Total synthesis of asterredione

Article abstract of DOI:10.1021/jo4028177

The first total synthesis of asterredione was efficiently accomplished over five linear steps and in 21.5% overall yield. As the crucial step, the 2-quaternary 1,3-cyclopentenedione skeleton of asterredione was readily achieved using the Darzens/ring-expansion strategy developed in our laboratory. The structure of synthesized asterredione was fully confirmed by X-ray crystallography.

Full text of DOI:10.1021/jo4028177

Article
pubs.acs.org/joc
Total Synthesis of Asterredione
Sinan Gai, Qing Zhang, and Xiangdong Hu*
Department of Chemistry & Material Science, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the
Ministry of Education of China, Northwest University, Xi’an 710069, China
*
S Supporting Information
ABSTRACT: The first total synthesis of asterredione was efficiently accomplished over five linear steps and in 21.5% overall
yield. As the crucial step, the 2-quaternary 1,3-cyclopentenedione skeleton of asterredione was readily achieved using the
Darzens/ring-expansion strategy developed in our laboratory. The structure of synthesized asterredione was fully confirmed by
X-ray crystallography.
INTRODUCTION
efficient strategy for 1,3-cyclopentenedione units. However, the
,3-cyclopentenedione obtained in our previous research has
■
1
Rhizosphere soil-derived microorganisms provide an important
resource for the research of secondary metabolites possessing
one hydrogen on C2, which enabled the formation of the
expected product through enolization. In this article, we sought
to achieve the quaternary carbon center in 1 through a new
version of Darzens/ring-expansion process. From the retro-
synthetic analysis shown in Scheme 1, the synthesis starts from
three commercially available materials: indole 7, dimethyl
squarate 8, and 3-indoleacetic acid 10. Fragments 4 and 5 were
designed for the Darzens/ring-expansion cascade, which would
form the 2-quaternary-1,3-cyclopentenedione skeleton and
generate key intermediate 2. Lastly, 1 would be obtained
through the removal of two protecting groups in 2.
1
,2
therapeutic potential. In addition, rhizospheres of desert
plants have also been considered to be a unique opportunity to
discover unusual secondary metabolites. Through extensive
investigations on the rhizosphere microflora of Sonoran desert
plants, asterredione (1; Scheme 1) was discovered from
Aspergillus terreus existing in the rhizosphere of Opuntia
3
4
versicolor by Gunatilaka in 2003. The biological study showed
that 1 exhibited moderate anticancer activity against three
sentinel cancer cell lines: the NCI-H460 nonsmall cell lung
cancer, MCF-7 breast cancer, and SF-268 CNS glioma cell
lines.
Structurally, 1 is an unusual alkaloid characterized by a
congested 2-quaternary 1,3-cyclopentenedione core and two
indole motifs. Gunatilaka proposed a biosynthetic pathway to 1
through a hydroperoxy-mediated ring contraction of the
Our synthesis began with the preparation of fragments 4 and
5 (Scheme 2). Bromide 6 was prepared in 97% yield from
14
indole 7 through bromination and protection treatments. The
in situ formed organlithium reagent from bromine−lithium
exchange between n-butyllithium and 6 smoothly attacked
dimethyl squarate 8 at −110 °C. After the following acid-
promoted rearrangement, fragment 4 was generated with 76%
yield in one pot. Starting from 3-indoleacetic acid 10, ester 9
was obtained in 94% yield from the esterification and
4
homologous natural product asterriquinone D. Although the
biological activity and the congested structure make this
compound an attractive target, there has been no report on the
synthesis of 1 in the 10 years since its discovery. Herein, we
describe the first total synthesis of 1.
15
protection transformations. Bromination of 9 was successfully
achieved under the radical conditions of NBS and AIBN rather
than through the employment of LiHMDS and NBS. Because
RESULTS AND DISCUSSION
■
16
of the instant decomposition, fragment 5 was obtained in
In the synthesis, constructing the 2-quaternary 1,3-cyclo-
pentenedione unit of 1 was the major challenge that we
faced. The ring expansion of squaric acid derivatives and
cyclobutenediones is an attractive research field to organic
worse purity and yield after chromatography. Therefore, crude
5
was subjected to the next step directly.
With fragments 4 and 5 in hand, we next moved our
attention to the construction of the 2-quaternary 1,3-cyclo-
pentenedione skeleton of 1, namely, the synthesis of
5
,6
7,8
synthetic chemists in which Moore,
Liberskind,
Pa-
9
,10
11,12
quette,
Burnell,
and others have made great contribu-
tions. As a new development in this field, a Darzens/ring-
expansion process was developed during our study on the total
synthesis of linderaspirone A and bilinderone, affording an
Received: December 23, 2013
Published: February 11, 2014
13
©
2014 American Chemical Society
2111
dx.doi.org/10.1021/jo4028177 | J. Org. Chem. 2014, 79, 2111−2114

The Journal of Organic Chemistry
Article
Scheme 1. Retrosynthetic Pathway to Asterredione (1)
The final target, asterredione (1), was eventually obtained in
1% yield through the deprotection treatment of 2 with
8
TBSOTf in dichloromethane (Scheme 3). The identity of
synthesized 1 was initially confirmed by the comparison of the
1
H NMR spectral data of the solution in deuterated chloroform
24
with that of natural asterredione. Fortunately, we secured the
single crystal of synthesized 1 from its solution in a mixture of
methanol, dichloromethane, and hexane. The structure of
synthesized 1 was unambiguously confirmed by X-ray crystallo-
graphic analysis (see the ORTEP diagram in Scheme 4).
CONCLUSIONS
■
The total synthesis of asterredione was achieved for the first
time. The entire approach requires only five linear steps,
affording asterredione in 21.5% total yield. Meanwhile, the
Darzens/ring-expansion strategy developed in our laboratory
was confirmed to be an efficient approach to access 1,3-
cyclopentenedione units containing quaternary carbon on C2.
EXPERIMENTAL SECTION
tert-Butyl-3-bromo-1H-indole-1-carboxylate (6). A solution of
Br (2.3 mL, 45.7 mmol) in DMF (20 mL) was added dropwise to
■
2
indole 7 (1.63g, 13.91 mmol) in DMF (80 mL) at 0 °C. After 30 min,
the mixture was poured into the mixed solution of NaHCO (3.6g,
3
4
4.68 mmol) and NaHSO (4.6 g, 44.7 mmol) at 0 °C. After 24 h of
3
stirring, the precipitate was isolated by filtration, washed with H O,
2
and dried in vacuum to afford crude 3-bromo-1H-indole as a white
solid powder. Then, Et N (0.15 mL, 0.1 mol), DMAP (250 mg, 2.0
3
mmol), and di-tert-butyl dicarbonate (3.9 mL, 16.7 mmol) was added
to a solution of 3-bromo-1H-indole (2.73 g, 13.9 mmol) in DCM (20
mL) at room temperature. The mixture was stirred for 3 h at room
intermediate 2 (Scheme 3). Toward this end, the mixture of
fragments 4 and 5 was treated with various bases to validate the
Darzens/ring-expansion process. The countercation ion in the
base has been proven to have an important effect on the
reaction as commercially available hexamethyldislazides are
applied. The best result came from the employment of
NaHMDS, which afforded 2 in 40% yield over two steps
from 9. Yields of 2 of only 10 and 5% were obtained using
LiHMDS and LDA as bases, respectively.
temperature. The reaction mixture was quenched with a NH Cl
4
saturated aqueous solution and extracted with DCM. The organic layer
was washed with water and brine and dried over Na SO . The solvent
2
4
was removed under reduced pressure. The product was purified by
silica gel chromatography (PE/EtOAc, 10:1) to afford 6 (4.0 g, 97%)
in two steps as yellow solid powder. mp 54−55 °C. IR (neat) ν
max
−1
1
2
981, 1730, 1450, 1380, 1248, 1157, 1060, 739 cm . H NMR (400
MHz, CDCl ) δ 8.14 (br s, 1H), 7.64 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H),
3
1
3
7.37 (t, J = 12.0 Hz, 1H), 7.30 (t, J = 16.0 Hz, 1H), 1.66 (s, 1H).
NMR (100 MHz, CDCl ) δ 148.8, 134.5, 129.3, 125.3, 124.7, 123.2,
19.5, 115.1, 97.9, 84.2, 28.1. We failed to collect the mass spectra
C
Regioselectivity is usually an important concern in the
nucleophilic addition of cyclobutenediones because the
addition to different carbonyl groups will lead to completely
3
1
because of the ready decomposition of 6.
17−19
tert-Butyl-3-(2-methoxy-3,4-dioxocyclobut-1-enyl)-1H-in-
dole-1-carboxylate (4). To a solution of 6 (668 mg, 2.25 mmol) in
THF (15 mL) was added n-butyllithium (2.40 M in hexanes, 1.10 mL,
different products.
However, it is not the case in this event.
Although there would be two intermediates, 3a and 3b, formed
in the process, their ring expansions, through a semipinacol
2
.6 mmol) slowly under an argon atmosphere at −110 °C. After 10
20−23
rearrangement of epoxides,
in the end.
will furnish the same product 2
min, a solution of dimethyl squarate 8 in THF (2.0 mL) was added
into the mixture. After 0.5 h of stirring at −110 °C, 12 N HCl in THF
Scheme 2. Synthesis of Fragments 4 and 5
2
112
dx.doi.org/10.1021/jo4028177 | J. Org. Chem. 2014, 79, 2111−2114

The Journal of Organic Chemistry
Article
Scheme 3. Synthesis of Asterredione (1)
Scheme 4. X-ray-Derived ORTEP of Asterredione (1)
product was purified by silica gel chromatography (PE/EtOAc, 20:1)
to afford 9 (7.9 g, 94%) in two steps as yellow oil. IR (neat) ν 2979,
max
−1 1
1
737, 1692, 1455, 1373, 1259, 1157, 1014, 752 cm . H NMR (400
MHz, CDCl ) δ 8.18−8.16 (br s, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.0
3
Hz, 1H), 7.36 (t, J = 12.0 Hz, 1H), 7.29 (t, J = 12.0 Hz, 1H), 3.75 (s,
2
1
8
H), 3.74 (s, 3H), 1.67 (s, 9H). 13C NMR (100 MHz, CDCl ) δ
3
71.4, 149.5, 135.3, 130.0, 124.5, 124.4, 122.6, 118.9, 115.2, 113.0,
+
+
3.5, 52.1, 30.8, 28.1. HRMS (ESI ) m/z: [M + Na] calcd for
C H NNaO , 312.1206; found, 312.1224.
16
19
4
Di-tert-butyl-3,3′-(4-methoxy-1-(methoxycarbonyl)-2,5-di-
oxocyclopent-3-ene-1,3-diyl)bis(1H-indole-1-carboxylate) (2).
To a solution of 9 (290 mg, 1.01 mmol) in CCl (15 mL) were
4
added 2.20 equiv of NBS (400 mg, 2.27 mmol) and 0.05 equiv of
AIBN (8.0 mg, 0.05 mmol). The mixture was heated under reflux in an
argon atmosphere for 24 h. After cooling to room temperature, the
reaction mixture was quenched with water and extracted with DCM.
The organic layer was washed with water and brine and dried over
was added slowly to the reaction mixture (adjusting the pH value to
3
−4). After warming to room temperature, the reaction mixture was
Na SO . Crude 5 was obtained after the solvent was removed under
quenched with a NaHCO saturated aqueous solution and extracted
2
4
3
16
reduced pressure. Because of its ready decomposition, crude 5 was
with EtOAc. The organic layer was washed with water and brine and
dried over Na SO . The solvent was removed under reduced pressure.
used for next step directly without purification. NMR data of crude 5:
2
4
1
The product was purified by silica gel chromatography (PE/EtOAc,
:1) to give 4 (562.7 mg, 76.3%) in two steps as yellow solid powder.
mp 84−85 °C. IR (neat) ν 2985, 1593, 1741, 1396, 1315, 1159,
H NMR (400 MHz, CDCl ) δ 8.17−8.15 (br s, 1H), 7.90 (s, 1H),
3
7
7.73 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 16.0 Hz, 1H), 7.30 (t, J = 16.0 Hz,
1H), 5.69 (s, 1H), 3.83 (s, 3H), 1.66 (s, 9H). 13C NMR (100 MHz,
max
−1 1
1
041, 758 cm . H NMR (400 MHz, CDCl ) δ 8.32 (s, 1H), 8.12 (d,
CDCl ) δ 168.2, 149.0, 135.5, 127.7, 125.7, 125.0, 122.9, 119.7, 115.3,
3
3
J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 16.0 Hz, 1H),
114.8, 84.3, 53.3, 38.8, 28.0.
13
7
.30 (t, J = 8.0 Hz, 1H), 4.56 (s, 1H), 1.72 (s, 1H). C NMR (100
Crude product 5 (400 mg, 1.1 mmol) and 4 (260 mg, 0.79 mmol)
were dissolved in THF (7.0 mL) at −78 °C. In another roud-
bottomed flask, sodium bis(trimethylsilyl) amide (2.0 M, in THF, 0.55
mL, 1.11 mmol) was dissolved in THF (7.0 mL) at −78 °C. Then, the
two parts of the solution were added simultaneously to a third round-
bottomed flask (25 mL) using two double-ended needles. After stirring
for 5 min, the reaction mixture was quenched with water and extracted
with EtOAc. The organic layer was washed with water and brine and
dried over Na SO . The solvent was removed under reduced pressure.
MHz, CDCl ) δ 191.6, 190.4, 169.1, 148.5, 135.1, 128.7, 126.5, 125.6,
3
+
1
23.9, 122.1, 115.1, 109.5, 85.6, 61.4, 27.9. HRMS (ESI ) m/z: [M +
K] calcd for C H KNO , 366.0738; found, 366.0755.
+
18
17
5
tert-Butyl-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxy-
late (9). To a solution of 3-indoleacetic acid 10 (5.1 g, 29.1 mmol) in
dry MeOH (200 mL) precooled to 0 °C was added SOCl (11.0 mL,
2
1
45.0 mmol) slowly. After being stirred for 4 h at room temperature,
the reaction mixture was poured into an NaHCO (200 mL) saturated
3
2
4
aqueous solution precooled at 0 °C. The mixture was stirred for 10
min and extracted with EtOAc. The organic layer was washed with
saturated NaHCO3 aqueous solution and brine and dried over
Na SO . The solvent was removed under reduced pressure to give
The product was purified by silica gel chromatography (PE/Et O, 7:1)
2
to give 2 (194.72 mg, 40%) in two steps as yellow oil. IR (neat) ν
max
−1
1
2
979, 1737, 1616, 1454, 1373, 1257, 1155, 1083, 746 cm . H NMR
2
4
(
400 MHz, CDCl ) δ 8.35 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.16 (d, J
crude methyl ester (5.28 g) as yellow oil. To the solution of crude
3
=
(
1
4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.65
s, 1H), 7.40−7.24 (m, 5H), 4.44 (s, 1H), 3.82 (s, 1H), 1.69 (s, 1H),
.64 (s, 1H). 13C NMR (100 MHz, CDCl ) δ 191.1, 190.7, 166.3,
methyl ester (5.28 g, 27.90 mmol) in DCM (50 mL) were added Et N
3
(
0.35 mL, 0.1 mmol), DMAP (0.67 g, 5.5 mmol), and di-tert-butyl
dicarbonate (9.8 mL, 42.0 mmol) under an argon atmosphere at room
temperature. After stirring for 5 h, the reaction mixture was quenched
3
162.8, 149.2, 149.1, 135.3, 130.6, 129.7, 128.5, 128.0, 125.5, 125.0,
124.8, 123.2, 122.9, 122.5, 121.4, 115.2, 112.5, 108.5, 84.8, 84.2, 63.8,
with a NH Cl saturated aqueous solution and extracted with DCM.
4
+
+
The organic layer was washed with water and brine and dried over
Na SO . The solvent was removed under reduced pressure. The
60.6, 53.7, 28.1. HRMS (ESI ) m/z: [M + Na] calcd for
C H N NaO , 637.2157; found, 637.2153.
2
4
34 34
2
9
2
113
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The Journal of Organic Chemistry
Article
2
4
Asterredione (1). To a solution of 2 (110 mg, 0.18 mmol) in 10
(9) Negri, J.; Morwick, T.; Doyon, J.; Wilson, P. D.; Hickey, E. R.;
Paquette, L. A. J. Am. Chem. Soc. 1993, 115, 12189−12190.
(10) Dong, S.; Parker, G. D.; Tei, T.; Paquette, L. A. Org. Lett. 2006,
8, 2429−2431.
(11) Crane, S. N.; Burnell, D. J. J. Org. Chem. 1998, 63, 5708−5710.
(12) Gao, F.; Burnell, D. J. J. Org. Chem. 2006, 71, 356−359.
(13) Xiao, F.; Liu, W.; Wang, Y.; Zhang, Q.; Li, X.; Hu, X. Asian J.
Org. Chem. 2013, 2, 216−219.
(14) For a previous report on the preparation of 6, see: James, C. A.;
Coelho, A. L.; Gevaert, M.; Forgione, P.; Snieckus, V. J. Org. Chem.
2009, 74, 4094−4103.
(15) For a previous report on the preparation of 9, see: Ghosh, N.;
Nayak, S.; Sahoo, A. K. J. Org. Chem. 2011, 76, 500−511.
(16) For a previous report on the preparation and decomposition of
mL of dry CH Cl was added TBSOTf (0.1 mL, 0.45 mmol) slowly.
2
2
After stirring for 2 h, the mixture was quenched with a NaHCO3
saturated aqueous solution and extracted with DCM. The organic layer
was washed with water and brine and dried over Na SO . The solvent
was removed under reduced pressure. The product was purified by
silica gel chromatography (PE/Et O, 1:2) to give asterredione (1)
2
4
2
(
60.4 mg, 81%) as yellow solid. The yellow rhombus crystal of 1 was
obtained from the crystallization of the solution of 1 in a mixture of
methanol, dichloromethane, and hexane (1:3:8). 1: mp 113−115 °C.
: IR (neat) ν 3388, 1744, 1678, 1599, 1454, 1425, 1370, 1318,
1
1
1
7
1
max
−
1 1
259, 1131, 1103, 744 cm . H NMR (400 MHz, CDCl ) δ 8.69 (s,
3
H), 8.25 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H),
.81 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz,
H), 7.30 (d, J = 2.4 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 8.4
Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 12.0 Hz, 1H), 4.47 (s,
H), 3.81 (s, 1H). H NMR (400 MHz, DMSO-d ) δ 12.07 (s, 1H),
1.30 (s, 1H), 8.23 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0
Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.29 (s,
H), 7.21 (t, J = 14.4 Hz, 1H), 7.15−7.08 (m, 2H), 7.00 (t, J = 14.4
Hz, 1H), 4.39 (s, 1H), 3.74 (s, 1H). C NMR (100 MHz, DMSO-d )
δ 192.8, 190.6, 167.1, 159.9, 136.4, 132.5, 131.1, 125.7, 125.2, 125.0,
22.5, 122.4, 121.5, 120.5, 119.2, 112.2, 111.8, 106.8, 103.7, 64.2, 60.2,
5.0, 53.3. HRMS (ESI ) m/z: [M + Na] calcd for C H N NaO ,
37.1108; found, 437.1125.
5, see: Suarez-Castillo, O. R.; Melendez-Rodrıg
́
́
́
uez, M.; Cano-
Escudero, I. C.; De Ita-Gutierrez, S. L.; Sanchez-Zavala, M.;
́
́
1
1
1
́
6
Morales-Rıos, M. S.; Joseph-Nathan, P. Heterocycles 2010, 81, 1169−
182.
17) Packard, E.; Pascoe, D. D.; Maddaluno, J.; Gonca
Harrowven, D. C. Angew. Chem., Int. Ed. 2013, 52, 13076−13079.
(18) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003,
1
(
̧ lves, T. P.;
1
13
6
1
(
25, 13155−13164.
19) Verma, S. K.; Fleischer, E. B.; Moore, H. W. J. Org. Chem. 2000,
65, 8564−8573.
20) For reviews on semipinacol rearrangement of epoxides, please
1
5
4
+
+
24
18
2
5
(
see refs 20−23 in: Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59,
ASSOCIATED CONTENT
737−799.
■
(21) Milstein, D.; Buchman, O.; Blum, J. Tetrahedron Lett. 1974, 15,
*
S
Supporting Information
2
(
257−2260.
1
H and 13C NMR spectra of related compounds and X-ray
22) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39,
crystallographic data for asterredione (1). This material is
available free of charge via the Internet at http://pubs.acs.org.
2
7
323−2367.
(23) Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523−
556.
(
24) We failed to collect the 13C NMR spectra of synthesized 1
AUTHOR INFORMATION
■
*
because of its very poor solubility and instability in deuterated
chloroform. NMR spectral data of 1 were obtained in good quality
using deuterated dimethyl sulfoxide as the solvent. Please see the
Supporting Information for details.
Corresponding Author
xiangdonghu@nwu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (NSF nos. 21002078 and
21372184), the State Education Ministry Scientific Research
Foundation for the Returned Overseas Chinese Scholars, and
the Shaanxi Province Technology Foundation for Selected
Overseas Chinese. Qing Zhang was supported by a project for
National Basic Science Personnel Training Funding (nos.
J1103311 and J1210057).
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114
dx.doi.org/10.1021/jo4028177 | J. Org. Chem. 2014, 79, 2111−2114