Synthesis of tricrozarin b, a pigment of Tritonia crocosmaeflora

Full text of DOI:10.1007/s10600-013-0650-9

Chemistry of Natural Compounds, Vol. 49, No. 3, July, 2013 [Russian original No. 3, May–June, 2013]
SYNTHESIS OF TRICROZARIN B, A PIGMENT
OF Tritonia crocosmaeflora
*
O. P. Shestak and V. F. Anufriev
UDC 547.655.6
Tricrozarin B (1) was isolated from bulbs of Tritonia crocosmaeflora Lemoine (Iridaceae) [1]. It, lomazarin (2) [2,
3], and tricrozarin A [4] are rare examples of polymethoxynaphthazarins isolated from higher plants. Tricrozarin B exhibited
cytotoxic activity in vitro against Hela-S cells and antitumor activity in vivo against murine sarcoma S-180 [1] and melanoma
3
B-16 [5].
The preparative production of tricrozarin B is interesting for further research of its biological activity and for use as
starting material in the synthesis of other natural products and their analogs because of its poor availability.
Long before it was observed in nature, trimethoxynaphthazarin 1 was known as a derivative of spinochrome D,
a pigment of the sea urchins Pseudocentrotus depressus and Echinotrix calamaris [3, 6], that was prepared by its methylation
using diazomethane [6, 7].
Tricrozarin B (1) was obtained earlier in three steps in overall yield ~10% using cycloacylation of
dihydroxydimethoxybenzene 3 by chloromaleic anhydride (4) in an AlCl :NaCl melt, methylation of the resulting
3
dihydroxynaphthazarin 5 by diazomethane to protect the ꢀ-hydroxy groups, and substitution of the Cl atom by methoxy in the
resulting dimethoxynaphthazarin 6 using saturated MeONa in MeOH and refluxing for 48 h (Scheme 1) [8]. The conversion
6ꢁ1 required an enormous excess of reagent. Considering the overall low yield, this made this approach unsuitable for
preparative production of 1.
OH
OH
O
OH
O
O
8
1
ꢀ
ꢀ
HO
8a
OCH
OCH
OR
OR
3
3
Cl
7
3
+
O
4
4a
H CO
3
H CO
3
Cl
5
O
OCH
OH
O
OH
O
3
4
3
5, 6
5: R = H
6: R = CH
1
3
OH OH
O
OH
OH
O
O
OCH
OCH
OCH
3
3
3
3
H CO
OCH
HO
3
OH
O
2
7
Scheme 1
Conversion of lomazarin (2) into the dimethyl ether of spinochrome D (7) in 50% yield via base hydrolysis (1%
NaOH aqueous solution) was reported [9]. The resulting diether 7 was readily transformed into tricrozarin B (1) by diazomethane
(Scheme 1).
In the two-step synthesis of 1 proposed by us, the starting material was the dimethyl ether of chlorohydroquinone (8),
which gave trichloronaphthazarin (10) through the action of dichloromaleic anhydride (9) under double acylation reaction
conditions. Compound 10 was converted to 1 by treatment with CsF:MeOH:Al O (Scheme 2). The overall yield of 1 could
2
3
G. B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Russian
Federation, 690022, Vladivostok, Prosp. 100 Let Vladivostoku, 159, fax: 8 (423) 231 40 50, e-mail: shestak@piboc.dvo.ru.
Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2013, pp. 429–430. Original article submitted March 5,
2013.
©
0009-3130/13/4903-0503 2013 Springer Science+Business Media New York
503

be increased by 20 times compared to that reported in the patent literature [5] by using the dimethyl ether of hydroquinone (8)
in the cycloacylation step instead of hydroquinone (11) and CsF:MeOH:Al O in the substitution step instead of conc. MeONa
2
3
in MeOH.
OR
OH
O
OH
O
O
O
Cl
Cl
Cl
Cl
OCH
OCH
3
3
+
Cl
Cl
H CO
3
O
OR
OH
O
OH
O
8, 11
9
10
1
8: R = CH
11: R = H
3
Scheme 2
Cycloacylation of 8 by 9 in a melt of anhydrous AlCl :NaCl at 195°C for 5 min gave 5,8-dihydroxy-2,3,6-trichloro-
3
1,4-naphthoquinone (10) in 78% yield, C H Cl O , mp 174–176°C (Me CO); lit. mp 151–152°C (dec.) [10]. PMR spectrum
10
3
3
4
2
13
(300 MHz, CDCl , ꢂ, ppm, J/Hz): 7.45 (1H, d, J = 0.3, H-7), 12.31 (1H, s, 8-OH), 12.74 (1H, d, J = 0.3, 5-OH). C NMR
3
spectrum (75 MHz, CDCl , ꢂ, ppm): 109.62 (C-8a), 110.79 (C-4a), 130.56 (C-7), 137.53 (C-6), 141.53 (C-3), 142.47 (C-2),
3
+
159.56 (C-5), 162.81 (C-8), 174.37 (C-1), 175.19 (C-4). Mass spectrum (m/z, I , %): 293/295/297/299 ([M + 1] , 13),
292/294/296/298 ([M] , 100), 258/260/262 ([M – Cl + 1] , 11), 257/259/261 ([M – Cl] , 14), 223 ([M – 2Cl + 1] , 15).
PMR and C NMR spectra were recorded on a BrukerAvance DPX-300 spectrometer. Mass spectra (EI) were obtained on an
rel
+
+
+
+
13
AMD 604 S instrument with direct introduction at ionization energy 70 eV.
The bifunctional reagent K(Cs)F:MeOH:Al O was proposed earlier for substitution of halogens in chloronaphthazarins
2
3
by methoxyls [11]. The fluoride ion acts as a Lewis base that activates the weak nucleophile (MeOH);Al O , a Lewis acid that
2
3
activates the substrate to nucleophilic substitution of the Cl atom. We used 10 in this reaction for the first time as a substrate.
The mixture of well dried 10, anhydrous CsF, and activated neutral Al O in anhydrous MeOH was stirred and heated at 95°C
2
3
in a sealed vessel for 9 h. The work-up afforded 5,8-dihydroxy-2,3,6-trimethoxy-1,4-naphthoquinone (1) in 69% yield,
C H O , mp 169–171°C (Me CO); lit. mp 161–162°C [7, 8]; 176–177°C [1]; and 169–173°C [9]. PMR spectrum
13 12
7
2
(300 MHz, CDCl , ꢂ, ppm): 3.96 (3H, s, 6-OCH ), 4.07 (3H, s, 3-OCH ), 4.15 (3H, s, 2-OCH ), 6.41 (1H, s, H-7), 12.93 (1H,
3
3
3
3
13
s, 5-OH), 13.03 (1H, s, 8-OH).
C NMR spectrum (75 MHz, CDCl , ꢂ, ppm): 56.71 (6-OCH ), 61.56 (3-OCH ), 61.62
3 3 3
(2-OCH ), 105.01 (C-8a), 107.50 (C-7), 109.37 (C-4a), 146.86 (C-3), 149.52 (C-2), 159.18 (C-6), 161.39 (C-5), 170.17
3
(C-8), 172.25 (C-1), 174.65 (C-4).
The physicochemical characteristics of synthesized 1 were identical to those of tricrozarin B that was isolated earlier
from T. crocosmaeflora [1].
ACKNOWLEDGMENT
The work was financed by the Russian Academy of Sciences (RAS Presidium Grant No. 12-I-P6-11 Molecular and
Cellular Biology, a grant of the RAS FEB, SB, and UB No. 12-II-SU-05-006, and a grant of the FEB RAS No. 12-III-A-05-062).
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