Total syntheses of graphisin A and sydowinin B

Article abstract of DOI:10.1021/ol301107m

Efficient syntheses of the highly substituted benzophenone graphisin A and the xanthone sydowinin B are described. Key steps involve aryl anion addition to substituted benzaldehyde derivatives, subsequent methyl ester installation, and dehydrative cycliza

Full text of DOI:10.1021/ol301107m

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2862–2865
Total Syntheses of Graphisin A and
Sydowinin B
Andrew Little and John A. Porco Jr.*
Department of Chemistry and Center for Chemical Methodology and Library
Development CMLD-BU), Boston University, Boston, Massachusetts 02215,
United States
porco@bu.edu
Received April 25, 2012
ABSTRACT
Efficient syntheses of the highly substituted benzophenone graphisin A and the xanthone sydowinin B are described. Key steps involve aryl anion
addition to substituted benzaldehyde derivatives, subsequent methyl ester installation, and dehydrative cyclization. Oxidation of graphisin A led
to a spirodienone derived from a highly substituted benzoquinone intermediate.
Acremoxanthone A2 (1), xanthoquinodin A3 (2), and
acremonidin A (3)4 (Figure 1) are members of a class of
heterodimeric natural products originally isolated from
Acremonium sp. BCC31806, Humicola sp. FO888, and
Acremonium sp. LL-Cyan 416, respectively. These natural
products share structurally related anthraquinone and
xanthone-derived monomer units which are linked by a
unique bicyclo[3.2.2] ring system.5 We have initiated syn-
thetic studies toward these targets with syntheses of the
requisite xanthone and benzophenone fragments present in
the natural product frameworks. In our initial studies, we have
targeted the highly functionalized, tetra-ortho-substituted
benzophenone graphisin A6 (4) and the corresponding
cyclized xanthone sydowinin B7 (5). Herein, we report
the total synthesis of the highly substituted benzophenone8
graphisin A using a suitably functionalized benzophenone
as well as preparation of the derived xanthone sydowinin B
via dehydrative cyclization.
(1) Presented in part at the 240th American Chemical Society Na-
tional Meeting, Aug 22À26, 2010, Boston; abstract ORGN 410.
(2) Isaka, M.; Palasarn, S.; Auncharoen, P.; Komwijit, S.; Jones,
E. B. Tetrahedron Lett. 2008, 50, 284–287.
(3) Tabata, N.; Tomoda, H.; Matsuzaki, K.; Omura, S. J. Am. Chem.
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J.; Blein, J. P.; Lallelmand, J. Y. J. Am. Chem. Soc. 1992, 114, 1478–1479.
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Soc. 1992, 114, 5967–5971.
(6) Pittayakhajonwut, P.; Sri-indrasutdhi, V.; Dramae, A.; Lapanun,
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(7) Hamasaki, T.; Sato, Y.; Hatsuda, Y. Agr. Biol. Chem. 1975, 39,
2341–2345.
Figure 1. Acremoxanthone A and related natural products.
Our initial plan (Figure 2) was to prepare benzophenone
nitrile 6 via aryl anion addition to a substituted benzalde-
hyde according to literature precedent.9 We envisioned
that acidic methanolysis10 of aryl nitrile 6 followed by
(8) For syntheses of highly substituted benzophenones, see: (a)
Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994,
116, 8402–8403. (b) Kaiser, F.; Schwink, L.; Velder, J.; Schmalz, H. G. J.
Org. Chem. 2002, 67, 9248–9256. (c) Slavov, N.; Cvengros, J.; Neudorfl,
J. M.; Schmalz, H. G. Angew. Chem., Int. Ed. 2010, 49, 7588–7591.
(9) Hollinshead, S. P.; Nichols, J. B.; Wilson, J. W. J. Org. Chem.
1994, 59, 6703–6709.
(10) Clarke, H. T.; Taylor, E. R. Org. Synth. Collect. 1943, 2, 588.
r
10.1021/ol301107m
Published on Web 05/23/2012
2012 American Chemical Society

global deprotection should provide graphisin A (4). Sydo-
winin B (5) could then be accessed through dehydrative
cyclization.11
FeCl3,17 TMSCl,18 and H2SO419) resulted in mixtures of
partially and fully MOM-deprotected compounds with the
aryl nitrile remaining intact.
Scheme 1. Synthesis of Aryl Nitrile 6
Figure 2. Initial synthetic plan.
In our forward synthesis, benzaldehyde 7 was regiose-
lectively brominated and protected as a bis-MOM ether in
82% yield over two steps (Scheme 1). Regioselective
deprotonation of 8 with n-BuLi, followed by addition of
aldehyde 9 at 0 °C, provided benzylic alcohol 10 in 56%
yield with the remainder of the mass balance consisting of
byproducts derived from competitive lithiumÀhalogen
exchange of the ortho aryl bromide. Oxidation of 10 with
2-iodoxybenzoic acid (IBX) provided bromobenzophe-
none 11 (75%). We had initially planned to utilize 11
directly in palladium-catalyzed carbonylative methyl ester
formation (Pd(dppf)Cl2, CO, NEt3, DMF/MeOH);12
however, this substrate was found to be unreactive likely
due to the highly electron-rich and bis-ortho-substituted
aryl ring. Efforts to install the methyl ester on either bro-
mobenzaldehyde 9 or its corresponding acetal-protected
derivatives were also unsuccessful. Similarly, anion chem-
istry (e.g., lithiumÀhalogen exchange, Grignard for-
mation) of aryl bromide substrates was also found to be
unproductive.8c However, compound 11 was found to
undergo smooth cyanation using Pd(PPh3)4 and Zn(CN)2
under microwave heating to afford aryl nitrile 6 in 60%
yield.13
In light of the apparent incompatibility of the MOM
protecting groups with nitrile hydrolysis conditions, we
elected to fully deprotect benzophenone 6 to tetraphenol
13 prior to hydrolysis (Scheme 2). Accordingly, treatment
of nitrile 6 with p-TsOH in MeOH at 40 °C produced a
deep red solution whereby the protecting groups were
globally removed to afford benzophenone 13 in 50% yield.
Purification of polyphenol 13 on silica gel was found to be
difficult due its high polarity and propensity to form an
intractable, red-colored salt with residual p-TsOH. An
example of a highly substituted benzophenone nitrile
hydrolysis has been reported.20 However, standard acidic
hydrolysis9 (H2SO4 or HCl, MeOH, 60°C) of 13resultedin
recovered starting material and minor formation of xanthone
14, whereas standard basic conditions21 (NaOH) resulted in
decomposition.
Initial attempted hydrolysis of aryl nitrile 6 to the
derived acid or ester 12 (aq NaOH or H2SO4) resulted in
either decomposition or partial MOM deprotection
(Scheme 2). Attempted partial hydrolysis of the primary
Scheme 2. Synthesis of Sydowinin B via an Aryl Nitrile
14
amide with K2CO3 and H2O2 resulted in no reaction.
Similarly, treatment of 6 with methyl triflate in CH2Cl2
followed by a methanolysis to access the imidate in a
Ritter-type reaction was also unsuccessful.15 Attempts to
hydrolyze the nitrile in the presence of methanol (BF3,16
(11) (a) Jeso, V.; Nicolaou, K. C. Tetrahedron Lett. 2009, 50, 1161–
1163. For recent reviews of xanthone syntheses, see: (b) Sousa, M. E;
Pinto, M. M. Curr. Med. Chem. 2005, 12, 2447–2479. (c) Diderot, N. T.;
Silvere, N.; Etienne, T. Adv. Phytomed. 2006, 2, 273–298. (d) Pinto,
M. M. M.; Castanheiro, R. A. P. Nat. Prod. 2009, 520–675.
(12) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int.
Ed. 2009, 48, 4114–4133.
(13) Tschaen, D. M.; Desmond, R.; King, A. O; Fortin, M. C.; Pipik,
B.; King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887–890.
(14) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989, 12, 949–
950.
At this juncture, we elected to optimize the xanthone
formation/nitrile methanolysis sequence. We observed
dehydrative cyclization to the xanthone when attempting
(18) Luo, F. T.; Jeevanadam, A. Tetrahedron Lett. 1998, 39, 9455–
9456.
(15) Booth, B. L.; Jibodu, K. O.; Proenca, M. F. J. Chem. Soc.,
Perkin Trans. 1 1983, 1067–1068.
(16) Jayachitra, G.; Yasmeen, N.; Srinivasa, K.; Ralte, S. L.; Singh,
(19) Anzalone, L.; Hirsch, J. A. J. Org. Chem. 1985, 50, 2128–2133.
(20) Storm, J. P.; Andersson, C. M. J. Org. Chem. 2000, 65, 5264–
5274.
A. K. Synth. Commun. 2003, 33, 3461–3466.
(17) Srinivasan, R.; Rao, K. S.; Jayachitra, G.; Ralte, S. L. Synth.
Commun. 2006, 36, 2883–2886.
(21) Staab, H. A.; Hauck, R.; Popp, B. Eur. J. Org. Chem. 1998, 1,
631–642.
Org. Lett., Vol. 14, No. 11, 2012
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to hydrolyze nitrile 13 with DOWEX-50 resin in water
under microwave heating.22 We later observed clean con-
version of 13 to xanthone 14 using microwave heating with
aqueous ZnCl2.23 A ground state model of nitrile 13
(Figure 3) shows that the benzophenone exists substan-
tially in a bisected conformation with hydrogen bonding
maintained between the C-6 and C-10 phenols and the C-8
ketone. However, internal hydrogen-bonding of the phe-
nolsmay bedisruptedinwater suchthat rotation can occur
prior to cyclization to form xanthone 14. Xanthone 14
was finally subjected to acidic methanolysis conditions
(3 M H2SO4, MeOH, 60 °C) which afforded sydowinin B
(5) in 50% yield (two steps).
18 (H2, Pd(OH)2, MeOH) resulted in complete con-
version to the over-reduced product 19, analogous to a
product25 reported by Snider and co-workers for a similar
substrate.26 However, hydrogenolysis of 18 using Pd/C in
THF/MeOH (3:1) led to the desired hydroxybenzophe-
none 20 (Scheme 5). It is apparent that sole use of a polar
protic solvent activates 20 toward hemiketal formation
which undergoes further hydrogenolysis to the corre-
sponding dihydroisobenzofuran 19.
Scheme 4. Dihydroisobenzofuran Formation
A three-step oxidationÀmethylation sequence was next
conducted on the protected benzophenone 20 involving
sequential Dess-Martin and Pinnick oxidations followed
by treatment with excess TMSCH2N2 in 1:1 MeOH/Et2O
to provide methyl ester 12 in 65% yield over three steps
(Scheme 5).25 Compound 12 was fully deprotected with
p-TsOH in MeOH to provide graphisin A (4) in 77% yield.
1
Analytical data for 4 including H and 13C NMR spectra
Figure 3. DFT minimized model of nitrile 13.
Scheme 3. Alternative Route to Graphisin A
were in agreement with those reported for the natural
product.6 Graphisin A (4) could also be converted to
sydowinin B (5) in 58% yield by dehydrative cyclization
with aqueous ZnCl2 under microwave conditions (120 °C).23
Scheme 5. Synthesis of Sydowinin B via Graphisin A
To enable installation of the requisite methyl ester and
access graphisin A (4) without dehydrative cyclization, we
implemented the alternative route shown in Scheme 3.
Bromoaldehyde24 9 was reduced and benzyl-protected to
afford aryl bromide 15 in 80% yield (two steps). Regiose-
lective deprotonation of 8 and subsequent quenching with
DMF provided benzaldehyde 16 (78%). LithiumÀ
halogen exchange of aryl bromide 15 at À78 °C in ether with
t-BuLi followed by a rapid quench with aldehyde 16
provided benzyl alcohol 17 (61%). Subsequent IBX oxida-
tion afforded ketone 18 in 78% yield (Scheme 4). Initial
attempted conditions for selective benzyl deprotection of
It has been proposed that the biosynthesis of various
members of the blennolide/secalonic acid27 family of nat-
ural products proceeds through oxidation/reduction of
functionalized benzophenone intermediates resembling
(25) Yu, M.; Snider, B. B. Org. Lett. 2011, 13, 4224–4227.
(26) We observed aryl and MOM ether peak broadening in the H
1
and 13C NMR spectra for compound 19 similar to a 2,6-disubstituted
aryl dihydroisobenzofuran reported in ref 25 (see Supporting Informa-
tion for details).
(22) Lindstrom, U. Green Chem. 2006, 8, 22–24.
(23) For Zn(II)-mediated dehydration of amides in water, see:
Manjula, K.; Pasha, M. A. Synth. Commun. 2007, 37, 1545–1550.
(24) Goddard, M. L.; Tabacchi, R. Tetrahedron Lett. 2006, 47, 909–
911.
€
(27) (a) Zhang, W.; Krohn, K.; Florke, U.; Pescitelli, G.; Di Bari, L.;
Antus, S.; Kurtan, T.; Rheinheimer, J.; Draeger, S.; Schulz, B. Chem.;
€
Eur. J. 2008, 14, 4913–4923. (b) Gerard, E. M. C.; Brase, S. Chem.;Eur.
J. 2008, 14, 8086–8089. (c) Qin, T.; Johnson, R. P.; Porco, J. A. J. Am.
Chem. Soc. 2011, 133, 1714–1717.
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Org. Lett., Vol. 14, No. 11, 2012

Scheme 6. Oxidation of Graphisin A
Figure 4. DFT minimized model of proposed benzoquinone
intermediate 21.
23 in 89% yield. This result supports the intermediacy of
benzoquinone21enrouteto23. While both6-endo-trigand
5-exo-trig cyclization modes of 21 are possible,33 the
observed isomer 23 is likely favored due to the bisected
conformation34 of proposed intermediate 21 which places
one ortho-phenol in favorable alignment with the π*-
orbital of the C-7 quinone carbon (Figure 4).
In conclusion, an efficient synthesis of graphisin A has
been accomplished employing aryl anion addition to a
benzaldehyde, followed by oxidation to a highly substi-
tuted benzophenone, subsequent methyl ester installation,
and global deprotection. Graphisin A was further con-
verted by dehydrative cyclization under microwave condi-
tions to the xanthone sydowinin B. Oxidation of graphisin
A led to formation of a spirodienone likely from a highly
substituted and bisected benzoquinone intermediate.
Further studies employing graphisin A and sydowinin B
toward the synthesis of acremoxanthones and related
natural products are currently in progress and will be
reported in due course.
graphisin A.28 Accordingly, we conducted preliminary
investigations as to whether graphisin A (4) could be
converted to dienone 22 via oxidation to benzoquinone
21 followed by oxa-Michael addition (Scheme 6).29 Treat-
ment of graphisin A (4) with phenyliodine diacetate
(PIDA) resulted in clean oxidative cyclization to spirodie-
none 23.30 Oxidations of hydroxybenzophenones to simi-
lar spiro-dienones are known25,31and are thought to occur
via a phenoxide radical that is aligned to favor the five-
membered ring due to a bisected conformation of the
highly substituted benzophenone. Spirodienone 23 was
treated under acidic conditions25 to provide a mixture of
rearrangedacid24(57%) and depsidone25(12%). Acid24
could be further cyclized to depsidone 25 by heating with
TFAA in toluene (68%). In a similar fashion, oxidation of
4 with FeCl3 provided a mixture of 24 (39%) and 25 (44%)
as the sole products.
Following reported dehydrogenation conditions that
likely proceed through quinone intermediates,32 treatment
of graphisin A (4) withPd/CÀO2 also provided spirodienone
Acknowledgment. Financial support from the National
Institute of Health (RO1 CA137270 and CA 099920) is
gratefully acknowledged. We thank Prof. P. Pittayakha-
jonwut, Bioresources Research Laboratory, Thailand for
providing a sample of natural graphisin A and Tian Qin
(Boston University) for helpful discussions.
(28) (a) Kurobane, I.; Vining, L. C. Tetrahedron Lett. 1978, 16, 1379–
1382. (b) Kurobane, I.; Vining, L. C.; McInnes, A. C. J. Antibio. 1979,
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2009, 109, 3903–3990.
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anthones, see: (a) Franck, B.; Stockigt, U.; Franckowiak, G. Chem. Ber.
1973, 106, 1198–1220. (b) Nicolaou, K. C.; Li, A. Angew. Chem., Int. Ed.
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Supporting Information Available. Detailed experimen-
tal procedures and spectral data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
€
Brase, S. Chem.;Eur. J. 2011, 17, 13706–13711. For xanthone forma-
tion, see: (d) Tisdale, E. J.; Kochman, D. A.; Theodorakis, E. A.
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(30) See Supporting Information for details on characterization.
(31) (a) Hendrickson, J. B.; Ramsay, M. V. J.; Kelly, T. R. J. Am.
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quinones to xanthones, see: Nichols, A. L.; Zhang, P.; Martin, S. F. Org.
Lett. 2011, 13, 4696–4699.
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The authors declare no competing financial interest.
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