The preparation of ketone constituents from Echinacea pallida

Article abstract of DOI:10.1016/j.tet.2011.08.031

Efficient syntheses of two ketones from Echinacea pallida are described.

Full text of DOI:10.1016/j.tet.2011.08.031

Tetrahedron 67 (2011) 8235e8237
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The preparation of ketone constituents from Echinacea pallida
*
George A. Kraus , Feng Liu
Iowa State University Department of Chemistry, Ames, IA 50011, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2011
Received in revised form 9 August 2011
Accepted 10 August 2011
Available online 16 August 2011
Efficient syntheses of two ketones from Echinacea pallida are described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Echinacea
Natural products
Synthesis
Ketones
Acetylene
1. Introduction
human cancer cell lines, including leukemia (Jurkat and HL-60),
breast carcinoma (MCF-7), and melanoma (MeWo) cells.5 Binns
has reported that the ketones from E. pallida are potent antifungal
agents.6 Related acetylenic ketones have been reported by Bohl-
mann in Centaurea ferox roots.7 Despite the potential value of the
ketones from E. pallida, few reports of synthesis of authentic
standards or analogs have been reported. Crombie and co-workers
reported the first syntheses of related amides using organome-
tallic coupling reactions.8 Wailes has also reported the synthesis of
related dienamides.9 Kraus reported the synthesis of ketones 110
and 2.11 Recently, Benvenuti and Prati reported a clever synthe-
sis of 3.12
Although we reported the first synthesis of 2, the number of
steps and low overall yield limited the amount of ketone that could
be prepared for biological testing. We report herein a more efficient
synthesis via a phosphonium salt route. Both 2 and 3 can be syn-
thesized from acetylene 4 and aldehyde 5,13 shown in Scheme 1.
Echinacea angustifolia, Echinacea pallida, and Echinacea purpurea
are the main Echinacea species and have been used to treat in-
fections and enhance the immune system.1 Echinacea has ranked
among the leading botanical supplements sold worldwide. In re-
cent years, the treatment of rhinoviruses using Echinacea has been
the focus of a number of studies, several of which have failed to
show the efficacy of Echinacea.2 Commercial Echinacea is often
a mixture of species and there is no standardization of the chemical
components. As part of a program designed to define the chemical
fingerprint of Echinacea species as a necessary step toward stan-
dardization, we report herein the syntheses of two bioactive ketone
components of E. pallida.3
As shown in Fig. 1, ketones 1e3 from E. pallida exhibit a range
of biological activities.4 Recently, Chicca and co-workers reported
that 3 showed a concentration dependent cytotoxicity on several
Fig. 1. Structures of 1,2, and 3.
* Corresponding author. E-mail address: gakraus@iastate.edu (G.A. Kraus).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.031

8236
G.A. Kraus, F. Liu / Tetrahedron 67 (2011) 8235e8237
boiled for 24 h. The solvent was removed in vacuo to give com-
pound 7 (711 mg, 100% yield). Compound 7 is pure enough for next
step reaction without further purification.
1H NMR (300 MHz, CDCl3): 2.83e2.95 (m, 2H), 3.77e3.85 (m,
2H), 5.35e5.38 (d, J¼9.0 Hz, 1H), 6.09e6.11 (d, J¼6.0 Hz, 1H),
7.54e7.74 (m, 15H).
Scheme 1.
Alcohol 6, prepared in one step from 4 by the method of
Kende,14 was converted into phosphonium salt 7 in two steps.
Phosphonium salt 7 underwent an exclusively cis-selective Wittig
reaction14 with aldehyde 5 to generate a dieneyne 8 in 60% yields.
Transformation of the chloroalkene into an acetylene using n-butyl
lithium at ꢀ78 ꢁC15 was a clean reaction. There was no evidence of
products derived from deprotonation of the methylene group be-
tween the acetylene and the alkene. The ketal protecting group was
removed with HCl, providing ketone 2 in 24% overall yield from 4
over six steps (Scheme 2).
2.2. 2-((6Z,11Z)-12-Chlorododeca-6,11-dien-9-ynyl)-2-methyl-
1,3-dioxolane (8)
To a solution of compound 7 (241 mg, 0.50 mmol) in 7 mL of dry
THF was added 1.0 M sodium bis(trimethylsilyl)amide (NaHMDS)
(0.5 mL) at ꢀ78 ꢁC under argon. The mixture was stirred at ꢀ78 ꢁC
for 20 min. A solution of compound 5 (79 mg, 0.46 mmol) in 3 mL of
dry THF was added. The mixture was warmed to room temperature
in 1.5 h and stirred at room temperature for 12 h. Saturated NH4Cl
Scheme 2.
Coupling tosylate 916 with cis-1-bromopropene afforded tosy-
late 10 that could be converted into phosphonium salt 11 in two
steps. The cis-selective Wittig reaction of 11 with aldehyde 5 gave
ketal 12 in 76% yield. Hydrolysis of ketal 12 with HCl produced
ketone 3 in 29% overall yield from 4 over six steps (Scheme 3).
The strategy described above represents a significant improve-
ment over the previous synthetic routes. The route to ketones 2 and
3 is direct and quite flexible with regard to the introduction of
additional functional groups.
solution was added to quench the reaction. The aqueous layer was
extracted three times with 5 mL of ethyl acetate. The combined
organic layers were dried over Na2SO4. After removing solvents in
vacuo, the residue was purified by preparative TLC (hexanes/
EtOAc¼10:1) to give compound 8 (56 mg, 60% yield).
1H NMR (300 MHz, CDCl3): 1.30e1.43 (m, 9H), 1.58e1.65 (m,
2H), 2.03e2.09 (m, 2H), 3.13e3.14 (d, J¼3.0 Hz, 2H), 3.88e3.98 (m,
4H), 5.41e5.54 (m, 2H), 5.82e5.86 (m, 1H), 6.28e6.31 (d, J¼9.0 Hz,
1H). 13C NMR (100 MHz, CDCl3): 18.3, 24.0, 24.2, 27.4, 29.5, 29.7,
Scheme 3.
2. Experimental
39.4, 64.8, 74.5, 97.5, 110.3, 112.6, 123.6, 127.2, 132.5. HRMS (Mþ1):
calculated for C16H24ClO2: 283.1459; found: 283.1458.
2.1. (Z)-(6-Chlorohex-5-en-3-ynyl)iodotriphenylphosphorane
(7)
2.3. (Z)-Tetradeca-8-en-11,13-diyn-2-one (2)
To 7 mL of dry dichloromethane were added in order: triphe-
nylphosphine (473 mg, 1.8 mmol), imidazole (123 mg, 1.8 mmol),
and iodine (458 mg, 1.8 mmol). A solution of compound 6 (217 mg,
1.6 mmol) in 7 mL of dry dichloromethane was added. The mixture
was stirred at room temperature under argon for 2.5 h. The solvent
was removed in vacuo and the residue was purified by silica gel
flash chromatography (hexanes/EtOAc¼1:1) to give the iodide
(335 mg, 87% yield). A solution of the iodide (335 mg,1.4 mmol) and
triphenylphosphine (367 mg,1.4 mmol) in 10 mL of acetonitrile was
To a solution of compound 8 (56 mg, 0.2 mmol) in 3 mL of dry
THF was added 2.5 M n-BuLi (0.08 mL) at ꢀ78 ꢁC under argon. The
mixture was stirred at ꢀ78 ꢁC for 30 min. Saturated NH4Cl solution
was added to quench reaction. The aqueous layer was extracted
three times with 5 mL of ethyl acetate. The combined organic layers
were dried over Na2SO4. After removing solvents in vacuo, the
residue was purified by silica gel flash chromatography (hexanes/
EtOAc¼4:1) to give terminal alkyne compound (26 mg, 53% yield).
To the solution of terminal alkyne compound (26 mg, 0.11 mmol) in

G.A. Kraus, F. Liu / Tetrahedron 67 (2011) 8235e8237
8237
1.5 mL of THF was added 1.5 mL of 1 N HCl. The mixture was stirred
at room temperature for 1 h and quenched with water. The aqueous
layer was extracted three times with 5 mL of ethyl acetate. The
combined organic layers were dried over Na2SO4. After removing
solvents in vacuo, the residue was purified by flash chromatogra-
phy (hexanes/EtOAc¼4:1) to give compound 2 (19 mg, 89% yield).
Both 1H and 13C NMR spectra of 2 were identical to spectra reported
in the literature.11
reaction. The aqueous layer was extracted three times with 5 mL of
ethyl acetate. The combined organic layers were dried over Na2SO4.
After removing solvents in vacuo, the residue was purified by
Preparative TLC (hexanes/EtOAc¼4:1) to give compound 12 (78 mg,
76% yield).
1H NMR (300 MHz, CDCl3): 1.30e1.42 (m, 9H), 1.59e1.64 (m,
2H), 1.82e1.85 (dd, J¼3.0, 6.0 Hz, 3H), 2.02e2.08 (m, 2H), 3.08e3.09
(d, J¼3.0 Hz, 2H), 3.87e3.97 (m, 4H), 5.42e5.47 (m, 3H), 5.83e5.93
(m, 1H). 13C NMR (100 MHz, CDCl3): 16.0, 18.2, 23.9, 24.2, 27.9, 29.5,
29.7, 39.4, 64.8, 77.1, 93.2, 110.3, 110.5, 124.5, 131.8, 137.4. HRMS
(Mþ1): calculated for C17H27O2: 263.2006; found: 263.2004.
2.4. (Z)-Hept-5-en-3-yn-1-yl 4-methylbenzenesulfonate (10)
To a solution of cis-1-bromo-1-propene (0.51 mL, 6 mmol) in
12 mL of Et2NH were added CuI (60 mg, 0.3 mmol) and
Pd(PPh3)2Cl2 (421 mg, 0.6 mmol) at room temperature under argon.
The mixture was stirred at room temperature for 5 min. A solution
of compound 9 (1344 mg, 6 mmol) in 18 mL of Et2NH was added.
The mixture was stirred at room temperature for 10 h. The solution
was treated with H2O and extracted with EtOAc. The combined
organic layers were dried over Na2SO4. After removing solvents in
vacuo, the residue was purified by flash chromatography (hexanes/
EtOAc¼4:1) to give compound 10 (872 mg, 55% yield).
2.7. (8Z,13Z)-Pentadeca-8,13-dien-11-yn-2-one (3)
To the solution of compound 12 (78 mg, 0.3 mmol) in 4 mL of
THF was added 4 mL of 1 N HCl. The mixture was stirred at room
temperature for 1 h. Water was added to quench the reaction. The
aqueous layer was extracted three times with 5 mL of ethyl acetate.
The combined organic layers were dried over Na2SO4. After re-
moving solvents in vacuo, the residue was purified by flash chro-
matography (hexanes/EtOAc¼4:1) to give compound 3 (56 mg, 86%
yield). Both 1H and 13C NMR spectra of 3 were identical to spectra
reported in the literature.12
1H NMR (300 MHz, CDCl3): 1.75e1.77 (d, J¼6.0 Hz, 3H), 2.41 (s,
3H), 2.65e2.71 (td, J¼3.0, 9.0 Hz, 2H), 4.06e4.11 (t, J¼9.0 Hz, 2H),
5.31e5.37 (m, 1H), 5.84e5.94 (m, 1H), 7.30e7.33 (d, J¼9.0 Hz, 2H),
7.75e7.78 (d, J¼9.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): 15.9, 20.5,
21.7, 68.0, 79.4, 88.3, 109.7, 128.0, 130.0, 132.9, 138.5, 145.0. HRMS
(Mþ1): calculated for C14H17O3S: 265.0893; found: 265.0890.
Acknowledgements
We thank the National Institute of Health (Grant P01 ES12020)
and the Office of Dietary Supplements for financial support through
the Center for Research on Botanical Dietary Supplements at Iowa
State University.
2.5. (Z)-Hept-5-en-3-ynyliodotriphenylphosphorane (11)
A solution of compound 10 (116 mg, 0.44 mmol) and NaI
(116 mg, 0.77 mmol) in 12 mL of acetone was boiled for 6 h. After
cooling to room temperature, the solution was treated with H2O
and extracted with EtOAc. The combined organic layers were dried
over Na2SO4. After removing solvents in vacuo, the residue was
purified by flash chromatography (hexanes/EtOAc¼4:1) to give the
iodide (86 mg, 89% yield). A solution of the iodide (85 mg,
0.39 mmol) and triphenylphosphine (102 mg, 0.39 mmol) in 5 mL
of acetonitrile was boiled for 24 h. The solvent was removed in
vacuo to give compound 11 (188 mg, 100% yield). Compound 11 is
pure enough for next step reaction without further purification.
1H NMR (300 MHz, CDCl3): 1.46e1.49 (dd, J¼3.0, 6.0 Hz, 3H),
2.78e2.89 (m, 2H), 3.71e3.79 (m, 2H), 4.82e4.85 (d, J¼9.0 Hz, 1H),
5.58e5.69 (m, 1H), 7.52e7.70 (m, 15H).
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To a solution of compound 11 (188 mg, 0.39 mmol) in 5 mL of
dry THF was added 1.0
M sodium bis(trimethylsilyl)amide
(NaHMDS) (0.4 mL) at ꢀ78 ꢁC under argon. The mixture was stirred
at ꢀ78 ꢁC for 20 min. A solution of compound 5 (118 mg,
0.63 mmol) in 3 mL of dry THF was added. The mixture was
warmed to room temperature in 1.5 h and stirred at room tem-
perature for 12 h. Saturated NH4Cl solution was added to quench