Biomimetic semisynthesis of arglabin from parthenolide

Article abstract of DOI:10.1021/jo300888s

The semisynthesis of arglabin, an anticancer drug in clinical application, is developed from abundant natural product parthenolide via three steps. Each step in this sequence is highly stereoselective, and the substrate-dependent stereoselectivity in the epoxidation step can be explained by computational calculations. The success of chemical semisynthesis of arglabin suggests that the biosynthesis of arglabin might proceed in a similar pathway.

Full text of DOI:10.1021/jo300888s

Note
pubs.acs.org/joc
Biomimetic Semisynthesis of Arglabin from Parthenolide
Jia-Dai Zhai,† Dongmei Li,† Jing Long,† Hao-Liang Zhang,† Jian-Ping Lin,† Chuan-Jiang Qiu,‡
Quan Zhang,*,† and Yue Chen*,†
†State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
‡Accendatech Co., Ltd., Tianjin 300384, P. R. China
S
* Supporting Information
ABSTRACT: The semisynthesis of arglabin, an anticancer drug in clinical
application, is developed from abundant natural product parthenolide via three
steps. Each step in this sequence is highly stereoselective, and the substrate-
dependent stereoselectivity in the epoxidation step can be explained by
computational calculations. The success of chemical semisynthesis of arglabin
suggests that the biosynthesis of arglabin might proceed in a similar pathway.
atural products are the most consistently successful
sources in drug discovery.1−3 However, natural product
evidence to identify the biosynthetic pathway of arglabin from
parthenolide.
N
drugs are often produced in trace quantities, and sometimes
another natural product can serve as a starting material for the
semisynthesis of the target drug. For example, the development
of paclitaxel (Taxol) was severely hampered by the scarcity of
its original source, the bark of Taxus brevifolia. The compound
supply issue was solved by semisynthesis from 10-deacetylbac-
catin III, which is readily available from the needles of various
Taxus species, a renewable resource.4−6
Scheme 1. Proposed Biosynthesis of Germacranolide Type
SL to Guaianolides Type SL in the Literature
Sesquiterpene lactones (SLs) are a large family of plant-
derived compounds; they have been shown to have
considerable biological activities against inflammation and
cancer.7 Guaianolides, which consist of a tricyclic 5,7,5-ring
system, represent a subgroup of SLs.8 Arglabin (1, Figure 1), a
However, parthenolide is also low-yielding from its tradi-
tional natural source feverfew (Tanacetum parthenium); only
0.14−0.74% of parthenolide can be observed in dried feverfew
leaves.16 Fortunately, we found that parthenolide can be readily
extracted in high yield (3.1−8.0%) from the root bark of
Magnolia delavayi.17 Magnolia delavayi is very abundant in
several provinces in China, since its bark and flower are
important traditional Chinese herbs. Moreover, removal of a
small percentage of root bark every year has negligible effect on
the population of Magnolia delavayi plants, because the root of
Magnolia delavayi can be regenerated. Parthenolide also has
multiple biological activities,18,19 such as against cancer stem
cells,20−22 and its water-soluble analogue DMAPT is currently
Figure 1. Stuctures of arglabin and arglabin-DMA.
prominent member of guaianolides, shows promising cytotox-
icity against different tumor cell lines.9 Arglabin has been
modified to water-soluble form Arglabin-DMA, and Arglabin-
DMA is a registered antitumor substance in the Republic of
Kazakstan for the treatment of breast, colon, ovarian, and lung
cancers.10 Arglabin can be isolated from Artemisia glabella11 but
comprises only 0.27% of the aerial parts of the plant, and its
purification procedures is very tedious.12
Up to date, the only synthesis of arglabin is reported by
Reiser.13 Moreover, although it has been proposed that
parthenolide is the starting material in the biosynthesis of the
guaianolide type of SLs micheliolide or kauniolide through a
transition state A (Scheme 1),14,15 there is still no direct
Received: May 21, 2012
Published: July 31, 2012
© 2012 American Chemical Society
7103
dx.doi.org/10.1021/jo300888s | J. Org. Chem. 2012, 77, 7103−7107

The Journal of Organic Chemistry
Note
Scheme 2. Retrosynthetic Analysis of Arglabin
in clinical trial.23,24 With a bulk amount of parthenolide, we
pursued the synthesis of arglabin from parthenolide.
Scheme 3. Synthetic Route 1 for Synthesis of Arglabin from
Micheliolide
Parthenolide possesses a trans-6α,12-lactone moiety and so
constitutes a good starting material for the syntheses of
guaianolides.25 Retrosynthetic analysis of arglabin indicates that
there are two possible routes to synthesize arglabin from
parthenolide (Scheme 2): route 1, epoxidation of te 1(10)
double bond of compound 3 to yield compound 4 and then
dehydration to afford arglabin, and route 2, dehydration of
compound 3 to give compound 5, followed by epoxidation to
provide arglabin.
A biogenetic hypothesis proposes that germacrolides and
their epoxide derivatives represent the precursors for other
skeletal types of sesquiterpene lactones.26 For instance, Lewis
acid catalyzes reactions of parthenolide (2) into guaianolides at
room temperature (RT), but these reactions produce complex
mixtures and poor yields of each product (Table 1, entries 1
as a directing substituent, which is known not only for the
epoxidation of allylic but also for homoallylic alcohols.30−33
Surprisingly, epoxidation of compound 3 with m-chloroper-
benzoic acid (m-CPBA) afforded a clean desired β-epoxide 4 as
a single stereoisomer in 75% yield, which was confirmed by X-
ray analysis (Scheme 3).
Table 1. Conversion of Compound 2 to Compound 3
With the key intermediate 4 in hand, the next aim is to
achieve selective dehydration to provide the 3(4) double bond
of arglabin. We initially tried the dehydration of compound 4
using base-promoted elimination of the corresponding
sulfonate (Table 2, entry 1), acetate (Table 2, entries 2 and
3), or trifluoroacetate (Table 2, entries 4 and 5). Unfortunately,
all of these conditions failed to provide a significant amount of
elimination product. The elimination employing Tf2O and
pyridine gave arglabin in a moderate yield of 29% (Table 2,
entry 6), which is lower than that of Pedro’s reaction34 and
Reiser’s reaction13 in the syntheses of similar compounds.
Treated compound 4 with commonly used dehydrating
reagents such as Burgess reagent,35 Lawensson’s reagent,36
and DIAD/PPh3 afforded no product (Table 2, entries 7−9),
whereas with DEAD/PPh3 (Table 2, entry 10),37 13% of
arglabin can be isolated, and with SOCl2, and POCl3 in pyridine
at room temperature, arglabin were prepared in 27% and 28%
yield, respectively (Table 2, entries 11 and 12). At a lower
temperature of 0 °C, POCl3 treatment of compound 4
provided arglabin with improved yield of 51% (Table 2, entry
13). An important advance was obtained when Martin’s
sulfurane38 was used as dehydrating reagent; treatment of
compound 4 with Martin’s sulfurane in CH2Cl2 at RT afforded
1 in a yield of 67% (Table 2, entry 14). This product was
a
entry
conditions
yield (%)
1
2
3
BF3·OEt2, toluene, RT
p-TSA, MeOH, RT
p-TSA, CH2Cl2, RT
1325
2626
90
a
Yield of isolated compound 3.
and 2).25−29 However, in our modified procedure, parthenolide
(2) was submitted to treatment with p-toluenesulfonic acid (p-
TSA) in dichloromethane, and then natural micheliolide 3 was
isolated by crystallization in 90% yield (Table 1, entry 3). This
reaction can be preceded in kilogram scale without the need of
chromatographic purification. Compound 3 was identified by
comparing its 1H and 13C NMR data with those reported in the
literature.29
Using micheliolide 3, the next step is epoxidation of the
1(10) double bond of compound 3 to yield compound 4. The
structure of compound 3 revealed that both faces of the seven-
membered ring are exposed to epoxidation (Scheme 3).
However, epoxidation from the β face (top) has to overcome
steric shielding from the upward methyl group at the C-4
position. Furthermore, the hydroxyl group at C-4 might serve
7104
dx.doi.org/10.1021/jo300888s | J. Org. Chem. 2012, 77, 7103−7107

The Journal of Organic Chemistry
Note
Table 2. Dehydrative Elimination of Compound 4 for
Synthesis of Arglabin
a
entry
conditions
yield (%)
1
TsCl, DMAP, pyridine, CH2Cl2, RT
Ac2O, pyridine, CH2Cl2, RT
Ac2O, pyridine, RT
0
0
2
3
0
4
TFAA, Et3N, CH2Cl2, RT
TFAA, pyridine, CH2Cl2, RT
Tf2O, pyridine, CH2Cl2, RT
Burgess reagent, CH3CN, 80 °C
Lawensson’s reagent, toluene, 110 °C
DIAD, PPh3, pyridine, THF, RT
DEAD, PPh3, pyridine, THF, RT
SOCl2, pyridine, RT
0
5
5
6
29
0
7
Figure 2. Optimized geometries of β-epoxide 4 and possible α-epoxide
isomer.
8
0
9
0
10
11
12
13
14
13
27
28
51
67
POCl3, pyridine, RT
POCl3, pyridine, 0 °C
Martin’s sulfurane, CH2Cl2, RT
a
Yield of isolated purified arglabin.
corresponded in all spectroscopic data with those reported in
the literature.39
For the second route (Scheme 4), compound 3 was treated
with POCl3 in pyridine at −40 °C and afforded compound 5 in
65% yield. Epoxidation of compound 5 with 1.1 equiv of m-
CPBA provided 1β,10β-epoxide (arglabin), 1α,10α-epoxide 6,
and 3β,4β-epoxide 7 in 1.2%, 27.1%, and 37.8% yields,
respectively. For the 1,10-epoxidation of compound 5, a
preference of 22:1 for the α face was observed, which is
consistent with the epoxidation of a similar starting material.40
To explain the reversal of stereoselectivity in the epoxidation
of similar compounds 3 and 5, we resorted to computational
studies. We first optimized the geometries of the epoxide
products (see Figure 2 and 3) and compared the free energies
of the different isomers. To explain the stereoselectivity
kinetically, we also explored the epoxidation reaction paths
and revealed the transition states (TSs). Geometries for all
species were optimized using the B3LYP method with the 6-
31G* basis set. Vibrational frequency calculations were carried
out to ensure that the optimized geometries are indeed
associated with local minima on the potential energy surfaces
and to determine the zero-point vibration energies and thermal
corrections to the Gibbs free energies. Then, the optimized
geometries at the B3LYP/6-31G* level were used to carry out
single-point energy calculations with a larger basis set, 6-311+
+G**. The solvent effects (dichloromethane) were modeled
using the PCM solvation method.
Figure 3. Optimized geometries of arglabin and compound 6.
Table 3. Relative Free Energies (kcal/mol) of Different
Isomers of Epoxide and Relative Free Energies (kcal/mol) of
the TS Species in the Epoxidation of 3 and 5
a
ΔG of β-epoxide and α-epoxide
4 (β-epoxide)
−4.6
4 (α-epoxide)
arglabin (β-epoxide)
6 (α-epoxide)
0.0
0.8
0.0
b
ΔGTS of β-epoxidation and α-epoxidation
β-epoxidation
of 3
α-epoxidation
of 3
β-epoxidation
of 5
α-epoxidation
of 5
−0.9
0.0
1.5
0.0
a
b
ΔG = G − G(α). ΔG = GTS − GTS(α)
α-epoxide isomer. We also notice that the free energy of the
transition state in β-epoxidation of 3 is lower than the α-
epoxidation by 0.9 kcal/mol. Theses results allow us to
conclude that β-attack is kinetically and thermodynamically
favored in the epoxidation of 3, and the stereoselectivity is
consistent with the result in our reaction. The stereoselectivity
is reversed to the α-epoxidation in compound 5, and this can
also be explained by the stability of α-epoxide 6 product and
the lower free energy of the TS for α-epoxidation.
To date, there is no biosynthesis study of arglabin. According
the result above, we propose that the possible biosynthesis of
arglabin might start with parthenolide, the carbocation involved
cyclization of parthenolide results in the formation micheliolide,
In Table 3, we present the calculated relative free energies of
β- and α-epoxide products, as well as the relative free energies
of the TSs of β- and α-epoxidation in compound 3 and 5. It is
seen from Table 3 that the free energy of β-epoxide 4 is lower
than that of α-epoxide isomer by 4.6 kcal/mol. This energy
difference reveals that the β-epoxide 4 is more stable than the
Scheme 4. Synthetic Route 2 for Synthesis of Arglabin from Micheliolide
7105
dx.doi.org/10.1021/jo300888s | J. Org. Chem. 2012, 77, 7103−7107

The Journal of Organic Chemistry
Note
concentrated under reduced pressure to give crude residue. Then
the residue was chromatographed on a silica gel column to afford
arglabin (9.97 g, yield 51%).
the next step is more likely to be epoxidation of the
tetrasubstituted olefin in micheliolide, and then the final step
is dehydration.
In summary, we have developed the semisynthesis of the
guaianolide arglabin from an abundant starting material,
parthenolide. The convenient and efficient semisynthesis of
arglabin was achieved in three steps from parthenolide with an
overall yield of 45%. The high stereoselectivities in these three
steps suggest that biosynthesis of arglabin might proceed in a
similar pathway.
Synthesis of Compound 5. To a stirred solution of POCl3 (0.09
mL, 0.95 mmol) in pyridine (1 mL) was slowly added micheliolide
(100 mg, 0.40 mmol) in CH2Cl2 (1 mL) at −40 °C. The reaction
mixture was stirred for 36 h at −40 °C. The reaction was quenched
with NaHCO3 and extracted with CH2Cl2. The organic layer was
successively washed with NaHCO3 and brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure to give crude
residue. Then the residue was chromatographed on a silica gel column
1
to afford compound 5 (60.6 mg, yield 65%). H NMR (400 MHz,
CDCl3) δ 6.06 (d, J = 3.2 Hz, 1H), 5.47 (s, 1H), 5.35 (d, J = 3.2 Hz,
1H), 3.60 (t, J = 10.0 Hz, 1H), 3.34 (d, J = 10.0 Hz, 1H), 2.92 (br d,
2H), 2.77−2.71 (m, 1H), 2.26 (t, J = 13.2 Hz, 1H), 2.15−2.02 (m,
2H), 1.89 (s, 3H), 1.67 (s, 3H), 1.37−1.27 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 170.0, 140.5, 139.8, 135.3, 131.2, 126.1, 117.5,
85.3, 56.1, 53.0, 37.7, 33.8, 25.8, 23.1, 17.7.
EXPERIMENTAL SECTION
■
The starting material parthenolide was obtained from Accendatech
Co., Ltd. The used solvents were purified and dried according to
common procedures. NMR spectra were recorded with a 400 MHz
(1H, 400 MHz; 13C, 100 MHz) spectrometer and referenced to the
solvent peak for CDCl3. Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. =
broad, m = multiplet), coupling constants, and integration.
p-Toluenesulfonic Acid Catalyzed Transformation of Par-
thenolide (2) to Micheliolide (3). To a solution of p-toluenesulfonic
acid (43.7 g, 2.5 mmol) in CH2Cl2 (15.8 kg) was added dropwise a
solution of parthenolide (1.75 kg, 7.06 mol) in CH2Cl2 (3.5 kg) at 20
°C for 8 h. The resulting reaction mixture was stirred at room
temperature for 15 h. The reaction was quenched with 9.1% NaHCO3
(550 g). The organic layer was washed with saturated brine (2 × 2 kg),
decolorized with activated carbon (100 g), and concentrated under
reduced pressure to give a crude residue, which was recrystallized from
Epoxidation of Compound 5 with m-CPBA. A solution of
compound 5 (160 mg, 0.70 mmol) and m-CPBA (189 mg, 1.1 mmol)
in CH2Cl2 (10 mL) was stirred at room temperature overnight. The
reaction mixture was successively washed with Na2SO3, NaHCO3, and
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure to give crude residue. Then the residue was chromatographed
on a silica gel column to provide arglabin (2 mg, 1.2%), compound 6
(43 mg, 27.1%), and compound 7 (60 mg, 37.8%).
1
Compound 6: H NMR (400 MHz, CDCl3) δ 6.16 (d, J = 3.2 Hz,
1H), 5.59 (s, 1H), 5.45 (d, J = 3.2 Hz, 1H), 3.78 (t, J = 10.4 Hz, 1H),
2.84 (br d, J = 18.0 Hz, 1H), 2.65 (m, 2H), 2.35 (m, 1H), 2.14 (br d, J
= 16.8 Hz, 1H), 1.97 (br s, 3H), 1.84 (br d, J = 14.0 Hz, 1H), 1.60−
1.43 (m, 2H), 1.34 (s, 3H).
1
acetone to yield a colorless needle, compound 3 (1.58 kg, 90%). H
1
Compound 7: H NMR (400 MHz, CDCl3) δ 6.15 (d, J = 3.2 Hz,
NMR (CDCl3, 400 MHz) δ 6.20 (d, J = 3.2 Hz, 1H), 5.49 (d, J = 3.2
Hz, 1H), 3.81 (t, J = 10.4 Hz, 1H), 2.70 (d, J = 10.4 Hz, 1H), 2.65−
2.62 (m, 2H), 2.40−2.34 (m, 1H), 2.07−2.26 (m, 4H), 1.73−1.86 (m,
2H), 1.68 (s, 3H), 1.36−1.28 (m, 4H); 13C NMR (CDCl3, 100 MHz)
δ 169.8, 138.7, 131.7, 130.8, 119.5, 84.1, 80.2, 58.5, 49.5, 38.2, 34.8,
30.0, 25.7, 23.9, 23.6.
1H), 5.40 (d, J = 2.8 Hz, 1H), 3.87 (t, J = 10.4 Hz, 1H), 3.32 (s, 1H),
2.86 (d, J = 10.0 Hz, 1H), 2.73−2.66 (m, 2H), 2.49 (d, J = 18.4 Hz,
1H), 2.27−2.02 (m, 3H), 1.66(br d, J = 10.0 Hz, 5H), 1.38−1.25 (m,
2H).
Synthesis of Compound 4. A solution of micheliolide (30 g, 121
mmol) and m-CPBA (32.4 g, 187.7 mmol) in CH2Cl2 (1.8 L) was
stirred at room temperature overnight. The reaction mixture was
washed with Na2SO3 (3 × 500 mL), NaHCO3 (3 × 500 mL), and
saturated brine (3 × 200 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give a crude residue, which
was recrystallized from acetone to yield compound 4 as crystalline
ASSOCIATED CONTENT
* Supporting Information
Copies of the NMR spectra of compounds 1 and 3−7 and X-
ray data of compound 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
1
solid (24 g, 75%). Mp: 160−165 °C; H NMR (400 MHz, CDCl3) δ
AUTHOR INFORMATION
Corresponding Author
*E-mail: (Q.Z.) zhangquan612@163.com; (Y.C.) yuechen@
nankai.edu.cn.
■
6.14 (d, J = 3.2 Hz, 1H), 5.44(s, 1H), 5.44 (t, J = 2.4 Hz, 1H), 4.01 (t,
J = 10.4 Hz, 1H), 2.85 (br.s, 1H), 2.33−2.17 (m, 4H), 1.96−1.78 (m,
4H), 1.65−1.59 (m, 1H), 1.43 (s, 4H), 1.36 (m, 1H), 1.25 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 169.7, 138.1, 119.6, 81.8, 79.7, 69.8,
62.2, 55.5, 49.3, 37.3, 33.3, 29.5, 23.3, 23.2, 21.9; HRMS (ESI) for
[C15H20O4Na]+ calcd 287.1259, found 287.1258.
Notes
The authors declare no competing financial interest.
Dehydration of Compound 4 with Martin’s Sulfurane. A
solution of Martin’s sulfurane (4.54 g, 6.75 mmol) in CH2Cl2 (36 mL)
was slowly added to a solution of compound 4 (1.19 g, 4.5 mmol) in
CH2Cl2 (72 mL) under an atmosphere of Ar. The mixture was stirred
at room temperature for 24 h. The reaction mixture was concentrated
under reduced pressure to give a residue, which was purified by silica
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (NSFC) (no. 81001377 to Q.Z. and no.
21072106 to Y.C.), Fok Ying Tong Education Foundation (No.
122037), and The Natural Science Foundation of Tianjin
(TJNSF) (No. 09JCZDJC21900).
gel column chromatography to afford arglabin (0.74 g, 67%). [α]24
=
D
+105° (3 mg/mL, CHCl3)41, 1H NMR (400 MHz, CDCl3) δ 6.14 (d, J
= 3.2 Hz, 1H), 5.57 (s, 1H), 5.41 (d, J = 3.2 Hz, 1H), 4.00 (t, J = 10.4
Hz, 1H), 2.93 (br.d, J = 10.8 Hz, 1H), 2.77 (br.d, J = 17.6 Hz, 1H),
2.27−2.12 (m, 3H), 2.03 (m, 1H), 1.97 (br.s, 3H), 1.84 (br.d, J = 14.0
Hz, 1H), 1.48 (m, 1H), 1.35 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
170.6, 140.7, 139.2, 125.0, 118.4, 83.0, 72.6, 62.8, 52.9, 51.2, 39.8, 33.6,
22.9, 21.6, 18.4.
REFERENCES
■
(1) Cragg, G. M.; Newman, D. J.; Snader, K. M. J. Nat. Prod. 1997,
60, 52−60.
(2) Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003,
66, 1022−1037.
Dehydration of Compound 4 with POCl3. To a stirred solution
of compound 4 (21.0 g, 79.5 mmol) in pyridine (656 mL) was added
POCl3 (18.6 mL, 199 mmol) at 0 °C. The mixture was stirred for 2 h,
Et2O (1 L) was added, and the organic layer was washed successively
with NaHCO3 and brine, dried over anhydrous MgSO4, and
(3) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461−477.
́ ́
(4) Denis, J.-N.; Greene, A. E.; Guenard, D.; Gueritte-Voegelein, F.;
Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917−5919.
(5) Baloglu, E.; Kingston, D. G. I. J. Nat. Prod. 1999, 62, 1068−1071.
7106
dx.doi.org/10.1021/jo300888s | J. Org. Chem. 2012, 77, 7103−7107

The Journal of Organic Chemistry
Note
(6) Hu, Z.; Ou, L. L.; Zhang, G. L.; Yu, Y. P. Chin. Chem. Lett. 2008,
19, 130−132.
(39) Jalmahanbetova, R. I.; Rakhimova, B. B.; Raldugin, V. A.;
Bagryanskaya, Y. I.; Gatilov, Y. V.; Shakirov, M. M.; Kulyjasov, A. T.;
Adekenov, S. M.; Tolstikov, G. A. Russ. Chem. Bull. Int. Ed. 2003, 52,
748−751.
(40) Ando, M.; Yoshimura, H. J. Org. Chem. 1993, 58, 4127−4131.
(41) Zdero, C.; Bohlmann, F. Phytochemistry 1990, 29, 189−194.
(7) Ghantous, A.; Gali-Muhtasib., H.; Vuorela, H.; Najat A. Saliba, N.
A.; Darwiche, N. Drug Discovery Today 2010, 15, 668−678.
(8) Schall, A.; Reiser, O. Eur. J. Org. Chem. 2008, 14, 2353−2364.
(9) Shaikenov, T. E.; Adekenov, S. M.; Williams, R. M.; Prashad, N.;
Baker, F. L.; Madden, T. L.; Newman, R. Oncol. Rep. 2001, 8, 173−
179.
(10) Zhangabylov, N. S.; Dederer, L. Y.; Gorbacheva, L. B.;
VasilLeva, S. V.; Terekhov, A. S.; Adekenov, S. M. Pharm. Chem. J.
2004, 38, 651−653.
(11) Adekenov, S. M.; Mukhametzhanov, M. N.; Kagarlitskii, A. D.;
Kupriyanov, A. N. Khim. Prir. Soedin. 1982, 5, 655−656.
(12) Adekenov, S. M. U.S. Patent 6,770,673, Aug. 3, 2004.
(13) Kalidindi, S.; Jeong, W. B.; Schall, A.; Bandichhor, R.; Nosse, B.;
Reiser, O. Angew. Chem., Int. Ed. 2007, 46, 6361−6363.
(14) Song, Q.; Gomez-Barrios, M. L.; Hopper, E. L.; Hjortso, M. A.;
Fisher, N. H. Phytochemistry 1995, 40, 1659−1665.
(15) Drew, D. P.; Rasmussen, S. K.; Avato, P.; Simonsen, H. T.
Phytochem. Anal. 2012, 23, 44−51.
(16) Nelson, M. H.; Cobb, S. E.; Shelton, A. J. Am. J. Health-Syst.
Pharm. 2002, 59, 1527−1531.
(17) Zhang, Q.; Chen, Y.; Fan, H. X.; Long, J.; Zhai, J. D. C. N.
Patent 2,011,110,187,388.7, July 6, 2011. We are currently obtaining
parthenolide in yields of 31−80 g per kilogram of dry root barks of
Magnolia delavayi, and we have scaled up to 10 kg production of pure
parthenolide.
(18) Knight, D. W. Nat. Prod. Rep. 1995, 12, 271−276.
(19) Groenewegen, W. A.; Knight, D. W.; Heptinstall, S. Prog. Med.
Chem. 1992, 29, 217−238.
(20) Guzman, M. L.; Rossi, R. M.; Kamischky, L. K.; Li, X.; Peterson,
D. R.; Howard, D. S.; Jordan, C. T. Blood 2005, 105, 4163−4169.
(21) Liu, Y.; Lu, W.-L.; Guo, J.; Du, J.; Li, T.; Wu, J.-W.; Wang, G.-L.;
Cheng, J.; Wang, J.-C.; Zhang, X.; Zhang, Q. J. Controlled Release 2008,
129, 18−25.
(22) Kawasaki, B. T.; Hurt, E. M.; Kalathur, M.; Duhagon, M. A.;
Milner, J. A.; Kim, Y. S.; Farrar, W. L. Prostate 2009, 67, 827−837.
(23) Roboz, G. J.; Guzman, M. Expert Rev. Hematol. 2009, 2, 663−
672.
(24) Peese, K. Drug Discovery Today 2010, 15, 322.
(25) Castaneda-Acosta, J.; Fischer, N. H.; Vargas, D. J. Nat. Prod.
̃
1993, 56, 90−98.
(26) Neukirch, H.; Kaneider, N. C.; Wiedermann, C. J.; Guerriero,
A.; D’ambrosio, M. Bioorg. Med. Chem. 2003, 11, 1503−1510.
(27) Govindachari, T. R.; Joshi, B. S.; Kamat, V. N. Tetrahedron
1965, 21, 1509−1519.
(28) Ogura, M.; Cordell, G. A.; Farnsworth, N. R. Phytochemistry
1978, 17, 957−961.
(29) Jacobsson, U.; Kumar, V.; Saminathan, S. Phytochemistry 1995,
39, 839−843.
(30) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307−1370.
(31) Chamberlain, T.; Fu, X.; Pechacek, J. T.; Peng, X.; Wheeler, D.
M. S.; Wheeler, M. M. Tetrahedron Lett. 1991, 32, 1707−1710.
(32) Ikegami, S.; Katsuki, T.; Yamaguchi, M. Chem. Lett. 1987, 16,
83−84.
(33) Koco
̌
vsky, P. J. Chem. Soc., Perkin Trans. 1 1994, 1759−1763.
(34) Blay, G.; Bargues, V.; Cardona, L.; Collado, A. M.; García, B.;
Munoz, M. C.; Pedro, J. R. J. Org. Chem. 2000, 65, 2138−2144.
̃
(35) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90,
4744−4745.
(36) Zhang, Q.; Jiang, Z.-Y.; Luo, J.; Cheng, P.; Ma, Y.-B.; Zhang, X.-
M.; Zhang, F.-X.; Zhou, J.; Chen, J.-J. Bioorg. Med. Chem. Lett. 2008,
18, 4647−4650.
(37) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.;
Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551−2651.
(38) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003−
5010.
7107
dx.doi.org/10.1021/jo300888s | J. Org. Chem. 2012, 77, 7103−7107