Spinazarin and ethylspinazarin, pigments of the sea urchin Scaphechinus mirabilis

Article abstract of DOI:10.1007/s11172-007-0122-0

2,3,5,8-Tetrahydroxy-1,4-naphthoquinone (spinazarin) and 6-ethyl-2,3,5,8-tetrahydroxy-1,4-naphthoquinone (ethylspinazarin) were first isolated from the sea urchin Scaphechinus mirabilis. The structures of spinazarins were established based on analysis of spectroscopic data. A preparative synthetic route to ethylspinazarin was proposed.

Full text of DOI:10.1007/s11172-007-0122-0

Russian Chemical Bulletin, International Edition, Vol. 56, No. 4, pp. 819—822, April, 2007
819
Spinazarin and ethylspinazarin, pigments
of the sea urchin Scaphechinus mirabilis
A. Ya. Yakubovskaya, N. D. Pokhilo, N. P. Mishchenko, and V. F. Anufrievꢀ
Pacific Institute of Bioorganic Chemistry of the FarꢀEastern Branch of the Russian Academy of Sciences,
159 prosp. 100 let Vladivostoku, 690022 Vladivostok, Russian Federation.
Fax: +7 (423 2) 31 4050. Eꢀmail: anufriev@piboc.dvo.ru
2,3,5,8ꢀTetrahydroxyꢀ1,4ꢀnaphthoquinone (spinazarin) and 6ꢀethylꢀ2,3,5,8ꢀtetrahydroxyꢀ
1,4ꢀnaphthoquinone (ethylspinazarin) were first isolated from the sea urchin Scaphechinus
mirabilis. The structures of spinazarins were established based on analysis of spectroscopic
data. A preparative synthetic route to ethylspinazarin was proposed.
Key words: 5,8ꢀdihydroxyꢀ1,4ꢀnaphthoquinone, naphthazarin; 2,3,5,8ꢀtetrahydroxyꢀ1,4ꢀ
naphthoquinone, spinazarin; 6ꢀethylꢀ2,3,5,8ꢀtetrahydroxyꢀ1,4ꢀnaphthoquinone, ethylꢀ
spinazarin; sea urchin, Scaphechinus mirabilis.
Among natural products containing a 5,8ꢀdihydroxyꢀ
1,4ꢀnaphthoquinonoid (naphthazarin) fragment, considꢀ
erable interest is aroused by the group of echinodermata
pigments (spinochromes).1 Some spinochromes such as
echinochrome and its synthetic analogs are known as bioꢀ
logically active compounds2 and drugs.3 However, no data
on isolation of new compounds of this type have been
reported during the last two decades.4 Amineꢀcontaining
polyhydroxynaphthazarins, echinamines A and B, isoꢀ
lated recently from the sea urchin Scaphechinus mirabilis
are the only exception.
The sea urchin S. mirabilis is the main source of
echinochrome, the substance of a cardiological and
ophthalmological drug;3 therefore, study of the pigments
present in this material has not only a fundamental but
also a practical value. Data on the structure and biological
activities of echinochromeꢀaccompanying pigments form
the basis for standardization of a drug and a factor deterꢀ
mining its quality.
To continue research along this line, using chromaꢀ
tography, we isolated two minor pigments from the alꢀ
cohol extract of S. mirabilis. According to IR and
NMR spectroscopy and mass spectrometry data, one of
these was identified as 2,3,5,8ꢀtetrahydroxyꢀ1,4ꢀnaphthoꢀ
quinone (spinazarin, 1). The structure of the isolated pigꢀ
ment 1 was confirmed by direct comparison with a synꢀ
thetic sample.6 It is noteworthy that this pigment was
isolated for the first time from a natural source.
attests unambiguously to the 6ꢀethylꢀ2,3,5,8ꢀtetrahydrꢀ
oxyꢀ1,4ꢀnaphthoquinone structure (ethylspinazarin, 2).
Ethylspinazarin (2) is a new compound isolated from a
natural material. The isomeric ethylmompain was previꢀ
ously isolated from the sea urchins Echinothrix,7 while
ethylisomompain was synthesized.8
We found that ethylspinazarin (2) is present as an
impurity in synthetic echinochrome prepared from pyroꢀ
gallol A (3).9 The content of spinochrome 2 in the synꢀ
thetic echinochrome samples varies within 0.12—0.63%.
Unlike spinazarin (1), the molecule of the second comꢀ
pound isolated from the extract contained an ethyl fragꢀ
1
ment, as shown by H NMR (δ 1.24 and 2.72) and mass
spectrometry. The methylene protons of this fragment
and the proton of the naphthazarin nucleus exhibit an
allylic spin—spin coupling constant (J = 0.9 Hz), which
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 788—791, April, 2007.
1066ꢀ5285/07/5604ꢀ0819 © 2007 Springer Science+Business Media, Inc.

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Yakubovskaya et al.
naphthazarin 8. The replacement of chlorine atoms in
compound 8 by methoxy groups followed by hydrolysis of
the resulting dimethyl ether 9 furnishes the final product 2.
As noted above, pigments 1 and 2 are minor compoꢀ
nents, their content in S. mirabilis being ~0.0003%. Thereꢀ
fore, synthesis appears to be the only reliable source of
these compounds in amounts required to study their bioꢀ
logical properties. Our task was to develop the synthesis of
ethylspinazarin (2), because the methods for the synthesis
of pigment 1 have been described previously.6
While implementing Scheme 1 for this purpose, we
found that over broad ranges of concentrations and temꢀ
peratures, including those described previously,10b hydroꢀ
quinone diacetate (4) is converted only into a 1 : 1 mixꢀ
ture of monoacyl derivative 10a and acetylhydroquinone
acetate 10b.* However, reduction of compound 10b unꢀ
der the Clemmensen reaction conditions is accompanied
by hydrolysis of the ester group to give finally ethylꢀ
hydroquinone (11a),10b which is methylated yielding diꢀ
methyl ether 11b. The subsequent transformations
11b→8→9→2 proceeded in full agreement with Scheme 1.
As was to be expected, the physicochemical characterisꢀ
tics of the synthetic product were identical to those of
ethylspinazarin (2) isolated previously from the sea urchin
S. mirabilis, which unambiguously conformed its structure.
Spinochrome 2 is apparently formed from diacetate 4,
which is present in minor amounts in pyrogallol A (chemiꢀ
cally pure grade) and undergoes the same transformations
during the echinochrome synthesis as the major compoꢀ
nent 3 (Scheme 1).
Scheme 1
R = H (10a, 11a), Ac (10b), Me (11b)
To conclude, two new pigments were isolated for the
first time from the sea urchin S. mirabilis: spinazarin (1)
known previously as a synthetic product and ethylꢀ
spinazarin (2). A preparative synthetic route to comꢀ
pound 2 was proposed.
Experimental
Melting points were determined on a Boetius hot stage and
not corrected. IR spectra were measured on a Bruker Vector 22
1
spectrophotometer in CHCl3. H and 13C NMR spectra were
recorded on a Bruker ACꢀ250 spectrometer (250.13 MHz for 1H
and 62.9 MHz for 13C) in CDCl3 and acetoneꢀd6 (Me4Si as the
internal standard). MS (EI) were run on an LKBꢀ9000S instruꢀ
ment with direct sample inlet with an ionizing energy of 18
and 70 eV. The reactions were monitored and the purity of the
products was checked by TLC on Merсk 60Fꢀ254 plates in a 3 : 1
hexane—acetone system. The individual compounds were isoꢀ
According to the above presumptive scheme, hydroꢀ
quinone diacetate (4) undergoes a double Fries rearꢀ
rangement to give diacetylhydroquinone (5).10 The
Clemmensen reduction of intermediate 5 affords diethylꢀ
hydroquinone (6a), which is methylated to yield diꢀ
ether 6b. The double acylation of compound 6b with
dichloromaleic anhydride (7) is accompanied by eliminaꢀ
tion of one ethyl group9 giving finally dichloroethylꢀ
* This casts doubt on the correctness of product structure deterꢀ
mination reported previously.11

Spinazarins from seaꢀurchin
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
821
lated from product mixtures by preparative TLC on plates
(20×20 cm) with an unfixed silica gel layer (H+ꢀform),11
5—40 µm, or by column chromatography on a column with
silica gel L 40/100 µm (H+ꢀform). The yields of the obtained
compounds were not optimized. The elemental analysis was
carried out on a Flash EA1112 C, H, Nꢀanalyzer. HPLC analyꢀ
sis was carried out on an Agilent 1100 chromatograph with
a variable wavelength detector and an Eclipce® XDBꢀC8
ZORBAX column (150ꢀmm long, an internal diameter of
4.6 mm, and 5 µm grain size). The column was maintained at
C(1)OH). 1H NMR, 10b (CDCl3), δ: 2.31 (s, 3 H, Me); 2.62 (s,
3 H, Me); 6.99 (d, 1 H, H(6), J = 8.5 Hz); 7.21 (dd, 1 H, H(5),
J1 = 8.5 Hz, J2 = 2.9 Hz); 7.45 (d, 1 H, H(3), J = 2.9 Hz); 12.13
(s, 1 H, C(1)OH).
2ꢀEthylhydroquinone (11a). Solid zinc amalgam (160 g),13
the mixture of compounds 10a and 10b (13 g), and conc. HCl
(200 mL) were placed into a 3ꢀL flask. The reaction mixture was
heated to reflux with vigorous stirring and, after 30 min, an
additional portion of the mixture of 10a and 10b (13 g) and
conc. HCl (200 mL) were added. The mixture was stirred at
reflux for additional 3 h, and the hot solution was decanted and
left for 12 h. The white precipitate was separated, washed with
ice water (30 mL), and dried to a constant weight to give 8.6 g of
product 11a, m.p. 94—95 °C. IR (CHCl3), ν/cm–1: 3604 (O—H);
1602, 1504 (C=C). 1H NMR (acetoneꢀd6), δ: 1.16 (t, 3 H, Me,
J = 7.6 Hz); 2.57 (q, 2 H, CH2, J = 7.6 Hz); 6.49 (dd, 1 H,
H(5), J1 = 8.5 Hz, J2 = 2.9 Hz); 6.61 (d, 1 H, H(3), J = 2.9 Hz);
6.65 (d, 1 H, H(6), J = 8.5 Hz); 7.59 (s, 1 H, OH); 7.64 (s,
1 H, OH). MS (EI, 70 eV), m/z (Irel (%)): 138 [M]+ (100),
123 [M – Me]+ (57). Compound 11a was used for the preparaꢀ
tion of 1,4ꢀdimethoxyꢀ2ꢀethylbenzene (11b) without purifiꢀ
cation.
2ꢀEthylꢀ1,4ꢀdimethoxybenzene (11b). Crude 2ꢀethylhydroꢀ
quinone (11a) (8.6 g) was treated with 10% NaOH (60 mL) with
vigorous stirring under nitrogen and then with Me2SO4 (14.3 g,
0.11 mol), the temperature of the mixture being maintained
below 40 °C. After the addition of Me2SO4, the reaction mixture
was heated for 30 min on a boiling water bath. The mixture was
cooled, the organic layer was separated, and the aqueous layer
was extracted with benzene. The combined organic solutions
were washed with 5% NaOH and water, and dried with anꢀ
hydrous CaCl2. The solvent was removed at a reduced pressure.
The residue was fractionated in vacuo. The fraction with b.p.
98—100 °C (7 Torr) was the target product 11b, yield 7 g.
IR (CDCl3), ν/cm–1: 1590, 1501 (C=C). 1H NMR (CDCl3), δ:
1.19 (t, 3 H, Me, J = 7.8 Hz); 2.64 (q, 2 H, CH2, J = 7.8 Hz);
3.77, 3.76 (both s, 3 H each, OCH3); 6.67 (dd, 1 H, H(5), J1 =
8.8 Hz, J2 = 2.9 Hz); 6.75 (d, 1 H, H(3), J = 2.9 Hz); 6.76 (d,
1 H, H(6), J = 8.8 Hz). MS (EI, 70 eV), m/z (Irel (%)): 166 [M]+
(40), 153 (10), 152 (100), 151 (17), 137 (41).
30 °C. The flow rate of the mobile phase was 1 mL min–1
.
Solvent A: 1% acetic acid, solvent B: acetonitrile containing
1% (v/v) of acetic acid. Linear gradients with solvent B: 10→30%
for 6 min, 30→70% from 6 to 20 min, 70→30% from 20 to 25 min,
and column recovery for 5 min. The results were analyzed using
the ChemStationΤ program.
Spinazarin (1) and ethylspinazarin (2) were isolated from an
alcohol extract of sea urchins S. mirabilis (2 kg) by a previously
described procedure.5,12 Commercially available dichloromaleic
anhydride (Fluka) was used.
2,3,5,8ꢀTetrahydroxyꢀ1,4ꢀnaphthoquinone (spinazarin, 1),
yield 5 mg, red crystals, m.p. 268—270 °C (cf. Ref. 6: m.p.
279—279.5 °C (from AcOH)). UV (CHCl3), λmax/nm (logε):
230 (4.19), 246 (4.20), 302 sh (3.66), 460 (3.74), 489 (3.81),
525 sh (3.64). IR (CHCl3), ν/cm–1: 3520, 3433 (C—OH); 1601
1
(C=O, C=C). H NMR (acetoneꢀd6), δ: 7.26 (s, 2 H, Harom);
9.10 (br.s, 2 H, βꢀOH); 12.02 (s, 2 H, αꢀOH). MS (EI, 70 eV),
m/z (Irel (%)): 222 [M]+ (43), 221 [M – 1]+ (100), 193
[M – COH]+ (100), 164 (21). MALDI spectrum: negative
ions, 222 [M]– (100), 221 [M – H]– (50); positive ions, 224
[M + 2H]+. Retention time 8.52 min.
6ꢀEthylꢀ2,3,5,8ꢀtetrahydroxyꢀ1,4ꢀnaphthoquinone (ethylꢀ
spinazarin, 2), yield 3 mg, red crystals, m.p. 230—234 °C.
Found (%): C, 57.73; H, 4.01. C12H10O6. Calculated (%):
C, 57.60; H, 4.03.UV (EtOH) λmax/nm (logε): 204 (4.25), 253
(4.10), 292 (3.67), 460 (3.70), 485 (3.75), 510 sh (3.62), 522 sh
(3.58). IR, (CHCl3), ν/cm–1: 3430, 3354 (C—OH); 2929, 2856,
1605 (C=O, C=C). 1H NMR (acetoneꢀd6), δ: 1.24 (t, 3 H, Me,
J = 7.6 Hz); 2.72 (qd, 2 H, CH2, J1 = 7.6 Hz, J2 = 0.9 Hz); 7.12
(t, 1 H, Harom, J = 0.9 Hz); 9.10 (br.s, 2 H, βꢀOH); 12.06, 12.57
1
(both s, 1 H each, αꢀOH). H NMR (CDCl3), δ: 1.26 (t, 3 H,
2,3ꢀDichloroꢀ6ꢀethylꢀ5,8ꢀdihydroxyꢀ1,4ꢀnaphthoquinone (8).
A mixture of 2ꢀethylꢀ1,4ꢀdimethoxybenzene (11b) (7 g, 0.04 mol)
and dichloromaleic anhydride (7) (12 g, 0.07 mol) was added at
140 °C with vigorous stirring to a melt of anhydrous AlCl3 (64 g,
0.48 mol) and NaCl (12.6 g, 0.22 mol). The temperature of the
mixture was raised to 195 °C and the melt was stirred for 5 min.
The reaction mixture was cooled and hydrolyzed with a solution
of concentrated HCl (75 mL) in H2O (1.0 L). The precipitate
formed within 12 h was separated, washed with hot H2O (0.5 L),
dried, and subjected to column chromatography using a 50 : 1
hexane—acetone mixture for elution to give 10.6 g (88%) of
Me, J = 7.6 Hz); 2.73 (qd, 2 H, CH2, J1 = 7.6 Hz, J2 = 1.0 Hz);
6.66 (br.s, 1 H, βꢀOH); 6.69 (br.s, 1 H, βꢀOH); 7.07 (d, 1 H,
H
arom, J = 1.0 Hz); 11.71, 12.16 (both s, 1 H each, αꢀOH).
13C NMR (CDCl3), δ: 183.1, 182.2, 157.9, 157.1, 147.5,
137.8, 137.5, 127.4, 108.1, 107.0, 23.2, 12.7. MS (EI, 18 eV),
m/z (Irel (%)): 251 [M + 1]+ (18), 250 [M]+ (100), 222 (9), 208
(27), 190 (7), 162 (7). Retention time 13.41 min.
Fries rearrangement of hydroquinone diacetate (4). Hydroꢀ
quinone diacetate (31 g, 0.16 mol) (4) was added in portions
with vigorous stirring at 140 °C to a melt of anhydrous AlCl3
(145 g, 1.1 mol) and NaCl (27 g, 0.5 mol). The temperature of
the mixture was raised to 195 °C and the melt was stirred for
9 min. The reaction mixture was cooled and hydrolyzed with a
solution of conc. HCl (150 mL) in H2O (2.0 L). The solid that
precipitated within 12 h was separated, washed with hot H2O
(0.5 L), and dried to give 26 g of a mixture of acetylhydroquinone
(10a) and acetylhydroquinone acetate (10b). 1H NMR, 10a
(CDCl3), δ: 2.60 (s, 3 H, Me); 4.62 (s, 1 H, C(4)OH); 6.89 (d,
1 H, H(6), J = 8.5 Hz); 7.03 (dd, 1 H, H(5), J1 = 8.5,
J2 = 2.9 Hz); 7.19 (d, 1 H, H(3), J = 2.9 Hz); 11.81 (s, 1 H,
product 8, red crystals, m.p. 123—125 °C. IR (CDCl3), ν/cm–1
:
1
1617 (C=O); 1575, 1562 (C=C). H NMR (CDCl3), δ: 1.27 (t,
3 H, Me, J = 7.3 Hz); 2.73 (dq, 2 H, CH2, J1 = 7.3 Hz, J2 =
1.4 Hz); 7.06 (t, 1 H, H(7), J = 1.4 Hz); 12.56, 12.90 (both s,
1 H each, αꢀOH). MS (EI, 70 eV), m/z (Irel (%)): 286/288/290
[M]+ (100), 285/287/289 [M – 1]+ (21), 271/273/275
[M – Me]+ (7), 268/270/272 [M – H2O]+ (8), 258/260/262
[M – CO]+ (12), 257/259/261 (5).
6ꢀEthylꢀ5,8ꢀdihydroxyꢀ2,3ꢀdimethoxyꢀ1,4ꢀnaphthoquinone
(9). A mixture of thoroughly dried substrate 8 (460 mg,

822
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
Yakubovskaya et al.
1.6 mmol), anhydrous CsF (1700 mg, 11.2 mmol), and activated
Al2O3 (1630 mg, 16.0 mmol) in anhydrous MeOH (80 mL) was
stirred at reflux under Ar for 6 h. Then the reaction mixture was
cooled, and the sorbent was filtered off and washed with acetone
(5 mL) with addition of 10% HCl (0.5 mL). The combined
extract was concentrated in vacuo and the residue was diluted
with water (10 mL) and extracted with CHCl3. The organic
solution was washed with water, dried with anhydrous Na2SO4,
and concentrated. Column chromatography (hexane → hexꢀ
ane—benzene, 10 : 1) followed by preparative TLC (hexane—acꢀ
etone, 3 : 1) gave compound 9, 138 mg (31%), m.p. 68—70 °C.
1H NMR (CDCl3), δ: 1.25 (t, 3 H, Me, J = 7.6); 2.73 (dq, 2 H,
CH2, J1 = 7.6 Hz, J2 = 1.0 Hz); 4.11, 4.13 (both s, 3 H each,
OMe); 7.06 (t, 1 H, Harom, J = 1.0 Hz); 12.46, 12.90 (both s,
1 H each, αꢀOH). MS (EI, 70 eV), m/z (Irel (%)): 279 (17),
278 [M]+ (100), 277 (25), 263 (35), 262 (10), 260 (21), 249 (9),
248 (9). Apart from compound 8, a mixture of 3ꢀchloroꢀ6ꢀethylꢀ
2ꢀmethoxyꢀ and 2ꢀchloroꢀ6ꢀethylꢀ3ꢀmethoxynaphthazarins was
isolated (5%, 43 : 57 ratio). For 3ꢀchloroꢀ6ꢀethylꢀ2ꢀmethoxyꢀ
naphthazarin, 1H NMR (CDCl3), δ: 1.27 (t, 3 H, Me, J =
7.6 Hz); 2.75 (q, 2 H, CH2, J = 7.3 Hz); 4.33 (s, 3 H, OMe);
7.08 (br.s, 1 H, Harom); 12.44, 13.03 (both s, 1 H each,
αꢀOH). For 2ꢀchloroꢀ6ꢀethylꢀ3ꢀmethoxynaphthazarin,
1H NMR (CDCl3), δ: 1.27 (t, 3 H, Me, J = 7.6 Hz); 2.75 (q,
2 H, CH2, J = 7.3 Hz); 4.30 (s, 3 H, OMe); 7.11 (br.s, 1 H,
Harom); 12.60, 12.84 (both s, 1 H, αꢀOH).*
References
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6ꢀEthylꢀ2,3,5,8ꢀtetrahydroxyꢀ1,4ꢀnaphthoquinone (2). A soꢀ
lution of substrate 9 (60 mg, 0.22 mmol) was refluxed in a
HBr—AcOH mixture (1 : 1, 10 mL) for 45 min, the course of
the reaction being monitored by TLC. The reaction mixture was
diluted with H2O (200 mL) and extracted with ethyl acetate.
The organic phase was dried with anhydrous Na2SO4 and
concentrated. Preparative TLC (hexane—benzene—acetone,
3 : 1 : 1) gave 49 mg (91%) of product 2.
10. L. F. Fieser, M. Fieser, Reagents for Organic Synthesis,
J. Wiley and Sons, New York—London—Sydney, 1968.
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This work was partially supported by the Russian
Academy of Sciences (the Program "Molecular and
Cell Biology", the grant of the Presidium of the RAS;
Interdisciplinary Integration Project of the FarꢀEastern
and Siberian Branches of the RAS No. 07ꢀIIꢀSOꢀ05ꢀ020),
and the Russian Foundation for Basic Research (Projects
No. 06ꢀ04ꢀ48068, No. 05ꢀ04ꢀ08103, and No. 06ꢀ04ꢀ
96974).
* The assignment is ambiguous.
Received March 23, 2007