A concise approach to anthraquinone-xanthone heterodimers

Article abstract of DOI:10.1021/jacs.8b03110

A synthetic approach to anthraquinone-xanthone heterodimers is described. The route to the pentacyclic core features an efficient assembly of a benzocycloheptenone via a new intramolecular oxidative arylation of an enol ether and a Hauser-Kraus annulation-aldol reaction sequence to access the characteristic bicyclo[3.2.2]nonene motif. Acremoxanthone A is synthesized in 10 steps from commercially available material to demonstrate the application of this approach.

Full text of DOI:10.1021/jacs.8b03110

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A Concise Approach to Anthraquinone-Xanthone Heterodimers
Stephen D. Holmbo, and Sergey V. Pronin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03110 • Publication Date (Web): 05 Apr 2018
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A Concise Approach to Anthraquinone-Xanthone Heterodimers
Stephen D. Holmbo and Sergey V. Pronin*
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Department of Chemistry, University of California, Irvine, California 92697-2025, United States
Supporting Information Placeholder
O
H
H
ABSTRACT: A synthetic approach to anthraquinone-
xanthone heterodimers is described. The route to the
pentacyclic core features an efficient assembly of a ben-
zocycloheptenone via a new intramolecular oxidative
arylation of an enol ether and a Hauser-Kraus annula-
tion-aldol reaction sequence to access the characteristic
bicyclo[3.2.2]nonene motif. Acremoxanthone A is syn-
thesized in 10 steps from commercially available mate-
rial to demonstrate the application of this approach.
O
3
OH
OMe
O
O
HO
O
2
HO
Me
O
OH
H
Br
MeO
Me
4a
O
O
OMe
MeO2C
HO
xanthoquinodine A1 (1)
5 + 6
H
O
OH
HO
O
HO
OH
Hauser–Kraus
annulation–
OH
OH
MeO2C
aldol–elimination
H
Me
HO
Anthraquinone-xanthone heterodimers belong to a
large family of fungal metabolites derived from aromatic
polyketides. These natural products exhibit a diverse set
of biological activities, including antiproliferative effects
and formation of ion channels through cellular mem-
branes by beticolins, anticoccidial activity of xantho-
quinodines, and antibacterial activity of acremonidines
and engyodontochones.1-4 The structures of anthraqui-
none-xanthone heterodimers contain a unique bicy-
clo[3.2.2]nonene fragment embedded into the polycar-
bonyl motif, which is found in various oxidation states
in different congeners (e.g. 1, 2, and 3, Figure 1). This
fragment is believed to arise from an unusual oxidative
heterodimerization of anthraquinone-derived subunits
and imparts a characteristic molecular shape, where the
two monomers are connected in a nearly perpendicular
fashion.5,6 The bridged polycyclic core of anthraqui-
none-xanthone heterodimers has become the subject of
synthetic studies by several research groups.7-8 Among
those, a recent report of the synthesis of an advanced
carbocyclic framework relevant to acremoxanthones by
Suzuki and co-workers is particularly noteworthy.8 Here,
we demonstrate an approach to anthraquinone-xanthone
heterodimers that allows a 5-step assembly of a func-
tionalized pentacyclic core of these natural products. As
a proof of concept, we also report a synthesis of acre-
moxanthone A (3)9 in 10 steps from commercially avail-
able material.
acremonidin B (2)
3
H
O
H
OH
OMe
O
HO
O
2
HO
Br
HO
CO2Me
OH
MeO
Me
4a
O
OAc
OMe
O
H
Me
4
acremoxanthone A (3)
Figure 1. Representative anthraquinone-xanthone hetero-
dimers, and our approach to the pentacyclic core.
cise assembly of the anthraquinone-xanthone heterodi-
mers. The aryl bromide moiety was expected to provide
a handle for installation of various xanthone-derived
fragments, and the tricarbonyl motif would serve as a
starting point for appropriate adjustments of the oxida-
tion states. We envisioned the construction of the penta-
cyclic core to commence with Hauser-Kraus annulation
of a phthalide derivative, represented by 5, with a substi-
tuted benzocycloheptenone, represented by 6.10 For-
mation of the quaternary center at C4a was expected to
render C3 of the aliphatic aldehyde fragment available
for an intramolecular aldol reaction with C2 of the ben-
zyl ketone fragment.11 Subsequent elimination of the
intermediate secondary alcohol would furnish the alkene
bridge, completing assembly of the desired bicy-
clo[3.2.2]nonene motif.
The brevity of the proposed route to the pentacyclic
core was expected to depend on efficient synthesis of the
benzocycloheptenone fragment. In contrast to the
phthalide derivatives, which can be readily prepared
We believed that rapid access to a functionalized pen-
tacyclic core (such as 4, Figure 1) would allow for con-
1
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Table 1. Oxidative Arylation of Enol Ethers
Page 2 of 5
from commercially available materials using established
protocols,10 assembly of the requisite annulation partner
finds very little precedent in the current literature.12 Ring
expansions of tetralin derivatives were previously used
in the synthesis of relevant benzocycloheptanones,13 but
were plagued by deleterious aromatizations of the
properly functionalized precursors in our investigations
en route to benzocycloheptenones. We reasoned that an
intramolecular oxidative arylation of an enol ether with a
pendant arene moiety or an equivalent transformation
would allow rapid and expedient access to the desired
bicyclic ketone. Application of previously reported con-
ditions was unsuccessful in the current setting,12,14 and
the following solution to the synthesis of a protected
version of 6 was devised. Sequential alkylation of sul-
fone 8 with commercially available allyl chloride 9 and
benzyl bromide 10 afforded oxidative arylation precur-
sor 11 in excellent yield (Scheme 1).15,16 Treatment of
1
2
3
4
5
6
7
8
OMe
OMOM
OMe
O
Br
Br
PhI(OAc)2, HFIP, MeCN
OMe
OMe
0.05 M, 0 ℃
88%
SO2Ph
SO2Ph
O
O
O
O
11
14
OMe
OMe
O
O
OMe
O
9
10
11
12
13
14
15
16
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18
19
20
21
22
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24
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N
OMe
OMe
O
OMe
PhO2S
Ts
15 (89%)
OMe
16 (75%)
17 (86%)
OMe
O
O
O
4
OMe
OMe
2
OMe
O
OMe
PhO2S
PhO2S
18 (71%)a
19 (43%)a,b
20 (54%)
Scheme 1. Synthesis of the Enone Component
aPIFA was used instead of PIDA. br. r. ≈ 15:1.
SO2Ph
Br
1 PhSO2Na, DMF
O
O
Preliminary evaluation of the substrate scope indicated
that the presence of the fully substituted center was not
necessary for the success of the cyclization, and ketone
15 could be obtained in high yield. Furthermore, ben-
zannulated heterocycles 16 and 17 were prepared with
comparable efficiency. Modifications of the aromatic
substituent were tolerated, but required application of
PIFA as an oxidant to minimize formation of the corre-
sponding α-acyloxyketones. Thus, ketone 18 was pre-
pared in good yield and contained a benzosuberone mo-
tif found in colchicine.21 Oxidative arylation en route to
ketone 19 proceeded with high regioselectivity, and only
traces of the corresponding 4-methoxy-substituted prod-
uct were observed.22 It is noteworthy that oxocane de-
rivative 20, an eight-membered homolog of ketone 16,
could be prepared using our protocol.
O
O
73%
7
8
MeO
2
n-BuLi, 9,
Cl
Br
10
THF, HMPA;
n-BuLi, 10,
HMPA; 95%
OMOM
9
Br
OMe
OMe
OMOM
OMe
O
Br
Br
3 PIFA, HFIP;
NaHCO3 aq.
OMe
OMe
80% (12:13 = 1:4)
SO2Ph
O
O
O
O
,
,
12 (α βΔ) + 13 (β γΔ)
11
enol ether 11 with [bis(trifluoroacetoxy)iodo]benzene
(PIFA) in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) fol-
lowed by mild basic work-up resulted in direct for-
mation of a 1:4 mixture of unsaturated ketones 12 and
13, respectively.17,18 Although the pronounced prefer-
ence for the β,γ-unsaturated isomer could be expected to
hinder application of this intermediate in our approach, a
synthetic sequence that utilized both isomers with ap-
parently equal efficiency was developed (see below).
Notably, our oxidative arylation protocol allowed access
to gram quantities of the mixture of 12 and 13 in three
steps from commercially available bromide 7. While
relevant iodine(III)-mediated arylations of 1,3-
dicarbonyl compounds or their equivalents were previ-
ously reported,19 similar transformations of simple enol
ethers remain unexplored. In accord with previous ob-
servations,19 we discovered that application of a non-
nucleophilic solvent with high hydrogen bond donor
ability was crucial to obtaining the desired outcome.20
Omission of the basic work-up prevented elimination of
phenylsulfinate and allowed for the isolation of oxida-
tive arylation product 14 (Table 1). In this setting, (diac-
etoxyiodo)benzene (PIDA) performed better than PIFA.
We discovered that treatment of the mixture of ketones
12 and 13 with a lithio derivative of cyanophthalide 21
followed by addition of a strong acid and heating result-
ed in direct formation of the desired pentacyclic product
23 in good yield (Scheme 2).23 The process likely in-
volves reversible conversion of styrene derivative 13 to
α,β-unsaturated ketone 12, and lithio-21 can serve as a
catalytic base in the isomerization. Indeed, the value of
the initial ratio of 12 to 13 had virtually no effect on the
outcome of the transformation. Subsequent Hauser-
Kraus annulation of lithio-21 with ketone 12 produces
intermediate 22.10 The efficient installation of the qua-
ternary center at C4a is noteworthy as relevant Michael-
Claisen cascades find only limited precedent in the cur-
rent literature.24 Formation of enolate 22 is supported by
observation of the corresponding enol as a major product
when subsequent treatment with a strong acid at elevated
temperatures was omitted. The latter accomplishes
deprotection of the dioxolane moiety and triggers an
intramolecular aldol reaction of the resulting aldehyde
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Scheme 3. Synthesis of (±)-Acremoxanthone A (3)
1
2
3
4
5
6
7
HO
3
H
H
H
OMe
OMe
O
O
10
H
OMe
O
2
Na2S2O4, NaHCO3
DMF, H2O
1
TCDI, o-DCB
140 ℃
HO
HO
Br
Br
HO
MeO
Me
MeO
Me
Br
MeO
Me
53%
d. r. > 20:1
ca. 100%
H
OMe
OMe
O
OMe
OH
O
23 (d. r. = 7:1)
4 (5 steps, 20% yield)
24
8
9
3
Pd(PPh3)4, DMA;
25, CuI, CO
62%
MeO
OMe
25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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Me3Sn
CO2Me
O
H
H
H
OMe
O
OH
O
10
O
OH
O
4
PBr3, DCM;
BBr3, -78 ℃
6
Cs2CO3
DMSO
OMe
OH
HO
HO
O
HO
CO2Me
OH
MeO
Me
HO
HO
Me
′
4 a
20%, 3 steps
5
NaOAc, AcOH
HFIP, 60 ℃
d. r. > 10:1
H
OMe
MeO2C
OAc
OMe
MeO2C
OAc
O
OH
H
H
Me
OMe
OH
26
acremoxanthone A (3)
27
with the 1,3-dicarbonyl motif, which could be replicated
in a separate experiment with the conjugate acid of 22.
The resulting secondary alcohol at C3 of pentacycle 23
was installed with good stereoselectivity, and the depict-
ed relative configuration of the major diastereomer was
supported by the results of the NOE experiments.
ration at C10. Nevertheless, the problem of stereoselec-
tivity was readily overcome later in the sequence (see
below). Carbonylative Stille cross-coupling of aryl bro-
mide 24 with arylstannane 25 was best performed in the
presence
of
stoichiometric
quantities
of
tetrakis(triphenylphosphine)palladium to deliver corre-
sponding benzophenone derivative 26 in good yield.26–28
Treatment of 26 with phosphorous tribromide followed
by addition of a large excess of boron tribromide ac-
complished conversion of the secondary alcohol moiety
to the corresponding alkyl bromide and deprotection of
all but one of the aryl methyl ether functionalities. Sol-
volysis of the crude bromide in a mixture of acetic acid
and HFIP delivered acetate 27 bearing the remaining
methoxy group at C4ʹa and the desired stereochemistry
at C10.29 Treatment of crude intermediate 27 with a
weak base at elevated temperatures resulted in cycliza-
tion to form the xanthone moiety30 and afforded acre-
moxanthone A (3) in 10 steps from commercially availa-
ble material.31
Scheme 2. Assembly of the Bridged Polycyclic Motif
OMe
OMe
O
O
Br
Br
lithio-21
O
O
O
O
OMe
OMe
initial
ratio 4:1
13
12
OMe
O
LiHMDS, DME, 65 ℃
then HCl, 65 ℃
68%, d. r. = 7:1
Hauser-Kraus
annulation
lithio-21
O
Me
21
CN
O
HO
3
H
O
H
OMe
OMe
O
LiO
O
HCl
HO
Br
Br
In summary, we disclose a concise approach to the
functionalized pentacyclic core of anthraquinone-
xanthone heterodimers featuring an efficient assembly of
a benzocycloheptenone via a new intramolecular oxida-
tive arylation of an enol ether and a Hauser-Kraus annu-
lation-aldol reaction sequence to access the characteris-
tic bicyclo[3.2.2]nonene motif. We also demonstrate a
short synthesis of (±)-acremoxanthone A, which serves
as a proof of concept for our approach. We anticipate
that the strategy reported herein will be applicable to the
synthesis of other anthraquinone-xanthone heterodimers,
implementation of which is currently underway.
MeO
MeO
Me
aldol
4a
OMe
OMe
O
O
Me
22
23
Elimination of the secondary alcohol 23 was readily
accomplished upon heating with thiocarbonyldiimidaz-
ole,25 completing construction of the desired pentacyclic
intermediate 4 in five steps from commercially available
material (Scheme 3). To demonstrate the application of
our strategy, we synthesized acremoxanthone A (3) in
five steps from ketone 4. Thus, reduction with sodium
dithionite produced benzyl alcohol 24 in high yield and
high diastereoselectivity, albeit with a preference for the
undesired configuration at C10. Crystallographic analy-
sis of 24 suggests that the methylene of the benzyl frag-
ment is blocking the approach to the carbonyl group
from the same face. Indeed, we were unable to identify
conditions that selectively installed the desired configu-
ASSOCIATED CONTENT
Experimental procedures and spectroscopic data for new
compounds as well as a CIF file for compound 24. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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(9) Isaka, M.; Palasarn, S.; Auncharoen, P.; Komwijit, S.; Jones, E.
B. G. Tetrahedron Lett. 2009, 50, 284–287.
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
Corresponding Author
(10) (a) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178–
180; (b) Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 19,
2263–2266. See also: (c) Mal, D.; Pahari, P. Chem. Rev. 2007, 107,
1892–1918 and references therein.
(11) Acremoxanthone A numbering is used. See ref. 9.
(12) Xu, Z.; Chen, H.; Wang, Z.; Ying, A.; Zhang, L. J. Am. Chem.
Soc. 2016, 138, 5515–5518.
(13) For selected examples see: (a) Taylor, E. C.; Chiang, C.-S.,
McKillop, A. Tetrahedron Lett. 1977, 18, 1827–1830; (b) Hossini, M.
S.; McCulloug, K. J.; McKay, R.; Proctor, G. R. Tetrahedron Lett.
1986, 27, 3783–3786; (c) Justik, M. W.; Koser, G. F. Molecules 2005,
10, 217–225.
(14) (a) Pandey, G.; Krishna, A.; Girija, K.; Karthikeyan, M. Tet-
rahedron Lett. 1993, 34, 6631–6634; (b) Pandey, G.; Karthikeyan,
M.; Murugan, A. J. Org. Chem. 1998, 63, 2867–2872.
(15) Benzyl bromide 10 was prepared in one step from the corre-
sponding commercially available alcohol. See Supporting Information
for details.
(16) Performing the alkylations in two separate steps did not offer
any advantages and led to a decrease in the overall yield of 11 from 8.
(17) Isomers 12 and 13 were distinguished by NOE experiments.
(18) Variations in the work-up conditions did not increase the con-
tent of 12 in the product mixtures.
(19) (a) Kita, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Tamura, Y.
Tetrahedron Lett. 1989, 30, 1119–1120; (b) Kita, Y.; Okunaka, R.;
Kondo, M.; Tohma, H.; Inagaki, M.; Hatanaka, K. J. Chem. Soc.,
Chem. Commun. 1992, 429–430; (c) Kita, Y.; Tohma, H.; Hatanaka,
K.; Takada, T.; Fujita, S.; Mitoh, S.; Sakurai, H.; Oka, S. J. Am.
Chem. Soc. 1994, 116, 3684–3691; (d) Arisawa, M.; Ramesh, N. G.;
Nakajima, M.; Tohma, H.; Kita, Y. J. Org. Chem. 2001, 66, 59–65.
(20) Application of 2,2,2-trifluoroethanol was less efficient.
(21) For examples of application of related intermediates in the
synthesis of colchicine see: a) Schreiber, J.; Leimgruber, W.; Pesaro,
M.; Schudel, P.; Eschenmoser, A. Angew. Chem. 1959, 71, 637-656;
b) van Tamelen, E. E.; Spencer, T. A.; Allen, D. S.; Orvis, R. L. J.
Am. Chem. Soc. 1959, 81, 6341–6342.
spronin@uci.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Funding from the School of Physical Sciences at the Uni-
versity of California, Irvine, Chao Family Comprehensive
Cancer Center, and Allergan (graduate fellowship to
S.D.H.) is gratefully acknowledged. S.V.P. is a Hellman
fellow. We thank Dr. Joseph Ziller and Michael Wojnar for
X-ray crystallographic analysis. We also thank Professors
Larry Overman, Chris Vanderwal, and Scott Rychnovsky
for providing routine access to their instrumentation and
helpful discussions.
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26
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available 2,5-dimethoxybenzoic acid. See Supporting Information for
details.
(28) For an example of the use of a preformed arylpalladium(II)
complex in the Stille cross-coupling in the context of synthesis see:
Zajac, M. A.; Vedejs, E. Org. Lett. 2004, 6, 237–240.
(29) The stereochemical outcome of the solvolysis can be rational-
ized following the logic found in the discussion of the reduction en
route to alcohol 24.
(30) For examples of relevant cyclizations see: Hintermann, L.;
Masuo, R.; Suzuki, K. Org. Lett. 2008, 10, 4859–4862.
(31) In this sequence, the bromination/deprotection step accounts
for the main loss of the material.
(3) (a) He, H.; Bigelis, R.; Solum, E. H.; Greenstein, M.; Carter, G.
T. J. Antibiot. 2003, 56, 923–9330; (b) Intaraudom, C.; Bunbamrung,
N.; Dramae, A.; Boonyuen, N.; Komwijit, S.; Rachtawee, P.; Pit-
tayakhajonwut, P. Tetrahedron Lett. 2016, 72, 1415–1421.
(4) Wu, B.; Wiese, J.; Wenzel-Storjohann, A.; Malien, S.;
Schmaljohann, R.; Imhoff, J. F. Chem. Eur. J. 2016, 22, 7452–7462.
(5) For proposed biosynthesis see refs. 1c and 2c.
(6) For relevant discussions see refs. 1b and 1d.
(7) (a) Duffault, J.-M.; Tellier, F. Synth. Commun. 1998, 28, 2467–
2481; (b) Kramer, C. S.; Nieger, M.; Bräse, S. Eur. J. Org. Chem.
2014, 2150–2159.
(8) Hirano, Y.; Tokudome, K.; Takikawa, H.; Suzuki, K. Synlett
2017, 28, 214–220.
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