Enantioselective total synthesis of (S)-bisoranjidiol, an axially chiral bisanthraquinone

Article abstract of DOI:10.1021/ol3001365

The first enantioselective total synthesis of the bisanthraquinone (S)-bisoranjidiol and an unnatural regioisomer has been accomplished. Key features of the synthesis include the asymmetric oxidative biaryl coupling of a hindered 8-substituted 2-naphthol,

Full text of DOI:10.1021/ol3001365

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1408–1411
Enantioselective Total Synthesis of
(S)-Bisoranjidiol, an Axially Chiral
Bisanthraquinone
Erin E. Podlesny and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United States
marisa@sas.upenn.edu
Received January 18, 2012
ABSTRACT
The first enantioselective total synthesis of the bisanthraquinone (S)-bisoranjidiol and an unnatural regioisomer has been accomplished. Key
features of the synthesis include the asymmetric oxidative biaryl coupling of a hindered 8-substituted 2-naphthol, selective para-quinone
formation, and regioselective tandem DielsꢀAlder/aromatization reactions.
(S)-Bisoranjidiol [(S)-1, Figure 1] is a photosensitizing
bisanthraquinone capable of interacting with molecular
oxygen to generate electronically excited singlet oxygen
and the ground state radical anion upon irradiation with
light.1 These photosensitizing properties are responsible
for the phototoxicity of the shrub Heterophyllaea pustulata
(genera Rubiaceae), from which it was isolated in 2006.2
Native to the Andean Mountains of Argentina and Boli-
via, the plant poses a danger to grazing livestock. Ingestion
of the plant and exposure to sunlight causes derma-
titis, keratoconjunctivitis (which may lead to blindness),
and behavioral changes, such as restlessness and
photophobia.3,4 The photosensitizing properties of (S)-1
make it an interesting natural product with potential
applications in photodynamic therapy.5 Recently, it has
been reported to be a good antibacterial agent6 and
photodynamically active toward cancer cells.7 To date,
neither asymmetric syntheses of bisanthraquinones nor
any synthesis of 1 has been achieved. In this letter, we
report the first total synthesis of (S)-bisoranjidiol (1) via a
route that would allow analog generation to optimize
biological properties.
Bisoranjidiol (1) is a member of a larger class of axially
chiral symmetrical bisanthraquinone natural products
possessing a biaryl linkage at the 1,10-positions (see
Figure 1). Spectroscopic analyses and chemical methods
established the structure and configuration of 1.2 Bisor-
anjidiol (1) is unique compared to the other bisanthraqui-
none natural products (2) as it lacks the 4,40-hydroxyl
groups and the meta-substitution pattern of the distal rings
shared by the other congeners.
ꢀ~
(1) Comini, L. R.; Nunez Montoya, S. C.; Sarmiento, M.; Cabrera,
€
J. L.; Arguello, G. A. J. Photochem. Photobiol., A 2007, 188, 185–191.
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(2) Nunez Montoya, S. C.; Agnese, A. M.; Cabrera, J. L. J. Nat.
Prod. 2006, 69, 801–803.
ꢀ~
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(3) Nunez Montoya, S. C.; Comini, L. R.; Rumie Vittar, B.; Fernandez,
I. M.; Rivarola, V. A.; Cabrera, J. L. Toxicon 2008, 51, 1409–1415.
(4) Aguirre, D. H.; Neumann, R. A. Med. Vet. 2001, 18, 487–490.
(5) (a) Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.;
Kessel, D; Korbelik, M.; Moan, J.; Peng, Q. J. Natl. Cancer Inst. 1998,
90, 889–905. (b) Dolmans, D. E.; Fukumara, D.; Jain, R. K. Nat. Rev.
Cancer 2003, 3, 380–387. (c) Hamblin, M. R.; Hasan, T. Photochem.
Photobiol. Sci. 2004, 3, 436–450. (d) Yano, S.; Hirohara, S.; Obata, M.;
Hagiya, Y.; Ogura, S.; Ikeda, A.; Kataoka, H.; Tanaka, M.; Joh, T.
J. Photochem. Photobiol., C 2011, 12, 46–67.
ꢀ~
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(6) Comini, L. R.; Nunez Montoya, S. C.; Paez, P. L.; Arguello,
G. A.; Albesa, I.; Cabrera, J. L. J. Photochem. Photobiol., B 2011, 102,
108–114.
ꢀ
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(7) Fernandez, I.; Comini, L.; Nigra, A.; Nunez, S.; Rumie Vittar, B.;
Cabrera, J.; Rivarola, V. A. Biocell 2009, 33, A266.
r
10.1021/ol3001365
Published on Web 02/24/2012
2012 American Chemical Society

employed in these types of reactions although less ornate
dienes such as Danishefsky’s diene14 have also been used.
Scheme 1. Retrosynthetic Analysis
Figure 1. Bisanthraquinone natural products.
Prior syntheses of symmetrical bisanthraquinones pos-
sessing a 1,10-biaryl linkage include biomimetic coupling of
an anthraquinone or anthrone monomer,8 the Ullman
reaction between brominated anthraquinones,9 and dou-
ble addition of an isobenzofuran-1,3-dione to a biphenyl
intermediate.10 However, the only bisanthraquinone nat-
ural products synthesized include skyrin (0.28ꢀ35% yield,
R1,2 = H, R3 = Me; Figure 1) and hinakurin (e58% yield,
R1 = H, R2,3 = Me; Figure 1), which were formed via
biomimetic syntheses8 and an Ullman reaction, respec-
tively.9a The total syntheses of related bisanthraquinones,
biphyscion, 2,20-epi-cytoskyrin A, and rugulosin have also
been reported; however, biphyscion contains a 2,20-biaryl
linkage,11 and the latter two possess a cage-like “skyrane”
motif.12
Retrosynthetic analysis of (S)-1 revealed a different,
nonbiomimetic approach to this structural subtype that
hinges on the much simpler prospect of forming a bis-
naphthol via oxidative coupling rather than the more
difficult oxidative coupling of an oxidation resistant an-
thraquinone. Specifically, a double DielsꢀAlder reaction
between a binaphtho-para-quinone [(S)-4a] and vinyl ke-
tene acetal 3, followed by aromatization, would readily
revealthe corebisanthraquinonestructure(Scheme1). The
DielsꢀAlder reaction of 1,4-naphthoquinones with vinyl-
ketene acetals, followed by aromatization, is well-known.13
Alkyl trimethylsilyl- or bis(trimethylsilyl)vinyl ketene
acetals, also referred to as Brassard dienes,13 are typically
The key binaphtho-para-quinone (S)-4a would, in turn,
require a selective oxidation of (S)-5, a heretofore unex-
plored undertaking. Enantioselective oxidative binaphthol
coupling of 7, containing substitution at the 8-position,
with our 1,5-diaza-cis-decalin copper catalyst,15 followed
by ester and protecting group removal would provide key
intermediate (S)-6. This asymmetric coupling reaction has
been an integral part of the syntheses of several other
axially or helically chiral naphthalene-based natural pro-
ducts from our group.16,17
Coupling precursor 7 was effectively prepared from
8 via a Fischer esterification and selective benzylation of
the less hindered phenol (Scheme 2). The enantioselective
biaryl coupling of substrate 7 with (R,R)-9 proceeded
(14) Danishefsky, S.; Kitaharai, T. J. Am. Chem. Soc. 1974, 96, 7807–
7808.
(15) (a) Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137–
1140. (b) Kozlowski, M. C.; Li, X.; Carroll, P. J.; Xu, Z. Organometallics
2002, 21, 4513–4522. (c) Xie, X.; Phuan, P.-W.; Kozlowski, M. C.
Angew. Chem., Int. Ed. 2003, 42, 2168–2170. (d) Mulrooney, C. A.; Li,
X.; DiVirgilio, E. S.; Kozlowski, M. C. J. Am. Chem. Soc. 2003, 125,
6856–6857. (e) Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.;
Kozlowski, M. C. J. Org. Chem. 2003, 68, 5500–5511. (f) Morgan, B. J.;
Xie, X.; Phuan, P.-W.; Kozlowski, M. C. J. Org. Chem. 2007, 72, 6171–
6182. (g) Hewgley, J. B.; Stahl, S. S.; Kozlowski, M. C. J. Am. Chem. Soc.
2008, 130, 12232–12233.
(8) (a) Franck, B.; Chahin, R.; Eckert, H.-G.; Langenberg, R.;
Radtke, V. Angew. Chem., Int. Ed. Engl. 1975, 14, 819–820. (b) Banks,
H. J.; Cameron, D. W.; Raverty, W. D. Aust. J. Chem. 1976, 29, 1509–
1521. (c) Cameron, D. W.; Edmonds, J. S.; Raverty, W. D. Aust. J.
Chem. 1976, 29, 1535–1548.
(9) (a) Tanaka, O.; Kaneko, C. Pharm. Bull. 1955, 3, 284–286. (b)
Shibata, S.; Tanaka, O.; Kitagawa, I. Pharm. Bull. 1955, 3, 278–283. (c)
Tanaka, O. Chem. Pharm. Bull. 1958, 2, 203–208. (d) Iio, H.; Zenfuku,
K.; Tokoroyama, T. Tetrahedron Lett. 1995, 36, 5921–5924.
(10) Scholl, R.; Liese, K.; Michelson, K.; Grunewald, E. Ber. 1910,
43, 512–518.
(11) Hauser, F. M.; Gauuan, P. J. F. Org. Lett. 1999, 1, 671–672.
(12) (a) Nicolaou, K. C.; Papageorgiou, C. D.; Piper, J. L.; Chadha,
R. K. Angew. Chem., Int. Ed. 2005, 44, 5846–5851. (b) Nicolaou, K. C.;
Lim, Y. H.; Piper, J. L.; Papageorgiou, C. D. J. Am. Chem. Soc. 2007,
129, 4001–4013.
(16) (a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc.
Rev. 2009, 38, 3193–3207. (b) DiVirgilio, E. S.; Dugan, E. C.; Mulroony,
C. A.; Kozlowski, M. C. Org. Lett. 2007, 9, 385–388. (c) O’Brien, E. M.;
Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int. Ed. 2008, 47, 6877–
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J. Am. Chem. Soc. 2009, 131, 9413–9425. (e) Morgan, B. J.; Mulrooney,
C. A.; O’Brien, E. M.; Kozlowski, M. C. J. Org. Chem. 2010, 75, 30–43.
(f) Morgan, B. J.; Mulrooney, C. A.; Kozlowski, M. C. J. Org. Chem.
2010, 75, 44–56. (g) O’Brien, E. M.; Morgan, B. J.; Mulrooney, C. A.;
Kozlowski, M. C. J. Org. Chem. 2010, 75, 57–68.
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Org. Lett., Vol. 14, No. 6, 2012
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surprisingly smoothly even with the C8-substitution,
which provides considerable steric hindrance to the cou-
pling at C1. As a result, (S)-618 was obtained in 62% yield
and 87% ee (61% yield, 92% ee with (S,S)-9). After one
trituration, material of >99% ee was readily obtained. To
the best of our knowledge, the only reported enantioselec-
tive binaphthol coupling reaction with substitution in the
hindered8-position isthecoupling ofnaphtho[2,1-b]furan-
8-ol in 50% yield and 75% ee.19
With (S)-12 in hand, the remaining key step was trans-
formation of the binaphtho-para-quinone into a bisan-
thraquinone via regioselective tandem DielsꢀAlder/aro-
matization reactions. Initial investigations revealed that
the use of Lewis acids, such as ZnCl2, provided control
over the regioselectivity of the cycloaddition, however, side
reactions and decomposition of the quinone consistently
resulted in low yields. Aside from Lewis acids, halogens are
often used as directing groups when working with vinyl
ketene acetals and para-quinones.20 Subsequent investiga-
tions on a monomeric system indicated that halogen
directing groups provided superior yields and complete
regiocontrol in the cycloaddition reaction.
Scheme 2. Synthesis of Biaryl
To install the desired bromine directing group, (S)-12
was brominated with Br2, followed by dehydrohalogena-
tion in acetic acid (Scheme 4). This procedure provided a
mixture of bromoquinones in 95% yield. The mixture was
comprised of the 6,60-, 6,70-, and 7,70-dibrominated regioi-
somers. Approximately equal ratios of the 6,60- and 6,70-
dibromoquinones [(S)-4a and (S)-4b; Scheme 4] were
obtained, plus 10% of the 7,70-dibromoquinone [(S)-4c].
The production of (S)-4a and (S)-4b was seen as an
opportunity to produce both a significant amount of
bisoranjidiol precursor [(S)-13a] and an unnatural bisan-
thraquinone regioisomer. Duetothe directing abilityof the
halogen in the cycloaddition reaction, we expected the
ratio of regioisomers 4aꢀc to be reflected in the product
bisanthraquinones. When diene 1421 was used in a test
reaction with a substrate analogous to 4aꢀc,22 this result
did occur, but interestingly, with diene 323 and 4aꢀc, the
process was very selective for (S)-13a. It appeared that (S)-
4b and (S)-4c were either not reacting as well as (S)-4a and/
or were decomposing. To evaluate the reasons for the
selectivity, the regioisomers (S)-4a and (S)-4b were sepa-
rated and treated separately with diene 3. The key inter-
mediate to bisoranjidiol, (S)-4a, reacted completely with
diene 3 in 2 days to afford the “outꢀout” bisanthraqui-
none (S)-13a in 80% yield, following aromatization over
silica (Scheme 4). Dibromoquinone (S)-4b, on the other
hand, stalled at the monocycloadduct stage and required
5ꢀ6 days to reach completion, with noticeably more
decomposition over the course of the reaction compared
to (S)-4a. Aromatization over silica provided “outꢀin”
(S)-13b in 46ꢀ71% yield. This was deprotected to give the
regioisomer of bisoranjidiol (Scheme 4). The minor isomer
After methylation of (S)-6, the esters were effectively
removed in 63% yield via a three-step sequence involving
DIBALH reduction to the alcohol, IBX promoted oxida-
tion to the aldehyde, and decarbonylation with RhCl-
(PPh3)3 (Scheme 3). In this instance, this combination was
found to be more efficient and reliable than decarboxylation.
Hydrogenolysis of the benzyl groups followed by a selective
salcomine catalyzed oxidation yielded the binaphtho-para-
quinone (S)-12 in 63% yield without loss of enantiopurity.
Approximately 23% of an unsymmetrical binaphtho-ortho,
para-quinone was also isolated. This side product could be
avoided by using (diacetoxyiodo)benzene, but yields were
much lower.
Scheme 3. Synthesis of Binaphtho-para-quinone
(18) The absolute configuration was assigned based upon analogy to
other binaphthols formed by the diaza-cis-decalin copper catalyst. This
coupling reaction has been demonstrated to be highly stereoregular. See
refs 15 and 16.
(19) Upadhyay, S. P.; Karnik, A. V. Tetrahedron Lett. 2007, 48,
317–318.
(20) For examples, see: (a) Cameron, D. W.; Riches, A. G. Aust. J.
Chem. 1999, 52, 1165–1171. (b) Tietz, L. F.; Gericke, K. M.; Schuberth,
I. Eur. J. Org. Chem. 2007, 4563–4577. (c) Danishefsky, S. J.; Uang, B. J.;
Quallich, G. J. Am. Chem. Soc. 1985, 107, 1285–1293.
(21) Tietz, L. F.; Gericke, K. M.; Singidi, R. R.; Schuberth, I. Org.
Biomol. Chem. 2007, 5, 1191–1200.
(22) The test reaction was carried out with a mixture of the “out”,
“out-in”, and “in” bromoquinones, analogous to 4aꢀc, but containing
3,30-methyl esters and 2,20-hydroxyls
(23) Kim, G. T.; Wenz, M.; Park, J. I.; Hasserodt, J.; Janda, K. D.
Bioorg. Med. Chem. 2002, 10, 1249–1262.
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Org. Lett., Vol. 14, No. 6, 2012

analysis to confirm the original stereochemical assignment
as S.2 Surprisingly, the authentic sample showed only 5%
ee of the (S)-enantiomer. Since the ee is small, it is also
possible that the natural sample is racemic. Concurrently,
we discovered that the enantiopurity of bisoranjidiol
eroded in MeOH (25 °C, t1/2 = 3.8 months; 80 °C,
Scheme 4. Synthesis of (S)-Bisoranjidiol and an Unnatural
Regioisomer
t1/2 = 1.8 h). As the isolation conditions involved refluxing
solvent (benzene) and exposure to base and acid,2 it is not
unreasonable that significant erosion of the enantiopurity
occurred during isolation and subsequent handling of the
material.
In summary, the first total synthesis of (S)-bisoranjidiol
has been completed in 12 steps and 4% overall yield from
commercially available 8. This synthesis also represents the
mostselective coupling of a 2-naphthol with substitution in
the hindered 8-position, as well as the first enantioselective
synthesis of a 1,10-linked bisanthraquinone. This approach
represents a more efficient entry into this natural product
series and also permits flexibility in the generation of
further analogs for study.
Acknowledgment. Financial support for this work was
provided by the National Science Foundation (CHE-
0911713). E.E.P. gratefully acknowledges the National
Institutes of Health for both an NRSA (F31-GM093515)
and Chemistry-Biology Interface (T32-GM071339) pre-
doctoral fellowships. Partial instrumentation support was
provided by the NIH for MS (1S10RR023444) and
ꢀ
NMR (1S10RR022442). We also thank Dr. Jose Cabrera
(Universidad Nacional de Cordoba, Argentina) for an
ꢀ
authentic sample of bisoranjidiol. Inaddition, weacknowl-
edge Dr. Barbara J. Morgan (University of Pennsylvania)
for her contributions to the biaryl coupling reaction, as
(S)-4c mostly led to decomposition. Presumably, the for-
mation of the “in” DielsꢀAlder adduct with the phenolic
substituent disposed to the hindered bay region of the
structure is highly disfavored on steric grounds.
€
well as Dr. Omer Koz (visiting researcher, Ege University,
Turkey), and undergraduates Xaira Lopez Corcino (REU
student), and Kenny Puk (University of Pennsylvania) for
scale-up of racemic material.
Finally, deprotection of (S)-13a with excess BBr3 pro-
vided (S)-bisoranjidiol, (S)-1, in 80% yield with no erosion
of the enantiomeric excess (Scheme 4). Both the chemical
Supporting Information Available. Experimental pro-
cedures, characterization data, NMR spectra, CD spec-
tra, HPLC traces. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
shifts and splitting patterns from the H and 13C NMR
data of the synthetic material were in accord with the
published spectroscopic data for the natural product.2
Using an authentic sample of the natural product kindly
provided by Dr. Cabrera,2 we undertook chiral HPLC
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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