Synthesis and Antimalarial Activity of Mallatojaponin C and Related Compounds

Article abstract of DOI:10.1021/acs.jnatprod.6b00347

The phloroglucinol mallotojaponin C (1) from Mallotus oppositifolius, which was previously shown by us to have both antiplasmodial and cytocidal activities against the malaria parasite Plasmodium falciparum, was synthesized in three steps from 2′,4′,6′-tr

Full text of DOI:10.1021/acs.jnatprod.6b00347

Article
pubs.acs.org/jnp
Synthesis and Antimalarial Activity of Mallatojaponin C and Related
Compounds
Alexander L. Eaton,† Seema Dalal,‡ M. Belen Cassera,‡ Shuqi Zhao,† and David G. I. Kingston*,†
†Department of Chemistry and the Virginia Tech Center for Drug Discovery and ‡Department of Biochemistry and the Virginia Tech
Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States
S
* Supporting Information
ABSTRACT: The phloroglucinol mallotojaponin C (1) from Mallotus oppositifolius, which was previously shown by us to have
both antiplasmodial and cytocidal activities against the malaria parasite Plasmodium falciparum, was synthesized in three steps
from 2′,4′,6′-trihydroxyacetophenone, and various derivatives were synthesized in an attempt to improve the bioactivity of this
class of compounds. Two derivatives, the simple prenylated phloroglucinols 12 and 13, were found to have comparable
antiplasmodial activities to that of mallotojaponin C.
he phloroglucinol mallotojaponin C (1) was first isolated
from Mallotus oppositifolius Muell. Arg., a member of the
alkenyl halide in 80% aqueous ethanol at room temperature;
the solvent was chosen based on a previous study of the effect
of solvent on the C-alkylation of phloroglucinols and on trials
of various solvents for the synthesis of 11.9,10 The use of
sodium hydroxide led to higher yields of 11, 12, 16, and 17
than the use of lithium hydroxide. Compounds 11,8,11−14
16,14−17 17,18,19 and 1817,20 have previously been synthesized,
and their structures were confirmed by MS and by comparison
T
Euphorbiaceae family,2 and was shown to have both cytostatic
and cytocidal activity against the chloroquine/mefloquine-
resistant Dd2 strain of Plasmodium falciparum. The related
compounds methylated mallotojaponin C (2), mallotophenone
(3), and mallotojaponin B (4) were also obtained, but had less
potent antimalarial activity than 1, indicating the importance of
the alkenyl side chain and the phenolic hydroxy substituents at
C-2 and C-6 for antiplasmodial activity. Many monomeric
phloroglucinols have been investigated for their antimalarial
activity,3−5 and some additional dimeric compounds from M.
oppositifolius have recently been shown to have trypanocidal
and antileishmanial activities.6 This paper describes the
syntheses and biological evaluations of mallotojaponin C and
various derivatives that were reported in 2015 in a Ph.D.
dissertation7 and complements the results in an excellent recent
paper by Cariou and Dubois et al.8
1
of their H and 13C NMR spectra with previously published
spectra. Thus, treatment of 10 with 3,3-dimethylallyl bromide
(prenyl bromide) in 80% aqueous ethanol with 1.1 equiv of
NaOH at room temperature for 16 h gave the monoprenylated
product 11 in 33% yield. Alkylation of 10 with geranyl bromide
and farnesyl bromide under the same conditions yielded the
corresponding geranylated and farnesylated products 12 and
13, with the yields decreasing with increasing chain length.
Purification of the final product was carried out in each case by
reversed-phase chromatography over C18-silica gel. Purification
of 11 over silica gel in the presence of 0.1% formic acid yielded
the hydroxylated product 14.
RESULTS AND DISCUSSION
■
Alkylation of 15 with prenyl, geranyl, and farnesyl bromides
gave the alkylated derivatives 16−18 in low to moderate yields.
The synthesis of dimeric phloroglucinols such as mallatoja-
ponin C (1) required the coupling of the monomeric
Synthesis of Mallatojaponin C and Analogues. The
prenylated monomeric phloroglucinols 11−14 and 16−18
(Scheme 1) were synthesized by prenylation of either 2,4,6-
trihydroxyacetophenone (15) or 2,6-dihydroxy-4-methoxyace-
tophenone (10) (Scheme 1). Prenylation of the precursors 10
and 15 was achieved by reaction of the phenol with either
sodium hydroxide or lithium hydroxide and the appropriate
Received: April 19, 2016
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.6b00347
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
Figure 1. Structures of mallatojapinin C (1), tetramethylmallatojapinin C (2), mallotophenone (3), and mallotojaponin B (4).
Scheme 1. Synthesis of Alkylated Phloroglucinols 11−18
Scheme 2. Synthesis of Dimeric Phloroglucinol Derivatives
compounds 10−12, 14, and 16−17. The initial coupling
conditions used were based upon previous work with similar
substrates,21−23 but it was apparent that the alkene moiety was
readily hydrated under the standard acidic conditions. Most of
the previously published work was on derivatives not
containing an alkene moiety, so this problem did not arise in
these cases. The coupling conditions were thus optimized by a
study of synthetic conditions for compound 8, and various
solvents, catalysts, and reaction durations were investigated.
The best conditions were found to be the use of acetonitrile as
solvent and a small amount of concentrated sulfuric acid as
catalyst to reduce hydration of the alkene. These conditions
allowed the reaction to be completed in less than 30 min, and
this short reaction time also reduced the amount of hydration.
Although the reaction yield was low, the desired product could
easily be purified. These conditions were then applied to the
synthesis of mallatojaponin C (1) and compounds 5−9. The
latter compounds were prepared in an attempt to improve
upon the antiparasitic activity of the coupled compounds and
specifically to investigate the effect of the length of the alkenyl
chain and the substituent at C-5 on the bioactivity of the
resulting compounds. In the case of the known compound 1
the structure was confirmed by comparison of spectroscopic
data with the published data,2 and the structures of the other
compounds were established by analysis of their spectroscopic
data.
Antiplasmodial Activities of Mallatojaponin C Ana-
logues. The synthetic compounds 1−18 were evaluated for
their antiplasmodial activities against the Dd2 strain of P.
falciparum. The results are presented in Table 1, together with
the data for some of the same compounds from the recent
Table 1. Antiparasitic Activities of Natural and Synthetic
Phloroglucinols and Analogues
compound number
(this work)
IC50 (μM)
Dd2 strain
compound
number (ref 8)
IC50 (μM) FcB1/
Columbia strain
a
1
0.64 0.1
8.1 0.8
1.7 0.8
>10
2
0.75 0.11
17.6 4.3
5
5a
12
6
6
0.4
b
7
NR
8
>20
NR
NR
NR
6
9
>10
The synthesis of other derivatives was attempted by replacing
formaldehyde with various aldehydes. The synthesis of the p-
fluorophenyl derivative 19 initially appeared to be successful, as
10
11
12
13
14
15
16
17
18
>20
1.7 0.4
0.57 0.09
0.56 0.07
>20
7.4 1.1
4.4 1.3
7
1
judged by its H NMR spectrum, consistent with its assigned
NR
NR
NR
NR
NR
NR
structure, and the compound showed promising bioactivity,
with an IC50 value in the 2−4 μM range. Unfortunately, the
compound proved to be unstable on storage in the freezer and
decomposed before MS data could be obtained and an accurate
IC50 value could be determined. Attempts to synthesize other
proposed derivatives were unsuccessful, presumably because of
the stability of the secondary benzylic carbocation that would
be formed in an acid-catalyzed retrocoupling reaction.
>20
>20
6.6 2.4
3.6 0.8
a
b
This value differs from that reported in ref 2. NR = not reported in
ref 8.
B
DOI: 10.1021/acs.jnatprod.6b00347
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Journal of Natural Products
Article
Cariou and Dubois et al. paper.8 The potencies against the two
different strains of P. falciparum show similar trends, but the
Dd2 strain is more sensitive to these compounds than the
FcB1/Columbia strain.
with MgSO4, and the solvent was removed under reduced pressure.
The residue was purified utilizing C18 HPLC (MeOH/H2O gradient
with 0.1% formic acid) to yield the alkylated phloroglucinol (11−14,
16−18).
Standard Procedure B for Synthesis of Dimeric Phloroglu-
cinol Derivatives 1 and 5−9. The following general procedure was
used. The alkylated phloroglucinol (10−12, 14, 16, or 17, 0.1−0.5
mmol) was dissolved in CH3CN. Formaldehyde (37% aqueous, 10
equiv) was added, followed by the addition of concentrated H2SO4 (1
drop). The reaction mixture was stirred for 5 min at rt. The reaction
mixture was diluted with water (10 mL) and extracted with EtOAc (3
× 10 mL). The organic solution was washed with saturated NaCl (10
mL) and dried with MgSO4, and the solvent was removed under
reduced pressure. The residue was purified utilizing C18 HPLC
(MeOH/H2O gradient with 0.1% formic acid) to yield the dimeric
phloroglucinol derivatives 1 and 5−9.
For the dimeric phloroglucinols (1, 5−9), it was found that
the prenyl side chain maximized the bioactivity, with the bis-
prenylated natural product 1 having the best potency. Both the
monoprenylated compound 4 and the bisgeranylated com-
pound 6 were less potent than 1 against the Dd2 strain.
Methylation at the 4-position is also very important. Thus, the
bisgeranyl compound 6, with methylation at both the 4- and 4′-
hydroxy groups, has an IC50 value of 1.7 0.8 μM, while the
corresponding unmethylated compound 8 is much less potent,
with an IC50 value greater than 20 μM. This difference may be
partly due to polarity, since the hydrated derivative 7 is much
less active than the unhydrated natural product 1.
Antiparasitic Bioassay. This assay was performed at Virginia
Tech as previously described.2
The situation is somewhat different with the monomeric
phloroglucinol derivatives. With these compounds potency
increases as the alkenyl side chain increases in length from
prenyl to geranyl to farnesyl in both the 4-methylated series
(compounds 11−13) and the unmethylated series (compounds
16−18). As with the dimeric phloroglucinols, the compounds
in the 4-methylated series are more potent than those in the
unmethylated series, but the differences are smaller. Thus, the
unmethylated farnesyl compound 18 is only about 9-fold less
potent than its methylated analogue 13.
Finally, the excellent potencies of the monomeric com-
pounds 12 and 13 are worth noting. Both compounds show
submicromolar activities, with the farnesylated compound 13
having an IC50 value of 0.56 μM against the Dd2 strain,
comparable to the dimeric lead compound 1. It is thus
conceivable that further explorations in this chemical space
could yield relatively simple compounds with significant
antiparasitic activities.
Synthesis of 11. Standard procedure A was used with NaOH to
convert 10 (495 mg, 2.72 mmol) to 11 (228 mg, 0.91 mmol, 33%).
Compound 11: UV (MeOH) λmax (log ε) 215 (4.06), 288 (4.09),
333 (3.36) nm; 1H NMR (MeOH-d4, 400 MHz) δ 1.60 (3H, s, H-5′),
1.71 (3H, s, H-4′), 2.60 (3H, s, −COCH3), 3.15 (2H, d, J = 7.2 Hz, H-
1′), 3.78 (3H, s, −OCH3), 5.10 (1H, m, H-2′), 5.96 (1H, s, H-5); 13
C
NMR (MeOH-d4, 100 MHz) δ 17.8, 22.0, 25.9, 33.1, 55.8, 90.9, 106.0,
108.9, 124.3, 131.1, 162.3, 163.5, 165.0, 205.0; HRESIMS [M + H]+
+
m/z 251.1274 (calcd for C14H19O4 251.1278), [M + Na]+ m/z
+
273.1114 (calcd for C14H18NaO4 273.1097).
Synthesis of 12. Standard procedure A was used with LiOH as
base to convert 10 (150 mg, 0.82 mmol) to 12 (78 mg, 0.25 mmol,
30%). When NaOH was used as base, the yield of 12 from 100 mg
(0.55 mmol) of 10 was 37 mg (0.12 mmol, 22%).
Compound 12: UV (MeOH) λmax (log ε) 216 (4.16), 289 (4.14),
1
333 (3.38) nm; H NMR (MeOH-d4, 400 MHz) δ 1.60 (3H, s, H-
10′), 1.67 (3H, s, H-9′), 1.87 (3H, s, H-8′), 2.08 (4H, m, H-4′, H-5′),
2.67 (3H, s, −COCH3), 3.33 (2H, d, J = 7.0 Hz, H-1′), 3.81 (3H, s,
−OCH3), 5.06 (1H, m, H-6′), 5.19 (1H, m, H-2′), 6.02 (1H, s, H-5);
13C NMR (MeOH-d4, 100 MHz) δ 16.2, 17.7, 21.4, 25.7, 26.3, 32.9,
39.7, 55.7, 91.8, 105.4, 121.6, 123.7, 131.9, 163.1, 203.7; HRESIMS [M
+ H]+ m/z 319.1896 (calcd for C19H27O4+ 319.1904), [M + Na]+ m/z
EXPERIMENTAL SECTION
General Experimental Procedures. Melting points were
■
+
341.1707 (calcd for C19H26NaO4 341.1723).
Synthesis of 13. Standard procedure A was used with LiOH as
base. The yield of 13 from 100 mg (0.55 mmol) of 10 was 61 mg (0.16
mmol, 29%).
obtained using a Buchi B-540 melting point apparatus. UV−vis
̈
spectra were recorded on a Shimadzu UV-1201 spectrophotometer.
NMR spectra were recorded on Varian 400 or Bruker Avance 500
MHz spectrometers. Mass spectra were obtained with an Agilent 6220
LC-TOF-MS. Preparatory HPLC separations were performed using
Shimadzu LC-8A pumps coupled with a Shimadzu SPD-M10A diode
array detector, a SCL-10A controller, and a Varian Dynamax C18
column (250 × 21.4 mm). Semipreparative HPLC separations were
performed using Shimadzu LC-10AT pumps coupled with a Shimadzu
SPD-M10A diode array detector, a SCL-10A system controller, and a
Phenomenex Luna C18 column (250 × 10 mm). Bioactive compounds
were checked for purity by analytical HPLC analysis using Shimadzu
LC-10AT pumps coupled with a Shimadzu SPD-M10A diode array
detector, a Sedex 75 evaporative light scattering detector, a SCL-10A
system controller, and a Phenomenex Luna C18 column (250 × 4.6
mm). Compounds 10 and 15 were purchased from Indofine Chemical
Company and tested for bioactivity without further purification.
Compounds 2 and 3 were isolated from M. oppositifolius, and
compound 4 was previously synthesized from 1.2 Geranyl bromide was
purchased from Alfa Aesar, and prenyl and farnesyl bromides were
purchased from Sigma-Aldrich.
Compound 13: UV (MeOH) λmax (log ε) 213 (4.21), 288 (4.14),
1
333 (3.38) nm; H NMR (MeOH-d4, 400 MHz) δ 1.60 (3H, s, H-
10′), 1.67 (3H, s, H-9′), 1.87 (3H, s, H-8′), 2.08 (4H, m, H-4′, H-5′),
2.67 (3H, s, −COCH3), 3.33 (2H, d, J = 7.0 Hz H-1′), 3.81 (3H, s,
−OCH3), 5.06 (1H, m, H-6′), 5.19 (1H, m, H-2′), 6.02 (1H, s, H-5);
13C NMR (MeOH-d4, 100 MHz) δ 16.2, 17.7, 21.4, 25.7, 26.3, 32.9,
39.7, 55.7, 91.8, 105.4, 121.6, 123.7, 131.9, 163.1, 203.7; HRESIMS [M
+ H]+ m/z 387.2535 (calcd for C24H35O4+ 387.2530), [M + Na]+ m/z
409.2346 (calcd for C24H34O4Na+ 409.2349).
Synthesis of 14. Standard procedure A was used with NaOH as
base. The residue was purified by column chromatography on silica gel
(9:1 hexanes/EtOAc/0.1% formic acid). The yield of 14 from 49.6 mg
(0.27 mmol) of 10 was 24 mg (0.096 mmol, 36%).
Compound 14: UV (MeOH) λmax (log ε) 216 (4.03), 290 (4.07),
331 (3.39) nm; 1H NMR (MeOH-d4, 400 MHz) δ 1.37 (6H, s, H-4′,
H-5′), 1.77 (2H, t, J = 6.9 Hz, H-3′), 2.53 (2H, t, J = 6.9 Hz, H-2′),
2.58 (3H, s, −COCH3), 3.83 (3H, s, −OCH3), 6.01 (1H, s, H-5); 13
C
NMR (MeOH-d4, 100 MHz) δ 17.4, 26.9, 32.5, 33.6, 56.2, 77.1, 92.3,
102.1, 107.0, 157.7, 165.2, 166.5, 204.7; HRESIMS [M − OH]+• m/z
Standard Procedure A for Synthesis of Alkylated Phlor-
oglucinols 11−14 and 16−18. The following general procedure
was used. Compound 10 or 15 (1 equiv) was dissolved in a solution of
80% EtOH (40 mL) containing LiOH or NaOH (2 equiv). Prenyl,
geranyl, or farnesyl bromide (1.1 equiv) was added, and the reaction
mixture was stirred for 16 h at rt. The reaction mixture was acidified
with 3 N HCl and extracted with CH2Cl2 (3 × 50 mL). The organic
solution was washed with saturated aqueous NaCl (50 mL) and dried
+
251.1278 (calcd for C14H19O4 251.1278), [M − C4H9O]+ m/z
+
195.0646 (calcd for C10H11O4 195.0652).
Synthesis of 16. Standard procedure A was used with LiOH as
base. The yield of 16 from 980 mg (5.8 mmol) of 15 was 365 mg (1.55
mmol, 27%).
Compound 16: 1H NMR (MeOH-d4, 400 MHz) δ 1.63 (3H, s, H-
5′) 1.73 (3H, s, H-4′), 2.60 (3H, s, −COCH3), 3.17 (2H, d, J = 7.2
C
DOI: 10.1021/acs.jnatprod.6b00347
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Hz, H-1′), 5.16 (1H, m, H-2′), 5.89 (1H, s, H-5); 13C NMR (MeOH-
d4, 100 MHz) δ 17.8, 22.1, 26.0, 32.8, 94.7, 105.5, 107.9, 124.5, 131.1,
161.8, 163.9, 164.8, 204.6; HRESIMS [M + H]+ m/z 237.1119 (calcd
27.0, 31.9, 33.8, 60.3, 75.6, 104.8, 108.2, 114.4, 155.2, 162.7, 163.4,
204.4.
Synthesis of 8. Standard procedure B was used. The reaction
mixture was stirred for 30 min at rt. The precipitate was filtered and
rinsed with MeOH to yield 8. The yield of 8 from 14.3 mg (0.061
mmol) of 16 was 3 mg (0.0062 mmol, 10%). The compound appeared
+
for C13H17O4 237.1121), [2M + NH4]+ m/z 490.2405 (calcd for
+
C26H36NO8 490.2435).
Synthesis of 17. Standard procedure A was used. With LiOH as
base the yield of 17 from 253 mg (1.5 mmol) of 15 with LiOH was
147 mg (0.48 mmol, 32%), and with NaOH as base the yield of 17
from 100 mg (0.60 mmol) of 15 was 65 mg (0.48 mmol, 35%).
1
to be >90% pure by H NMR spectroscopy.
Compound 8: 1H NMR (DMSO-d6, 400 MHz) δ 1.59 (6H, s, H-5′,
H-5″), 1.68 (6H, s, H-4′, H-4″), 2.63 (6H, s, 2 × −COCH3,), 3.23
(4H, d, J = 6.7 Hz, H-1′, H-1″), 3.68 (2H, s, H-5a), 5.04 (2H, m, H-2′,
H-2″); 13C NMR (DMSO-d6, 100 MHz) δ 17.0, 17.8, 21.5, 25.5, 32.6,
48.6, 105.8, 106.4, 108.1, 123.0, 130.4, 159.5, 203.7; HRESIMS [M +
1
Compound 17: H NMR (CDCl3, 400 MHz) δ 1.60 (3H, s, H-
10′), 1.68 (3H, s, H-9′), 1.82 (3H, s, H-8′), 2.10 (4H, m, H-4′, H-5′),
2.67 (3H, s, −COCH3), 3.37 (2H, d, J = 7.1 Hz, H-1′), 5.05 (1H, m,
H-6′), 5.25 (1H, H-2′), 5.85 (1H, s, H-5); 13C NMR (CDCl3, 100
MHz) δ 16.2, 17.7, 21.5, 25.7, 26.2, 32.9, 39.7, 95.3, 105.2, 105.4,
121.4, 123.6, 132.2, 140.1, 161.2, 203.6; HRESIMS [M + H]+ m/z
+
H]+ m/z 485.2140 (calcd for C27H33O8 485.2170), [M + Na]+ m/z
507.1946 (calcd for C27H32O8Na+ 507.1989).
Synthesis of 9. Standard procedure B was used. The yield of 9
from 49.3 mg (0.16 mmol) of 17 was 10.5 mg (0.017 mmol, 11%).
Attempts at recrystallizing the compound in MeOH/H2O were
unsuccessful and resulted in decomposition before MS data could be
obtained.
Compound 9: UV (MeOH) λmax (log ε) 208 (4.27), 230 (4.17),
292 (4.11) nm; 1H NMR (CDCl3, 400 MHz) δ 1.60 (6H, s, H-10′, H-
10″), 1.68 (6H, s, H-9′, H-9″), 1.83 (6H, s, H-8′, H-8″), 2.11 (8H, m,
H-4′, H-5′, H-4″, H-5″), 2.67 (2 × −COCH3, 6H, s), 3.41 (4H, d, J =
6.7 Hz, H-1′, H-1″), 3.79 (2H, s, H-5a,), 5.05 (2H, m, H-6′, H-6″),
5.21 (2H, m, H-2′, H-2″); partial 13C NMR (CDCl3, 100 MHz) δ
16.2, 17.7, 25.7, 26.2, 32.7, 39.6, 105.7, 121.4, 123.4, 132.2, 140.7,
204.2.
+
305.1744 (calcd for C18+H25O4 305.1747), [M + Na]+ m/z 327.1539
(calcd for C18H24NaO4 327.1567).
Synthesis of 18. Standard procedure A was used with LiOH as
base. The yield of 18 from 101 mg (0.60 mmol) of 15 was 61 mg (0.16
mmol, 27%).
Compound 18: light yellow powder; UV (MeOH) λmax (log ε) 214
(4.21), 291 (4.19) nm; 1H NMR (CD3OD, 400 MHz) δ 1.54 (3H, s,
H-15′), 1.56 (3H, s, H-14′), 1.65 (3H, s, H-13′), 1.79 (3H, s, H-12′),
1.97 (8H, m, H-4′, H-5′, H-8′, H-9′), 2.59 (3H, s −COCH3), 3.18
(2H, d, J = 7.1 Hz, H-1′), 5.05 (2H, m, H-6′, H-10′), 5.17 (1H, m, H-
2′), 5.89 (1H, s, H-5); 13C NMR (CD3OD, 100 MHz) δ 14.7, 14.7,
16.3, 20.6, 24.5, 26.0, 26.3, 31.4, 39.4, 39.4, 93.3, 104.1, 106.5, 123.3,
123.9, 124.1, 130.4, 133.0, 134.3, 160.4, 162.5, 163.4, 203.1; HRESIMS
[M + H]+ m/z 373.2366 (calcd for C2+3H33O4+ 373.2373), [M + Na]+
m/z 395.2169 (calcd for C23H32NaO4 395.2193).
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthesis of Mallotojaponin C (1). Standard procedure B was
used with 3 mL of CH3CN and HCl instead of H2SO4. The yield of 1
from 26.2 mg (0.1 mmol) of 11 was 6.1 mg (0.011 mmol, 10%).
Mallotojaponin C (1): light yellow powder; 1H NMR (CDCl3, 400
MHz) δ 1.68 (6H, s, H3-5′, H3-5″), 1.77 (6H, s, H3-4′, H3-4″) 2.70
(6H, s, 2 × −COCH3) 3.31 (4H, d, J = 6.5 Hz, H2-1′, H2-1″), 3.68
(2H, s, H2-5a), 3.98 (2 × −OCH3, 6H, s), 5.21 (2H, m, H-2′, H-2″),
9.06 (2H, s, −OH), 13.49 (2H, s, −OH); HRESIMS [M + H]+ m/z
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.6b00347.
1H and 13C NMR spectra of compounds 5−9, 11−14,
1
and 16−18, H NMR spectra of 1 and 5, and HPLC
chromatograms of 11−13 and 16−18 (PDF)
+
513.2469 (calcd for C29H37O8 513.2483), [M + Na]+ m/z 535.2297
(calcd for C29H36O8Na+ 535.2302).
AUTHOR INFORMATION
■
Synthesis of 5. Standard procedure B was used with 3 mL of
MeOH replacing CH3CN. The reaction mixture was stirred for 16 h at
rt. The residue was purified utilizing silica gel CC (1:1 hexanes/
EtOAc). The yield of 5 from 100 mg (0.55 mmol) of 10 was 53.7 mg
(0.14 mmol, 26%).
Corresponding Author
*Tel (D. G. I. Kingston): +1-540-231-6570. Fax: +1-540-231-
3255. E-mail: dkingston@vt.edu.
Notes
Compound 5: 1H NMR (DMSO-d6, 400 MHz) δ 2.56 (6H, s
−COCH3), 3.61 (2H, s, H-5a), 3.69 (6H, s, −OCH3), 6.00 (2H, s, H-
3), 10.87 (2H, s, −OH), 13.48 (2H, s, −OH); 13C NMR (DMSO-d6,
100 MHz) 15.2, 30.7, 32.7, 39.5, 55.4, 90.2, 104.4, 160.8, 162.3, 163.9,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
+
203.1; HRESIMS [M + H]+ m/z 377.1197 (calcd for C19H21O8+
This project was supported by the National Center for
Complementary and Integrative Health, NIH, under award 1
R01 AT008088-01; this support is gratefully acknowledged.
This work was also supported by the National Science
Foundation under Grant No. CHE-0619382 for purchase of
the Bruker Avance 500 NMR spectrometer and Grant No.
CHE-0722638 for the purchase of the Agilent 6220 mass
spectrometer. We thank Mr. B. Bebout for obtaining the mass
spectra.
377.1231), [M + Na]+ m/z 399.1020 (calcd for C19H20NaO8
399.1050).
Synthesis of 6. Standard procedure B was used. The yield of 6
from 49.9 mg (0.16 mmol) of 12 was 2.2 mg (0.0034 mmol, 2%).
Compound 6: UV (MeOH) λmax (log ε) 204 (4.32), 289 (3.95)
nm; 1H NMR (CDCl3, 400 MHz) δ 1.56 (6H, s, H-10′), 1.63 (6H, s,
H-9′), 1.77 (6H, s, H-8′), 1.98 (4H, m, H-5′), 2.05 (4H, bt, J = 7.4 Hz,
H-4′), 2.70 (6H, s, −COCH3), 3.31 (4H, d, J = 6.9 Hz, H-1′), 3.68
(2H, s, H-5a), 3.97 (6H, s, −OCH3), 5.04 (2H, m, H-6′), 5.22 (2H, m,
H-2′), 9.09 (2H, s, −OH), 13.47 (2H, s, −OH); 13C NMR (CDCl3,
100 MHz) δ 16.2, 17.7, 22.7, 25.7, 26.6, 33.7, 39.6, 62.8, 108.4, 109.0,
114.1, 122.6, 124.2, 131.3, 135.7, 157.4, 159.6, 162.7, 205.3; HRESIMS
REFERENCES
■
+
[M − H]+ m/z 647.3663 (calcd for C19H27O8 647.3579).
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Synthesis of 7. Standard procedure B was used. The yield of 7
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Compound 7: UV (MeOH) λmax (log ε) 213 (4.33), 287 (4.25),
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