Regiodefined synthesis of brominated hydroxyanthraquinones related to proisocrinins

Article abstract of DOI:10.3762/bjoc.12.52

Dibromobenzoisofuranone 12, synthesized in six steps, was regiospecifically annulated with 5-substituted cyclohexenones 13/36 in the presence of LiOt-Bu to give brominated anthraquinones 14/38 in good yields. Darzens condensation of 30 was shown to give c

Full text of DOI:10.3762/bjoc.12.52

Regiodefined synthesis of brominated
hydroxyanthraquinones related to proisocrinins
Joyeeta Roy, Tanushree Mal, Supriti Jana and Dipakranjan Mal*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 531–536.
Department of Chemistry, Indian Institute of Technology, Kharagpur-
721302, India, Fax: +913222282252
doi:10.3762/bjoc.12.52
Received: 03 October 2015
Accepted: 26 February 2016
Published: 16 March 2016
Email:
Dipakranjan Mal* - dmal@chem.iitkgp.ernet.in
* Corresponding author
Associate Editor: P. R. Hanson
Keywords:
© 2016 Roy et al; licensee Beilstein-Institut.
License and terms: see end of document.
brominated anthraquinones; Darzens condensation; Hauser
annulation; proisocrinins
Abstract
Dibromobenzoisofuranone 12, synthesized in six steps, was regiospecifically annulated with 5-substituted cyclohexenones 13/36 in
the presence of LiOt-Bu to give brominated anthraquinones 14/38 in good yields. Darzens condensation of 30 was shown to give
chain-elongated anthraquinone 32. Alkaline hydrolysis of 38 furnished 39 representing desulfoproisocrinin F.
Introduction
Anthraquinones constitute the largest group of naturally occur- 7.11, 6.64, and 7.42 μM, respectively [12]. Proisocrinins A–F
ring quinones [1-5]. Isolated mainly from fungal sources, they (6–11), recently isolated from the stalked crinoid Proisocrinus
display a wide range of biological activities which include anti- ruberrimus (Figure 1) are the first water soluble natural
inflammatory, antifungal, antiparasidal, and cytotoxic proper- anthraquinone pigments, and show promising antifeedant prop-
ties [6-11]. Anthraquinones are well-known as colorants in erties [16].
foods, drugs, and textile industries. They are also used as
chemical sensors and liquid crystals [1-5]. Halogenated A brief literature survey revealed that the routes for the
anthraquinones form a minor group of natural pigments [12-15]. synthesis of anthraquinones are primarily based upon five cate-
7-Bromoemodic acid (1), isolated from the crinoid Holopus gories, such as Friedel–Crafts reactions, Hauser annulations,
rangii, shows remarkable cytotoxic activities. Topopyrone B (2) Diels–Alder reactions, transition metal-mediated reactions and
stabilizes DNA topoisomerase I and DNA topoisomerase II. biomimetic aldol condensations [17-23], and reports on the syn-
Haloemodin (3) acts as an antibacterial agent inhibiting DNA thesis of brominated anthraquinones are scare [12-15]. Having
gyrase and bacterial topoisomerase I. 6-O-Methyl-7-chloroaver- inspired by the convergence and the regiochemical integrity of
atin (4) displays potent inhibitory activity against human tumor the Hauser annulation [24-30], we explored it for the construc-
cell lines SF-268, MCF-7, and NCI-H460, with IC50 values of tion of the bromoanthraquinone scaffolds of proisocrinins 6–11.
531

Beilstein J. Org. Chem. 2016, 12, 531–536.
Figure 1: Halogenated anthraquinones.
Results and Discussion
First synthetic route
For the synthesis of key synthon 12 (Scheme 2), we started
from cyclohexenone 19, which was prepared by base-catalyzed
Anthraquinone 14 was proposed to be synthesized by the condensation of methyl acetoacetate with methyl crotonate [24-
Hauser annulation of cyanophthalide 12 and cyclohexenone 13 30]. It was then treated with bromine in AcOH to afford 3,5-
(Scheme 1). A functional group manipulation of 14 was ex- dibromoorsellinate 20 in 81% yield [31-33]. Subsequent
pected to give anthraquinone carboxyaldehyde 15. Employ- O-methylation of 20 (using CH3I, K2CO3), and benzylic bromi-
ment of a Darzens condensation followed by bromination was nation of 21 with NBS followed by lactonization of 22 in a
considered for further elaboration of 15 to 16.
refluxing mixture of dioxane and water afforded phthalide 23 in
Scheme 1: Initially proposed synthetic scheme for proisocrinins 6–11.
532

Beilstein J. Org. Chem. 2016, 12, 531–536.
Scheme 2: Synthesis of cyanophthalide 12.
61% yield. NBS bromination of 23 afforded the 3-bromoph- sensitivity to aerial oxidation; it was directly aromatized by
thalide [33], which on treatment with dioxane/water furnished bubbling O2 through its DMF solution to give anthraquinone 28
phthalaldehydic acid 24 in 69% yield over two steps [34]. in the manner described in [43]. The acetate group in 28 was
Treatment of 24 with KCN furnished 3-cyanophathalide 12 in cleaved with an aqueous alkaline solution to furnish 29 in 80%
75% yield analogously as described in references [35-37]. The yield. The alcohol 29 was oxidized to the corresponding alde-
structure of phthalide 12 was confirmed by the appearance of a hyde 30 using PCC in dichloroethane. It was derivatized to its
singlet at δ 5.84 (s, 1H) in the 1H NMR spectrum and the ap- MOM derivative 31 using MOMCl and DIEPA in DCM.
pearance of a characteristic band for the C≡N stretching fre- Darzens glycidic ester condensation of 31 with methyl
quency at 2260 cm−1 in the IR spectrum. The characteristic car- 2-chloroacetate and sodium methoxide in methanol (Scheme 4)
bon for the cyano functionality appeared at δ 111.7 ppm in the afforded the desired epoxide 32 [44]. The epoxide 32 was char-
13C NMR spectrum.
acterized by the signals corresponding to two protons of the
epoxide at δ 4.18 and 3.54 [44]. Since the yield of 32 was low,
The Michael acceptor 13 was prepared according to the litera- we considered a Horner–Wadsworth–Emmons reaction of alde-
ture procedure starting from cyclohex-3-enecarbaldehyde (25) hyde 31 with triethyl phosphonoacetate as an alternative. Unfor-
[38]. The diol 26 was oxidized with activated MnO2, leading to tunately, it was not successful, probably due to the interference
selective oxidation of the secondary alcohol forming 27 in 83% of the anthraquinone moiety in 31.
yield. The cyclohexenone 27 was acetylated with acetyl chlo-
ride and pyridine to furnish 13 as an oil in 62% yield Second synthetic route
(Scheme 3).
Keeping in view the problems of functionalization of the alde-
hyde group in 31, we contemplated the use of already homolo-
In the next stage, Hauser annulation of cyanophthalide 12 with gated cyclohexenone 36 as the acceptor. Bicyclic lactone 33
cyclohexenone 13 was carried out in the presence of LiOt-Bu [45] was treated with DIBAL-H to afford lactol 34 in 85% yield
(LTB) in THF at −60 °C to furnish quinol A [39-42]. Due to its [46]. Treatment of lactol 34 with methylmagnesium bromide
Scheme 3: Synthesis of cyclohexenone 13.
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Beilstein J. Org. Chem. 2016, 12, 531–536.
Scheme 4: Darzens condensation route to proisocrinins.
afforded diol 35 in 72% yield. Selective oxidation of the allylic The Hauser annulation of cyanophthalide 12 with acceptor 36
alcohol group in 35 with MnO2, followed by acetylation of the formed hydroquinone 37, which was directly treated with
secondary hydroxy group with acetyl chloride, triethylamine bromine in DCM to give tribrominated quinone 38 in 58% yield
and DMAP furnished cyclohexenone 36 (Scheme 5).
(over two steps) (Scheme 6). The structure of bromo compound
Scheme 5: Synthesis of cyclohexenone 36.
Scheme 6: Synthesis of the proisocrinin core structure.
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Beilstein J. Org. Chem. 2016, 12, 531–536.
11.Akar, K. B.; Cakmak, O.; Büyükgüngör, O.; Sahin, E.
38 was proposed on the basis of the high chemical shift
(δ = 7.63 ppm) of the proton attached to the C-4 carbon of the
anthraquinone, and its comparison with that in similar struc-
tural analogs [47,48]. All attempts to demethylate 38 with BBr3
or HBr failed to give the monomethyl analog of 38 [49-52]. The
acetate 38 was treated with sodium hydroxide in THF/water
(1:1) to give tribromoanthraquinone 39.
Beilstein J. Org. Chem. 2011, 7, 1036–1045. doi:10.3762/bjoc.7.118
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Conclusion
The Hauser annulation of a dibromophthalide with 5-(2-
acetoxypropyl)cyclohexenone has been shown to provide a
regiospecific route to the scaffold of proisocrinin F. Further
studies on the completion of the synthesis of proisocrinins 6–11
are underway.
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Supporting Information
Supporting Information File 1
Detailed experimental procedures, characterization data and
copies of 1H and 13C NMR for all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-52-S1.pdf]
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Acknowledgements
Financial support was provided by the Council of Scientific and
Industrial Research (CSIR). J.R. gratefully acknowledges the
CSIR for her fellowship.
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