Synthesis study toward mayamycin

Article abstract of DOI:10.1002/cjoc.201201084

Natural product mayamycin is the first example in the angucycline class featuring a C-glycoside linkage at the C5-position of the benz[a]anthracenone core with remarkable biological activities. We successfully synthesized the two retrosynthetic fragments, but found that the final C-glycosylation did not occur. Alternatively, an A-ring saturated aglycon was prepared, but the proposed C-glycosylation still did not proceed. Finally, a simplified substrate was used and the subsequent C-glycosylation went through smoothly, giving a two-ring less analogue of mayamycin. Natural product mayamycin is the first example in the angucycline class featuring a C-glycoside linkage at the C5-position of the benz[a]anthracenone core with remarkable biological activities. We successfully synthesized the two retrosynthetic fragments, but the final C-glycosylation did not occur. Instead, a two-ring less analog was success fully prepared, suggesting the steric effect played an important role in the synthesis of mayamycin. Copyright

Full text of DOI:10.1002/cjoc.201201084

FULL PAPER
DOI: 10.1002/cjoc.201201084
Synthesis Study toward Mayamycin†
Kui Wu,a Meining Wang,b Qizheng Yao,*,a and Ao Zhang*,b
a Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing Jiangsu 210009, China
b Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, Shanghai 201203, China
Natural product mayamycin is the first example in the angucycline class featuring a C-glycoside linkage at the
C5-position of the benz[a]anthracenone core with remarkable biological activities. We successfully synthesized the
two retrosynthetic fragments, but found that the final C-glycosylation did not occur. Alternatively, an A-ring satu-
rated aglycon was prepared, but the proposed C-glycosylation still did not proceed. Finally, a simplified substrate
was used and the subsequent C-glycosylation went through smoothly, giving a two-ring less analogue of mayamy-
cin.
Keywords natural product, angucycline, mayamycin, total synthesis, C-glycosilation
Introduction
HO
O
1
3
Angucycline antibiotics, structurally represent a
unique class of polycyclic aromatic polyketides exhib-
iting diverse biological activities including antibacterial,
anti-viral, anticancer, as well as platelet aggregation and
enzyme inhibitory properties.[1] Very recently, Imhoff et
al[2] isolated a novel angucycline antibiotic, named ma-
yamycin, from the marine sponge Halichondria pana-
cea by variation of the culture condition. Different from
the majority of O-glycosidic analogues in the angucy-
cline family,[3,4] mayamycin features a C-glycoside
linkage connecting to an aminosugar moiety at the C5
aromatic position of the benz[a]anthracenone core.
Examples of angucyclines bearing an aminosugar frag-
ment are rare, and at this particular site, no other
C5-glycosidic bound sugar has been reported so far
(Figure 1). In addition, mayamycin was reported[2]
showing potent in vitro cytotoxicity against eight human
cancer cell line with IC50 values ranging between 0.13
－0.33 μmol/L. Further, it was also cytotoxic toward the
mouse fibroblast cell line NIH-3T3 with an IC50 value
of 0.22 µmol/L, which is 100-fold more potent than the
clinical drug tamoxifen (23.7 µmol/L). The unusual
structural architecture along with the remarkable anti-
bacterial and antitumor activities made mayamycin an
ideal target for both total synthesis study and subsequent
structural modification and drug profiling.
1'
7
5'
5
O
8
OH
OH
3'NHMe
O
OH
mayamycin
C-glycosilation
MeO
OMe
MeO
O
1'
3'
+
OBz
NHMe
OMe OMe OH
2
1
O
O
MeO
O
OBz
OMs
O
O
OH
4
3 (hatomarubigin)
Figure 1 Chemical structure of mayamycin and its retrosythetic
analysis.
could be accessed from another natural product 3
(hatomarubigin) that has been synthesized by several
groups[4-6] including ours.[7] The C5－C1' C-glycosidic
bond could be constructed by a Lewis acid-initiated
glycosilation reaction from 1 and aminosugar 2 or its
precursor 4. Herein, in this report we describe our syn-
thesis of fragments 1 and 2, and further efforts on the
assembly of natural product mayamycin.
As shown in Figure 1, mayamycin can be structur-
ally dissected to tetracyclic phenol 1 and aminosugar
component 2, with the formation of C5－C1' C-gly-
cosidic bond as the key step. The tetracyclic network 1
*
E-mail: aozhang@mail.shcnc.ac.cn, qz_yao@yahoo.com.cn; Tel.: 0086-021-50806035; Fax: 0086-021-50806035
Received November 4, 2012; accepted December 24, 2012; published online January 8, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201084 or from the author.
Dedicated to the Memory of Professor Weishan Zhou.
†
Chin. J. Chem. 2013, 31, 93—99
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
93

Wu et al.
FULL PAPER
Experimental
matography (CH2Cl2/PE＝2/1) gave compound 7 (84
mg, 82% yield) as red solid. 1H NMR (300 MHz, CDCl3)
δ: 10.95 (s, 1H), 7.76 (d, J＝7.2 Hz, 1H), 7.65－7.60 (m,
3H), 7.49 (s, 1H), 7.40－7.38 (m, 2H), 7.29－7.25 (m,
2H), 7.00 (s, 1H), 6.92 (s, 1H), 5.34 (s, 2H), 4.01 (s, 3H),
2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 191.3,
183.1, 157.9, 154.5, 153.0, 141.1, 138.8, 136.5, 136.4,
134.1, 132.4, 131.3, 128.6, 127.8, 126.9, 122.7, 120.0,
119.6, 119.4, 117.9, 117.4, 115.3, 71.2, 56.6, 21.2;
EI-MS m/z: 424 (M＋); HRMS calcd for C27H20O5 [M＋]:
424.1311, found 424.1311.
Reactions were performed under a nitrogen atmos-
phere in dry glassware with magnetic stirring. The sol-
vents were purified and dried according to the standard
methods prior to use. Commercially available reagents
were used without further purification. 1H NMR spectral
data were recorded on Varian Mercury 300 MHz NMR
spectrometer and 13C NMR data were recorded on Var-
ian Mercury 400 MHz NMR spectrometer using tetra-
methylsilane as an internal reference. Analytical thin-
layer chromatography (TLC) was carried out on 0.2 mm
Kieselgel 60F 254 silica gel plastic sheets (EM Science,
Newark). Column chromatography was used for the
routine purification of reaction products. The column
output was monitored with TLC.
6-(Benzyloxy)-8-methoxy-3-methyl-3,4-dihydro-
tetraphene-1,7,12(2H)-trione (6) To a solution of
hatomarubigin 3[4,7] (600 mg, 1.78 mmol) and potassium
carbonate (738 mg, 5.34 mmol) in DMF (30 mL), ben-
zylbromide (457 mg, 2.67 mmol) was added. The sus-
pension was stirred at r.t. for 7 h then quenched with
water (50 mL) and extracted with Et2O (100 mL×3).
The combined organic phase was washed with brine,
dried over anhydrous sodium sulfate and concentrated
under vacuum. Purification on silica gel column
(CH2Cl2/EA＝30/1) gave compound 6 (554 mg, 73%
6-(Benzyloxy)-1,7,8,12-tetramethoxy-3-methyl-
tetraphene (8) To a solution of compound 7 (84 mg,
0.19 mmol) and KOH (42 mg) in THF (15 mL), CH3I
(106 mg, 1.14 mmol) was added. The mixture was al-
lowed to stir for 7 h and filtered. The filtrate was con-
centrated under vacuum. To a solution of the resulting
residue (62 mg) and catalytic amount of tetrabutylam-
monium bromide in 10 mL of THF under an atmosphere
of nitrogen, sodium dithionite (195 mg, 1.12 mmol)
dissolved in water (2 mL) was added. The mixture was
allowed to stir for 30 min and then potassium hydroxide
(168 mg, 3 mmol) solution in 2 mL of water was added.
Dimethyl sulfate (0.113 mL) was added dropwise. The
mixture was then stirred for 18 h at r.t. until the starting
material was completely consumed. The mixture was
poured into 20 mL of saturated NH4Cl solution and ex-
tracted with ethyl acetate (25 mL×3). The combined
organic layers were washed with brine and dried over
Na2SO4. After evaporation of the solvents under reduced
pressure the residue was purified by silica gel column
chromatography (PE/EA＝15/1) to give compound 8
(50 mg, 61% yield for two steps) as light yellow solid.
1H NMR (300 MHz, CDCl3) δ: 7.97 (d, J＝8.4 Hz, 1H),
7.57 (d, J＝7.2 Hz, 2H), 7.39－7.35 (m, 4H), 6.95 (s,
1H), 6.84 (d, J＝7.8 Hz, 1H), 6.70 (s, 1H), 6.64 (s, 1H),
5.21 (s, 2H), 3.96 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H),
3.42 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ: 157.7, 157.1, 154.8, 150.7, 149.0, 138.3, 137.2, 134.5,
129.8, 128.4, 127.7, 126.2, 119.7, 119.0, 119.0, 117.7,
115.1, 112.8, 108.7, 105.6, 103.9, 71.2, 63.9, 60.8, 56.3,
56.1, 21.7; EI-MS m/z: 468 (M＋); HRMS calcd for
C30H28O5 [M＋]: 468.1937, found 468.1930.
1
yield) as light yellow powder. H NMR (300 MHz,
CDCl3) δ: 7.62－7.62 (m, 4H), 7.43－7.38 (m, 3H),
7.32－7.25 (m, 1H), 6.91 (s, 1H), 5.33 (s, 2H), 3.98 (s,
3H), 2.90－2.82 (m, 2H), 2.62－2.39 (m, 3H), 1.14 (d,
J＝6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 197.6,
186.3, 181.3, 159.7, 158.6, 150.3, 139.5, 136.9, 135.8,
134.2, 128.7, 128.0, 127.3, 126.7, 124.4, 123.4, 118.3,
116.9, 116.0, 70.9, 56.4, 47.4, 38.8, 30.5, 21.3; EI-MS
m/z: 426 (M＋ ); HRMS calcd for C27H22O5 [M＋ ]:
426.1467, found 426.1460.
6-(Benzyloxy)-1-hydroxy-8-methoxy-3-methyl-
tetraphene-7,12-dione (7) To a solution of compoud
6 (554 mg, 1.30 mmol ) and TEA (263 mg, 2.60 mmol)
in dry CH2Cl2 (20 mL), TMSOTf (433 mg, 1.95 mmol)
was added dropwise in ice bath. The mixture was stirred
for 30 min, quenched with saturated NaHCO3 solution
and extracted with CH2Cl2 (50 mL×3). The organic
phase was combined, washed with brine and dried over
anhydrous sodium sulfate. After evaporation of the sol-
vents under reduced pressure, the residue was purified
by silica gel column chromatography (EA/PE＝5/1) to
give trimethylsilyl ether in 76% yield. A solution of the
resulting trimethylsilyl ether (100 mg, 0.20 mmol),
Pd(OAc)2 (22.4 mg, 0.11 mmol) and p-benzenquinone
(10.8 mg, 0.11 mmol) was stirred in dry acetonitrile (15
mL) at r.t. under an atmosphere of nitrogen for 3 h and
quenched with 10% diluted chlohydric acid. The mix-
ture was extracted with CH2Cl2 (50 mL×3). The com-
bined organic phase was washed with brine, dried over
anhydrous sodium sulfate and concentrated under re-
duced pressure. Purification on silica gel column chro-
(2R,3S,4S,6S)-4-Hydroxy-6-methoxy-2-methyl-
tetrahydro-2H-pyran-3-yl benzoate (10)
Bromo-
pyranoside 9 (835 mg, 2.4 mmol) was dissolved in 10
mL EtOH, and then excess Raney nickel and triethyl-
amine (492 mg, 4.86mmol) were added. The mixture
was stirred under an atomsphere of H2 overnight. After
filtration, the filtrate was concentrated and the resulting
residue was purified over silica gel column chromatog-
raphy (PE/EA＝3/1) to give colorless oil 10 (446 mg,
70% yield). 1H NMR (300 MHz, CDCl3) δ: 8.04 (d, J＝
8.4 Hz, 2H), 7.53－7.51 (m, 1H), 7.43－7.38 (m, 2H),
5.33 (s, 1H), 4.68 (s, 1H), 4.09 (s, 1H), 3.46 (s, 1H),
3.35 (s, 3H), 2.48 (d, J＝6.9 Hz, 1H), 2.25 (d, J＝15.3
Hz, 1H), 2.00 (d, J＝15.0 Hz, 1H), 1.31 (d, J＝6.3 Hz,
3H).
94
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Chin. J. Chem. 2013, 31, 93—99

Synthesis Study toward Mayamycin
(2R,3R,4S,6S)-6-Methoxy-2-methyl-4-((methyl-
sulfonyl)oxy)tetrahydro-2H-pyran-3-yl benzoate (4)
To a solution of sugar 10 (520 mg, 1.95 mmol) and tre-
thylamine (395 mg, 3.87 mmol) in 20 mL dry DCM,
MsCl (336 mg, 2.9 mmol) was added dropwise under
ice bath. The mixture was stirred for 1 h and then the
solvent was removed. The resulting residue was purified
by silica gel column chromatography (PE/EA＝5/1) to
give colorless oil 4 (650 mg, 97% yield). 1H NMR (300
MHz, CDCl3) δ: 8.08 (d, J＝7.5 Hz, 2H), 7.60 (t, J＝7.5
Hz, 1H) , 7.46 (t, J＝7.5 Hz, 2H) , 5.68 (q, J＝3.0 Hz, 1H),
4.75 (d, J＝4.2 Hz, 1H), 4.57 (dd, J＝9.9, 3.0 Hz, 1H),
4.44－4.32 (m, 1H), 3.39 (s, 3H), 3.02 (s, 3H), 2.26 (dd,
J＝15.0, 3.5 Hz, 1H), 2.12 (dt, J＝15.3, 3.9 Hz, 1H), 1.36
(d, J＝6.3 Hz, 3H).
6-Ethoxy-8-methoxy-3-methyl-6-((trimethylsilyl)-
oxy)-1,3,4,12b-tetrahydrotetraphene-7,12(2H,6H)-
dione (16) n-BuLi (2 mL, 1.6 mol/L in hexane, 3.29
mmol) was added slowly to a solution of diisopropyl-
amine (0.5 mL, 3.29 mmol) in dry THF (3 mL) under
nitrogen at 0 ℃. The mixture was stirred at 0 ℃ for 30
min and then cool to –78 ℃. HMPA (0.45 mL, 2.63
mmol) was added. After 30 min, a solution of 14[8-10]
(400 mg, 2.19 mmol) in dry THF (2 mL) was added
slowly. The mixture was stirred at −78 ℃ for another 2
h before a solution of TBSCl (396 mg, 2.63 mmol) in
dry THF (3 mL) was added and moved to room tem-
perature directly. After 1 h, the solution was concen-
trated at reduced pressure and taken up by pentane and
filtrated. The solvent was removed under reduced
pressure and the residue containing compound 15 was
used directly in the next step. 2-Bromo-5-methoxy-
naphthalene-1,4-dione (100 mg, 0.749 mmol) was
added directly to the residue containing compound 15.
After stirring for 5 min, toluene was added and the
mixture was stirred over night. The mixture was concen-
trated at reduced pressure. The residue was purified by
chromatography on silica gel (PE/EA＝10/1) to afford
16 (50 mg). This product was used for further reaction
without NMR monitoring.
3.38 (d, J＝16.6 Hz, 1H), 3.17－3.00 (m, 1H), 2.87 (d,
J＝14.5 Hz, 1H), 2.45 (dd, J＝17.7, 11.0 Hz, 1H), 1.89
(d, J＝39.5 Hz, 3H), 1.06 (d, J＝6.5 Hz, 3H).
6-Hydroxy-8-methoxy-3-methyl-3,4-dihydrotetra-
p-hene-1,7,12(2H)-trione (3) Conpound 18 (85 mg,
0.26 mmol) was dissolved in EtOH (6 mL), and the
solution was stirred in the open air under sunlight for 3
h. After removal of the solvent, the residue was purified
on silica gel column chromatography (PE/EA＝3/1) to
1
give hatomarubigin 3 (72 mg, 85%) as yellow solid. H
NMR (300 MHz, CDCl3) δ: 13.02 (s, 1H), 7.76－7.70
(m, 2H), 7.28 (dd, J＝6.7, 2.7 Hz, 1H), 6.95 (s, 1H),
4.05 (s, 3H), 2.96－2.86 (m, 2H), 2.30－2.70 (m 3H),
1.16 (d, J＝6.3 Hz, 3H).
6-(Benzyloxy)-7,8,12-trimethoxy-3-methyl-1,2,3,4-
tetrahydrotetraphene (20) To a solution of com-
pound 18 (1450 mg, 4.5 mmol) and potassium carbonate
(1244 mg, 9 mmol) in DMF (50 mL), benzylbromide
(1154 mg, 6.75 mmol) was added. The suspension was
stirred at r.t. overnight and then quenched with water
(50 mL) and extracted with Et2O (100 mL×3). The
combined organic phase was washed with brine, dried
over anhydrous sodium sulfate and concentrated under
vacuum. Purification on silica gel column (CH2Cl2/
EA＝250/1) gave the ether intermediate. To a solution
of resultant ether (750 mg, 1.818 mmol) and tetrabutyl-
ammonium bromide (176 mg, 0.545 mmol) in 15 mL of
THF under an atmosphere of nitrogen, sodium dithionite
(2532 mg, 14.54 mmol) dissolved in 8 mL water was
added. The mixture was allowed to stir for 30 min and
then potassium hydroxide (2545 mg, 45.45 mmol)
solution in 15 mL of water was added. Dimethyl sulfate
(1.7 mL) was added dropwise after 30 min. The mixture
was stirred for 2 h at r.t., until the starting material was
completely consumed. KOH was added until pH＞7.
Water and ethyl acetate were added, and the combined
organic layer was washed with brine and then dried over
Na2SO4. After evaporation of the solvent under reduced
pressure the residue was purified by silica gel column
chromatography (PE/EA＝50/1) to give compound 20
1
6-Ethoxy-8-methoxy-3-methyl-1,2,3,4-tetrahydro-
tetraphene-7,12-dione (17) and 6-hydroxy-8-meth-
oxy-3-methyl-1,2,3,4-tetrahydrotetraphene-7,12-di-
one (18) Catalytic amount of TFA was added to a so-
lution of compound 16 in CH2Cl2. The reaction mixture
was stirred for 2 h. After removal of the solvent, the
residue was purified on silica gel column chromatogra-
phy (PE/EA＝10/1) to give ether 17 (36%) and phenol
(260 mg, 56%) as light yellow solid. H NMR (300
MHz, CDCl3) δ: 7.87 (dd, J＝8.8, 0.9 Hz, 1H), 7.63 (d,
J＝7.0 Hz, 2H), 7.47－7.32 (m, 4H), 6.77 (d, J＝7.4 Hz,
1H), 6.55 (s, 1H), 5.21 (s, 2H), 4.03 (s, 3H), 3.79 (d, J＝
1.9 Hz, 6H), 3.63－3.51 (m, 1H), 3.38－3.21 (m, 1H),
2.92 (dd, J＝16.6, 6.4 Hz, 1H), 2.53 (dd, J＝17.2, 10.0
Hz, 1H), 2.06－1.93 (m, 2H), 1.35 (dd, J＝12.8, 5.4 Hz,
1H), 1.14 (d, J＝6.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ: 157.13, 153.87, 150.98, 149.12, 137.63,
134.74, 129.11, 128.49, 127.82, 127.71, 125.86, 123.76,
119.58, 118.70, 114.90, 109.24, 103.87, 71.71, 63.94,
62.88, 56.20, 40.21, 32.54, 29.14, 28.54, 21.98; EI-MS
m/z: 422 (M＋ ); HRMS calcd for C29H30O4 [M＋ ]:
422.2144, found 422.2144.
1
18 (50%) as yellow solid. For ether 17: H NMR (300
MHz, CDCl3) δ: 7.63 (dd, J＝7.7, 1.1 Hz, 1H), 7.55 (dd,
J＝8.2, 7.7 Hz, 1H), 7.18 (d, J＝8.3 Hz, 1H), 6.95 (s,
1H), 4.22－4.10 (m, 2H), 3.96 (d, J＝3.6 Hz, 3H),
3.36－3.24 (m, 1H), 3.17－3.00 (m, 1H), 2.85 (dd, J＝
16.9, 3.2 Hz, 1H), 2.45 (dd, J＝17.1, 10.7 Hz, 1H),
2.01－1.77 (m, 3H), 1.50 (t, J＝7.0 Hz, 3H), 1.05 (d,
(2R,3R,4S,6R)-6-(2-Hydroxynaphthalen-1-yl)-2-
methyl-4-((methylsulfonyl)oxy)tetrahydro-2H-pyran-
3-yl benzoate (21) To a stirred solution of 2-naphthol
(9 mg, 0.033 mmol), sugar mesylate 4 (11 mg, 0.028
1
J＝6.5 Hz, 3H). For phenol 18: H NMR (300 MHz,
CDCl3) δ: 13.23 (s, 1H), 7.83 (d, J＝7.7 Hz, 1H), 7.68 (t,
J＝6.7 Hz, 1H), 7.29 (s, 1H), 6.98 (s, 1H), 4.05 (s, 3H),
Chin. J. Chem. 2013, 31, 93—99
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Wu et al.
FULL PAPER
mmol) and AgClO4 (6.8 mg, 0.033 mmol) in 1.2 mL of
CH2Cl2, TMSOTf (7.326 mg, 0.033 mmol) was added
via a syringe. The mixture was stirred for 5 min at 0 ℃
and then the temperature was gradually increased to r.t.
during 40 min. The reaction was quenched with satu-
rated sodium bicarbonate and the mixture was extracted
with CH2Cl2. The organic phase was dried with sodium
sulfate and concentrated to give 21 (12 mg, 65%) as
white solid after column chromatography (PE/EA＝2/1).
1H NMR (300 MHz, CDCl3) δ: 8.68 (s, 1H), 8.25 (d,
J＝8.4 Hz, 2H), 7.77－7.68 (m, 3H), 7.62－7.53 (m,
3H), 7.35－7.25 (m, 2H), 7.14 (d, J＝9.3 Hz, 1H), 6.02
－5.99 (m, 2H), 4.82 (d, J＝9.6 Hz, 1H), 4.41 (d, J＝
2.9 Hz, 1H), 3.12 (s. 3H), 2.43－2.41 (m, 2H), 1.56 (d,
J＝6.3 Hz, 3H).
us and others earlier through an Aldol-Michael addition
process, however, preparation of 1 with selective pro-
tection of the 1,8-dihydroxys and leaving 6-OH free for
introduction of the C-glycosilation is challenging.
As described in Scheme 1, our synthesis commenced
from hatomarubigin A (3), which was prepared in 24%
overall yield from acetyl naphthoquinone 5 through
Michael addition with 5-methyl-1,3-cyclohexan-dione
followed by intramolecular Aldol condensation.[4] In
turn, compound 5 was prepared in seven steps from
1,5-binaphthol in 15% overall yield.[4] Although com-
pound 3 could be used to the glycosilation reaction with
aminosugar 2 followed by aromatization of the tetra-
cyclic A-ring to furnish target compound mayamycin,
however, electron-deficient phenols generally are poor
substrates (sugar acceptors) in C-glycosilation reac-
tions.[27] Accordingly, ketone 3 was converted to elec-
tron-rich aglycone 1. Protection of 3 with benzyl group
provided ether 6 whose A ring was efficiently aroma-
tized via enol etherization combined with Pd(OAc)2-
mediated oxidation to afford phenol 7 in 60% overall
yield.[5] Protection of phenol 7 with MeI provided cor-
responding ether in 75% yield, which was then treated
with sodium hyposulfite followed by dimethyl sulfate
delivering anisole 8 in 81% yield.[28,29] Subsequent de-
benzylation of anisole 8 with Pd/C afforded electron-
rich phenol 1 in 85% yield. Compound 1 was found
highly unstable and readily shifted back to its quinone
version during storage. Therefore, phenol 1 has to be
prepared from 8 in situ for subsequent C-glycosilation
(Scheme 1).
(2R,3R,4S,6R)-3-Hydroxy-6-(2-hydroxynaphthal-
en-1-yl)-2-methyltetrahydro-2H-pyran-4-yl-methane-
sulfonate (22) To a solution of glycoside 21 (456 mg,
1 mmol) in MeOH (15 mL), K2CO3 (138 mg, 1 mmol)
was added. The mixture was allowed to stir at r.t.
overnight and filtered. The resulting filtrtate was
evaperated to give the residue which was further
purified on column chromatography (CHCl3/MeOH＝
1
100/1) to afford 22 (345 mg, 90%) as white solid. H
NMR (300 MHz, CDCl3) δ: 8.75 (s, 1H), 7.77－7.68 (m,
3H), 7.49 (t, J＝6.3 Hz, 1H), 7.43 (t, J＝6.0 Hz, 1H),
7.13 (d, J＝9.3 Hz, 1H), 6.00 (d, J＝9.3 Hz, 1H),
4.61－4.58 (m, 2H), 4.40－4.30 (m, 1H), 3.21 (s, 1H),
3.17 (s, 3H), 2.40－2.20 (m, 2H), 1.46 (d, J＝6.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 152.6, 130.7,
129.9, 128.8, 128.6, 126.9, 122.1, 120.4, 119.7, 113.3,
81.9, 71.7, 70.5, 66.3, 38.8, 37.2, 18.1.
Scheme 1 Synthesis of the phenol 1
(2S,3R,4S,6R)-6-(2-Hydroxynaphthalen-1-yl)-2-
methyl-4-(methylamino)tetrahydro-2H-pyran-3-ol
(23) Compound 22 (97 mg, 0.25 mmol) was dissolved
in 30% methylamine alcoholic solution (30 mL) in
sealed tube. The mixture was stirred under 70 ℃ for 2
h and the solvent was evaporated. The residue was puri-
fied on column chromatography (CHCl3/MeOH＝30/1)
to give 23 (120 mg, 45%) as white solid. 1H NMR (300
MHz, CDCl3) δ: 7.87 (d, J＝8.7 Hz, 1H), 7.75－7.64 (m,
2H), 7.44－7.38 (m, 1H), 7.30－7.25 (m, 1H), 7.08 (d,
J＝8.7 Hz, 1H), 4.92－4.90 (m, 1H), 4.58 (s, 1H), 4.10
(s, 1H), 2.71 (s, 1H), 2.51 (s, 3H), 2.27－2.17 (m, 3H),
1.40 (d, J＝6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
155.3, 132.6, 129.4, 128.7 128.3, 126.5, 122.5, 120.8,
118.4, 112.9, 80.4, 70.7, 66.0, 65.8, 65.5, 40.7, 39.9.
EI-MS m/z: 287 (M＋).
O
OH
3 steps
7 steps
24% yield
15% yield
O
O
O
O
OH
5
O
O
O
O
a
b,c
O
OH
OBn
OMe O
3, Hatomarubigin A
6
HO
O
MeO
OMe
d,e
f
1
OMe O
OBn
OMe OMe OBn
7
8
Results and Discussion
Reagents and conditions: (a) K2CO3, BnBr, DMF, 73%; (b)
TMSOTf, TEA, −40 ℃, 76%; (c) Pd(OAc)2, MeCN, 82%; (d) MeI,
KOH, THF; (e) Na2S2O4, TBAB, Me2SO4, KOH, 61% for two steps;
(f) H2, Pd/C, THF, 85%.
Since the tetracyclic angucyclinone framework (e.g.
1, 3) is a common glycosilation acceptor in the synthesis
of angucycline antibiotics,[11a-11c] various strategies have
been developed, including Au-catalyzed ring closure,[11d]
Diels-Alder reaction,[12-22] Co2＋ -mediated [2＋2＋2]
cycloadditions[23-25] and Michael-type cyclization.[26]
The skeleton of angucyclinone 1 has been reported by
With glycosyl receptor 1 in hand, we then set out to
prepare aminosugar 2. In the synthesis of C2-glycosyla-
tion natural products benzanthrins, Parker and co-
96
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 93—99

Synthesis Study toward Mayamycin
workers[5] reported that the existence of a basic amino
group in the sugar component was unfavorable for sub-
sequent Lewis acid-catalyzed glycosylation, therefore
we decided to prepare its precursor 4 and explore its
reaction with phenol 1. As shown in Scheme 2, bromide
9 was prepared from α-D-mannopyranoside in 4
steps,[30-32] and subjected to debromination with Raney
Ni-directed hydrogenation providing 10 in 70% yield.
Subsequent mesylation of 10 using a typical procedure
(MsCl, TEA) led to 3-sulfonate sugar 4 in 97% yield.
Scheme 3 Glycosilation of phenol 1 with 3-sulfonate sugar 4
MeO
OMe
MeO
OMe
4
8
O
Lewis acid
OMe OMe OH
OMe OMe OH
no reaction!
OBz
1
11
OMs
MeNH2
MeO
OMe
Scheme 2 Synthesis of the sugar fragment 4
mayamycin
Br
O
O
OMe
O
OMe
OH
OMe
HO
HO
O
b
a
OMe OMe OH
4
OBz
NHMe
BzO
12
BzO
OH
OH
OH
10
9
Reagents and conditions: (a) Raney Ni, H2, 70%; (b) MsCl, TEA,
by using a Diels-Alder reaction as the key step. Al-
though D-A reaction[12-22] has been widely used to syn-
thesize polycyclic angucyclinone analogues, however,
97%.
only
a few cases were reported dealing with
With both key fragments 1 and 4 readily synthesized,
we decided to explore the optimum condition to assem-
ble the natural product mayamycin. In 1990, Suzuki et
al[33] reported a similar C-glycosydic bond formation
through a two-step process including O-glycosylation
first followed by an O- to C-glycoside migration in the
presence of an appropriate Lewis acid, including SnCl4,
BF3•EtO2 and Cp2HfCl2-AgClO4. Later, Matsumura et
al also reported this type reaction by employing a mild
Lewis acid TMSOTf or a combination of TMSOTf-
AgClO4 exclusively affording the corresponding
C-glycosidic products in high yields.[34] Nevertheless, in
the synthesis of kidamycin, another natural product
structurally similar to mayamycin, SnCl4 proved to be
efficient in the corresponding C-glycosylation.[35] In this
regard, we initially took advantage of SnCl4 to promote
the C-glycosylation reaction of sugar moiety 4 with
aglycon 1. As outlined in Scheme 3, aglycon 1 was
freshly prepared from benzyl ether 8 by hydrogenation,
and then treated with 3-sulfonate sugar 4 equivalently
under initiation of excessive SnCl4 (1 mol/L solution in
CH2Cl2) at −78 ℃, leading to no product, except the
decomposition of sugar 4. Extending reaction time or
raising temperature to 0 ℃ or r.t. gave no benefit ex-
cept producing a dark complex without any major
product. Likewise, other reported catalysts, including
TMSOTf/AgClO4, Cp2HfCl2/AgClO4, or BF3•EtO2
were used, and the proposed C-glycosylation still did
not occur.
C6-hydroxyl products. Krohn et al[8-10] have ever re-
ported the synthesis of angucyclinone core with a
C6-OH by using ketene acetal as diene in the Diels-
Alder reaction. Inspired by this pioneer work, we de-
veloped
a modified procedure to approach our
C6-hydroxyl angucyclinone 13. Deprotonation of ester
14[8-10] with LDA at C6 or C2 followed by silylation
with TBSCl provided the crude regio- and/or E/Z mix-
ture of ketene ketals 15. Diels-Alder reaction of the
mixture 15 with 5-methoxynaphthalene-1,4-dione pro-
ceeded smoothly, and upon acidification with
CF3COOH provided tetracyclic product 18 as the major
product in 50% overall yield, together with another mi-
nor product in 36% yield which was originally assumed
to be the regioisomer 19. However, NMR examination
of the minor product proved that it was indeed ether 17.
This result in turn confirmed that ketene ketals 15 were
only E/Z mixture rather than regioisomers, probably due
to the methyl steric effect. In Krohn’s report,[8-10] they
installed a more steric dimethylphenylsilyl group at the
C3 of ester 14 to control regioselectivity, while in our
case the C3 methyl was sufficient to achieve the same
regioselectivity. Phenol 18 was readily oxidized to
hatomarubigin 3 in the open air under sunlight in 67%
yield after 12 h further confirming the structure of 18.
Similar to the preparation of 1, electron-deficient phenol
18 was transformed to electron-rich phenol 13 following
a set of similar reactions including C6-hydroxy protec-
tion, quinoline-reduction, etherization and debenzoyla-
tion in 20% overall yield.
Although the exact reason for the failure of
C-glycosylation reaction was unclear, the instability of
aglycon 1 may be one key issue. To avoid the air- and
sunlight-sensitivity of the large aromatic system of 1,
we chose to use the more chemo-stable aliphatic A-ring
precursor 13 as a replacement.
Quite disappointingly, the reaction of glycosyl donor
4 with phenol 13 under various Lewis acids as men-
tioned above did not go through at all, except the recov-
ery of phenol 13. In view of the fact that mayamycin is
the only reported example among both natural and syn-
thetic angucycline analoguess bearing a C-5 glycosydic
As described in Scheme 4, phenol 13 was synthesized
Chin. J. Chem. 2013, 31, 93—99
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
97

Wu et al.
FULL PAPER
Scheme 4 Synthesis of the phenol 13
more appropriate.
3
O
Conclusions
a
b
2
6
1
We successfully synthesized the two retrosynthetic
fragments of natural product mayamycin, but found that
the subsequent C-glycosylation did not occur. Alterna-
tively, an A-ring saturated aglycon was prepared
through a D-A cycloaddition process. However, the
proposed C-glycosylation still did not proceed. Finally,
a simplified substrate was used and the subsequent
C-glycosylation went through smoothly. Although a
two-ring less analogue of mayamycin was obtained,
much more work is needed to access the exact natural
product.
EtO
EtOOC
OTBS
EtO
OMe O
OTBS
14
16
15
O
O
c
+
OMe O
OR
OMe O
OH
19 (none)
17 (R = Et)
18 (R = H)
g
d,e
f
from 18
References
3
OMe 1
O
O
OMe
[1] Kharel, M. K.; Pahari, P.; Shepherd, M.; Tibrewal, N.; Nybo, S.;
Shaaban, K.; Rohr, J. Nat. Prod. Rep. 2012, 29, 264.
[2] Schneemann, I.; Kajahn, I.; Ohlendorf, B.; Zinecker, H.; Erhard, A.;
Nagel, K.; Wiese, J.; Imhoff, J. J. Nat. Prod. 2010, 73, 1309.
[3] O'Keefe, B.; Mans, D.; Kaelin, D. Jr; Martin, S. J. Am. Chem. Soc.
2010, 132, 15528
6
OMe OMe OH
OMe OMe OBn
OMe O
3, Hatomarubigin
OH
13
20
[4] Parker, K.; Ding, Q. Tetrahedron 2000, 56, 10255.
[5] Parker, K.; Ding, Q. Tetrahedron 2000, 56, 10249.
[6] Kaelin, D. Jr; Sparks, S.; Plake, H.; Martin, S. J. Am. Chem. Soc
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[7] Ding, C.; Tu, S.; Li, F.; Wang, Y.; Yao, Q.; Hu, W.; Xie, H.; Meng,
L.; Zhang, A. J. Org. Chem. 2009, 74, 6111.
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2-Bromo-5-methoxynaphthalene-1,4-dione, (c) CF3COOH, for 17,
36%, and for 18, 50%; (d) K2CO3, BnBr, 12 h, 46%; (e) TBAB,
Na2S2O4, KOH, Me2SO4, 4 h, 56%; (f) Pd/C, H2, 80%; (g) sunlight,
air 85%.
[8] Krohn, K.; Khanbabaee, K.; Florke, U.; Jonesb, P.; Chrapkowskib,
A. Liebigs Ann. Chem. 1994, 471.
[9] Krohn, K.; Khanbabaee, K. Liebigs Ann. Chem. 1994, 1109.
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1529.
[11] (a) Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188, 128; (b) Car-
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[12] Larsen, D. S.; O'Shea, M. D. J. Chem. Soc., Perkin Trans. 1 1995,
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Chem. Soc., Perkin Trans. 1 2001, 1826.
linkage, our failure in reactions of both aglycons 1 and
13 with sugar 4 may reflect the C5 as an unfavorable
site for C-glycosylation (likely due to steric effect). To
confirm our analysis, we decided to use a simplified
substrate 2-naphthol as the aminosugar acceptor
(Scheme 5). As expected, reaction of 2-naphthol with
sugar 4 went through smoothly under several Lewis acid
promotion, and high yield of 65% was achieved in the
case of combined promoter TMSOTf-AgClO4. Subse-
quent saponification of benzoate 21 followed by SN2
substitution with methylamine in refluxing ethanol fur-
nished C-glycosidic product 23 in 43% overall yield.
This result supported our analysis that C5 position of
angucyclinones is not suitable for direct C-glycosylation,
and other strategies including introduction of the ami-
nosugar moiety in the earlier synthetic process may be
[18] Kaliappan, K. P.; Ravikumar, V. J. Org. Chem. 2007, 72, 6116.
[19] Carreno, M. C.; Urbano, A.; Fischer, J. Angew. Chem., Int. Ed. 1997,
36, 1621.
Scheme 5 A model of glycosylation reaction
[20] Carreno, M. C.; Somoza, A.; Ribagorda, M.; Urbano, A. Chem. Eur.
J. 2007, 23, 879.
O
c
4
a
[21] Larsen, D. S.; O’Shea, M. D. J. Org. Chem. 1996, 61, 5681.
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[25] Kasenheimer, C.; Groth, U. Org. Lett. 2006, 8, 2507.
[26] Brown, P. M.; Thomson, R. H. J. Chem. Soc., Perkin Trans. 1 1976,
997.
O
OH
OH
OR
OH
OH
MeHN
23
OMs
21 (R = Bz)
22 (R = H)
b
Reagents and conditions: (a) TMSOTf-AgClO4, DCM, 0 ℃, 65%;
(b) K2CO3, MeOH, 90%; (c) MeNH2, EtOH, sealed tube, 80 ℃, 45%.
[27] Matsuo, G.; Miki, Y.; Nakata, M.; Matsumura, S.; Toshima, K. J.
98
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 93—99

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Chin. J. Chem. 2013, 31, 93—99
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
99