Facile and efficient total synthesis of taspine

Article abstract of DOI:10.1055/s-0029-1217393

The facile and efficient total synthesis of taspine was achieved in 10 steps in high yield (16.5% overall) from commercially available isovanillin. Key steps in the synthesis are preparation of a symmetrical homodimer employing a classical Ullmann coupling reaction, and introduction of an allyl substituent by the Claisen rearrangement reaction. Significantly, the facile synthetic scheme proposed in this work has the characteristics of mild reaction conditions, inexpensive reagents, higher yield, and simple operation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217393

PAPER
2501
Facile and Efficient Total Synthesis of Taspine
aspine Cheng,a Sanqi Zhang,a Liyong Zhu,b Jie Zhang,a Qiang Li,a Ailin Shan,a Langchong He*a
A
N
ew Total Syn
i
thesis
of
T
a
Research & Engineering Center for Natural Medicine, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, P. R. of China
Fax +86(29)82655451; E-mail: helc@mail.xjtu.edu.cn
b
College of Chemistry & Materials Science, Shannxi Normal University, Xi’an 710062, P. R. of China
Received 27 February 2009; revised 16 April 2009
MeO
NMe2
MeO
Abstract: The facile and efficient total synthesis of taspine was
achieved in 10 steps in high yield (16.5% overall) from commercial-
ly available isovanillin. Key steps in the synthesis are preparation of
a symmetrical homodimer employing a classical Ullmann coupling
reaction, and introduction of an allyl substituent by the Claisen re-
arrangement reaction. Significantly, the facile synthetic scheme
proposed in this work has the characteristics of mild reaction condi-
tions, inexpensive reagents, higher yield, and simple operation.
CHO
O
O
O
O
O
O
O
O
OMe
OMe
1
2
MeO
Key words: taspine, natural product, total synthesis, Ullmann cou-
pling, Claisen rearrangement
MeO
O
O
COR1
OH
O
R1OC
O
O
Taspine is an alkaloid isolated from Radix et Rhizoma
Leonticis.1 In recent years, studies on taspine have attract-
ed increasing attention due to its various pharmaceutical
properties. These include bacteriostasis,2 wound healing,3
cytotoxicity,4 immunosuppression,5 acetylcholinesterase
inhibition,6 and inhibition of the activity of tumor angio-
genesis.7
OMe
OMe
3
4
MeO
HO
COR1
R1OC
OH
Taspine (1) has a unique molecular structure, namely, a
biphenyl bislactonic skeleton with one phenyl ring pos-
sessing a 2-(dimethylamino)ethyl side chain (Figure 1).
This makes taspine synthesis very difficult. Kelly and Xie
reported the first total synthesis of taspine in 1998,8 but
the synthetic scheme had complicated reaction conditions,
expensive reagents, and lower overall yield (9.6%). We
report the facile and efficient total synthesis of taspine un-
der mild reaction conditions using inexpensive reagents to
produce higher overall yield (16.5%).
Br
OMe
5
COR1
Br
R1 = OMe, OEt, NHEt, NHPr, etc.
R2 = Bn, MEM, Ac, etc.
MeO
OR2
Our strategy for the total synthesis of taspine (1) is shown
in Scheme 1. The 2-(dimethylamino)ethyl side chain of
taspine (1) was prepared from an allyl side-chain precur-
sor 3, which was introduced by a Claisen rearrangement
of 4. The biphenyl skeleton 5 was generated from a mono-
cyclic precursor 6 by symmetrical Ullmann coupling.
6
Scheme 1
We used commercially available isovanillin (7) as the
starting material (Scheme 2). The key intermediate 11 was
constructed as follows. Isovanillin (7) was converted into
2-bromoisovanillin (8) by reaction with bromine in 79%
yield.9 After protection of 8 as benzyl ether,10 the alde-
hyde group in 9 was oxidized to the carboxyl group to give
10.11 Esterification of 10 afforded the monocyclic precur-
sor 1112 for the Ullmann reaction. Compared with the
method reported by Kelly, our method of preparation for
the monocyclic precursor for coupling 11 used the cheap-
er agent benzyl chloride to protect the hydroxy group and
bromine as the leaving group.
MeO
NMe2
O
O
O
O
OMe
Figure 1 Structure of taspine (1)
Biphenyl dimethyl ester 12 was prepared by dimerization
of 11 employing a classical symmetrical Ullmann reaction
in high yield (85%).13 Compound 13 could be readily ob-
SYNTHESIS 2009, No. 15, pp 2501–2504
x
x.
x
x
.
2
0
0
9
Advanced online publication: 08.06.2009
DOI: 10.1055/s-0029-1217393; Art ID: F04709SS
© Georg Thieme Verlag Stuttgart · New York

2502
B. Cheng et al.
PAPER
CHO
CHO
Br
CHO
Br
Fe, NaOAc
AcOH, Br2
BnCl
K2CO3
NaH2PO4
NaClO2, 30% H2O2
MeO
MeO
MeO
79%
quant
quant
OH
OH
OBn
7
8
9
MeO
CO2Me
COOH
Cu
DMF
MeCOCl
MeOH
BnO
CO2Me
Pd/C, H2
quant
MeO
Br
MeO
Br
MeO2C
OBn
89%
85%
OBn
OBn
11
OMe
10
12
MeO
MeO
MeO
HO
CO2Me
OH
allyl bromine
K2CO3, DMF
O
O
O
O
OsO4, NaIO4
68%
210–220 °C
94%
MeO2C
MeO2C
O
O
56%
O
OMe
OMe
13
OMe
14
3
MeO
CHO
O
MeO
NMe2
NHMe2/THF
NaBH(OAc)3
O
O
O
O
77%
O
O
O
OMe
OMe
2
1
Scheme 2
tained by deprotection of benzyl ethers of 12 under catal- In summary we have reported here a facile and efficient
ysis with palladium-on-carbon.14 Compound 13 had poor total synthesis of taspine (1) from commercially available
solubility, but had some solubility in DMF.
isovanillin (7) in ten steps in high yield (16.5% overall
yield). The key intermediate, methyl 3-benzyloxy-2-bro-
mo-4-methoxybenzoate (11), was obtained through bro-
mination, benzyl protection, oxidation, and esterification,
respectively. The biphenyl dimethyl ester 12 was then
prepared by a symmetrical Ullmann coupling. One of the
hydroxy groups was allylated after debenzylation with
palladium-on-carbon. Taspine (1) was then obtained by
Claisen rearrangement, allyl oxidation, and reductive am-
ination. The method has the advantages of mild reaction
conditions, easy manipulation, low cost, and higher yield
than the synthesis described by Kelly.
Our scheme highlights the utility of the Claisen rearrange-
ment to introduce an allyl side chain. The method involves
skillful design and uses inexpensive reagents than the
method reported by Kelly. One of the hydroxy groups in
13 was etherified with allyl bromide in anhydrous DMF in
the presence of potassium carbonate,15 and the other hy-
droxy group in 13 was transesterified simultaneously in
one-pot.16 The yield of 14 was improved by controlling
the molar ratio of reagents (13/allyl bromide/potassium
carbonate = 1:1.2:1.5) and the reaction temperature
(60 °C). Compound 3 was obtained by the Claisen rear-
rangement of 14.17 The other intramolecular transesterifi-
cation reaction was processed in one-pot at high
temperature as we expected. The starting material of the
Claisen rearrangement did not transform completely, and
there were many by-products if the reaction temperature
was <200 °C. A solvent-free Claisen rearrangement at
210–220 °C was achieved using an oil bath in 94% yield.
Compound 3 was oxidized by osmium tetroxide and sodi-
Solvents were purified before use by previously reported methods.
Petroleum ether (PE) used refers to the fraction boiling in the range
60–90 °C. All reactions except those in aqueous media were carried
out by standard techniques for moisture exclusion. Anhydrous reac-
tions were carried out over dried glassware under N2. Reactions
were monitored by TLC on 0.25 mm silica gel plates (60GF254) and
visualized with ultraviolet light. Melting points were obtained on
electrothermal melting point apparatus and are uncorrected. IR
um metaperiodate to generate aldehyde 2 in 68% yield.18 spectra were recorded on a Shimadzu FTIR-8100 spectrophotome-
1
ter. H NMR and 13C NMR spectra were measured with a Bruker
Reductive amination of 2 with dimethylamine and sodium
triacetoxyborohydride gave taspine (1) in 77% yield.8
Synthetic 1 was identical to taspine isolated from plant in
all aspects: TLC, 1H NMR, 13C NMR, MS, IR, and melt-
ing point.
Avance 300 MHz or Varian Inova 400 MHz spectrometer. Quoted
chemical shifts (d) are relative to TMS. Coupling constants are giv-
en in hertz. Mass spectra were obtained on a Shimadzu GC-MS-
QP2010 instrument. Elemental analyses were done on an Elementar
Vario EL III instrument.
Synthesis 2009, No. 15, 2501–2504 © Thieme Stuttgart · New York

PAPER
A New Total Synthesis of Taspine
2503
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (8)
1H NMR (300 MHz, CDCl3): d = 7.64 (d, J = 8.6 Hz, 1 H, ArH),
7.57–7.36 (m, 5 H, ArH), 6.89 (d, J = 8.5 Hz, 1 H, ArH), 5.01 (s, 2
H), 3.91 (s, 6 H).
To a mixture of 7 (25.0 g, 0.164 mol), NaOAc (26.94 g, 0.325 mol),
and Fe powder (0.75 g, 0.015 mol) was added glacial AcOH (150
mL). The mixture was stirred at r.t. for 30 min. Br2 (9 mL, 0.18 mol)
in glacial AcOH (40 mL) was added dropwise into the above mix-
ture at 23–25 °C. The mixture was stirred at the same temperature
for 3 h. Ice water (325 mL) was added to the mixture and stirred for
another 1 h and filtered. The solid obtained was dried and recrystal-
lized from EtOH to give 8 (30.0 g, 79%) as a gray solid; mp 206–
207 °C.
MS (EI, 70 eV): m/z (%) = 91.0 (100), 351.0 (20, [M + H]+).
Dimethyl 6,6¢-Dibenzyloxy-5,5¢-dimethoxybiphenyl-2,2¢-dicar-
boxylate (12)
To a solution of 11 (22.32 g, 0.064 mol) in anhyd DMF (150 mL)
was added freshly activated Cu (40.81 g, 0.64 mol) under N2, and
the mixture refluxed for 4 h at 150–160 °C. The mixture was filtered
and DMF evaporated under vacuum. The residue was extracted
with CHCl3 (2 × 150 mL), and the combined organic layers were
washed with aq 2 M HCl (3 × 60 mL) and brine (2 × 60 mL), dried
(Na2SO4), and concentrated. The residue was chromatographed on
silica gel (PE–EtOAc, 5:1) to give 12 (14.6 g, 85%) as a white solid;
mp 124.5–125 °C.
IR (KBr): 3235, 2890, 1669, 1593 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.26 (s, 1 H), 7.58 (d, J = 8.5 Hz,
1 H, ArH), 6.93 (d, J = 8.5 Hz, 1 H, ArH), 6.07 (s, 1 H), 4.01 (s, 3
H).
MS (EI, 70 eV): m/z = 230.9 (100%, [M + H]+).
IR (KBr): 3023, 2947, 2841, 1711, 1592 cm–1.
3-Benzyloxy-2-bromo-4-methoxybenzaldehyde (9)
To a suspension of 8 (15.0 g, 0.065 mol) in dehydrated alcohol
(150 mL) were added anhyd K2CO3 (27 g, 0.196 mol) and benzyl
chloride (11.3 mL, 0.098 mol). The mixture was refluxed for 4 h.
Filtration and evaporation of alcohol was done in a vacuum. The
residue was extracted with EtOAc (2 × 100 mL). The combined or-
ganic layers were washed with H2O (3 × 50 mL), aq 1 M NaOH
(3 × 50 mL), aq 2 M HCl (3 × 50 mL), and brine (2 × 50 mL), dried
(Na2SO4), and concentrated to give 9 (23.05 g, quant) as a yellow
solid; mp 79–81 °C.
1H NMR (300 MHz, CDCl3): d = 7.88 (d, J = 8.6 Hz, 2 H, ArH),
7.16–6.93 (m, 12 H, ArH), 4.85 (d, J = 11.1 Hz, 2 H), 4.71 (d, J =
11.1 Hz, 2 H), 3.92 (s, 6 H), 3.58 (s, 6 H).
MS (EI, 70 eV): m/z (%) = 91 (100), 542.1 (10, [M]+).
Dimethyl 6,6¢-Dihydroxy-5,5¢-dimethoxybiphenyl-2,2¢-dicar-
boxylate (13)
To a solution of 12 (10.53 g) in THF (200 mL) was added 10% Pd/
C (3.16 g) under H2 atmosphere. The mixture was stirred at r.t. until
no starting material could be observed by TLC. Pd/C was filtered
and washed with EtOH (100 mL), CH2Cl2 (100 mL), EtOAc (100
mL), and DMF (100 mL). The combined filtrates were evaporated
under vacuum to give 13 (7.13 g, quant) as a gray solid; mp 165–
202 °C (dec.).
IR (KBr): 2940, 2839, 1713, 1593 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.27 (s, 1 H), 7.76 (d, J = 8.4 Hz,
1 H, ArH), 7.54–7.35 (m, 5 H, ArH), 6.98 (d, J = 9.2 Hz, 1 H, ArH),
5.03 (s, 2 H), 3.96 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 91.1 (100), 320.9 (15, [M + H]+).
IR (KBr): 3374, 2944, 1710, 1607 cm–1.
3-Benzyloxy-2-bromo-4-methoxybenzoic Acid (10)
1H NMR (300 MHz, DMSO-d6): d = 7.43 (d, J = 8.5 Hz, 2 H, ArH),
6.96 (d, J = 8.6 Hz, 2 H, ArH), 3.87 (s, 6 H), 3.46 (s, 6 H).
To a solution of 9 (20.87 g, 0.065 mol) in THF (200 mL) was added
distilled H2O (60 mL) and NaH2PO4 (4.68 g, 0.039 mol). The mix-
ture was stirred at r.t. for 10 min. NaClO2 (19.40 g, 0.215 mol) and
30% H2O2 (14.8 mL, 0.143 mol) in distilled H2O (60 mL) were add-
ed into the above mixture. The mixture was stirred at the same tem-
perature for 3 h. THF was evaporated under vacuum and the residue
was extracted with EtOAc (2 × 150 mL). The combined organic
layers were washed with H2O (3 × 50 mL) and the product was ex-
tracted with aq 2 M NaOH (5 × 50 mL). The aqueous phase was
acidified with concd HCl and the solid obtained was collected by
filtration and dried to give 10 (21.94 g, quant) as a white solid; mp
159–161 °C.
13C NMR (100 MHz, DMSO-d6): d = 165.705, 149.772, 142.765,
126.199, 121.960, 120.871, 108.386, 55.238, 55.165, 50.634,
50.561.
MS (EI, 70 eV): m/z (%) = 298 (100), 362.1 (16, [M]+).
Anal. Calcd for C18H18O8: C, 59.67; H, 5.01. Found: C, 59.53; H,
4.99.
Methyl 10-(Allyloxy)-4,9-dimethoxy-6-oxo-6H-ben-
zo[c]chromene-1-carboxylate (14)
To a solution of 13 (1g, 2.8 mmol) in DMF (30 mL) was added an-
hyd K2CO3 (0.58 g, 4.2 mol) and allyl bromide (0.29 mL, 3.3 mol)
under N2. The mixture was stirred at 60 °C in a water bath for 4 h.
The mixture was filtered and DMF was evaporated under vacuum.
The residue was extracted with CHCl3 (2 × 25 mL), and the com-
bined organic layers were washed with H2O (3 × 15 mL), aq 2 M
HCl (3 × 15 mL), and brine (2 × 15 mL), dried (Na2SO4), and con-
centrated. The residue was chromatographed on silica gel (PE–
EtOAc, 5:1) to give 14 (0.57 g, 56%) as a white solid; mp 161–
162 °C.
IR (KBr): 2940, 2639, 1695 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.87 (d, J = 9.1 Hz, 1 H, ArH),
7.56–7.37 (m, 5 H, ArH), 6.93 (d, J = 9.2 Hz, 1 H, ArH), 5.03 (s, 2
H), 3.94 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 91.1 (100), 336.9 (9, [M + H]+).
Methyl 3-Benzyloxy-2-bromo-4-methoxybenzoate (11)
AcCl (10.5 mL, 0.147 mol) was added to MeOH (300 mL) at 0 °C.
The mixture was stirred at r.t. for 30 min. Compound 10 (24.75 g,
0.074 mol) was added to the above mixture and refluxed for 4 h.
MeOH was evaporated under vacuum and the residue was extracted
with CHCl3 (2 × 150 mL). The combined organic extracts were
washed with H2O (3 × 60 mL), aq sat. NaHCO3 (3 × 60 mL), and
brine (2 × 60 mL), dried (Na2SO4), and concentrated. The residue
was chromatographed on silica gel (PE–EtOAc, 5:1) to give 11
(22.97 g, 89%) as an oil.
IR (KBr): 2946, 2844, 1729, 1597 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.19 (d, J = 8.7 Hz, 1 H, ArH),
7.63 (d, J = 8.5 Hz, 1 H, ArH), 7.20 (m, 1 H, ArH), 7.03 (d, J = 8.6
Hz, 1 H, ArH), 5.81 (m, 1 H), 5.03 (m, 2 H), 4.23 (d, J = 6.2 Hz, 2
H), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.75 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.489, 160.106, 157.793,
149.674, 143.968, 141.095, 132.994, 128.855, 127.339, 125.955,
124.461, 118.992, 115.869, 115.573, 113.446, 110.464, 75.001,
56.241, 51.979.
Synthesis 2009, No. 15, 2501–2504 © Thieme Stuttgart · New York

2504
B. Cheng et al.
PAPER
MS (EI, 70 eV): m/z (%) = 313.0 (100), 370.1 (24, [M]+).
Acknowledgment
Anal. Calcd for C20H18O7: C, 64.86; H, 4.90. Found: C, 64.86; H,
4.79.
This work was supported by the National Natural Science Founda-
tion of China (grant number 30730110).
3,8-Dimethoxy-1-(prop-2-enyl)[1]benzopyrano[5,4,3-
cde][1]benzopyran-5,10-dione (3)
References
Compound 14 (0.57g) was stirred at 210–220 °C for 50 min under
N2. The residue was purified by column chromatography (CHCl3)
to give 3 (0.49 g, 94%) as a white solid; mp 275–290 °C (dec.).
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Chem. Abstr. 2008, 149, 87126.
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IR (KBr): 1748, 1603 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 8.7 Hz, 1 H, ArH),
7.31 (d, J = 8.8 Hz, 1 H, ArH), 7.14 (s, 1 H, ArH), 6.06 (m, 1 H),
5.13 (m, 2 H), 4.12 (m, 2 H, partially hidden underneath aromatic
MeO peaks), 4.11 (s, 3 H), 4.10 (s, 3 H).
(3) (a) Dong, Y.; He, L.; Chen, F. Zhongguo Yao Xue Za Zhi
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MS (EI, 70 eV): m/z (%) = 323 (100), 338.1 (40, [M]+).
3,8-Dimethoxy-1-(2-oxoethyl)[1]benzopyrano[5,4,3-cde][1]ben-
zopyran-5,10-dione (2)
To a suspension of 3 (240 mg, 0.7 mmol) in a mixture of CH2Cl2,
H2O, and t-BuOH (100 mL, 3:1:1) was added OsO4 (9 mg, 0.035
mmol). The mixture was stirred at r.t. for 30 min in dark. NaIO4
(600 mg, 2.8 mmol) was added to the above mixture and stirred at
r.t. away from light for another 20 h. The residue was extracted with
CH2Cl2 (2 × 100 mL), and the combined organic layers were
washed with H2O (3 × 40 mL), aq 0.5% NaHSO3 (2 × 30 mL) and
brine (2 × 40 mL), dried (Na2SO4), and concentrated. The residue
was purified by column chromatography (CHCl3–MeOH, 50:1) to
give 2 (164 mg, 68%) as a white solid; mp the white solid turned
yellow at 220 °C and decomposed at 278 °C.
IR (KBr): 2917, 1738, 1601 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.69 (s, 1 H), 8.05 (d, J = 8.8
Hz, 1 H, ArH), 7.56 (d, J = 9.2 Hz, 1 H, ArH), 7.32 (s, 1 H), 4.27 (s,
2 H), 4.04 (s, 3 H), 4.03 (s, 3H).
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(9) Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 14785.
MS (ESI): m/z = 340.9 (100%, [M + H]+).
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H.; Renard, P.; Pierre, A.; Enriz, R. D.; Cortes, D.; Cabedo,
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69, 4116.
1-[2-(Dimethylamino)ethyl]-3,8-dimethoxy[1]benzopyra-
no[5,4,3-cde][1]benzopyran-5,10-dione (1, Taspine)
To a suspension of 2 (60 mg, 0.18 mmol) in CH2Cl2 (60 mL) was
added Me2NH (0.18 mL, 0.21 mmol) in THF under N2 and stirred
at r.t. for 20 min. NaBH(OAc)3 (47 mg, 0.21 mmol) was added in
three batches to the mixture, and the mixture stirred at r.t. for 4 h.
The solvent was evaporated under vacuum, and the residue separat-
ed by column chromatography (CHCl3–MeOH, 10:1) to give 1
(50.2 mg, 77%) as a white solid; mp 365 °C (dec).
IR (KBr): 2950, 1742, 1601 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.19 (d, J = 8.8 Hz, 1 H, ArH),
7.30 (d, J = 8.8 Hz, 1 H, ArH), 7.19 (s, 1 H, ArH), 4.11 (s, 6 H), 3.51
(t, J = 8.0 Hz, 2 H), 2.68 (t, J = 7.6 Hz, 2 H), 2.41 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 158.585, 157.560, 151.108,
150.812, 144.287, 137.675, 136.569, 126.843, 118.924, 118.209,
116.465, 113.569, 111.338, 109.002, 60.152, 56.541, 56.446,
45.180, 32.927.
MS (ESI): m/z = 370.1 (100%, [M + H]+).
Anal. Calcd for C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C,
64.94; H, 5.21; N, 3.80.
Synthesis 2009, No. 15, 2501–2504 © Thieme Stuttgart · New York