Concise total synthesis of biologically interesting mallotophilippens C and E

Article abstract of DOI:10.1021/jo800367r

(Chemical Equation Presented) This paper describes a new and efficient synthetic approach for biologically interesting natural mallotophilippens C and E. The key strategies involved ethylenediamine diacetate-catalyzed benzopyran formation reactions and ba

Full text of DOI:10.1021/jo800367r

oxide (NO) induced by interferon-γ (IFN- γ) and LPS activated
RAW 264.7 cells.3 They also strongly inhibit inducible nitric
oxide synthesis (iNOS), cyclooxygenase-2 (COX-2), interleu-
kin-6 (IL-6), and interleukin-1ꢀ (IL-1 ꢀ) mRNA expression.3
These effects are expected to be used for the development of
new drugs to treat rheumatoid arthritis, which involves excessive
NO production.
Concise Total Synthesis of Biologically Interesting
Mallotophilippens C and E
Yong Rok Lee,* Xin Li, and Jung Hee Kim
School of Chemical Engineering and Technology, Yeungnam
UniVersity, Gyeongsan 712-749, Korea
yrlee@yu.ac.kr
ReceiVed February 14, 2008
FIGURE 1. Natural products isolated from Mallotus philippinensis.
One synthetic approach to mallotophilippen C (1) was
recently reported,5 but this synthetic approach has a limitation
due to the large number of reaction steps (11 steps). Therefore,
there is still a demand for a more concise and efficient method
that can provide biologically interesting mallotophilippen C (1).
In particular, there are no synthetic approaches to mallotophil-
ippen E (3) with the biologically interesting prenyl moiety
reported thus far. Interestingly, natural mallotophilippen E (3)
has a chiral carbon but is isolated as a racemate.3
This paper describes a new and efficient synthetic approach
for biologically interesting natural mallotophilippens C and
E. The key strategies involved ethylenediamine diacetate-
catalyzed benzopyran formation reactions and base-catalyzed
aldol reactions.
Recently, we developed a new and useful methodology for
preparing a variety of benzopyrans using ethylenediamine
diacetate-catalyzed reactions of resorcinols to R,ꢀ-unsaturated
aldehydes.6 These reactions involve a formal [3+3]-cycload-
dition via 6π-electrocyclization. Using this methodology as a
key step, we also described a rapid route for the synthesis of
biologically interesting pyranochalcone natural products.7 As a
part of an ongoing study into the synthetic efficacy of these
methodologies, this study examined the synthesis of naturally
occurring mallotophilippens C (1) and E (3). We report the very
concise total synthesis of mallotophilippen C (1) and the first
efficient total synthesis of mallotophilippen E (3).
Scheme 1 shows the retrosynthetic strategy for mallotophil-
ippen C (1). Mallotophilippen C (1) could be prepared from
base-catalyzed aldol reactions of compound 6 to the corre-
sponding benzaldehyde protected by a SEM group. The crucial
intermediate 6 could be generated from geranylated phloroac-
Pyranochalcones are an abundant subclass of flavonoids that
are distributed widely in nature.1 Some pyranochalcones have
been reported to exhibit antimutagenic, antimicrobial, antiulcer,
and antitumor activities, and some plants containing these
compounds have been used in traditional medicines in China
and Europe.2 This wide range of biological properties has
stimulated interest in the synthesis of naturally occurring
pyranochalcones. Among these, mallotophilippens C (1), D (2),
and E (3) with the pyranochalcone moiety were isolated from
Mallotus philippinensis, a deciduous tree distributed widely
throughout tropical Asia, Australia, and the Philippines (Figure
1).3 Kamara, a red powder consisting of the glandular hairs from
this plant, has been used in traditional medicine as an anthel-
mintic and cathartic.4 Mallotophilippens C (1), D (2), and E
(3) have been shown to potently inhibit the production of nitric
(1) (a) Wagner, H.; Farkas, L. In The FlaVonoids; Harorne, J. B., Mabry,
T. J., Mabry, H., Eds.; Academic Press: New York, 1975; p 127. (b) Gripenberg,
J. In The Chemistry of FlaVonoid Compounds; Geissman, T. A., Ed.; MacMillan:
New York, 1962; p 409. (c) Wollenweber, E. In The FlaVonoids; Harborne,
J. B., Ed.; Chapman & Hall: London, UK, 1994; p 259. (d) The Handbook of
Natural Products; Harborne, J. B., Baxter, H., Eds.; John Wiley & Sons Ltd.;
London, UK, 1999; Vol. 2, p 1.
SCHEME 1. Retrosynthetic Analysis of Mallotophilippen C
(1)
(2) (a) Welton, A. F.; Tobias, L. D.; Fiedler-Nagy, C.; Anderson, W.; Hope,
W.; Meyers, K.; Coffey, J. W. In Plant FlaVonoids in Biology and Medicine:
Biochemical Pharmacological and Structure-ActiVity Relationships; Cody, V.;
Middleton, E., Jr.; Harborne, J. B. Eds.; Alan R. Liss, Inc: New York, 1986; p
231. (b) Miranda, C. L.; Stevens, J. F.; Helmrich, A.; Henderson, M. C.;
Rodriguez, R. J.; Yang, Y.-H.; Deinzer, M. L.; Barnes, D. W.; Buhler, D. R.
Food Chem. Toxicol. 1999, 37, 271. (c) Han, A.-R.; Kang, Y.-J.; Windono, T.;
Lee, S. K.; Seo, E.-K. J. Nat. Chem. 2006, 69, 719.
(5) Li, Y.; Luo, Y.; Hung, W.; Wang, J.; Lu, W. Tetrahedron Lett. 2006,
47, 4153.
(6) (a) Lee, Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett. 2005, 46,
7539. (b) Lee, Y. R.; Kim, J. H. Synlett 2007, 2232. (c) Wang, X.; Lee, Y. R.
Synthesis 2007, 3044. (d) Wang, X.; Lee, Y. R. Tetrahedron Lett. 2007, 48,
6275. (e) Lee, Y. R.; Lee, W. K.; Noh, S. K.; Lyoo, W. S. Synthesis 2006, 853.
(7) (a) Lee, Y. R.; Xia, L. Synthesis 2007, 3240. (b) Lee, Y. R.; Kim, D. H.
Synthesis 2006, 603.
(3) Daikonya, A.; Katsuki, S.; Kitanaka, S. Chem. Pharm. Bull. 2004, 52,
1326.
(4) (a) Daikonya, A.; Katsuki, S.; Wu, J.-B.; Kitanaka, S. Chem. Pharm.
Bull. 2002, 50, 1566. (b) Gupta, S. S.; Verma, P.; Hishikar, K. Indian J. Physiol.
Pharmacol. 1984, 19, 103.
10.1021/jo800367r CCC: $40.75
Published on Web 04/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4313–4316 4313

SCHEME 2. Synthesis of Mallotophilippen C (1)
SCHEME 3. Retrosynthetic Analysis of Mallotophilippen E
(3)
SCHEME 4. Synthesis of Mallotophilippen E (3)
etophenone 5 via ethylenediamine diacetate-catalyzed benzopy-
ran formation reactions. Compound 5 could be obtained from
commercially available 2,4,6-trihydroxyacetophenone (4).
The total synthesis of mallotophilippen C (1) was carried out
by using the sequence shown in Scheme 2. With use of a known
method, the treatment of 2,4,6-trihydroxyacetophenone (4) and
geranyl bromide with anhydrous potassium carbonate in dry
acetone under reflux for 24 h afforded the product 5 in 74%
yield.8 A reaction of compound 5 with 3-methyl-2-butenal in
the presence of 20 mol % of ethylenediamine diacetate
in methylene chloride for 5 h gave benzopyran 6 in 66% yield.
In this reaction, the remarkable regioselectivity for cyclization
may result from the presence of a bulky geranyl group. This
similar selectivity was observed by Li’s group in the case of a
cyclization reaction of the geranylated polyhydroxychalcone to
give flavanone natural products.9 Compound 6 was next
protected with 1.1 equiv of methoxymethyl chloride to give
product 7 in 94% yield. The selective methoxymethylation of
achieved with prenyl bromide in the presence of either potassium
hydroxide10 or potassium carbonate.11 Under these conditions,
the desired product 10 was obtained in 30-34% yield. Another
base was used to increase the yield. A reaction of compound 4
with prenyl bromide in the presence of DBU in THF gave
compound 10 in 40% yield. Treatment of compound 10 with
citral in the presence of 20 mol % of ethylenediamine diacetate
in methylene chloride at room temperature for 8 h provided
the products 11 and 12 in 78% and 17% yield, respectively.
Compound 10, which contains a less bulky prenyl group,
showed a reduced regioselectivity. These two compounds were
readily separated by column chromatography and assigned by
spectral analysis. Protection of compound 11 with 1.1 equiv of
SEMCl provided compound 13 in 93% yield, which was
condensed with the aldehyde 14 in ethanolic KOH solution at
room temperature for 48 h to give pyranochalcone 15 in 72%
yield. Attempts to deprotect compound 15 with TBAF or
magnesium bromide diethyl etherate12 did not give the desired
product 3. Fortunately, all the SEM groups were easily removed
by treatment with HCl in methanol at room temperature for 1 h
to yield compound 3 in 56% yield. The spectroscopic data of
synthetic material 3 were in agreement with those reported in
the literature
1
compound 6 was confirmed by an analysis of the H NMR
spectrum. The signal for the proton of one hydroxyl group in
the benzopyran ring of compound 7 was observed as a singlet
associated with a hydrogen bond to a carbonyl group at δ 13.72
ppm, and a methoxy signal of MOM ether was observed as a
singlet at δ 3.53 ppm. Condensation of compound 7 with
aldehyde 8 protected with a SEM group was next accomplished
in an ethanolic KOH solution at room temperature for 48 h to
afford the pyanochalcone 9 in 76% yield. Deprotection of
compound 9 by a treatment with 3 N HCl in methanol at room
temperature for 1 h gave mallotophilippen C (1) in 65% yield.
The spectral data of the synthetic material 1 were in agreement
with those reported in the literature.3
Scheme 3 shows the retrosynthetic approach for synthesizing
the natural product, mallotophilippen E (3). Mallotophilippen
E (3) could be prepared by base-catalyzed aldol reactions of
benzopyran 11 to the corresponding benzaldehyde protected with
SEM groups. The key intermediate 11 also could be generated
from the prenylated phloroacetophenone (10) by using ethyl-
enediamine diacetate-catalyzed benzopyran formation reactions.
The prenylated phloroacetophenone 10 could be derived from
commercially available 2,4,6-trihydroxyacetophenone (4).
The total synthesis of mallotophilippen C (3) was attempted
starting from 2,4,6-trihydroxyacetophenone (4), as shown in
Scheme 4. Prior work has shown that C-prenylation can be
In summary, this paper described a concise and efficient
synthetic route for biologically interesting natural products,
mallotophilippens C and E, with a pyranochalcone moiety
through a five-step process starting from 2,4,6-trihydroxyac-
etopheneone.
Experimental Section
Compound 5. A mixture of 4 (1.009 g, 6.0 mmol), geranyl
bromide (1.303 g, 6.0 mmol), and K2CO3 (1.659 g, 12.0 mmol) in
dry acetone (50 mL) was refluxed for 24 h. Evaporation of acetone,
addition of 2 N HCl solution (30 mL), extraction with EtOAc (3
(10) Diller, R. A.; Riepl, H. M.; Rose, O.; Frias, C.; Henze, G.; Prokop, A.
Chem. BiodiVersity 2005, 2, 1331.
(8) Huang, C.; Zhang, Z.; Li, Y. J. Nat. Prod. 1998, 61, 1283.
(11) Yang, Y.-G.; Zhang, Y.; Cao, X.-P. Huaxue Xuebao 2005, 63, 1901.
(12) Vakalopoulos, A.; Hoffmann, H. M. R. Org. Lett. 2001, 3, 2185.
(9) Wang, Y.; Tan, W.; Li, W. Z.; Li, Y. J. Nat. Prod. 2001, 64, 196.
4314 J. Org. Chem. Vol. 73, No. 11, 2008

× 50 mL), and removal of the solvent followed by flash column
chromatography on silica gel with hexane/EtOAc (7:1) gave 5
(1.351 g, 74%) as a solid: mp 113-114 °C; H NMR (300 MHz,
18.1, 16.7; IR (neat) 3447, 2957, 1632, 1589, 1549, 1510, 1418,
1341, 1235, 1144, 1090 cm-1; EIMS m/z (%) 648 (M+, 2), 414
(23), 370 (16), 369 (20), 355 (11), 285 (13), 271 (10), 247 (32),
231 (55), 219 (12), 183 (55), 129 (13), 115 (100), 91 (10); HRMS
m/z (M+) calcd for C38H52O7Si 648.3482, found 648.3486.
Mallotophilippen C (1). To a solution of 9 (0.405 g, 0.62 mmol)
in ethanol (10 mL) was added HCl (5 drops) and the reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with saturated NaHCO3 solution (30 mL) and
extracted with EtOAc (3 × 30 mL). Removal of solvent and
purification by column chromatography on silica gel with hexane/
EtOAc (10:1) gave 1 (0.191 g, 65%) as an oil: 1H NMR (300 MHz,
CDCl3) δ 14.6, (1H, s), 8.00 (1H, d, J ) 15.6 Hz), 7.73 (1H, d, J
) 15.6 Hz), 7.48 (2H, d, J ) 8.6 Hz), 6.85 (2H, d, J ) 8.6 Hz),
6.57 (1H, d, J ) 9.9 Hz), 6.41 (1H, s), 5.61 (1H, s), 5.45 (1H, d,
J ) 9.9 Hz), 5.28 (1H, t, J ) 7.0 Hz), 5.03 (1H, t, J ) 6.8 Hz),
3.41 (2H, d, J ) 7.1 Hz), 2.17-2.09 (4H, m), 1.80 (3H, s), 1.67
(3H, s), 1.58 (3H, s), 1.51 (6H, s); 13C NMR (75 MHz, CDCl3) δ
193.0, 163.8, 157.7, 157.5, 154.7, 142.1, 140.3, 132.4, 130.2, 128.6,
125.5, 124.8, 123.5, 121.8, 116.8, 116.2, 106.2, 105.5, 102.4, 77.8,
39.8, 28.0, 26.3, 25.7, 21.7, 17.6, 16.1; IR (neat) 3450, 2975, 1605,
1537, 1452, 1350, 1263, 1166 cm-1; EIMS m/z (%) 474 (M+, 91),
460 (22), 459 (69), 405 (20), 391 (14), 389 (15), 352 (26), 351
(96), 339 (18), 335 (18), 323 (12), 286 (10), 285 (52), 269 (16),
243 (12), 232 (14), 232 (82), 230 (14), 229 (12), 216 (14), 215
(100), 189 (15), 183 (18), 149 (14), 147 (16), 135 (11), 115 (35),
69 (29); HRMS m/z (M+) calcd for C30H34O5 474.2406, found
474.2405.
1
CDCl3) δ 11.67 (1H, s), 9.70 (1H, s), 5.94 (1H, s), 5.20 (1H, t, J
) 7.0 Hz), 5.02 (1H, t, J ) 6.8 Hz), 3.27 (2H, d, J ) 7.0 Hz), 2.61
(3H, s), 2.20-1.84 (4H, m), 1.75 (3H, s), 1.62 (3H, s), 1.54 (3H,
s); 13C NMR (75 MHz, CDCl3) δ 203.7, 161.3, 140.1, 132.2, 123.5,
121.4, 105.4, 105.2, 95.3, 39.7, 32.8, 26.2, 25.7, 21.5, 17.7, 16.2;
IR (KBr) 3407, 2920, 1628, 1597, 1559, 1453, 1402, 1372, 1289
cm-1; EIMS m/z (%) 304 (M+, 38), 289 (3), 261 (9), 235 (25),
219 (22), 181 (100); HRMS m/z (M+) calcd for C18H24O4 304.1675,
found 304.1677.
Compound 6. To a solution of 5 (0.850 g, 2.79 mmol) and
3-methyl-2-butenal (0.469 g, 5.58 mmol) in CH2Cl2 (20 mL) was
added ethylenediamine diacetate (0.101 g, 0.58 mmol). The reaction
mixture was stirred at room temperature for 5 h. Evaporation of
solvent and purification by column chromatography on silica gel
with hexane/EtOAc (20:1) gave 6 (0.683 g, 66%) as a solid: mp
63-65 °C; 1H NMR (300 MHz, CDCl3) δ 14.1 (1H, s), 6.52 (1H,
d, J ) 9.9 Hz), 6.38 (1H, s), 5.40 (1H, d, J ) 9.9 Hz), 5.24 (1H,
t, J ) 7.0 Hz), 5.01 (1H, t, J ) 6.8 Hz), 3.37 (2H, d, J ) 7.0 Hz),
2.68 (3H, s), 2.15 (3H, s), 2.21-2.02 (4H, m), 1.79 (3H, s), 1.64
(3H, s), 1.58 (3H, s), 1.46 (6H, s); 13C NMR (75 MHz, CDCl3) δ
203.4, 162.9, 157.6, 155.3, 140.3, 132.3, 124.8, 123.5, 121.7, 116.6,
105.7, 105.2, 102.0, 77.7, 39.7, 33.2, 30.9, 27.9, 26.1, 25.7, 21.5,
17.7, 16.1; IR (KBr) 3297, 2971, 2924, 1645, 1607, 1564, 1466,
1427, 1381, 1317, 1256, 1200, 1175, 1132, 1094 cm-1; EIMS m/z
(%) 370 (M+, 58), 356 (13), 355 (52), 301 (35), 285 (24), 247
(42), 246 (15), 232 (15), 231 (100), 219 (10), 213 (16), 115 (14);
HRMS m/z (M+) calcd for C23H30O4 370.2144, found 370.2145.
Compound 7. Methoxymethyl chloride (0.121 g, 1.50 mmol)
was added to a solution of 6 (0.505 g, 1.36 mmol) and diisopro-
pylethylamine (0.879 g, 6.80 mmol) in dry CH2Cl2 (10 mL). The
reaction mixture was stirred at room temperature for 10 h and then
water (20 mL) was added. The reaction mixture was extracted with
CH2Cl2 (3 × 30 mL).The combined organic extracts were washed
with saturated NH4Cl solution (20 mL) and evaporated in vacuo.
Flash chromatography on silica gel with hexane/EtOAc (20:1)
Compound 10. A mixture of 4 (2.018 g, 12.0 mmol), prenyl
bromide (1.788 g, 12.0 mmol), and DBU (1.827 g, 12.0 mmol) in
dry THF (50 mL) was stirred at room temperature for 12 h. Addition
of 2 N HCl solution (50 mL), extraction with EtOAc (3 × 50 mL),
washing with brine (50 mL), and removal of the solvent followed
by flash column chromatography on silica gel with hexane/EtOAc
(5:1) gave 10 (1.134 g, 40%) as a solid: mp 166-167 °C; 1H NMR
(300 MHz, CDCl3) δ 5.82 (1H, s), 5.22 (1H, t, J ) 7.0 Hz), 3.33
(2H, d, J ) 7.1 Hz), 2.64 (3H, s), 1.80 (3H, s), 1.75 (3H, s); 13C
NMR (75 MHz, CDCl3) δ 203. 6, 163.5, 162.1, 160.5, 132.4, 122.9,
106.5, 104.9, 94.7, 32.8, 25.9, 21.4, 17.9; IR (KBr) 3418, 1634,
1402, 1370, 1285, 1235, 1150, 1073 cm-1; EIMS m/z (%) 236 (M+,
60), 221 (29), 193 (29), 181 (100), 165 (40), 153 (17), 69 (24);
HRMS m/z (M+) calcd for C13H16O4 236.1049, found 236.1050.
Compounds 11 and 12. To a solution of 10 (0.795 g, 3.36 mmol)
and citral (1.023 g, 6.72 mmol) in CH2Cl2 (20 mL) was added
ethylenediamine diacetate (0.121 g, 0.67 mmol). The reaction
mixture was stirred at room temperature for 8 h. Evaporation of
solvent and purification by column chromatography on silica gel
with hexane/EtOAc (20:1) gave 11 (0.971 g, 78%) and 12 (0.212
1
afforded 7 (0.530 g, 94%) as an oil: H NMR (300 MHz, CDCl3)
δ 13.72 (1H, s), 6.48 (1H, d, J ) 9.9 Hz), 5.44 (1H, d, J ) 9.9
Hz), 5.18 (1H, t, J ) 7.0 Hz), 5.02 (1H, t, J ) 6.8 Hz), 4.96 (2H,
s), 3.51 (3H, s), 3.27 (2H, d, J ) 6.2 Hz), 2.65 (3H, s), 2.01-1.95
(4H, m), 1.73 (3H, s), 1.69 (3H, s), 1.53 (3H, s), 1.45 (6H, s); 13
C
NMR (75 MHz, CDCl3) δ 204.6, 163.8, 158.5, 155.2, 135.6, 131.7,
126.2, 124.8, 123.1, 118.3, 115.5, 108.8, 107.1, 100.5, 58.3, 40.1,
34.0, 28.1, 27.0, 26.1, 22.9, 18.1, 16.6; IR (neat) 2930, 1616, 1424,
1364, 1287, 1161, 1134, 1049 cm-1; EIMS m/z (%) 414 (M+, 66),
399 (22), 370 (17), 369 (58), 367 (11), 313 (10), 291 (17), 285
(25), 271 (26), 259 (12), 247 (54), 246 (15), 245 (12), 232 (15),
231 (100), 217 (14), 213 (13), 69 (14); HRMS m/z (M+) calcd for
C25H34O5 414.2406, found 414.2408.
1
g, 17%). 11: H NMR (300 MHz, CDCl3) δ 14.1 (1H, s), 6.56
(1H, d, J ) 9.9 Hz), 6.30 (1H, s), 5.37 (1H, d, J ) 9.9 Hz), 5.24
(1H, t, J ) 7.1 Hz), 5.07 (1H, t. J ) 7.1 Hz), 3.36 (2H, d, J ) 7.2
Hz), 2.64 (3H, s), 2.17-2.03 (2H, m), 1.85-1.80 (2H, m), 1.81
(3H, s), 1.76 (3H, s), 1.64 (3H, s), 1.55 (3H, s), 1.41 (3H, s); 13C
NMR (75 MHz, CDCl3) δ 203.3, 162.9, 157.4, 155.5, 136.5, 132.1,
123.7, 123.4, 121.7, 117.0, 80.5, 41.5, 33.3, 26.5, 25.9, 25.6, 23.1,
21.5, 17.9, 17.6; IR (neat) 3349, 2930, 1615, 1429, 1372, 1294
cm-1; EIMS m/z (%) 370 (M+, 34), 355 (13), 315 (12), 303 (29),
288 (20), 287 (100), 285 (10), 247 (11), 235 (12), 232 (11), 231
(68), 219 (14), 213 (10); HRMS m/z (M+) calcd for C23H30O4
370.2144, found 370.2146. 12: 1H NMR (300 MHz, CDCl3) δ 13.55
(1H, s), 6.66 (1H, d, J ) 9.9 Hz), 5.39 (1H, d, J ) 9.9 Hz), 5.17
(1H, t, J ) 7.1 Hz), 5.06 (1H, t. J ) 7.1 Hz), 3.31 (2H, d, J ) 7.2
Hz), 2.63 (3H, s), 2.10-2.0 (2H, m), 1.82 (3H, s), 1.81-1.70 (2H,
m), 1.75 (3H, s), 1.63 (3H, s), 1.55 (3H, s), 1.36 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 203.5, 159.3, 158.5, 157.4, 135.8, 131.8, 124.2,
123.8, 122.9, 121.5, 116.6, 105.0, 102.1, 80.3, 41.5, 33.0, 26.8,
25.8, 25.6, 22.6, 21.2, 17.8, 17.6; IR (neat) 2974, 1615, 1429, 1370,
1294 cm-1; EIMS m/z (%) 370 (M+, 45), 369 (10), 355 (22), 331
(10), 318 (21), 315 (21), 304 (13), 303 (62), 301 (13), 289 (10),
Compound 9. To a solution of 7 (0.450 g, 1.09 mmol) in ethanol
(10 mL) was added KOH (0.306 g, 5.45 mmol) and aldehyde 8
(0.331 g, 1.31 mmol). The reaction mixture was stirred at room
temperature for 48 h. Evaporation of ethanol, addition of 2 N HCl
(30 mL), extraction with EtOAc (3 × 50 mL), washing with brine
(30 mL), and removal of the solvent followed by flash column
chromatography on silica gel with hexane/EtOAc (20:1) gave 9
1
(0.538 g, 76%) as an oil: H NMR (300 MHz, CDCl3) δ 13.96
(1H, s), 7.97 (1H, d, J ) 15.6 Hz), 7.76 (1H, d, J ) 15.6 Hz), 7.53
(2H, d, J ) 8.8 Hz), 7.06 (2H, d, J ) 8.8 Hz), 6.52 (1H, d, J ) 9.9
Hz), 5.50 (1H, d, J ) 9.9 Hz), 5.49 (2H, s), 5.25 (2H, s), 5.20 (1H,
t, J ) 7.0 Hz), 5.04 (1H, t, J ) 6.8 Hz), 3.74 (2H, dd, J ) 8.4, 8.3
Hz), 3.57 (3H, s), 3.31 (2H, d, J ) 6.3 Hz), 2.06-1.97 (4H, m),
1.75 (3H, s), 1.62 (3H, s), 1.55 (3H, s) 1.52 (6H, s), 0.94 (2H, dd,
J ) 8.4, 8.3 Hz), -0.03 (9H, s); 13C NMR (75 MHz, CDCl3) δ
194.0, 164.0, 159.4, 158.4, 154.6, 142.8, 135.5, 132.2, 131.6, 130.3,
129.6, 126.0, 124.8, 123.3, 118.5, 117.0, 116.7, 115.8, 109.3, 107.4,
100.6, 94.6, 94.5, 78.0, 58.3, 56.7, 56.6, 40.1, 28.2, 27.1, 26.1, 23.1,
J. Org. Chem. Vol. 73, No. 11, 2008 4315

288 (22), 287 (100), 285 (21), 273 (11), 259 (10), 247 (23), 235
(26), 233 (12), 232 (11), 231 (62), 219 (21), 81 (13); HRMS m/z
(M+) calcd for C23H30O4 370.2144, found 370.2145.
m), 0.00 (27H, s); 13C NMR (75 MHz, CDCl3) δ 193.2, 165.5,
159.4, 155.9, 150.7, 148.9, 144.1, 133.3, 132.7, 130.8, 127.1, 125.7,
124.9, 124.6, 124.2, 119.7, 117.0, 116.5, 116.3, 109.8, 107.8, 99.4,
94.5, 81.0, 68.7, 67.4, 67.3, 41.9, 27.1, 26.3, 26.2, 23.5, 23.3, 18.7,
18.6, 18.5, 18.4, 18.1, -1.0; IR (neat) 2955, 1632, 1589, 1553,
1508, 1416, 1381, 1341, 1254, 1094 cm-1; EIMS m/z (%) 881 (M+,
23), 798 (21), 667 (11), 343 (24), 215 (14), 103 (11), 75 (10), 73
(100), 69 (10); HRMS m/z (M+) calcd for C48H76O9Si3 880.4797,
found 880.4800.
Mallotophilippen E (3). To a solution of 15 (0.320 g, 0.36
mmol) in ethanol (10 mL) was added HCl (5 drops) and the reac-
tion mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with saturated NaHCO3 solution (30 mL) and
extracted with EtOAc (3 × 30 mL). Removal of solvent at reduced
pressure left an oily residue, which was then purified by column
chromatography on silica gel with hexane/EtOAc (20:1) to give 3
(0.099 g, 56%) as an oil: 1H NMR (300 MHz, benzene-d6) δ 15.4
(1H, s), 8.23 (1H, d, J ) 15.5 Hz), 8.00 (1H, d, J ) 15.6 Hz),
7.05-6.96 (2H, m), 6.87 (1H, d, J ) 10.0 Hz), 6.62 (1H, br s),
6.30 (1H, br s), 5.16 (1H, d, J ) 10.0 Hz), 5.18-5.11 (2H, m),
3.47 (2H, d, J ) 7.1 Hz), 2.28-2.14 (2H, m), 1.87-1.67 (2H, m),
1.61 (3H, s), 1.49 (3H, s), 1.45 (6H, s), 1.31 (3H, s); 13C NMR (75
MHz, benzene-d6) δ 193.9, 165.2, 158.3, 155.9, 147.3, 145.0, 143.5,
136.2, 132.5, 129.7, 126.5, 124.8, 124.2, 123.2, 122.8, 118.2, 116.2,
115.5, 107.2, 106.6, 102.8, 80.9, 42.0, 26.8, 26.1, 25.9, 23.8, 22.4,
18.0, 17.9; IR (neat) 23389, 2973, 1597, 1520, 1447, 1354, 1283,
1152 cm-1; EIMS m/z (%) 490 (M+, 53), 475 (13), 435 (10), 408
(26), 407 (100), 271 (15), 215 (41); HRMS m/z (M+) calcd for
C30H34O6 490.2355, found 490.2353.
Compound 13. 2-(Trimethylsilyl)ethoxymethyl chloride (0.233
g, 1.40 mmol) was added to a solution of 11 (0.470 g, 1.27 mmol)
and diisopropylethylamine (0.821 g, 6.35 mmol) in dry CH2Cl2 (10
mL). The reaction mixture was stirred at room temperature for 12 h
and then water (20 mL) was added. The reaction mixture was
extracted with CH2Cl2 (3 × 30 mL) and the combined organic
extracts were washed with saturated NH4Cl solution (30 mL) and
water (20 mL), then evaporated in vacuo. Flash chromatography
on silica gel with hexane/EtOAc (30:1) afforded 13 (0.591 g, 93%)
1
as an oil: H NMR (300 MHz, CDCl3) δ 13.72 (1H, s), 6.55 (1H,
d, J ) 10.0 Hz), 5.40 (1H, d, J ) 10.0 Hz), 5.18 (1H, t, J ) 6.6
Hz), 5.05 (1H, t. J ) 6.6 Hz), 5.00 (2H, s), 3.80 (2H, dd, J ) 7.7,
7.5 Hz), 3.26 (2H, d, J ) 6.5 Hz), 2.64 (3H, s), 2.17-2.04 (2H,
m), 1.86-1.70 (2H, m), 1.73 (3H, s), 1.66 (3H, s), 1.61 (3H, s),
1.52 (3H, s), 1.40 (3H, s), 0.95 (2H, dd, J ) 7.7, 7.5 Hz), -0.02
(9H, s); 13C NMR (75 MHz, CDCl3) δ 203.7, 163.3, 157.9, 154.9,
131.8, 131.1, 124.1, 123.5, 122.9, 118.4, 114.8, 108.0, 106.4, 98.2,
80.0, 67.6, 53.3, 41.2, 33.4, 26.1, 25.6, 25.5, 23.0, 22.4, 18.0, 17.7,
17.4, -1.63; IR (neat) 3567, 2971, 1616, 1422, 1283, 1055 cm-1
;
EIMS m/z (%) 500 (M+, 4), 427 (17), 360 (26), 359 (100), 213
(11), 73 (20); HRMS m/z (M+) calcd for C29H44O5Si 500.2958,
found 500.2961.
Compound 15. To a solution of 13 (0.390 g, 0.78 mmol) in
ethanol (10 mL) was added KOH (0.219 g, 3.90 mmol) and
aldehyde 14 (0.373 g, 0.94 mmol). The reaction mixture was stirred
at room temperature for 48 h. Evaporation of ethanol, addition of
2 N HCl (30 mL), extraction with EtOAc (3 × 50 mL), washing
with brine (30 mL), and removal of the solvent followed by flash
column chromatography on silica gel with hexane/EtOAc (30:1)
Acknowledgment. This work was supported by grant No.
RTI04-01-04 from the Regional Technology Innovation Program
of the Ministry of Commerce, Industry, and Energy (MOCIE).
1
gave 15 (0.495 g, 72%) as an oil: H NMR (300 MHz, CDCl3) δ
14.08 (1H, s), 7.95 (1H, d, J ) 15.5 Hz), 7.74 (1H, d, J ) 15.5
Hz), 7.45 (1H, s), 7.30-7.20 (2H, m), 6.57 (1H, d, J ) 10.0 Hz),
5.45 (1H, d, J ) 10.0 Hz), 5.31 (2H, s), 5.30 (2H, s), 5.20 (1H, t,
J ) 6.6 Hz), 5.03 (3H, m), 3.85-3.75 (6H, m), 3.30 (2H, d, J )
6.0 Hz), 2.14-2.10 (2H, m), 1.89-1.70 (2H, m), 1.75 (3H, s), 1.67
(3H, s), 1.59 (3H, s), 1.51 (3H, s), 1.43 (3H, s), 0.98-0.91 (6H,
Supporting Information Available: Copies of 1H NMR and
13C NMR for all product. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO800367R
4316 J. Org. Chem. Vol. 73, No. 11, 2008