G.
Hughes Jr, S. A. Mizsak, T. A. Scahill, J. Am. Chem. Soc. 1984,
106, 1524–1526; b) J. Kobayashi, G. C. Harbour, J. Gilmore,
K. L. Rinehart Jr., J. Am. Chem. Soc. 1984, 106, 1526–1528; c)
K. L. Rinehart Jr., J. Kobayashi, G. C. Harbour, J. Gilmore,
M. Mascal, T. G. Holt, L. S. Shield, F. Lafargue, J. Am. Chem.
Soc. 1987, 109, 3378–3387.
[2] a) J. Kobayashi, H. Nakamura, Y. Ohizumi, Y. Hirata, Tetrahe-
dron Lett. 1986, 27, 1191–1194; b) J. Kobayashi, J.-f. Cheng, T.
Ohta, S. Nozoe, Y. Ohizumi, T. Sasaki, J. Org. Chem. 1990,
55, 3666–3670; c) O. Murata, H. Shigemori, M. Ishibashi, K.
Sugama, K. Hayashi, J. Kobayashi, Tetrahedron Lett. 1991, 32,
3539–3542.
General Procedure for the Preparation of Eudistomins Y1–Y7 (1–7):
Compound 14 or 15 (1.000 mmol) was dissolved in a mixed solvent
of acetic acid (20 mL) and aqueous HBr solution (40% w/w;
10 mL). The mixture was heated and stirred at 110 °C for 24–50 h.
When the reaction was complete (checked by TLC), the acetic acid
was removed by vacuum distillation. Ethyl acetate (50 mL) was
added. While the mixture was vigorously stirred, potassium car-
bonate (20% w/w aq.) was slowly added to adjust the pH to 8.5.
The two phases were separated, and the aqueous phase was ex-
tracted with EtOAc (2ϫ 15 mL). The organic extracts were com-
bined and washed successively with water (10 mL) and brine
(10 mL). After being dried with anhydrous MgSO4, the organic
solution was concentrated under vacuum. The solid crude residue
was purified by flash chromatography (eluent: CHCl3/EtOAc = 4:1)
to give eudistomins Y1–Y7 (1–7) in 92, 93, 92, 95, 95, 94, and 93%
yields, respectively.
[3] K. F. Kinzer, J. H. Cardellina II, Tetrahedron Lett. 1987, 28,
925–926.
[4] A. Badre, A. Boulanger, E. Abou-Mansour, B. Banaigs, G.
Combaut, C. Francisco, J. Nat. Prod. 1994, 57, 528–533.
[5] R. A. Davis, A. R. Carroll, R. J. Quinn, J. Nat. Prod. 1998, 61,
959–960.
[6] P. Schupp, T. Poehner, R. Edrada, R. Ebel, A. Berg, V. Wray,
P. Proksch, J. Nat. Prod. 2003, 66, 272–275.
[7] W. Wang, S.-J. Nam, B.-C. Lee, H. Kang, J. Nat. Prod. 2008,
71, 163–166.
[8] T. H. Won, J.-e. Jeon, S.-H. Lee, B. J. Rho, K.-B. Oh, J. Shin,
Bioorg. Med. Chem. 2012, 20, 4082–4087.
Eudistomin Y1 (1): Pale yellow solid. m.p. 220 °C (dec.). Character-
ization data were identical with the reported data.[9]
Eudistomin Y2 (2): Pale yellow solid. m.p. 245 °C (dec.). Character-
ization data were identical with the reported data.[9]
3276
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Total Synthesis of Eudistomins Y1–Y7
[9]
[11] L. S. Santos, R. A. Pilli, V. H. Rawal, J. Org. Chem. 2004, 69,
1283–1289.
[12] M. D. Garcia, A. J. Wilson, D. P. G. Emmerson, P. R. Jenkins,
Chem. Commun. 2006, 2586–2588.
[13] J. Dong, X.-X. Shi, J.-J. Yan, J. Xing, Q. Zhang, S. Xiao, Eur.
J. Org. Chem. 2010, 6987–6992.
J. P. Kennedy, M. L. Breininger, C. W. Lindsley, Tetrahedron
Lett. 2009, 50, 7067–7069.
[10] a) W. M. Whaley, T. R. Govindachari, Org. React. 1951, 6, 74–
150; b) A. Bischler, B. Napieralski, Ber. Dtsch. Chem. Ges.
1893, 26, 1903–1908; c) G. Fodor, S. Nagubandi, Tetrahedron
1980, 36, 1279–1300; d) M. Movassaghi, M. D. A. Hill, Org.
Lett. 2008, 10, 3485–3488.
Received: January 16, 2013
Published Online: April 5, 2013
Eur. J. Org. Chem. 2013, 3271–3277
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3277