Synthesis of proposed structure of rennellianone B: A study on rearrangement of anthraquinonyl propargyl ether toward 2H-pyranoanthraquinone

Article abstract of DOI:10.1016/j.tetlet.2016.12.080

Rennellianone B was originally reported as a natural 2H-pyranoanthraquinone, isolated from the root of Rennellia elliptica Korth. An efficient synthesis of the proposed structure of rennellianone B was accomplished, starting from alizarin. The key feature of the synthesis involves the Claisen rearrangement of the anthraquinonyl propargyl ether intermediate to provide a 2H-pyranoanthraquinone moiety. In addition, intensive studies on rearrangement reaction conditions of anthraquinonyl propargyl ether toward the 2H-pyranoanthraquinone skeleton were described.

Full text of DOI:10.1016/j.tetlet.2016.12.080

Accepted Manuscript
Synthesis of proposed structure of rennellianone B: A study on rearrangement
of anthraquinonyl propargyl ether toward 2H-pyranoanthraquinone
Young Taek Han
PII:
S0040-4039(16)31736-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.080
TETL 48492
Reference:
Tetrahedron Letters
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2 December 2016
21 December 2016
28 December 2016
Please cite this article as: Han, Y.T., Synthesis of proposed structure of rennellianone B: A study on rearrangement
of anthraquinonyl propargyl ether toward 2H-pyranoanthraquinone, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.12.080
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Tetrahedron Letters
Synthesis of proposed structure of rennellianone B: A study on rearrangement of
anthraquinonyl propargyl ether toward 2H-pyranoanthraquinone
Young Taek Han
College of Pharmacy, Dankook University, Chenan 31116, Korea
This paper is dedicated to Professor Young-Ger Suh on the occasion of his 65th birthday
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Rennellianone B was originally reported as a natural 2H-pyranoanthraquinone, isolated from the
root of Rennellia elliptica Korth. An efficient synthesis of the proposed structure of
rennellianone B was accomplished, starting from alizarin. The key feature of the synthesis
involves the Claisen rearrangement of the anthraquinonyl propargyl ether intermediate to
provide a 2H-pyranoanthraquinone moiety. In addition, intensive studies on rearrangement
reaction conditions of anthraquinonyl propargyl ether toward the 2H-pyranoanthraquinone
skeleton were described.
Available online
Keywords:
Rennellianone B
Pyranoanthraquinone
Claisen rearrangement
Hydroarylation
2016 Elsevier Ltd. All rights reserved.
Anthraquinonyl propargyl ether
Introduction
Anthraquinones (9,10-dioxoanthracenes) are widely found in
nature, and an important class of natural and synthetic
compounds with strong and broad varieties of biological
efficacies including anticancer, anti-inflammatory, anti-
tyrosinase, antibacterial, and antiviral effects.1 In this connection,
anthraquinone has been regarded as an attractive scaffold in
terms of both synthetic and medicinal chemistry.2 Recently,
rennellianone B 1, a 2H-pyranoanthraquinone, was isolated by
Osman et al. from the root of Rennellia elliptica Korth, used as
traditional medicine in South East Asia.3 It was also revealed that
several anthraquinones isolated from R. elliptica have
therapeutically useful properties.4 Considering not only
therapeutic properties of anthraquinones and R. elliptica, as
mentioned above, but also its structure embedded with a
privileged benzopyran substructure,5 rennellianone B is strongly
expected to possess therapeutically useful biological activities.
Figure 1. Proposed structure of rennellianone B and its
retrosynthetic analysis
Results and Discussion
Synthesis of rennellianone B commenced with the selective
protection of a 2-hydroxyl group of alizarin 3 to provide
anthraquinonyl propargyl ether, a precursor of rearrangement
reaction (Scheme 1). Etherification of 3 with chloroethyl methyl
ether using Hunig’s base afforded 2-ethoxymethyoxy alizarin 4
in high yield without regioisomeric 1-ethoxymethyoxy alizarin.
Methylation of the 4 gave a high yield of the 1-methyl ether 5,
which was then subjected to deprotection using concentrated
hydrochloric acid to afford alizarin-1-methyl ether 6, a natural
analog of alizarin. All of the spectral data of the synthetic
alizarin-1-methyl ether 6 were identical to those of the reported
data.8 The key intermediate, anthraquinonyl propargyl ether 2,
could be obtained in high yield by propargylation of the 6 with 1-
bromo-2-pentyne. On the other hand, the propargylation of
alizarin 3 without a protection group at 1-hydroxyl group
afforded only regioisomeric mixtures along with di-ether as
previously reported.9 Thermal Claisen rearrangement of
As shown in Figure 1, it was envisioned that the 2H-pyran
moiety of rennellianone B 1 could be readily synthesized from
anthraquinonyl propargyl ether 2 via a rearrangement reaction
such
as
transition
metal-catalyzed
intramolecular
hydroarylations6 and a Claisen rearrangement.7 In addition, the
rearrangement precursor 2 was expected to be conveniently
prepared from alizarin 3, a natural 1,2-dihydroxyanthraquinone,
via consecutive etherification reactions. Herein, it is reported that
the concise synthesis of a proposed structure of rennellianone B
via Claisen-rearrangement, as well as investigations on the
rearrangement of an anthraquinonyl propargyl ether intermediate
toward a 2H-pyranoanthraquinone skeleton.

2
Tetrahedron Letters
anthraquinonyl propargyl ether 2 in triethylene glycol at 220–
hydroarylation product 7, but resulted in a mixture of side
products. Interestingly, ketone 8, probably resulted from
unintended intramolecular hydroarylation with trace vapor, was
observed among the diverse undesired products (entry 5–6). This
observation seemed to imply that the electron-deficient
anthraquinone moiety is not nucleophilic enough to react with the
alkyne-platinum complex.10 Next, the Claisen-rearrangement
reaction of anthraquinonyl propargyl ether 2 was investigated
focused on solvent and reaction temperature. When the
anthraquinonyl propargyl ether 2 was heated at 180°C in PhNEt2
(entry 7) and triethylene glycol (TEG) (entry 8), only starting 2
was recovered. The desired pyranoanthraquinone 7 could be
obtained in moderate yield (64%) when the 2 was heated for 4 h
at a higher temperature (220–230°C; entry 10) in TEG. While
Claisen rearrangement in PhNEt2 at a higher temperature
(refluxed; entry 9) afforded an unidentifiable mixture of side
products.
230°C afforded the pyranoanthraquinone 7 in moderate yield
(64%). Demethylation of the 7 using boron trichloride readily
afforded the proposed structure of rennellianone B 1. Synthesis
of the proposed structure of 1 was accomplished in 6 steps (44%
yield) from cheap and readily available alizarin. The structure of
the 2H-pyran moiety of synthesized 1 was assigned and
confirmed by 2D-NMR analysis including nuclear overhauser
effect spectroscopy (NOESY) and correlation spectroscopy
(COSY). Selected correlations and spectra are shown in Figure 2.
However, it was hard to confirm that the reported structure by
Osman et al. is identical with synthetic 1, because previous 13C-
NMR data of 1 were reported incompletely probably due to the
use of a small quantity of the isolated compound (0.5 mg).3
Although H-NMR and 13C-NMR in this study differed slightly
1
from the reported data, considering comprehensive NMR spectra
analysis on the synthetic 1 as well as all of the synthetic
intermediates including known alizarin methyl ether 6,
assignment in this paper seems to be more reasonable.
Table 1. Study on the synthesis of 2H-pyranoanthraquinone from
propargyl ether
Catalyst
No.
Conditiona
Result
(mol%)
Intramolecular hydroarylation reactions
1
2
3
4
5
6
InI3 (5)
InI3 (20)
InI3 (20)
InI3 (20)
PtCl4 (5)
PtCl4 (5)
CH2Cl2, rt, 12h
CH2Cl2, rt, 12h
No reaction
CH2Cl2, reflux, 12h
toluene, reflux, 12h
dioxane, rt, 12h
Scheme 1. Synthesis of proposed structure of rennellianone B
Mixture of side
products including 8b
dioxane, reflux, 4h
Claisen rearrangement reactions
7
8
PhNEt2, 180°C, 12h
No reaction
No reaction
TEG, 180°C, 12h
PhNEt2, reflux, 12h
TEG, 220–230°C, 4h
An unidentifiable
mixture of side
products
9
Figure 2. Selected NOE and COSY correlations for synthesized
rennellianone B.
10
7 (64%)c
a 0.05 M solution of 2; b Yield of 8 was not dertermined; c Isolated
Construction of 2H-pyranoanthraquinone skeleton by
rearrangement of anthraquinonyl propargyl ether 2 was a
formidable task. Traditionally, cyclization of arene-alkyne
substrate toward benzopyran moiety has been accomplished by
either Claisen rearrangement or electrophilic intramolecular
hydroarylation using a transition metal catalyst such as Pt(IV),
In(III).6 Based on the previous studies, intramolecular
hydroarylation of anthraquinonyl propargyl ether 2 was initially
attempted (entry 1–6, Table 1). Indium(III)-catalyzed
hydroarylation6a in CH2Cl2 at room temperature using 5 mol %
InI3 (entry 1) did not provide any products. Instead, the starting
anthraquinonyl propargyl ether 2 was recovered. It was also
observed that modifications in the loading amount of catalyst,
reaction temperature and solvent did not promote the indium(III)-
catalyzed hydroarylation (entry 2–4). Platinum(IV)-catalyzed
hydroarylation6d also did not afford the desired intramolecular
yield.
Conclusion
In summary, this article describes an efficient synthesis of the
proposed structure of rennellianone B via Claisen rearrangement
of an anthraquinoyl propargyl ether intermediate, easily prepared
from
cheap
and
readily
available
natural
1,2-
dihydroxyanthraquinone alizarin. The spectral data of the
synthesized rennellianone B did not agree with previous report. A
2H-pyran moiety of the synthesized rennellianone B was
confirmed by careful 2D-NMR analysis. To find the appropriate
reaction condition for the synthesis of the 2H-
pyranoanthraquinone skeleton, intensive studies on the
intramolecular hydroarylation and Claisen rearrangement

6.
(a) Qui, W.-W.; Surendra, K.; Yin, L.; Corey, E. J. Org. Lett.
2011, 13, 5893–5895; (b) Alonso-Maranon, L.; Martinez, M. M.;
Sarandeses, L. A., Sestelo, J. P. Org. Biomol. Chem. 2015, 13,
379–387; (c) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett.
2003, 5, 1055–1058; (d) Pastine, S. J.; Youn, S. W.; Sames, D.
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Ashok, D.; Rangu, K.; Hanumantha Rao, V; Gundu, S., Srilata, B.,
Vijjulatha, M. Med. Chem. Res. 2016, 25, 501–514.
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Zhang, Q.-Y.; Wu, J.-Z. Molecules 2009, 14, 573–583.
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Synth. Commun. 1988, 18, 1379–1384.
reaction of anthraquinoyl propargyl ether were performed, and it
was hypothesized that electron-deficient anthraquinone would be
an inadequate nucleophile for hydroarylation of alkynes. To my
best knowledge, this study is the first example of synthesis of
2H-pyranoanthraquinone from anthraquinonyl propargyl ether.
And, it would be helpful in the synthesis of derivatives of 2H-
pyranoanthraquinone.
7.
8.
9.
References and notes
10. Soriano, E.; Marco-Contelles, J. Organometallics 2006, 25, 4542–
1.
(a) Abu, N.; Ali, N. M.; Ho, W. Y.; Yeap, S. K.; Aziz, M. Y.;
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4553.
Supplementary Material
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Lett. 2016, 16, 225–229.
Osman, C. P.; Ismail, N. H.; Ahmad, R.; Ahmat, N.l Awang, K.
Jaafa, F. M. Molecules 2010, 15, 7218–7226.
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9953.
Supplementary data (experimental section and copies of
spectra for all of compounds) associated with this article can be
found, in the online version, at http://
4.
5.

3
Graphical Abstract
Synthesis of proposed structure of
rennellianone B: A study on rearrangement
of anthraquinonyl propargyl ether toward
2H-pyranoanthraquinone
Leave this area blank for abstract info.
Young Taek Han

Tetrahedron Letters
4
Highlights
 The efficient synthesis of the proposed
structure of rennellianone B was presented.
 The first practical example of the Claisen
rearrangement of anthraquinonyl propargyl
ether toward 2H-pyranoanthraquinone.
 Study
on
the
rearrangement
of
anthraquinonyl propargyl ether toward
pyranoanthraquinone skeleton was also
described.