Synthesis of hyrtiosin B, a bis-indole alkaloid from the Okinawan marine sponge Hyrtios erecta

Article abstract of DOI:10.1055/s-1999-3439

The bis-indole alkaloid hyrtiosin B (1) has been prepared in good yield from 5-benzyloxyindole (4a) or 5-methoxyindole (4b), involving a coupling reaction of the zinc metallated indoles with the corresponding glyoxylyl chlorides 5a-b, and finally debenzyl

Full text of DOI:10.1055/s-1999-3439

580
SHORT PAPER
Synthesis of Hyrtiosin B, a Bis-indole Alkaloid from the Okinawan Marine
Sponge Hyrtios erecta
Jan Bergman,* Tomasz Janosik, Ann-Louise Johnsson
Department of Organic Chemistry, KI, Novum Research Park, SE-141 57 Huddinge, Sweden
Fax +46(8)6081501; E-mail: jabe@cnt.ki.se
Received 16 July 1998; revised 23 November 1998
yields (36–65%) (Scheme). Acylation of zincated indoles
Abstract: The bis-indole alkaloid hyrtiosin B (1) has been prepared
has previously been shown to give yields superior to those
in good yield from 5-benzyloxyindole (4a) or 5-methoxyindole
resulting from acylation of indole magnesium halides.6
The final O-dealkylation was accomplished by treatment
(4b), involving a coupling reaction of the zinc metallated indoles
with the corresponding glyoxylyl chlorides 5a–b, and finally de-
benzylation or demethylation using boron tribromide to yield the of 6a–b with boron tribromide in dichloromethane to give
title compound 1.
hyrtiosin B (1) in good yields (79–81%) after purification
by column chromatography. The benzyl derivative 6a was
debenzylated easily with BBr3 (4 equiv), whereas demeth-
ylation of 6b required a larger excess of BBr3 (12 equiv)
and longer reaction times. Attempted catalytic debenzyla-
tions of 6a in ethanol or methanol failed, as did attempted
dealkylations using Prey's method7 (reflux in pyridine hy-
drochloride). The spectral data of synthetic hyrtiosin B
were identical in all respects with those of the natural
product. The possibility to prepare a wide diversity of un-
symmetrical derivatives was demonstrated by preparation
of compound 6c by treatment of 1-indolylmagnesium
bromide with 5a as outlined in the Scheme.
Key words: hyrtiosin B, bis-indole alkaloids, transmetallation,
O-dealkylation
Several classes of compounds have been isolated from
marine organisms belonging to the genus Hyrtios, such as
terpenoids1 and sterols.2 In 1990, the first isolation of al-
kaloids from this genus was reported;3 hyrtiosin B (1), a
bis-indole alkaloid, was found in the Okinawan marine
sponge Hyrtios erecta together with the related com-
pounds hyrtiosin A (2) and the previously reported 5-hy-
droxyindole-3-carboxaldehyde
(3),4
and
was
demonstrated to possess cytotoxic activity against human
epidermoid carcinoma KB cells in vitro.
Cl
O
(COCl)2, Et2O
0˚C, 1h
O
X
X
H
N
N
H
N
H
OH
O
4a X=OBn
4b X=OMe
5a X=OBn (87%)
5b X=OMe (88%)
O
HO
1
H
N
N
H
1. EtMgBr
2. ZnCl2
3. 5a or 5b
4. H+
O
Y
Y
CHO
O
OH
HO
HO
O
N
H
X
N
N
4a Y=OBn
4b Y=OMe
4c Y=H
H
H
N
H
2
3
6a X=Y=OBn (65%)
6b X=Y=OMe (36%)
6c X=OBn, Y=H (52%)
BBr3, CH2Cl2
-78˚C to r.t. 18-72h
We now describe a short and efficient synthesis of 1 in
three steps from 5-benzyloxyindole (4a) or 5-methoxyin-
dole (4b). The indoles 4a or 4b were transformed in excel-
lent yields into the corresponding indole-3-glyoxylyl
chlorides 5a–b according to the procedure of Speeter and
Anthony.5 The key step in our approach is a coupling re-
action involving transmetallation of the indole magne-
sium halides based on the indoles 4a or 4b with anhydrous
zinc chloride,6 and subsequent treatment of the resulting
zincated indoles with acid chlorides 5a–b, which afforded
the symmetrical coupled products 6a–b in moderate
1 X=Y=OH (79% from 6a, 81% from 6b)
7 X=OH, Y=H (82%)
Scheme
The monobenzyloxy substituted compound 6c was simi-
larly debenzylated using boron tribromide to yield the hy-
droxy derivative 7, a compound closely related to
hyrtiosin B (1). A compound structurally related to 7 (Cl
instead of OH) has previously been prepared by Van
Synthesis 1999, No. 4, 580–582 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Hyrtiosin B
581
Vranken et al.8 using the technique previously developed
by Bergman and Venemalm.6
1,2-Di(5-methoxyindol-3-yl)ethane-1,2-dione (6b)
To a solution of EtMgBr prepared from Mg (102 mg, 4.20 mmol)
and bromoethane (0.315 mL, 4.22 mmol) in Et2O (10 mL) was add-
ed a solution of 4b (588 mg, 4.00 mmol) in Et2O (15 mL) at r.t. After
15 min a 1.0 M Et2O solution of ZnCl2 (4.1 mL, 4.1 mmol) was add-
ed and the mixture was stirred for 30 min. Compound 5b (954 mg,
4.01 mmol) was then added in one portion, and the stirring was con-
tinued for 3.5 h. Workup with sat. aq NH4Cl solution (50 mL) and
extraction with EtOAc (100 mL) [in this case addition of MeOH (2
mL) was necessary in order to obtain a clear two-phase mixture],
washing of the organic extracts with brine, drying (MgSO4) and
subsequent evaporation of the solvent gave a residue that afforded
6b (455 mg) as a pink solid after trituration with EtOH (15 mL). A
second crop (50 mg) was collected after concentration of the mother
liquor; yield: 505 mg (36%); mp 309–310°C.
5-Benzyloxyindole and 5-methoxyindole were purchased from
Lancaster and Aldrich respectively. ZnCl2 (1.0 M solution in Et2O)
was purchased from Aldrich. BBr3 (1.0 M solution in CH2Cl2) was
purchased from Lancaster. All solvents were purified by distilla-
tion, Et2O was stored over sodium wire. The equipment for the an-
hydrous reactions was dried in an oven and was assembled hot.
NMR spectra were recorded on a Bruker DPX 300 spectrometer
(300 MHz, TMS) and the IR spectra were recorded using a Perkin
Elmer 1600 FT-IR instrument. Mass spectra were obtained using a
Micromass Platform II spectrometer. Elemental analyses were per-
formed by H. Kolbe Mikroanalytisches Laboratorium, Mülheim an
der Ruhr, Germany. Melting points were taken on a Büchi Melting
Point B-545 apparatus and are uncorrected. Chromatography was
performed on Merck silica gel 60, TLC analyses were run on Merck
silica gel F254 plates.
IR (KBr): n = 3190, 1606, 1477, 1426, 1265, 1211, 783, 710 cm–1.
1H NMR (DMSO-d6): d = 3.83 (s, 6 H), 6.92 (dd, J = 2.5, 8.8 Hz, 2
H), 7.44 (d, J = 8.8 Hz, 2 H), 7.79 (d, J = 2.4 Hz, 2 H), 8.17 (s, 2 H),
12.13 (br s, 2H).
13C NMR (DMSO-d6): d = 55.3 (q), 103.1 (d), 112.4 (s), 113.2 (d),
(5-Benzyloxyindol-3-yl)glyoxylyl Chloride (5a)
113.4 (d), 126.6 (s), 131.5 (s), 137.4 (d), 155.9 (s), 188.7 (s).
A solution of 5-benzyloxyindole (4a; 1.12 g, 5.04 mmol) in anhyd
Et2O (20 mL) was cooled to 0°C. Oxalyl chloride (0.45 mL, 5.15
mmol) was added dropwise, producing an orange precipitate. The
mixture was stirred at 0°C for 1 h, thereafter 5a was collected as an
orange solid, washed with anhyd Et2O and dried; yield: 1.38 g
(87%). The product was used immediately in the next step, or was
stored in a dessicator; mp 149–151°C (dec) [Lit.5 mp 146–150°C
(dec)].
MS (EI, 70 eV): m/z = 348 (M+, 5), 175 (11), 174 (100), 159 (18),
146 (17), 131 (23), 119 (11), 103 (17), 76 (14).
HRMS (EI): m/z Calcd for C20H16N2O4: 348.1110. Found:
348.1094.
Hyrtiosin B (1) by Debenzylation of 6a
A 1.0 M solution of BBr3 in CH2Cl2 (4.0 mL, 4.0 mmol) was added
dropwise to a stirred suspension of 6a (500 mg, 1.00 mmol) in
CH2Cl2 (20 mL) at –78°C under N2 atmosphere. The mixture was
allowed to reach r.t. over 18 h and H2O (30 mL) was added. Extrac-
tion of the mixture with three portions of EtOAc (total 120 mL),
washing of the combined extracts with brine, drying (MgSO4) and
finally evaporation of the solvent gave a brown residue, which was
subjected to column chromatography using EtOAc as eluent to yield
pure hyrtiosin B (1) (254 mg, 79%) as a pale green solid; mp
>400°C (Lit.3 mp >310°C).
IR(KBr): n = 3189, 1784, 1630, 1474, 1430, 1266, 988, 775, 716
cm–1.
(5-Methoxyindol-3-yl)glyoxylyl Chloride (5b)
The same procedure as above was used, with 5-methoxyindole (4b;
735 mg, 5.00 mmol) and oxalyl chloride (0.45 mL, 5.15 mmol);
yield: 1.05 g (88%); orange solid; mp 137–138°C (dec) (Lit.9 mp
134°C).
IR(KBr): n = 3195, 1781, 1624, 1476, 1427, 1267, 991, 774, 706
cm–1.
IR(KBr): n = 3259 (br), 1595, 1514, 1466, 1421, 1202, 786, 723
cm–1.
1,2-Di(5-benzyloxyindol-3-yl)ethane-1,2-dione (6a)
1H NMR (DMSO-d6): d = 6.76 (dd, J = 2.3, 8.7 Hz, 2 H), 7.32 (d, J
= 8.7 Hz, 2 H), 7.66 (d, J = 2.0 Hz, 2 H), 8.03 (d, J = 3.3 Hz, 2 H),
9.13 (br s, 2 H), 11.97 (d, J = 2.7 Hz, 2 H).
13C NMR (DMSO-d6): d = 105.8 (d), 112.1 (s), 113.0 (d), 113.1 (d),
126.8 (s), 130.8 (s), 136.9 (d), 153.6 (s), 188.8 (s).
To a solution of EtMgBr prepared from Mg (78 mg, 3.21 mmol) and
bromoethane (0.24 mL, 3.22 mmol) in Et2O (10 mL) was added a
solution of 4a (670 mg, 3.01 mmol) in Et2O (15 mL) at r.t. The mix-
ture was allowed to stir for 15 min, then a 1.0 M Et2O solution of
ZnCl2 (3.1 mL, 3.1 mmol) was added, and the stirring was contin-
ued for 30 min, followed by addition of 5a (941 mg, 3.00 mmol) in
one portion. After stirring at r.t. for 3.5 h, the mixture was quenched
with sat. aq NH4Cl solution (50 mL), and extracted with EtOAc
(100 mL). The organic phase was washed with brine (30 mL), dried
(MgSO4) and evaporated to dryness. Trituration of the residue with
EtOH (15 mL) afforded 6a as a yellow solid (710 mg). A second
crop (260 mg) was collected after concentration of the mother li-
quor; total yield: 970 mg (65%); mp 233°C.
Anal. Calcd for C18H12N2O4: C, 67.50; H, 3.78; N, 8.75. Found: C,
67.38; H, 3.84; N, 8.62.
Hyrtiosin B (1) by Demethylation of 6b
A 1.0 M solution of BBr3 in CH2Cl2 (6.0 mL, 6.0 mmol) was added
to a suspension of 6b (174 mg, 0.50 mmol) in CH2Cl2 (15 mL) at
–78°C under a N2 atmosphere. The mixture was allowed to reach r.t.
over 72 h. The same workup procedure as above yielded hyrtiosin
B (1) (130 mg, 81%) as a pale green solid, in all respects identical
with the sample prepared by debenzylation of 6a.
IR(KBr): n = 3386, 3319, 1596, 1506, 1425, 1252, 1188, 1113, 784
cm–1.
1H NMR (DMSO-d6): d = 5.20 (s, 4 H), 7.00 (dd, J = 2.5, 8.8 Hz, 2
H), 7.33–7.52 (m, 12 H), 7.89 (d, J = 2.2 Hz, 2 H), 8.16 (d, J = 2.9
Hz, 2 H), 12.15 (d, J = 2.2 Hz, 2 H).
13C NMR (DMSO-d6): d = 69.7 (t), 104.6 (d), 112.4 (s), 113.4 (d),
113.7 (d), 126.5 (s), 127.6 (d), 127.7 (d), 128.4 (d), 131.7 (s), 137.4
(d), 154.9 (s), 188.7 (s).
1-(5-Benzyloxyindol-3-yl)-2-(indol-3-yl)-ethane-1,2-dione (6c)
1-Indolylmagnesium bromide in Et2O (15 mL), prepared from Mg
(102 mg, 4.20 mmol), bromoethane (0.315 mL, 4.22 mmol) and in-
dole (468 mg, 4.00 mmol), was transmetallated by treating with a
1.0 M solution of ZnCl2 in Et2O (4.1 mL, 4.1 mmol) at r.t. The re-
sulting mixture was stirred for 30 min. Compound 5a (1.25 g, 3.92
mmol) was added in one portion, and stirring was continued for 16
h. The mixture was quenched with sat. aq NH4Cl solution (50 mL)
Anal. Calcd for C32H24N2O4: C, 76.79; H, 4.83; N, 5.60. Found: C,
76.88, H, 4.81; N, 5.62.
Synthesis 1999, No. 4, 580–582 ISSN 0039-7881 © Thieme Stuttgart · New York

582
J. Bergman et al.
SHORT PAPER
and extracted with EtOAc (100 mL). The organic extract was
washed with brine (50 mL) and dried (MgSO4). Evaporation of the
solvent gave an orange residue, which was triturated with Et2O (20
mL) containing EtOH (1 mL) to give 6c (810 mg, 52%) as a cream
coloured solid; mp 210.5–211.5°C.
2.2 Hz, 1 H), 8.06 (s, 1 H), 8.19 (s, 1 H), 8.24-8.27 (m, 1 H), 9.16
(br s, 1 H), 12.08 (br s, 2 H).
13C NMR (DMSO-d6): d = 105.6 (d), 112.1 (s), 112.5 (d), 112.6 (s),
113.0 (d), 113.2 (d), 121.3 (d), 122.4 (d), 123.4 (d), 125.6 (s), 126.8
(s), 130.8 (s), 136.7 (s), 137.0 (d), 137.2 (d), 153.6 (s), 188.5 (s),
189.1 (s).
IR(KBr): n = 3232 (br), 1598, 1511, 1436, 1241, 1122, 782, 742
cm–1.
1H NMR (DMSO-d6): d = 5.17 (s, 2 H), 7.01 (dd, J = 2.5, 8.8 Hz, 1
H), 7.28–7.57 (m, 9 H), 7.90 (d, J = 2.4 Hz, 1 H), 8.17 (d, J = 3.2
Hz, 1 H), 8.23 (d, J = 3.1 Hz, 1 H), 8.27–8.30 (m, 1 H), 12.16 (d, J
= 2.5 Hz, 1 H), 12.25 (d, J = 2.4 Hz, 1 H).
MS (EI, 70 eV): m/z = 304 (M+, 11), 160 (90), 144 (100), 132 (42),
116 (53), 105 (33), 89 (73), 77 (27).
HRMS (EI): m/z Calcd for C18H12N2O3: 304.0848. Found:
304.0844.
13C NMR (DMSO-d6): d = 69.7 (t), 104.7 (d), 112.4 (s), 112.5 (s),
112.6 (d), 113.4 (d), 113.7 (d), 121.3 (d), 122.4 (d), 123.4 (d), 125.6
(s), 126.5 (s), 127.6 (d), 127.7 (d), 128.4 (d), 131.7 (s), 136.7 (s),
137.3 (d), 137.4 (d), 137.4 (s), 154.9 (s), 188.6 (s), 188.8 (s).
MS (EI, 40 eV): m/z = 394 (M+, 2), 251 (11), 250 (67), 160 (14), 159
(30), 144 (76), 131 (29), 116 (21), 103 (11), 91 (100), 89 (14).
References
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Helv. Chim. Acta 1983, 66, 1672.
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690.
HRMS (EI): m/z Calcd for C25H18N2O3: 394.1317. Found:
394.1320.
(2) Koch, P.; Djerassi, C.; Lakshmi, V.; Schmitz, F. J. Helv.
Chim. Acta 1983, 66, 2431.
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25, 435.
1-(5-Hydroxyindol-3-yl)-2-(indol-3-yl)-ethane-1,2-dione (7)
To a suspension of 6c (197 mg, 0.50 mmol) in CH2Cl2 (15 mL) at
–78°C under N2 atmosphere was added a 1.0 M solution of BBr3 in
CH2Cl2 (3.0 mL, 3.0 mmol). The mixture was allowed to reach r.t.
over 24 h, H2O (30 mL) was added, followed by extraction with
EtOAc (75 mL). The aqueous phase was extracted once more with
EtOAc (25 mL). Washing of the combined organic extracts with
brine, drying (MgSO4), evaporation of the solvent and finally col-
umn chromatography (elution with EtOAc) gave 7 as a pale green
solid (125 mg, 82%); mp 271–272°C.
(5) Speeter, M. E.; Anthony, W.C. J. Am. Chem. Soc. 1954, 76,
6208.
(6) Bergman, J.; Venemalm, L. Tetrahedron 1990, 46, 6061.
(7) (a) Prey, V. Ber. Dtsch. Chem. Ges. 1941, 74, 1219.
(b) Prey, V. Ber. Dtsch. Chem. Ges. 1942, 75, 350.
(8) Gilbert, E. J.; Ziller, J. W.; Van Vranken, D. L. Tetrahedron
1997, 53, 16553.
IR(KBr): n = 3408, 3291, 3244, 1597, 1508, 1423, 1240, 1112, 780,
729 cm–1.
1H NMR (DMSO-d6): d = 6.77 (dd, J = 2.3, 8.7 Hz, 1 H), 7.25–7.29
(m, 2 H), 7.33 (d, J = 8.7 Hz, 1 H), 7.52-7.55 (m, 1 H), 7.68 (d, J =
(9) Takatori, K.; Takashima, M. Yakugaku Zasshi 1963, 83, 795.
Synthesis 1999, No. 4, 580–582 ISSN 0039-7881 © Thieme Stuttgart · New York