Total synthesis of graphislactone G

Article abstract of DOI:10.1016/j.tetlet.2010.04.024

We present a total synthesis of the fungal natural product graphislactone G, a chlorinated resorcylic lactone. The key step is a Suzuki coupling used for the construction of the central biaryl bond. Graphislactone G was prepared in 13 steps with 22% yield

Full text of DOI:10.1016/j.tetlet.2010.04.024

Tetrahedron Letters 51 (2010) 3092–3094
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of graphislactone G
*
Judith Cudaj, Joachim Podlech
Institut für Organische Chemie, Karlsruher Institut für Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 February 2010
Revised 1 April 2010
Accepted 7 April 2010
Available online 11 April 2010
We present a total synthesis of the fungal natural product graphislactone G, a chlorinated resorcylic lac-
tone. The key step is a Suzuki coupling used for the construction of the central biaryl bond. Graphislac-
tone G was prepared in 13 steps with 22% yield starting with orcinol and phloroglucinic acid, where the
longest linear sequence consists of nine steps.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Polyketides
Fungal metabolites
Resorcylic lactones
Cross Coupling
Suzuki reaction
1. Introduction
2. Results and discussion
The metabolisms of fungi1 and lichens2—a symbiosis of algae
and fungi, where the latter supply the lichens with secondary
metabolites—are very similar. Graphislactone A was identified as
reduction product of the fungal metabolite botrallin in 1968,3 but
it was first isolated as a natural product from the lichen Graphis
scripta var. pulverulenta4 in the late nineties together with graphis-
lactones B–D.4a–d Graphislactones E and F have been isolated from
Graphis scripta and Graphis prunicola4d and graphislactones G and H
have been isolated from the endophytic fungus Cephalosporium
acremonium IFB-E007.5 The biosynthesis of the graphislactones is
strongly related to that of alternaria metabolites,4d,6 in fact, 3-
desmethylgraphislactone A was identified in the metabolism of
alternaria toxins.7
Retrosynthesis of the target compound suggested a Suzuki cou-
pling11 as key step for the construction of the central biaryl bond.
Boronate 4 suitable for this transformation could be prepared
according to a published procedure10 starting with commercially
available acetal-protected phloroglucinic acid 2 (Scheme 1) or—
with one more step necessary—from phloroglucinic acid (1).
The other component required for a Suzuki coupling was pre-
pared essentially according to a known protocol12 starting with
commercially available orsellinic acid (6), which can be easily pre-
pared in two steps from orcinol (5) with 65% yield (Scheme 3).13
The methyl ester 7 was obtained with methyl iodide and potas-
A number of biological activities have been reported for graph-
islactones. Graphislactone A is an antioxidant and a scavenger of
free radicals;8 graphislactones A, G, and H were found to be active
against the SW1116 cell line (IC50 8.5, 21, and 12 mg/mL, respec-
tively);5 and graphislactone A is a moderate inhibitor of AChE.4e
Total syntheses of graphislactones A–F and H have been published
by Abe et al.9 and by our group,10 where we were able to supply
revised structures of graphislactones E and F. No total synthesis
has been published for graphislactones G up to date. Herein we re-
port the first total synthesis of graphislactone G.
1) MeOH,
1
2
OH
O
O
DEAD, Ph3P
acetone, SOCl2
DMAP
CO2H
OH
2) Tf2O, pyridine
O
74%
43%
HO
HO
OH
O
O
3
O
O
4
O
O
B
H
O
O
O
Pd(PPh3)4, Et3N
88%
MeO
OTf
MeO
B
O
* Corresponding author. Tel.: +49 721 608 3209; fax: +49 721 608 7652.
E-mail addresses: joachim.podlech@kit.edu, joachim.podlech@ioc.uka.de (J.
Podlech).
Scheme 1. Synthesis of boronate 4 suitable for Suzuki coupling.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.024

J. Cudaj, J. Podlech / Tetrahedron Letters 51 (2010) 3092–3094
3093
R1O
O
OH
O
4
12
O
O
OH
O
O
Br
OR2
O
O
OH
MeO
MeO
R1, R2 = H:
+
HO
MeO
B
O
OMe
OMe
OMe
Cl
graphislactone A
graphislactone C
R1 = Me, R2 = H: graphislactone B
R1 = H, R2 = Me: graphislactone H
OH
O
O
Pd(OAc)2, S-Phos
Cs2CO3
O
OH
O
MeO
MeO
O
72%
O
OMe
RO
MeO
Cl
graphislactone G
HO
HO
OMe
Scheme 3. Suzuki coupling yielding graphislactone G.
OMe
OH
HO
R = Me: graphislactone E
R = H: graphislactone F
graphislactone D
bromide 12 suitable for a Suzuki coupling was obtained by bromin-
ation with N-bromosuccinimide. The correct constitution of com-
pound 12 was unambiguously proven by analysis of proton
NOESY spectra.
Suzuki coupling of aryl bromide 12 and boronate 4 with con-
comitant lactonization was achieved with a protocol, which previ-
ously proved itself suitable for the synthesis of similar
compounds,10,16 thus yielding the natural product graphislactone
G in 72% (Scheme 3). The reaction occurred with complete che-
moselectivity. No Suzuki coupling of the chloro function was
observed.
OH
O
OH
O
6
5O
O
7
Me
9
MeO
MeO
1
3
OMe
HO
OMe
Cl
O
graphislactone G
botrallin
Figure 1. Graphislactones and related compounds.
Comparison of NMR spectra obtained for the synthesized mate-
rial with published data obtained from the natural product con-
firmed the identity of both compounds, furthermore giving
unambiguous evidence for the proposed structure of the natural
product (Table 1).
sium carbonate (91%).14 Chlorination with freshly distilled sulfuryl
chloride afforded chlorinated methyl orsellinate 8 in 95% yield,
while the dichlorinated substrate 9 was obtained in traces. Separa-
tion was simply achieved by recrystallization (Scheme 2).15
Selective methylation of the 4-hydroxyl group with subsequent
saponification (?10) and decarboxylation using 2,2-bipyridyl in
the presence of CuO2 at elevated temperature (160 °C) furnished
the known compound 11 with 58% yield (Scheme 3).12 The aryl
Table 1
Comparison of NMR data for natural and synthesized graphislactone G
Signala
Natural productb
Synthesized material
D
d [ppm] (multiplicity)
d [ppm] (multiplicity)
1-CH3
9-OCH3
3-OCH3
8-H
H-4
H-10
OH
2.88 (s)
3.92 (s)
3.96 (s)
6.56 (d, J = 2.1 Hz)
6.8 (s)
2.89 (s)
3.92
3.97 (s)
6.57 (d, J = 2.2 Hz)
6.75 (s)
0.01
0.00
0.01
0.01
0.05
0.01
0.01
5
OH
OH
6
1) POCl3, DMF
2) NaClO2
HO2C
7.19 (d, J = 2.1 Hz)
11.78 (br s)
7.20 (d, J = 2.2 Hz)
11.79
65%
OH
OH
d [ppm]
d [ppm]
Dc
9
8
OH
OH
Cl
1-CH3
9-OCH3
3-OCH3
C-4
22.0 (q)
56.5 (q)
57.3 (q)
99.7 (d)
21.3
55.8
56.5
98.9
99.3
99.7
105.5
112.1
121.6
135.7
137.2
150.9 (s)
156.0
165.2 (s)
165.0 (s)
166.4 (s)
ꢀ0.7
ꢀ0.7
ꢀ0.8
ꢀ0.8
ꢀ0.9
ꢀ0.8
ꢀ0.8
ꢀ0.8
ꢀ0.8
ꢀ0.8
ꢀ0.7
ꢀ5.2d
ꢀ1.2d
ꢀ0.7
ꢀ0.8
ꢀ0.8
1) MeI, K2CO3
2) SO2Cl2
MeO2C
MeO2C
Cl
+
OH
OH
C-8
100.2 (d)
100.5 (s)
106.3 (d)
112.9 (s)
122.3 (s)
136.5 (s)
137.9 (s)
156.1 (s)d
157.2 (s)d
165.9 (s)
165.8 (s)
167.2 (s)
Cl
C-6a
C-10
C-10b
C-2
86%
traces
C-1
10
OH
8
OH
Cl
1) Me2SO4
C-10a
C-4a
C-3
C-7
C-6
MeO2C
HO2C
2) NaOH
58%
OH
OMe
Cl
C-9
a
b
c
Numbering see Figure 1.
Chemical shifts as published in Ref. 5.
The average deviation of ꢀ0.77 ppm (not counting for the deviation at C-4a)
OH 11
OH 12
2,2'-bipyridine
Br
CuO2, Δ
NBS
92%
suggests a shifted calibration of the spectra which could be confirmed by inspection
quant.
OMe
Cl
OMe
of the original spectrum (Dd for CDCl3: +0.8 ppm).
d
The original 13C NMR spectrum has a low signal-to-noise ratio. Significant
spikes are present in the relevant range at d = 150.3, 151.6, and ꢁ156.8 ppm (with
correctionc at d = 149.5, 150.8, and ꢁ156.0 ppm).
Cl
Scheme 2. Synthesis of aryl bromide 12 suitable for Suzuki coupling.

3094
J. Cudaj, J. Podlech / Tetrahedron Letters 51 (2010) 3092–3094
HRMS (C16H1335ClO5, EI): found 320.0449; calcd 320.0452. The
3. Experimental section
data are in full agreement with published data for the natural
product,5 except for the 13C NMR signal of C-4a (see Table 1).
Experimental procedures and detailed spectroscopic data for all
compounds are given as Supplementary data.
Acknowledgements
3.1. 4-Bromo-4-chloro-5-methoxy-3-methylphenol (12)
We cordially thank Ren Xiang Tan and Hua Wei Zhang for pro-
viding NMR spectra of graphislactone G.
NBS (0.141 g, 0.791 mmol) was added at 0 °C under an argon
atmosphere to phenol 11 (0.130 g, 0.753 mmol) in anhydrous
CCl4 (7 mL) and the yellow mixture was stirred for 30 h at 0 °C.
The mixture was filtered and the filtrate was concentrated to yield
bromide 12 (0.175 g, 0.696 mmol, 92%) as a yellow solid. Rf = 0.76
(CH2Cl2/MeOH, 50:1). mp: 100–103 °C. 1H NMR (400 MHz, CDCl3):
d = 2.51 (s, 3H, ArMe), 3.90 (s, 3H, OMe), 5.63 (br s, 1H, OH), 6.56 (s,
1H, ArH). 13C NMR (101 MHz, CDCl3): d = 19.9 (q), 55.3 (d), 96.6 (q),
103.2 (s), 113.8 (s), 135.5 (s), 150.3 (s), 154.3 (s). Assignment of
NMR-spectroscopical daꢀta1 was made according to NOESY spectra.
~
Supplementary data
Supplementary data (Experimental procedures and spectro-
scopic data for all compounds. Spectra of graphislactone G) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.04.024.
References and notes
IR (DRIFT):
m = 3468 cm (s), 3171 (s), 3102 (m), 2965 (s), 2942
(s), 2288 (w), 2038 (w), 1590 (s), 1451 (s), 1416 (s), 1344 (s),
1292 (s), 1227 (s), 944.1 (m), 812.9 (s), 696 (s). MS (EI, 140 °C):
m/z (%) = 254 (22) [C8H881Br37ClO2], 252 (100) [C8H879Br37ClO2
and C8H881Br35ClO2], 250 (76) [C8H879Br35ClO2], 209 (22), 207
(16), 171 (2) [C8H835ClO2þ], 128 (13), 89 (8), 58 (24). HRMS
(C8H835Cl79BrO2, EI): found 249.9394; calcd 249.9396.
1. (a) Keller, N. P.; Turner, G.; Bennett, J. W. Nat. Rev. Microbiol. 2005, 3, 937–947;
(b) Ehrlich, K. C.. In Polyketides: Biosynthesis, Biological Activity and Genetic
Engineering (ACS Symposium Series); Oxford University Press: New York, 2007;
Vol. 955, pp 68–80.
2. (a) Huneck, S. Naturwissenschaften 1999, 86, 559–570; (b) Müller, K. Appl.
Microbiol. Biotechnol. 2001, 56, 9–16; (c) Boustie, J.; Grube, M. Plant Genet.
Resour. 2005, 3, 273–287.
3. (a) Overeem, J. C.; Van Dijkman, A. Rec. Trav. Chim. Pays-Bas 1968, 87, 940–944;
(b) Kameda, K.; Aoki, H.; Namiki, M.; Overeem, J. C. Tetrahedron Lett. 1974, 15,
103–106.
4. (a) Tanahashi, T.; Kuroishi, M.; Kuwahara, A.; Nagakura, N.; Hamada, N. Chem.
Pharm. Bull. 1997, 45, 1183–1185; (b) Hamada, N.; Tanahashi, T.; Goldsmith, S.;
Nash, T. H., III Symbiosis 1997, 23, 219–224; (c) Hamada, N.; Tanahashi, T.;
Miyagawa, H.; Miyawaki, H. Symbiosis 2001, 31, 23–33; (d) Tanahashi, T.;
Takenaka, Y.; Nagakura, N.; Hamada, N. Phytochemistry 2003, 62, 71–75; (e)
Hormazabal, E.; Schmeda-Hirschmann, G.; Astudillo, L.; Rodriguez, J.;
Theoduloz, C. Z. Naturforsch., C: Biosci. 2005, 60, 11–21; (f) Kock, I.; Krohn, K.;
Egold, H.; Draeger, S.; Schulz, B.; Rheinheimer, J. Eur. J. Org. Chem. 2007, 2186–
2190.
5. Zhang, H.-W.; Huang, W.-Y.; Song, Y.-C.; Chen, J.-R.; Tan, R.-X. Helv. Chim. Acta
2005, 88, 2861–2864.
6. Thomas, R. Biochem. J. 1961, 80, 234–240.
7. (a) Stinson, E. E. J. Food Prot. 1985, 48, 80–91; (b) Aly, A. H.; Edrada-Ebel, R.;
Indriani, I. D.; Wray, V.; Müller, W. E. G.; Totzke, F.; Zirrgiebel, U.; Schächtele,
C.; Kubbutat, M. H. G.; Lin, W. H.; Proksch, P.; Ebel, R. J. Nat. Prod. 2008, 71, 972–
980.
8. Song, Y. C.; Huang, W. Y.; Sun, C.; Wang, F. W.; Tan, R. X. Biol. Pharm. Bull. 2005,
28, 506–509.
9. Abe, H.; Nishioka, K.; Takeda, S.; Arai, M.; Takeuchi, Y.; Harayama, T.
Tetrahedron Lett. 2005, 46, 3197–3200.
10. Altemöller, M.; Gehring, T.; Cudaj, J.; Podlech, J.; Goesmann, H.; Feldmann, C.;
Rothenberger, A. Eur. J. Org. Chem. 2009, 2130–2140.
3.2. 2-Chloro-7-hydroxy-3,9-dimethoxy-1-methyl-6H-
benzo[c]chromen-6-one, graphislactone G
A mixture of bromide 12 (0.055 g, 0.22 mmol), boronate 4
(0.095 g, 0.28 mmol), Cs2CO3 (0.214 g, 0.656 mmol), Pd(OAc)2
(1.47 mg, 6.56 lmol), and S-Phos (purity 97%, 5.6 mg, 0.013 mmol)
in degassed solvent (dioxane/H2O, 7:1, 14 mL) under an argon
atmosphere was stirred at 80 °C for 2 h. The mixture was cooled
to room temperature, saturated aqueous NH4Cl-solution (10 mL)
was added, and the mixture was extracted with EtOAc
(4 ꢂ 25 mL). The organic layers were dried (Na2SO4), concentrated,
and purified by chromatography (silica gel, hexanes/EtOAc, 10:1)
yielding graphislactone G (50.3 mg, 0.219 mmol, 72%) as a colour-
less solid. mp: 243–245 °C (242–244 °C).5 1H NMR (400 MHz,
CDCl3): d = 2.89 (s, 3H, 1-Me), 3.92 (s, 3H, 9-OMe), 3.97 (s, 3H, 3-
OMe), 6.57 (d, 3J = 2.2, 1H, 8-H), 6.75 (s, 1H, 4-H), 7.20 (d, 3J = 2.2,
1H, 10-H), 11.79 (br s, 1H, OH). 13C NMR (101 MHz, CDCl3):
d = 21.3 (q, 1-Me), 55.8 (q, 9-OMe), 56.5 (q, 3-OMe), 98.9 (d, C-4),
99.3 (d, C-8), 99.7 (s, C-6a), 105.5 (d, C-10), 112.1 (C-10b), 121.6
(s, C-2), 135.7 (s, C-1), 137.2 (s, C-10b), 150.0 (s, C-4a), 156.0 (s,
C-3), 165.0 (s, C-6), 165.2 (s, C-7), 166.4 (s, C-9). IR (DRIFT):
~
11. (a) Suzuki, A. Proc. Jpn. Acad. 2004, 80, 359–371; (b) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–4696; (c)
Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64, 3047–3101; (d)
Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–1473.
12. Pulgarin, C.; Gunzinger, J.; Tabacchi, R. Helv. Chim. Acta 1985, 68, 945–948.
13. Wang, P.; Zhang, Z.; Yu, B. J. Org. Chem. 2005, 70, 8884–8889.
14. Nicolaou, K. C.; Maria Rodríguez, R.; Mitchell, H. J.; Suzuki, H.; Fylaktakidou, K.
C.; Baudoin, O.; van Delft, F. L. Chem. Eur. J. 2000, 6, 3095–3115.
15. Mahandru, M. M.; Tajbakhsh, A. J. Chem. Soc., Perkin Trans. 1 1983, 413–416.
16. (a) Altemöller, M.; Podlech, J.; Fenske, D. Eur. J. Org Chem. 2006, 1678–1684; (b)
Altemöller, M.; Podlech, J. Eur. J. Org. Chem. 2009, 2275–2282; (c) Altemöller,
M.; Podlech, J. J. Nat. Prod. 2009, 72, 1288–1290.
m
= 3417 (w), 2946 (w), 2851 (w), 1670 (m), 1627 (w), 1595 (w),
1460 (w), 1421 (w), 1351 (m), 1281 (m), 1235 (m), 1204 (m),
1162 (w), 836 (w), 823 (w), 771 cmꢀ1 (w). UV/VIS: kMeOH = 343,
302, 291, 256 nm. MS (EI, 140 °C): m/z (%)
= 322 (35)
[C16H1337ClO5þ], 321 (20) [(C16H1335ClO5+1)+], 320 (100)
[C16H1335ClO5þ]. 285 (3) [C16H13O5þ], 277 (13) [(MꢀCOꢀMe)+].