A highly diastereoselective oxa-Pictet-Spengler approach to (+)-astropaquinone B and (+)-astropaquinone C and the formation of astropaquinone B dimer

Article abstract of DOI:10.1016/j.tetasy.2013.09.001

A concise and highly diastereoselective synthesis of (+)-astropaquinone B and (+)-astropaquinone C is reported. The synthetic strategy is based on an efficient combination of Doetz benzannulation using a chiral alkyne to construct the naphthalene unit and

Full text of DOI:10.1016/j.tetasy.2013.09.001

Tetrahedron: Asymmetry 24 (2013) 1281–1285
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A highly diastereoselective oxa-Pictet-Spengler approach
to (+)-astropaquinone B and (+)-astropaquinone C and the formation
of astropaquinone B dimer
⇑
Rodney A. Fernandes , Sandip V. Mulay
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2013
Accepted 3 September 2013
A concise and highly diastereoselective synthesis of (+)-astropaquinone B and (+)-astropaquinone C is
reported. The synthetic strategy is based on an efficient combination of Dötz benzannulation using a chi-
ral alkyne to construct the naphthalene unit and a highly diastereoselective oxa-Pictet-Spengler reaction
to install the trans-configured pyran ring as the key steps.
Ó 2013 Elsevier Ltd. All rights reserved.
OMe
O
OR
OMe
O
O
1. Introduction
O
Pyranonaphthoquinone antibiotics are isolated from various
strains of bacteria and fungi, most of them being of microbial ori-
gin.1 This class of antibiotics shows activity against various gram-
positive bacteria, pathogenic fungi, and yeasts, as well as having
antiviral activity.1 Several pyranonaphthoquinones have been
proposed to act as effective bioreductive alkylating agents.2 Wang
et al.3 isolated three new naphthoquinones: astropaquinone A 1
O
MeO
MeO
O
1 astropaquinone A
2 R = Me; astropaquinone B
3 R= H; astropaquinone C
OMe
O
O
O
O
OMe
O
O
OR
O
and the pyranonaphthoquinones with
a unique lactol ring,
MeO
OH
MeO
astropaquinones B 2, and C 3 (Fig. 1) from the cultures of the fresh
water fungus Astrosphaeriella papuana YMF 1.01181, along with the
known compound 6-hydroxy-2,4-dimethoxy-7-methylanthraqui-
none 4. Their structures were determined by spectroscopic
techniques including 1D and 2D NMR. They showed moderate
antagonistic activity against fungi and bacteria.3 Astropaquinone
C 3 is a 7,9-dimethyl ether of pyranonaphthoquinone, (ꢀ)-thysa-
none 7,4 which was isolated from Thysanophora penicilloides (MF
5636, Merck Culture Collection). (ꢀ)-Thysanone 7 shows potent
activity against human rhinoviruses (HRVs) 3C-protease (IC50
4
ent-2 R = Me
ent-3 R= H
OH
OR
OH
O
OH
O
O
MeO
HO
O
7 (-)-thysanone
5 R = Me, ascomycone A
6 R = H, ascomycone B
13 l
g/mL). Related compounds ascomycones A 5 and B 65 were
Figure 1. Structures of astropaquinones 1–3, thysanone 7, and related molecules.
isolated from the culture of an unknown ascomycete found on
the bark of a dead twig in French Guiana. Recently, Zhang et al.6
isolated the enantiomers of astropaquinone B 2 and C 3, that is,
ent-2 and ent-3 from the fungus Torula herbarum. Brimble et al.7
reported the first and only total synthesis of both astropaquinones
B 2 and C 3 through a Staunton-Weinreb annulation.8 Due to the
significant biological activity of thysanone 7 against HRV-3C prote-
ase several approaches for its synthesis and those of its analogs
have been reported.9
In continuation of our research program aimed at the stereose-
lective synthesis of pyranonapthoquinones and related com-
pounds10 by employing the Dötz benzannulation11 reaction as a
key step, we became interested in the unique lactol containing
pyranonaphthoquinones: (+)-astropaquinone B 2 and (+)-astrop-
aquinone C 3. Demethylation of any of these could give thysanone
7. Herein we report a concise and highly diastereoselective synthe-
sis of (+)-astropaquinone B 2 and (+)-astropaquinone C 3 along with
the oxidative formation of a unique dimer of astropaquinone B 2.
⇑
Corresponding author. Tel.: +91 (22) 25767174; fax: +91 (22) 25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.09.001

1282
R. A. Fernandes, S. V. Mulay / Tetrahedron: Asymmetry 24 (2013) 1281–1285
OMe
OMe OMe
Cr(CO)5
2. Results and discussion
Br
a
b
Our retrosynthetic route to 2 and 3 is shown in Scheme 1.
The synthesis of compounds 2 and 3 could be envisioned from
the naphthyl alcohol 8 through an oxa-Pictet-Spengler reaction.
The substituted naphthalene ring could be easily accessed by a
Dötz benzannulation reaction of Fischer carbene 9 with chiral
alkyne 10. The TBDMS protection of the OH group para to the
carbene carbon on the Fischer carbene 9 was aimed to increase
the benzannulation reaction yield although its introduction adds
one step to the synthesis. It is reported in the literature12 that
Fischer carbenes with an electron donating group at the para
position of the aromatic ring (such as –OMe) give poor yields in
Dötz benzannulation reactions which is one of the key steps in
the synthesis.
TBDMSO
TBDMSO
11
9
OMe OMe
OMe OMe
OTBDMS
OTBDMS
c
TBDMSO
MeO
OH
OMe
12
13
OMe OMe
OMe OMe OMe
O
OH
d
e
MeO
MeO
OMe
OMe
The synthesis of 2 and 3 started from the known bromo com-
pound 1112 (Scheme 2). The Fischer carbene 9 was prepared from
11 in good yield (65%). The Dötz benzannulation reaction of 9 with
alkyne 1010e gave naphthol 12 in a moderate yield of 48%. A similar
Fischer carbene with an –OMe group instead of –OTBDMS gave
only 35% yield.10i The protection of the phenolic OH group using
NaH (1.2 equiv) in DMF solvent gave a mixture of compounds, in
which 13 was formed through aryl-OTBDMS deprotection and
methylation along with the expected TBDMS containing com-
pound. Increasing the base concentration (NaH, 2.2 equiv) resulted
in only 13 (70%) where the complete removal of the phenolic
TBDMS group occurred followed by methylation. The aliphatic-
OTBDMS group remained intact. Removal of this from 13 gave
the desired alcohol 8 in 96% yield. The latter was subjected to an
oxa-Pictet-Spengler13 reaction with trimethylorthoformate in the
presence of a catalytic amount of p-TsOH to furnish the trans-con-
figured pyran 14 exclusively in excellent yields (92%).14 No trace of
the cis-pyran product was observed within the detectable limits of
NMR. The oxidation of compound 14 using phenyliodinebis(trifluo-
roacetate) (PIFA) provided (+)-astropaquinone B 2 in 80% yield
14
8
OMe
O
OMe
O
OMe
O
OMe
O
f
+
MeO
MeO
O
O
O
OMe
(+)-astropaquinone B, 2 (80%)
O
g
OMe
O
OMe
OMe
O
O
OH
15 (10%)
O
MeO
(+)-astropaquinone C, 3
Scheme 2. Synthesis of (+)-astropaquinone B 2, (+)-astropaquinone C 3 and the
formation of dimer 15. Reagents and conditions: (a) (i) n-BuLi, Et2O, ꢀ50 °C, 15 min;
(ii) Cr(CO)6, Et2O, 0 °C, 1 h, rt, 2 h; (iii) Me3OBF4, CH2Cl2, 0 °C, 1 h, rt, 2 h, 65%, (b) 10,
THF, 45 °C, 12 h, 48%, (c) NaH, DMF, MeI, 0 °C to rt, 6 h, 70%, (d) TBAF, THF, rt, 6 h,
96%, (e) CH(OMe)3, p-TsOH, CH2Cl2, rt, 1 h, 92%, (f) PIFA, CH3CN–H2O, 0 °C, 5 min, 2
80% and 15 10%, (g) p-TsOH; H2O, benzene, reflux, 4 h, 75%.
{½a 2D5
ꢁ
¼ þ42:3 (c 0.12, CHCl3), lit.7
½
a 1D9
ꢁ
¼ þ35:0 (c 0.14, CHCl3),
lit.3
½
a 2D7:8
ꢁ
¼ þ45:1 (c 0.12, CHCl3)} along with a small amount of
dimerized product 15 (10%). The formation of 15 was ascertained
by the presence of only one aryl-H in the 1H NMR corresponding
to 8-ArH (and 80-ArH) and by mass analysis. The formation of 15
is similar to the dimerization of ventiloquinone L as observed by
Brimble et al.15 when quinone formation was carried out by using
cerium ammonium nitrate. Further treatment of 2 with a catalytic
amount of p-TsOH and water in benzene gave astropaquinone C 3
3. Conclusion
In conclusion,
a concise diastereoselective synthesis of
(+)-astropaquinone B and (+)-astropaquinone C has been achieved.
A unique dimer of the former was isolated during quinone forma-
tion. The synthetic strategy features an efficient combination of a
Dötz benzannulation reaction of a Fischer carbene with a chiral al-
kyne to construct the naphthalene unit and a highly diastereose-
lective oxa-Pictet-Spengler reaction to install the trans-configured
pyran ring as the key steps. The synthesis was completed from
the known compound 11 in six steps for 2 (15.4% overall yield)
and seven steps for 3 (11.6% overall yield).
in 75% yield {½a 2D5
ꢁ
¼ þ44:0 (c 0.1, CHCl3), lit.7 ½a D19
¼ þ31:1 (c 0.10,
ꢁ
CHCl3), lit.3
½
a 2D4:7
ꢁ
¼ þ53:9 (c 0.10, CHCl3)}. The spectroscopic data
of both 2 and 3 were in excellent agreement with that reported in
the literature.3,7
OMe
O
O
OR
OMe OMe
oxa-Pictet
Spengler
O
OH
4. Experimental
4.1. General
MeO
MeO
OMe
2 R = Me; astropaquinone B
8
3 R = H; astropaquinone C
Flasks were oven or flame dried and cooled in a desiccator. Dry
reactions were carried out under an atmosphere of Ar or N2.
Solvents and reagents were purified by standard methods. Thin
layer chromatography was performed on EM 250 Kieselgel 60
F254 silica gel plates. The spots were visualized by staining with
KMnO4 or by UV lamp. 1H NMR and 13C NMR were recorded at
400 and 100 MHz respectively, and chemical shifts are based on
TMS peak at d = 0.00 ppm for proton NMR, and CDCl3 peak at
d = 77.00 ppm (t) for carbon NMR. IR samples were prepared by
Dötz
benzannulation
OMe OMe
Cr(CO)5
OTBDMS
TBDMSO
10
9
Scheme 1. Retrosynthesis of astropaquinones B 2 and C 3.

R. A. Fernandes, S. V. Mulay / Tetrahedron: Asymmetry 24 (2013) 1281–1285
1283
evaporation from CHCl3 on CsBr plates. High-resolution mass spec-
tra were obtained using positive electrospray ionization.
d = ꢀ4.5, 18.2, 25.6, 56.1, 103.0, 105.0, 113.2, 133.0, 156.2, 156.4;
HRMS m/z calcd for [C13H21BrO2Si + H]+ 317.0567, found:
317.0567.
4.1.1. (4-Bromo-3-methoxyphenoxy)(tert-butyl)-dimethyl-silane
1112
4.1.2. (S)-7-(tert-Butyldimethylsilyloxy)-2-[2-(tert-butyldi-meth-
ylsilyloxy)propyl]-4,5-dimethoxynaphthalen-1-ol 12
To a solution of 11 (1.0 g, 3.15 mmol) in dry Et2O (25 mL) at
ꢀ50 °C was added n-BuLi (2.2 mL 3.49 mmol, 1.1 equiv, 1.6 M solu-
tion in hexane) and the reaction mixture was stirred for 15 min. It
To a stirred solution of 4-bromoresorcinol (3.0 g, 15.87 mmol)
in dry acetone (60 mL) were added K2CO3 (10.97 g, 79.36 mmol,
5.0 equiv) and TsCl (3.18 g, 16.7 mmol, 1.05 equiv). The reaction
mixture was refluxed for 16 h and then cooled to room tempera-
ture. To the reaction mixture was added MeI (2.47 mL, 39.67 mmol,
2.5 equiv) and further refluxed for 12 h. It was then cooled to room
temperature and the precipitated solid was filtered off. The filtrate
was concentrated under reduced pressure and the residue diluted
with water and EtOAc (1:1, 50 mL). The separated aqueous layer
was extracted with EtOAc (2 ꢂ 30 mL). The combined organic lay-
ers were washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1 to 4:1) as eluent to afford 4-bromo-
3-methoxyphenyl-4-methylbenzenesulfonate (5.05 g, 89%) as a
was then transferred to
a suspension of Cr(CO)6 (0.832 g,
3.78 mmol, 1.2 equiv) in dry Et2O (25 mL) at 0 °C. The reaction
mixture was stirred for 1 h at 0 °C and then at room temperature
for 2 h. Next, Et2O was evaporated off and the residue was dis-
solved in dry CH2Cl2 (25 mL). To this solution was added Me3OBF4
(0.70 g, 4.73 mmol, 1.5 equiv) in portions at 0 °C and the reaction
mixture was stirred for 1 h. It was warmed to room temperature
and stirred for 2 h. The red colored reaction mixture was concen-
trated and the residue was purified by silica gel column chroma-
tography using petroleum ether/CH2Cl2 (9:1 to 4:1) as eluent to
give 9 (0.968 g, 65%) as a red colored semisolid. This was used
immediately in the next step.
white solid: mp 68–70 °C; IR (CHCl3):
m = 3015, 2942, 2862,
1596, 1578, 1481, 1446, 1403, 1374, 1307, 1292, 1273, 1211,
1194, 1179, 1139, 1120, 1092, 1048, 1025, 949, 855, 816, 784,
To a solution of freshly prepared Fischer carbene 9 (0.94 g,
1.99 mmol) in dry and degassed THF (15 mL) was added a solution
of alkyne 10 (0.79 g, 3.98 mmol, 2.0 equiv 99% e.e.) in dry and de-
gassed THF (5 mL). The reaction mixture was heated at 45 °C for
12 h and then allowed to cool to room temperature, exposed to
air, and further stirred for 1 h. Next, the THF was removed and
the residue purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1 to 4:1) as eluent to afford 12
720, 703, 664 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 2.46 (s,
;
3H), 3.78 (s, 3H), 6.40 (dd, J = 8.6, 2.5 Hz, 1H), 6.59 (d, J = 2.5 Hz,
1H), 7.33 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.71 (d,
J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 21.7, 56.3, 106.9,
109.9, 115.2, 128.5, 129.8, 131.9, 133.2, 145.6, 149.5, 156.4; HRMS
m/z calcd for [C14H13BrO4S + Na]+ 378.9610, found: 378.9610.
To a stirred solution of the above 4-bromo-3-methoxyphenyl-4-
methylbenzenesulfonate (4.2 g, 11.76 mmol) in ethanol (30 mL)
was added KOH (1.32 g, 23.52 mmol, 2.0 equiv). The reaction mix-
ture was refluxed for 3 h and then cooled to room temperature. The
solvent was evaporated at reduced pressure and the residue di-
luted with water and EtOAc (1:1, 50 mL). The separated aqueous
layer was extracted with EtOAc (2 ꢂ 30 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), and concen-
trated. The residue was purified by silica gel column chromatogra-
phy using petroleum ether/EtOAc (4:1 to 7:3) as eluent to afford
4-bromo-3-methoxyphenol (2.1 g, 88%) as a white solid: mp
(0.484 g, 48%) as a light yellow semisolid; ½a D25
¼ ꢀ10:6 (c 1.2,
ꢁ
CHCl3); IR (CHCl3):
m = 3434, 2956, 2927, 2856, 1653, 1605, 1592,
1512, 1464, 1378, 1328, 1258, 1216, 1159, 1125, 1090, 1036,
985, 939, 838, 780, 759 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS):
;
d = ꢀ0.12 (s, 3H), 0.04 (s, 3H), 0.26 (s, 6H), 0.88 (s, 9H), 1.01 (s,
9H), 1.23 (d, J = 6.1 Hz, 3H), 2.88 (d, J = 5.2 Hz, 2H), 3.88 (s, 3H),
3.93 (s, 3H), 4.21–4.28 (m, 1H), 6.39 (s, 1H), 6.44 (d, J = 2.4 Hz,
1H), 7.26 (d, J = 2.4 Hz, 1H), 8.4 (s, 1H, OH); 13C NMR (100 MHz,
CDCl3): d = ꢀ5.3, ꢀ4.9, ꢀ4.44, ꢀ4.39, 17.9, 18.3, 23.1, 25.7, 25.8,
41.7, 56.1, 57.4, 71.7, 102.2, 102.6, 108.8, 113.4, 118.9, 129.6,
144.1, 150.2, 153.5, 157.7; HRMS m/z calcd for [C27H46O5Si2+H]+
507.2962, found: 507.2955.
74–76 °C; IR (CHCl3):
1468, 1450, 1430, 1297, 1267, 1199, 1168, 1128, 1047, 1024,
951, 830, 797, 758, 625 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS):
m = 3462, 3010, 2943, 1607, 1590, 1487,
;
d = 3.84 (s, 3H), 5.68 (s, 1H, OH), 6.34 (dd, J = 8.5, 2.7 Hz, 1H),
6.45 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 56.1, 100.5, 102.1, 108.6, 133.3, 156.1,
156.6; HRMS m/z calcd for [C7H7BrO2 + Na]+ 224.9522, found:
224.9523.
To a solution of the above 4-bromo-3-methoxyphenol (1.80 g,
8.87 mmol) in dry THF (30 mL) was added NaH (0.277 g,
11.53 mmol, 1.3 equiv) at 0 °C and stirred for 15 min. Next,
TBDMSCl (2.0 g, 13.31 mmol, 1.5 equiv) was added at 0 °C and then
slowly warmed to room temperature and the reaction mixture stir-
red for 12 h. After completion of the reaction, it was quenched with
sat. aq. NaHCO3 (20 mL). The solvent was evaporated at reduced
pressure and the aqueous layer extracted with EtOAc
(3 ꢂ 20 mL). The combined organic layers were washed with water
and brine, dried (Na2SO4), and concentrated. The residue was puri-
fied by silica gel column chromatography using petroleum ether/
EtOAc (9.5:0.5 to 9:1) as eluent to afford 11 (2.75 g, 98%) as a col-
4.1.3. (S)-tert-Butyldimethyl[1-(1,4,5,7-tetramethoxy-naphtha-
len-2-yl)propan-2-yloxy]silane 13
To a solution of 12 (0.4 g, 0.789 mmol) in dry DMF (15 mL) at
0 °C was added NaH (41.6 mg, 1.74 mmol, 2.2 equiv) and stirred
for 30 min. Next, MeI (0.2 mL, 3.16 mmol, 4.0 equiv) was added
and the reaction mixture was stirred for 6 h at room temperature.
Ice cooled water was added and the reaction mixture extracted
with EtOAc (3 ꢂ 20 mL). The combined organic layers were washed
with water and brine, dried (Na2SO4), and concentrated. The resi-
due was purified by silica gel column chromatography using petro-
leum ether/EtOAc (9:1 to 3:2) as eluent to give 13 (0.232 g, 70%) as
a colorless oil; ½a D25
ꢁ
¼ þ24:6 (c 0.25, CHCl3); IR (CHCl3):
m = 2956,
2930, 2856, 1676, 1621, 1606, 1468, 1404, 1380, 1246, 1155,
1124, 1083, 1061, 1006, 833 cmꢀ1 1H NMR (400 MHz, CDCl3/
;
TMS): d = ꢀ0.14 (s, 3H), ꢀ0.03 (s, 3H), 0.84 (s, 9H), 1.19 (d,
J = 6.0 Hz, 3H), 2.78 (dd, J = 13.1, 5.9 Hz, 1H), 2.92 (dd, J = 13.1,
7.0 Hz, 1H), 3.84 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H),
4.15–4.23 (m, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.54 (s, 1H), 6.96 (d,
J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = ꢀ5.0, ꢀ4.9, 18.1,
23.8, 25.8, 40.8, 55.2, 56.2, 56.6, 61.0, 69.2, 92.9, 98.3, 107.5,
113.0, 128.8, 132.0, 146.9, 153.0, 158.4, 158.6; HRMS m/z calcd
for [C23H36O5Si+H]+ 421.2410, found: 421.2398.
orless oil; IR (CHCl3):
1302, 1257, 1205, 1170, 1121, 1053, 1026, 979, 841, 781, 705,
670 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 0.20 (s, 6H), 0.98
m = 2956, 2930, 2858, 1589, 1486, 1448, 1404,
;
(s, 9H), 3.85 (s, 3H), 6.34 (dd, J = 8.5, 2.6 Hz, 1H), 6.41 (d,
J = 2.6 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3):

1284
R. A. Fernandes, S. V. Mulay / Tetrahedron: Asymmetry 24 (2013) 1281–1285
4.1.4. (S)-1-(1,4,5,7-Tetramethoxynaphthalen-2-yl)-propan-2-ol
8
3H), 2.23 (dd, J = 19.1, 11.0 Hz, 1H), 2.66 (dd, J = 19.1, 3.5 Hz, 1H),
3.56 (s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 4.19–4.25 (m, 1H), 5.54 (s,
1H), 6.72 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 20.9, 29.0, 55.9, 56.2, 56.4, 62.0, 93.7,
103.2, 104.3, 114.2, 135.7, 140.5, 140.9, 162.0, 164.5, 180.8,
184.9; HRMS m/z calcd for [C17H18O6 + H]+ 319.1182, found:
To a solution of compound 13 (0.2 g, 0.475 mmol) in dry THF
(20 mL) was added TBAF (0.95 mL, 0.95 mmol, 1 M solution in
THF, 2.0 equiv). The reaction mixture was stirred at room temper-
ature for 6 h. It was then quenched with water (10 mL) and THF
was removed under reduced pressure. The solution was extracted
with EtOAc (3 ꢂ 20 mL) and the combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography using petroleum
ether–EtOAc (9:1 to 3:2) as eluent to give 8 (0.140 g, 96%) as a col-
319.1181. Data for 15: mp = 155–165 °C (decomp); ½a D25
¼ þ19:6
ꢁ
(c 0.2, CHCl3); IR (CHCl3):
m = 3017, 2973, 2934, 1666, 1579, 1550,
1470, 1433, 1344, 1304, 1264, 1220, 1167, 1126, 1094, 1049,
978, 924, 831, 707, 669 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS):
;
d = 1.38 (d, J = 6.2 Hz, 6H), 2.28 (dd, J = 18.9, 11.2 Hz, 2H), 2.63
(dd, J = 18.9, 3.4 Hz, 2H), 3.56 (s, 6H), 4.02 (s, 6H), 4.03 (s, 6H),
4.14–4.23 (m, 2H), 5.53 (s, 2H), 6.76 (s, 2H); 13C NMR (100 MHz,
CDCl3): d = 20.9, 29.3, 56.1, 56.6, 56.7, 62.1, 93.4, 100.3, 114.7,
115.8, 130.9, 139.4, 142.2, 160.5, 160.7, 180.2, 184.2; HRMS m/z
calcd for [C34H34O12+H]+635.2128, found: 635.2132.
orless oil; ½a 2D5
ꢁ
¼ þ26:7 (c 0.4, CHCl3); IR (CHCl3):
m = 3481, 3018,
2965, 2939, 2843, 1619, 1606, 1511, 1467, 1450, 1404, 1381,
1355, 1263, 1173, 1154, 1121, 1082, 1060, 1004, 941, 930,
834 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 1.29 (d, J = 6.2 Hz,
;
3H), 2.90 (d, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H),
3.94 (s, 3H), 4.16–4.21 (m, 1H), 6.51 (s, 2H), 6.96 (d, J = 2.3 Hz,
1H); 13C NMR (100 MHz, CDCl3): d = 23.2, 40.4, 55.2, 56.3, 56.7,
61.0, 68.6, 92.9, 98.6, 106.5, 113.2, 127.9, 132.0, 146.8, 153.7,
158.7; HRMS m/z calcd for [C17H22O5+H]+ 307.1545, found:
307.1550.
4.1.7. (+)-Astropaquinone C 3
To a stirred solution of 2 (20 mg, 0.063 mmol) in benzene
(5 mL) and water (1 drop) was added p-TsOHꢃH2O (cat). The reac-
tion mixture was refluxed for 4 h. It was then quenched with satd
aq NaHCO3 (2 mL) and the aqueous layer extracted with EtOAc
(3 ꢂ 10 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated. The residue was purified by sil-
ica gel column chromatography using petroleum ether/EtOAc (4:1
to 2:1) as eluent to afford 3 (14.4 mg, 75%) as a yellow solid:
4.1.5. (1R,3S)-1,5,7,9,10-Pentamethoxy-3-methyl-3,4-dihydro-
1H-benzo[g]isochromene 14
To a solution of alcohol 8 (100 mg, 0.326 mmol) in CH2Cl2
(8 mL) were added trimethylorthoformate (0.36 mL, 3.26 mmol,
10.0 equiv) and p-TsOH.H2O (5.6 mg, 0.0294 mmol). The reaction
mixture was stirred at room temperature for 1 h and then
quenched with satd aq NaHCO3 (8 mL) and the solution extracted
with CH2Cl2 (3 ꢂ 15 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 4:1) as eluent to afford 14 (104 mg, 92%) as a
mp = 181–183 °C, lit.7 mp = 178–181 °C;
½
a 2D5
ꢁ
¼ þ44:0 (c 0.1,
CHCl3), lit.7
½
a 1D9
ꢁ
¼ þ31:1 (c 0.10, CHCl3), lit.3
½ ꢁ
a 2D4:7
¼ þ53:9
(c 0.10, CHCl3); IR (CHCl3):
m = 3434, 3011, 2925, 2854, 1658,
1595, 1563, 1463, 1380, 1347, 1321, 1277, 1217, 1160, 1122,
1081, 1031, 968, 941, 922, 863, 829, 667 cmꢀ1 1H NMR
;
(400 MHz, CDCl3/TMS): d = 1.40 (d, J = 6.2 Hz, 3H), 2.23 (dd,
J = 19.1, 11.1 Hz, 1H), 2.71 (dd, J = 19.1, 3.2 Hz, 1H), 3.96 (s, 3H),
3.97 (s, 3H), 4.28–4.36 (m, 1H), 6.02 (s, 1H), 6.74 (d, J = 2.4 Hz,
1H), 7.26(d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 20.9,
29.0, 56.0, 56.4, 62.9, 87.2, 103.6, 104.3, 113.9, 135.7, 140.4,
142.1, 162.1, 164.9, 182.1, 184.6; HRMS m/z calcd for
[C16H16O6+K]+ 343.0584, found: 343.0586.
colorless oil; ½a D25
ꢁ
¼ ꢀ89:7 (c 0.64, CHCl3); IR (CHCl3):
m = 2972,
2935, 2842, 1622, 1603, 1585, 1504, 1469, 1452, 1414, 1387,
1343, 1261, 1231, 1205, 1161, 1134, 1116, 1083, 1068, 1047,
1008, 974, 941, 849, 833, 669 cmꢀ1 1H NMR (400 MHz, CDCl3/
;
TMS): d = 1.43 (d, J = 6.2 Hz, 3H), 2.56 (dd, J = 17.0, 11.6 Hz, 1H),
3.03 (dd, J = 17.0, 3.3 Hz, 1H), 3.59 (s, 3H), 3.83 (s, 3H), 3.86 (s,
3H), 3.93 (s, 3H), 3.96 (s, 3H), 4.33–4.41 (m, 1H), 5.83 (s, 1H),
6.50 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 21.5, 30.2, 54.8, 55.2, 55.9, 60.1, 61.8, 63.0,
92.4, 96.0, 98.5, 115.2, 122.7, 124.8, 131.6, 147.6, 150.8, 157.6,
158.5; HRMS m/z calcd for [C19H24O6+H]+ 349.1651, found:
349.1657.
Acknowledgements
This work was financially supported by the Department of
Science and Technology, New Delhi (Grant No. SR/S1/OC-25/
2008) and Board of Research in Nuclear sciences (BRNS),
Government of India (Grant No. 2009/37/25 BRNS). S.V.M. thank
the Council of Scientific and Industrial Research (CSIR) New Delhi
for a senior research fellowship.
4.1.6. (+)-Astropaquinone B 2 and (1R,10R,3S,30S)-1,10,7,70,9,90-
hexamethoxy-3,30-dimethyl-3,30,4,40-tetrahydro-1H,10H-6,60-
dibenzo[g]isochromene-5,50,10,100-tetraone 15
References
To a stirred solution of 14 (50 mg, 0.144 mmol) in CH3CN (5 mL)
and water (5 mL) was added phenyliodine bis(trifluoroacetate)
(PIFA, 124 mg, 0.288 mmol, 2.0 equiv). The reaction mixture was
stirred at 0 °C for 5 min. It was then diluted with EtOAc (10 mL)
and the organic layer separated. The aqueous layer was extracted
with EtOAc (3 ꢂ 10 mL) and the combined organic extracts were
washed with water and brine, dried (Na2SO4), and concentrated.
The residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (4:1 to 7:3) as eluent to afford 2
(36.5 mg, 80%) as a yellow solid. Further elution with petroleum
ether/EtOAc (2:3) as eluent gave 15 (9.1 mg, 10%) as a yellow solid.
1. (a) Brimble, M. A.; Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999, 16, 267–281;
(b) Brimble, M. A.; Nairn, M. R.; Prabaharan, H. Tetrahedron 2000, 56, 1937–
1992; (c) Sperry, J.; Bachu, P.; Brimble, M. A. Nat. Prod. Rep. 2008, 25, 376–400.
2. (a) Moore, H. W. Science 1977, 197, 527–532; (b) Moore, H. W.; Czerniak, R.
Med. Res. Rev. 1981, 1, 249–280.
3. Wang, L.; Dong, J. Y.; Song, H. C.; Shen, K. Z.; Wang, L. M.; Sun, R.; Wang, C. R.;
Gao, Y. X.; Li, G. H.; Li, L.; Zhang, K. Q. Planta Med. 2009, 75, 1339–1343.
4. Singh, S. B.; Cordingley, M. G.; Ball, R. G.; Smith, J. L.; Dombrowski, A. W.; Goetz,
M. A. Tetrahedron Lett. 1991, 32, 5279–5282.
5. Opatz, T.; Kolshorn, H.; Thines, E.; Anke, H. J. Nat. Prod. 2008, 71, 1973–1976.
6. Geng, W. L.; Wang, X. Y.; Kurtan, T.; Mandi, A.; Tang, H.; Schulz, B.; Sun, P.;
Zhang, W. J. Nat. Prod. 2012, 75, 1828–1832.
7. Wadsworth, A. D.; Sperry, J.; Brimble, M. A. Synthesis 2010, 2604–2608.
8. (a) Evans, G. E.; Leeper, F. J.; Murphy, J. A.; Staunton, J. J. Chem. Soc., Chem.
Commun. 1979, 205–206; (b) Dodd, J. H.; Weinreb, S. M. Tetrahedron Lett. 1979,
20, 3593–3596; (c) Zhang, Z.; Yu, B. J. Org. Chem. 2003, 68, 6309–6313.
9. For the total synthesis of thysanone, see: (a) Gill, M.; Donner, C. D. Tetrahedron
Lett. 1999, 40, 3921–3924; (b) Donner, C. D.; Gill, M. J. Chem. Soc., Perkin Trans. 1
2002, 938–948; (c) Sperry, J.; Brimble, M. A. Synlett 2008, 1910–1912; (d)
Sperry, J.; Yuen, T. Y.; Brimble, M. A. Synthesis 2009, 2561–2569. For analogue
synthesis, see; (e) Brimble, M. A.; Elliott, R. J. R.; McEwan, J. F. Aust. J. Chem.
Data for 2: mp = 162–164 °C, lit.7 mp = 164–167 °C; ½a 2D5
ꢁ
= + 42.3
(c 0.12, CHCl3), lit.7
½
a 1D9
ꢁ
¼ þ35:0 (c 0.14, CHCl3), lit.3
½
a 2D7:8
ꢁ
¼ þ45:1 (c 0.12, CHCl3); IR (CHCl3):
m = 3015, 2963, 2930,
2852, 1659, 1594, 1563, 1467, 1457, 1385, 1339, 1322, 1196,
1160, 1089, 1071, 1055, 1038, 961, 940, 860, 840, 821, 720, 686,
667 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 1.38 (d, J = 6.3 Hz,
;

R. A. Fernandes, S. V. Mulay / Tetrahedron: Asymmetry 24 (2013) 1281–1285
1285
2000, 53, 571–576; (f) Brimble, M. A.; Elliott, R. J. R. Tetrahedron 2002, 58,
183–189; (g) Kraus, G. A.; Ogutu, H. Tetrahedron 2002, 58, 7391–7395; (h)
Bulbule, V. J.; Koranne, P. S.; Deshpande, V. H.; Borate, H. B. Tetrahedron 2007,
63, 166–170; (i) Brimble, M. A.; Houghton, S. I.; Woodgate, P. D. Tetrahedron
2007, 63, 880–887; (j) Sawant, R. T.; Jadhav, S. G.; Waghmode, S. B. Eur. J. Org.
Chem. 2010, 4442–4449. For the formal synthesis of thysanone, see:; (k) Bachu,
P.; Sperry, J.; Brimble, M. A. Tetrahedron 2008, 64, 4827–4834; (l) Sawant, R. T.;
Waghmode, S. B. Tetrahedron 2009, 65, 1599–1602.
Fernandes, R. A.; Ingle, A. B.; Chavan, V. P. Org. Biomol. Chem. 2012, 10, 4462–
4466; (j) Fernandes, R. A.; Chavan, V. P.; Mulay, S. V.; Manchoju, A. J. Org. Chem.
2012, 77, 10455–10460.
11. (a) Dötz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644–645; (b) Dötz, K. H.;
Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187–198.
12. Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.; Brandvold, T. A. J. Am.
Chem. Soc. 1991, 113, 9293–9319. See the Experimental section for its
preparation..
10. (a) Fernandes, R. A.; Chavan, V. P. Tetrahedron Lett. 2008, 49, 3899–3901; (b)
Fernandes, R. A.; Chavan, V. P.; Ingle, A. B. Tetrahedron Lett. 2008, 49,
6341–6343; (c) Fernandes, R. A.; Chavan, V. P. Eur. J. Org. Chem. 2010, 4306–
4311; (d) Fernandes, R. A.; Mulay, S. V. Synlett 2010, 2667–2671; (e) Fernandes,
R. A.; Mulay, S. V. J. Org. Chem. 2010, 75, 7029–7032; (f) Fernandes, R. A.;
Chavan, V. P.; Mulay, S. V. Tetrahedron: Asymmetry 2011, 22, 487–492; (g)
Fernandes, R. A.; Chavan, V. P. Tetrahedron: Asymmetry 2011, 22, 1312–1319;
(h) Fernandes, R. A.; Ingle, A. B. Eur. J. Org. Chem. 2011, 6624–6627; (i)
13. (a) Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; De Brabander, J. K. J. Am. Chem.
Soc. 2009, 131, 11350–11352; (b) Masquelin, T.; Hengartner, U.; Streith, J.
Synthesis 1995, 780–786; (c) Larghi, E. L.; Kaufman, T. S. Eur. J. Org. Chem. 2011,
5195–5231.
14. The assigned trans-stereochemistry was confirmed by converting it into 2.
15. Sperry, J.; Sajberg, J. J. P.; Stiemke, F. M.; Brimble, M. A. Org. Biomol. Chem. 2009,
7, 2599–2603.