Monomeric Dihydroanthraquinones: A Chemoenzymatic Approach and its (Bio)synthetic Implications for Bisanthraquinones

Article abstract of DOI:10.1002/chem.201705998

Modified bisanthraquinones are complex dimeric natural products containing a cage-like structural motif. For their biosynthesis, monomeric dihydroanthraquinones have been proposed as key intermediates despite not being isolated from natural sources or synthesized as of yet. Here, isolation and characterization of dihydroemodin, as well as dihydrolunatin, synthesized by a biomimetic and chemoenzymatic approach using NADPH-dependent polyhydroxyanthracence reductase (PHAR) from Cochliobolus lunatus followed by Pb(OAc)₄ oxidation is reported. Subsequent dimerization through a hetero-Diels–Alder reaction of the dihydroemodin and dihydrolunatin resulted in (?)-flavoskyrin (68 %) and (?)-lunaskyrin (62 %), respectively. Pyridine treatment of (?)-flavoskyrin and (?)-lunaskyrin gave (?)-rugulosin and (?)-2,2′-epi-cytoskyrin A in 64 % and 60 % yield, respectively, through a cascade that involves two dimeric intermediates. Implications of the described synthesis for the biosynthesis of bisanthraquinones by a combination of enzymatic and spontaneous steps are discussed.

Full text of DOI:10.1002/chem.201705998

A Journal of
Accepted Article
Title: Monomeric Dihydroanthraquinones: A Chemoenzymatic
Approach and its (Bio)synthetic Implications for
Bisanthraquinones
Authors: Nirmal Saha, Amit Mondal, Karina Witte, Shailesh Kumar
Singh, Michael Müller, and Syed Masood Husain
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Monomeric Dihydroanthraquinones: A Chemoenzymatic
Approach and its (Bio)synthetic Implications for
Bisanthraquinones
Nirmal Saha+,[a] Amit Mondal+,[a] Karina Witte,[a,b] Shailesh Kumar Singh,[a] Michael Müller,[b] and Syed
Masood Husain* [a]
Abstract: Modified bisanthraquinones are complex dimeric natural
products containing a cage-like structural motif. For their biosynthesis,
monomeric dihydroanthraquinones have been proposed as key
intermediates despite not being isolated from natural sources or
synthesized as yet. Herein, isolation and characterization of
dihydroemodin, as well as dihydrolunatin, synthesized via
a
biomimetic, chemoenzymatic approach using NADPH-dependent
polyhydroxyanthracence reductase (PHAR) from Cochliobolus
lunatus followed by Pb(OAc)4 oxidation is reported. Subsequent
dimerization via a hetero-Diels–Alder reaction of the dihydroemodin
and dihydrolunatin resulted in (–)-flavoskyrin (68%) and (–)-lunaskyrin
(62%), respectively. Pyridine treatment of (–)-flavoskyrin and (–)-
lunaskyrin gave (–)-rugulosin and (–)-2,2’-epi-cytoskyrin A in 64% and
60% yield, respectively, through a cascade that involves two dimeric
intermediates. Implications of the described synthesis for the
biosynthesis of bisanthraquinones by a combination of enzymatic and
spontaneous steps are discussed.
Emodin (1), one of the most widely distributed anthraquinones, is
found in various species of plants[1] and fungi.[2] It plays a crucial
role as a biosynthetic precursor for many fungal metabolites such
as the ergochromes (Penicillium oxalicum),[3] xanthones
(Aspergillus versicolor),[4] monodictyphenone (Aspergillus
nidulans),[5] and bisanthraquinones (Penicillium islandicum,[6]
Myrothecium verucaria,[7] and Penicillium rugulosum).[6c,8] The
astonishing molecular diversity is due to the versatile chemical
properties of anthraquinones: reduction or oxidation and
subsequent transformations may provide easy access to a variety
of monomeric and dimeric metabolites. For example,
chrysophanol (2), a precursor in monodictyphenone biosynthesis,
is formed by deoxygenation of emodin (1).[4,5,9] Detailed
investigation of the deoxygenation process by some of us led to
the discovery of dihydroanthracen-1(2H)-one 3 as a crucial
biosynthetic intermediate (Figure 1).[10] Compound 3 is formed by
the reduction of tautomers of emodin hydroquinone by NADPH-
dependent
Figure
1.
Monomeric
biosynthetic
intermediates
and
dimeric
bisanthraquinones.
MdpC (from the monodictyphenone biosynthetic gene cluster of
A. nidulans), which on elimination of water results in the formation
of chrysophanol (2).The same transformation is catalyzed by
analogous enzymes, AflM from Aspergillus parasiticus[11] and
‘17β-hydroxysteroid
Cochliobolus lunatus,[12] which further led to the elucidation of
dehydrogenase’
(17β-HSDcl)
from
[11]
deoxygenation steps in aflatoxin B1
biosynthesis.[13]
and cladofulvin
Another related biosynthetic intermediate, dihydroemodin (4a),
has been proposed as being involved in the biosynthesis of (–)-
flavoskyrin (5) and (–)-rugulosin (6), isolated from P. islandicum,
and (+)-rugulosin (7), isolated from P. rugulosum.[14,15] The
proposal was based on a series of monomeric anthraquinones
synthesized by Zahn and Koch almost 80 years ago, which tend
to dimerize via a hetero-Diels–Alder reaction into flavoskyrin-type
dimeric compounds.[15b,16] This has been reflected in the
biomimetic synthetic strategies to bisanthraquinones, evident
from the cascade syntheses of (+)-rugulosin (7) and its analogues
developed independently by the groups of Nicolaou[17] and
Snider, respectively.[18] Interestingly, both approaches involved
flavoskyrin-type dimeric intermediates which are formed by
dimerization of monomeric anthrahydroquinones, followed by a
synthetic cascade.[17] However, the proposed monomeric
intermediate, dihydroemodin (4a), and its naturally occurring
dimer, flavoskyrin (5), could not be synthesized so far, owing to
the presence of sensitive β-hydroxy ketone groups[19] which may
undergo elimination.
[a]
N. Saha,+ A. Mondal,+ K. Witte, S. K. Singh, Dr. S. M. Husain
Molecular Synthesis and Drug Discovery Unit, Centre for Biomedical
Research, Sanjay Gandhi Postgraduate Institute of Medical
Sciences Campus, Raebareli Road, Lucknow 226014 (India)
E-mail: smhusain@cbmr.res.in, smhusain.iitb@gmail.com
K. Witte, Prof. Dr. M. Müller
Institut für Pharmazeutische Wissenschaften
Albert-Ludwigs-Universität Freiburg
Albertstrasse 25, 79104 Freiburg (Germany)
These authors contributed equally to this work.
[b]
[+]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Scheme 1. Chemoenzymatic synthesis of (–)-rugulosin (6) and (–)-2,2’-epi-cytoskyrin A (21). Reduction of emodin (1) and lunatin (9) by His-tagged PHAR using
NADPH (regenerated using glucose/glucose dehydrogenase) in the presence of Na2S2O4. Oxidation of reduced anthrahydroquinones 3, 11 by Pb(OAc)4 in AcOH
gave reduced quinone intermediates 4, 12, dimeric compounds 5 (68%), 14 (64%), and deoxygenation products 2 (8%), 13 (10%). Treatment with base converts 5,
14 into modified bisanthraquinones 6 (64%), 21 (60%), and dianhydro compounds 15 (10%), 18 (12%), via intermediates 16, 19 and oxidized 17, 20.
spectroscopy, mass spectrometry, and CD revealed that it was
identical to (–)-flavoskyrin (5, Scheme 1). Further reaction
optimization and purification by chromatography with oxalic acid
Therefore, the existence of 4a and its role in the biosynthesis of
flavoskyrin and rugulosin remained elusive. In order to resolve this
long-pending issue, we focused on the synthesis of
impregnated silica gel resulted in 5 in 68% yield (see Supporting
dihydroemodin (4a). We hypothesized that 4a can be formed by
Information).
oxidation of reduced emodin hydroquinone 3. To test our
hypothesis, we used 17β-HSDcl, synonymous with polyhydroxy-
In order to purify and identify the unknown product,
anthracene reductase (PHAR), from the filamentous fungus
chromatography with oxalic acid impregnated silica gel was used
Curvularia lunata (teleomorph C. lunatus) to convert emodin (1)
with benzene/acetone (9:1) as eluent, which ultimately led to the
isolation of the orange product, monomeric dihydroemodin (4a)
(see Supporting Information). The configuration of the chiral
center in 4a is assumed to be the same as that of 3. In addition,
dihydroemodin exists as a mixture of tautomers 4a and 4b in a
ratio of 85:15 (1H NMR, acetone-d6) (Scheme 1). As the minor
tautomer 4b could not be isolated from the mixture, it was
characterized by 1D-TOCSY NMR experiments (see Supporting
into 3.[12] Emodin (1) on incubation with Na2S2O4 resulted in a
tautomeric mixture of emodin hydroquinones 8a/8b, which after
reduction with PHAR in the presence of NADPH gave reduced
emodin hydroquinone 3 in 75% yield (see Supporting Information)
(Scheme 1). In this transformation, NADPH was regenerated
using a glucose/glucose dehydrogenase system. To obtain 4a
from 3, we first applied MnO2 for oxidation, which mainly resulted
in the formation of chrysophanol (2), with no trace of monomeric
intermediate (4a). Alternatively, we used Pb(OAc)4/AcOH, as
Information).
employed by Seo et al.[15a,b] and later by Snider and Gao,[18] for
the selective oxidation of anthrahydroquinones. Addition of a
suspension of Pb(OAc)4 in AcOH to an ice-cold suspension of 3
in AcOH and stirring for 20 minutes resulted in the formation of
mainly two new products along with the expected chrysophanol
(2), with no starting material remaining. Purification by preparative
TLC provided a yellow compound in 30% yield (Rf = 0.43
MeOH/CHCl3 1:9), 8% chrysophanol (Rf = 0.90), and another
(orange) compound (Rf = 0.46) which decomposed during
isolation. Characterization of the yellow compound by NMR
Hence, the synthesis of monomeric dihydroemodin (4a) and its
dimerized product (–)-flavoskyrin (5) was realized through a two-
step chemoenzymatic approach. The results are consistent with
the formation of (–)-flavoskyrin via the hetero-Diels–Alder reaction
of two units of 4a/4b, formed by oxidation of 3. Biosynthesis of (–
)-flavoskyrin (5) might involve similar steps, either catalyzed by
enzymes or occurring spontaneously. It is important to note that
the cycloaddition will take place according to an exo–anti
arrangement as depicted in Scheme 1, to minimize the steric
hindrance between the two hydroxyl groups. To ascertain the
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generality of these results and to obtain monomeric intermediates
and flavoskyrin-type dimeric compounds of other unprotected
anthraquinones, we envisaged the synthesis of 2,2’-epi-
cytoskyrin A (21) starting from monomeric lunatin (9). Lunatin (9)
has already been proposed as being involved in the biosynthesis
of cytoskyrin A.[12] Both lunatin and (+)-cytoskyrin A have been
isolated from the fungus C. lunata[20] and their biosynthesis could
involve PHAR for the reduction of lunatin hydroquinones
10a/10b.[12] For this purpose, lunatin (9) was synthesized using
2,6-dichlorobenzoquinone and mixed vinyl ketene acetals via two
consecutive Diels–Alder reactions in 32% yield (see Supporting
Information). On reduction in the presence of Na2S2O4 using the
These results are in contrast with the previously postulated
biosynthesis of rugulosin.[15c] Accordingly, we propose an
alternative pathway for the conversion of 5 into 6, in which a
Michael-type addition in the presence of a base gives 16, which
subsequently oxidizes in air to form 17. Another intramolecular
Michael addition in 17 finally results in the formation of the third
C–C bond to give (–)-rugulosin (6). Similarly, treatment of (–)-
lunaskyrin (14) with pyridine under oxygen atmosphere resulted
in the formation of (–)-dianhydrocytoskyrin (18) and (–)-2,2’-epi-
cytoskyrin A (21), in 12% and 60% yield, respectively (Scheme 1).
The spectroscopic data of 21 match those of (+)-2,2’-epi-
cytoskyrin A isolated from the endophytic fungus Diaporthe sp,[22]
except for the optical rotation, which was expected based on the
(R)-configuration of 11 (see Supporting Information). The same
reaction under argon atmosphere led to the isolation of 19;
however, all attempts to isolate intermediate 20 failed as it
undergoes facile Michael addition to form 21. The
chemoenzymatic synthesis of (–)-lunaskyrin (14) and (–)-2,2’-epi-
cytoskyrin A (21) described herein points toward their putative
existence as natural products which are yet to be isolated
(Scheme 1).
PHAR/NADPH system,
9 gave (R)-3,8,9,10-tetrahydroxy-6-
methoxy-3,4-dihydroanthracen-1(2H)-one (11) in 64% yield. The
configuration was assigned by comparing the CD spectra of 3 and
11. In this transformation, 3-methoxychrysazine (13) was also
isolated as a side product (10%), formed by oxidation and
dehydration of 11 (see Supporting Information) (Scheme 1).
Although 13 has yet to be isolated from fungi, its isolation has
been reported from the plant Xyris pilosa.[21] In analogy to emodin
reduction, we assume that the tautomers 10a/10b of lunatin
hydroquinone are formed in situ and act as substrates for the
enzymatic reduction to give 11. Next, we subjected 11 to
Pb(OAc)4/AcOH oxidation. The reaction mixture was purified by
chromatography with oxalic acid impregnated silica gel;
benzene/acetone (9:1) as eluent gave the flavoskyrin-type
dimeric compound (–)-lunaskyrin (14) and 3-methoxychrysazine
(13) in 62% and 10% yield, respectively. Dimer 14 was
characterized by NMR spectroscopy, mass spectrometry, and CD
(see Supporting Information). To obtain dihydrolunatin (12a), the
reaction mixture was purified directly after extraction, resulting in
a tautomeric mixture of 12a and 12b in a ratio of 87:13 (1H NMR,
acetone-d6). The existence of tautomer 12b is supported by 1D-
TOCSY NMR experiments (see Supporting Information). Neither
dihydrolunatin (12a/12b) nor (–)-lunaskyrin (14) have been
isolated from natural sources or synthesized so far. Nevertheless,
their chemoenzymatic synthesis presented here renders this a
general biomimetic strategy toward such dimeric compounds.
Further, the ability of PHAR to catalyze the reduction of
anthrahydroquinones supports the putative involvement of such
enzymes in the biosynthesis of substituted bisanthraquinones.
Figure 2. Other naturally occurring, modified bisanthraquinones.
Next, we turned our focus to transform (–)-flavoskyrin (5) and (–)-
lunaskyrin (14) into (–)-rugulosin (6) and (–)-2,2’-epi-cytoskyrin A
(21), respectively. For this purpose, 5 was dissolved in pyridine
and kept for 19 hours at rt. This resulted in the formation of (–)-
rugulosin (6) and (–)-dianhydrorugulosin (15) in a ratio of 90:10
(1H NMR, DMSO-d6) (Scheme 1). Purification by chromatography
with oxalic acid impregnated silica gel and elution with
benzene/acetone (9:1 to 8:2) gave 6 and 15 in 64% and 10%
yield, respectively. (–)-Dianhydrorugulosin (15) can be formed by
elimination of two water molecules from (–)-flavoskyrin (5), which
has been proposed previously.[15] Moreover, when the same
reaction was performed under argon atmosphere, the yield of 6
was decreased considerably; instead, two new products were
formed, as observed by TLC. On purification and characterization
by NMR spectroscopy and mass spectrometry, the two
compounds were assigned the structures 16 and 17 (Scheme 1).
Similar biosynthetic steps are expected for the formation of (+)-
rugulosin C (25) isolated from Penicillium radicum using ω-
hydroxyemodin as a starting point (Figure 2).[24] The biosynthetic
steps proposed here could be verified with the identification of the
enzymes and their role in P. islandicum. The existence of (+)-
graciliformin (26) isolated from Cladonia graciliformis[25] and (+)-
cytoskyrin A (27) isolated from C. lunata[20] and the endophytic
fungus CR200 (Cytospora sp.)[26] require dimerization through an
exo–syn arrangement, possibly by the involvement of enzyme(s)
(Figure 2).
As no other flavoskyrin-type dimeric compound has been isolated
from natural sources, it is conceivable that the dihydroanthra-
quinones undergo oxidative coupling by, for example, cytochrome
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Acknowledgements
We are grateful to the Council of Scientific and Industrial
Research, New Delhi (Project No. 02(0258)/16/EMR-II) and
SERB-DST (YSS/2014/000792) for funding this research and
fellowships to A.M. and N.S., respectively. We are thankful to Dr.
Bikash Baishya and Ajay Verma for their expert help in NMR
spectroscopy and Dr. Michael A. Schӓtzle and Dr. David Conradt
for their helpful suggestions. We thank the Director, Centre of
Biomedical Research for research facilities.
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Keywords: Dihydroanthraquinones, modified
bisanthraquinones, hetero-Diels–Alder reaction, cascade
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Nirmal Saha, Amit Mondal, Karina Witte,
Shailesh Kumar Singh, Michael Müller,
Syed Masood Husain
Page No. – Page No.
Monomeric Dihydroanthraquinones:
A Chemoenzymatic Approach and its
(Bio)synthetic Implications for
Bisanthraquinones
Simple and elegant: (–)-flavoskyirn, (–)-lunaskyrin, (–)-rugulosin and (–)-2,2’-epi-cytoskyrin A were
prepared in 2–3 steps from respective anthraquinones following a rationally designed chemoenzymatic
synthesis.
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