First total synthesis of mappain with a prenylated and geranylated stilbene

Article abstract of DOI:10.1002/hlca.200900318

The first total synthesis of naturally occurring mappain has been achieved by a convergent sequence. The key strategy involved in the synthesis of mappain was a (E)-stilbene formation by Horner -Wadsworth -Emmons reaction of the corresponding prenylated b

Full text of DOI:10.1002/hlca.200900318

Helvetica Chimica Acta – Vol. 93 (2010)
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First Total Synthesis of Mappain with a Prenylated and Geranylated Stilbene
by Lakkoju Chakrapani, Eun Mi Jung, and Yong Rok Lee*
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Korea
(phone: þ 82-53-810 – 2529; fax: þ 82-53-810-4631; e-mail: yrlee@yu.ac.kr)
The first total synthesis of naturally occurring mappain has been achieved by a convergent sequence.
The key strategy involved in the synthesis of mappain was a (E)-stilbene formation by Horner– Wads-
worth – Emmons reaction of the corresponding prenylated benzaldehyde with a geranylated benzyl
phosphonate.
Introduction. – Molecules bearing the stilbene moiety are widely found in nature
[1], and have a variety of interesting biological activities and properties, including
antimicrobial [2], antimalarial [3], antioxidant [4], antileukemic [5], anti-platelet
aggregative [6], anticarcinogenic [7], anti-HIV [8], protein tyrosine kinase inhibitory
[9], anti-inflammatory [10], antimutagenic [11], antifungal [12], and hepatoprotective
[13] activities. In the course of the investigation to identify new anticancer lead
compounds from Asian botanical sources, mappain (1) with a prenylated and
geranylated stilbene was isolated from the leaves of Macaranga mappa (Fig.) [14].
The lipophilic crude extract of these leaves has shown potent cytotoxicity against both
drug-resistant (SKVLB-1) and drug-sensitive (SK-OV-3) ovarian cancer cell lines with
an IC50 value of 3.5 mg/ml [14].
Figure. Structure of mappain (1)
This range of important biological activities and properties has stimulated research
of the total synthesis of mappain (1). Even though the structure of this natural product
was well-established by spectroscopic analysis, its total synthesis remained unreported.
Recently, we developed efficient and useful synthetic routes for preparing stilbenes
[15]. As part of an ongoing study of the efficacy of this synthetic approach, the synthesis
of 1 with a prenylated and geranylated stilbene moiety has been attempted. Herein, the
first total synthesis of the naturally occurring mappain (1) is reported.
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Results and Discussion. – In Scheme 1, the retrosynthetic analysis for mappain (1)
through disconnection is shown. Mappain (1) could be prepared by a Horner– Wads-
worth – Emmons reaction of the arene-carbaldehyde 2 and the benzyl phosphonate 3.
Benzaldehyde 2 can be prepared from readily available methyl 4-bromo-3,5-
dihydroxybenzoate (4), while phosphonate 3 can be derived from 3-bromo-4,5-
dihydroxybenzaldehyde (5).
Scheme 1
The synthetic approach of benzaldehyde 2 as the left half of 1 is shown in Scheme 2.
Protection of ester 4 with methoxymethyl chloride (MOMCl) in the presence of N,N-
diisopropylethylamine (DIPEA) to give 6, followed by reduction with LiAlH4,
t
provided benzyl alcohol 7 in 81% yield (two steps). Reaction of 7 with BuMe2SiCl
(TBSCl) proceeded smoothly to afford silyl ether 8 in 90% yield. Transmetallation of 8
with BuLi in the presence of CuBr/dimethyl sulfide complex [16], followed by addition
of prenyl bromide to trap the intermediate anion derived from halogen – metal
exchange, afforded the expected prenylated compound, which was cleavaged with
Bu4NF (TBAF) to give benzyl alcohol 9 in 60% yield (two steps). Oxidation of 9 with
Dess – Martin periodinane (DMP) finally provided benzaldehyde 2 in 80% yield (cf.
[17]).
As shown in Scheme 3, the synthesis of phosphonate 3 as the right half of 1 began
with the readily available 3-bromo-4,5-dihydroxybenzaldehyde (5). Reaction of 5 with
2.2 equiv. of MOMCl in the presence of NaH afforded compound 10 in 85% yield.

Helvetica Chimica Acta – Vol. 93 (2010)
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Scheme 2
Reduction of 10 with NaBH4 in MeOH gave benzyl alcohol 11 in 90% yield. Treatment
of 11 with TBSCl in the presence of 1H-imidazole gave silyl ether 12 in 85% yield.
Compound 13 was produced in 61% yield (two steps) by halogen – metal exchange and
alkylation reaction using BuLi with geranyl bromide in THF, followed by cleavage of
the silyl ether with TBAF in THF. Alcohol 13 was then converted to the corresponding
iodide 14 (80%, two steps) by formation of the methanesulfonate, followed by
displacement with NaI. Reaction of 14 with P(OEt)3 in refluxing xylene for 12 h
afforded the desired phosphonate 3 in 98% yield (cf. [18]).
Scheme 3
To complete the total synthesis of natural mappain (1), stilbene formation was
carried out as shown in Scheme 4. The Horner– Wadsworth – Emmons reaction of
benzaldehyde 2 with phosphonate 3 in the presence of t-BuOK in THF gave the desired
(E)-stilbene 15 in 66% yield (cf. [19]). Deprotection of the four MOM ether groups of

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Helvetica Chimica Acta – Vol. 93 (2010)
compound 15 with concentrated HCl in MeOH at room temperature for 12 h afforded
mappain (1) in 62% yield. The spectral data of synthetic material 4 were in agreement
with those reported in [14].
Scheme 4
Conclusions. – The first total synthesis of mappain (1) has been accomplished by a
convergent sequence. The key strategy for the synthesis of mappain (1) was the (E)-
stilbene formation by a Horner– Wadsworth – Emmons reaction of benzaldehyde 2 and
phosphonate 3, synthesized from readily available benzoate 4 and 3-bromo-4,5-
dihydroxybenzaldehyde (5), respectively, in a straightforward fashion.
This work was supported by grant No. RTI04-01-04 from the Regional Technology Innovation
Program of the Ministry of Knowledge Economy (MKE).
Experimental Part
General. All experiments were carried out under N2. Anal. TLC: Merck pre-coated SiO2 plates (Art.
5554) with a fluorescent indicator. Flash column chromatography (FCC): SiO2 9385. IR Spectra: Jasco
FTIR 5300 spectrophotometer. 1H- and 13C-NMR spectra: Bruker Model ARX (300 and 75 MHz, resp.)
spectrometer; in CDCl3 as the solvent. HR Mass spectra were recorded at the Korea Basic Science
Institute.
Methyl 4-Bromo-3,5-bis(methoxymethoxy)benzoate (6). MeOCH2Cl (3.0 g, 37.5 mmol) was added
to a soln. of 4 (3.70 g, 15.0 mmol) and DIPEA (EtN(i-Pr)2; 9.675 g, 75.0 mmol) in dry CH2Cl2 (50 ml) at
r.t. The mixture was refluxed for 6 h, and then H2O (50 ml) was added. The mixture was extracted with
CH2Cl2 (3 ꢀ 50 ml), and the combined org. extracts were washed with sat. NH4Cl soln. (50 ml) and then
H2O (30 ml). The org. layers were dried (anh. Na2SO4), and removal of solvent at reduced pressure left
an oily residue, which was then purified by CC (SiO2; hexane/AcOEt 5 :1) to give 6 (4.50 g, 90%). Solid.
M.p. 128 – 1298. IR (KBr): 2938, 2834, 1722, 1592, 1436, 1320, 1242, 1156, 1045, 903, 762. 1H-NMR
(CDCl3, 300 MHz): 7.46 (s, 2 H); 5.28 (s, 4 H); 3.88 (s, 3 H); 3.50 (s, 6 H). 13C-NMR (CDCl3, 75 MHz):
166.1; 154.8; 130.3; 109.9; 109.4; 95.05; 56.5; 52.4. HR-MS: 334.0050 (Mþ, C12H15BrO6þ ; calc. 334.0052).

Helvetica Chimica Acta – Vol. 93 (2010)
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[4-Bromo-3,5-bis(methoxymethoxy)phenyl]methanol (7). To a soln. of 6 (3.35 g, 10.0 mmol) in dry
Et2O (20 ml), LiAlH4 (0.76 g, 20.0 mmol) was added carefully at 08, and the mixture was stirred at r.t. for
2 h. The reaction was quenched by the addition of H2O (40 ml), and the mixture was extracted with
AcOEt (3 ꢀ 30 ml). The org. layer was washed with sat. NH4Cl soln. (30 ml), then dried (anh. Na2SO4),
and concentrated under reduced pressure to afford the crude residue. The resulting residue was purified
by FCC (SiO2; hexane/AcOEt 3 :1) to give 7 (2.76 g, 90%). Liquid. IR (neat): 3252, 3150, 2953, 1592,
1443, 1311, 1243, 1157, 1041, 916, 831, 692, 645. 1H-NMR (CDCl3, 300 MHz): 7.30 (s, 2 H); 5.72 (s, 4 H);
5.06 (s, 2 H); 4.00 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 154.7; 141.8; 107.5; 102.5; 94.8; 64.4; 56.3. HR-
MS: 306.0101 (Mþ, C11H15BrOþ5 ; calc. 306.0103).
{[4-Bromo-3,5-bis(methoxymethoxy)benzyl]oxy}(tert-butyl)dimethylsilane (8). To a soln. of
7
(1.53 g, 5.0 mmol) in dry DMF (10 ml), 1H-imidazole (0.85 g, 12.5 mmol), and TBSCl (tBuMe2SiCl;
0.90 g, 6.0 mmol) were added. The mixture was stirred for 10 h. The reaction was quenched by the
addition of H2O (40 ml), and the mixture was extracted with AcOEt (3 ꢀ 30 ml). The org. layer was
washed with sat. NH4Cl soln. (30 ml), dried (anh. Na2SO4), and concentrated under reduced pressure to
afford the crude residue. The resulting residue was purified by FCC (SiO2; hexane/AcOEt 7:1) to give 8
(1.80 g, 90%). Liquid. IR (neat): 2952, 1677, 1589, 1445, 1255, 1157, 1103, 1051, 922, 843, 779, 684.
1H-NMR (CDCl3, 300 MHz): 6.82 (s, 2 H); 5.21 (s, 4 H); 4.65 (s, 2 H); 3.47 (s, 6 H); 0.91 (s, 9 H); 0.06 (s,
6 H). 13C-NMR (CDCl3, 75 MHz): 154.6; 142.4; 106.8; 101.4; 94.9; 64.3; 56.2; 25.7; 18.2; ꢁ 5.4. HR-MS:
420.0969 (Mþ, C17H29BrO5Siþ; calc. 420.0968).
[3,5-Bis(methoxymethoxy)-4-(3-methylbut-2-en-1-yl)phenyl]methanol (9). To a soln. of 8 (0.42 g,
1.0 mmol) in dry THF (10 ml) at ꢁ 788, BuLi (0.48 ml, 2.5m in hexane, 1.2 mmol) was added, and the
mixture was stirred for 1 h. Then, CuBr/DMS complex (0.205 g, 1.0 mmol) was added in one portion, the
resulting soln. was stirred for 20 min, and then prenyl bromide (0.224 g, 1.5 mmol) was added dropwise.
The mixture was stirred at ꢁ 788 for 2 h and allowed to stirred for 10 h at r.t. The org. layer was washed
with sat. NH4Cl soln. (30 ml), dried (anh. Na2SO4) and concentrated under reduced pressure to afford a
crude residue. To the soln. of the crude residue in THF (10 ml), TBAF (1.5 mmol) was added at 08, and
the mixture was stirred at r.t. for 3 h. The reaction was quenched by the addition of sat. NH4Cl soln.
(30 ml), and the mixture was extracted with AcOEt (3 ꢀ 30 ml). The org. layer was washed with H2O
(30 ml), dried (anh. Na2SO4), and concentrated under reduced pressure to afford the crude residue,
which was purified by CC (SiO2; hexane/AcOEt 4 :1) to afford 9 (0.178 g, 60%). Liquid. IR (neat): 3432,
2917, 1593, 1439, 1294, 1153, 1047, 927, 845, 693. 1H-NMR (CDCl3, 300 MHz): 6.78 (s, 2 H); 5.17 – 5.13 (m,
1 H); 5.14 (s, 4 H); 4.56 (s, 2 H); 3.44 (s, 6 H); 3.35 (d, J ¼ 7.2, 2 H); 1.76 (s, 3 H); 1.63 (s, 3 H). 13C-NMR
(CDCl3, 75 MHz): 155.6; 140.0; 131.0; 122.7; 119.2; 106.3; 94.2; 65.3; 55.9; 25.7; 22.6; 17.7. HR-MS:
296.1626 (Mþ, C16H24Oþ5 ; calc. 296.1624).
3,5-Bis(methoxymethoxy)-4-(3-methylbut-2-en-1-yl)benzaldehyde (2). To a stirred soln. of
9
(0.318 g, 1.1 mmol) in dry CH2Cl2 (10 ml) was added Dess – Martin periodane (0.458 g, 1.1 mmol) at
08, and the mixture was stirred at r.t. for 3 h. The reaction was quenched with sat. NaHCO3 soln. (30 ml),
and the mixture was extracted with CH2Cl2 (3 ꢀ 30 ml). The org. layers were washed with sat. sodium
thiosulfate soln. (20 ml) and H2O (30 ml), dried (anh. Na2SO4), and concentrated under reduced
pressure to afford a crude residue. The resulting residue was purified by CC (SiO2; hexane/AcOEt 9 :1)
to afford 2 (0.235g, 80%). Liquid. IR (neat): 3380, 2917, 2832, 2728, 1697, 1585, 1444, 1381, 1295, 1156,
1050, 934, 852, 732, 658. 1H-NMR (CDCl3, 300 MHz): 9.85 (s, 1 H); 7.28 (s, 2 H); 5.24 (s, 4 H); 5.13 (t, J ¼
7.0, 1 H); 3.46 (s, 6 H); 3.41 (d, J ¼ 7.0, 1 H); 1.77 (s, 3 H); 1.64 (s, 3 H). 13C-NMR (CDCl3, 75 MHz):
191.7; 155.9; 135.4; 132.2; 127.3; 121.3; 108.8; 94.3; 56.1; 25.8; 23.2; 17.8. HR-MS: 294.1469 (Mþ,
C16H22Oþ5 ; calc. 294.1467).
3-Bromo-4,5-bis(methoxymethoxy)benzaldehyde (10). To a stirred soln. of 5-bromo-3,4-dihydroxy-
benzaldehyde (5; 2.0 g, 9.2 mmol) in dry DMF (40 ml) at 08 was added NaH (2.20 g, 92.0 mmol), and the
soln. was stirred for 10 min. To the mixture, MOMCl (1.840 g, 23.0 mmol) was added slowly, and the
reaction was run for 1 h. The reaction was quenched by the addition of H2O (30 ml), and the mixture was
extracted with AcOEt (3 ꢀ 50 ml). The org. layer was washed with sat. NH4Cl soln. (30 ml), dried (anh.
Na2SO4), and concentrated under reduced pressure to afford a crude residue. FCC (SiO2; hexane/AcOEt
5 :1) afforded 10 (2.380 g, 85%). Liquid. IR (neat): 2956, 2833, 1696, 1568, 1478, 1380, 1276, 1158, 1082,
1011, 936, 745, 669. 1H-NMR (CDCl3, 300 MHz): 9.80 (s, 1 H); 7.70 (s, 1 H); 7.57 (s, 1 H); 5.26 (s, 2 H);

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Helvetica Chimica Acta – Vol. 93 (2010)
5.22 (s, 2 H); 3.61(s, 3 H); 3.46 (s, 3 H). 13C-NMR (CDCl3, 75 MHz): 189.5; 151.1; 149.2; 133.1; 128.7;
118.3; 115.2; 98.8; 95.1; 58.0; 56.5. HR-MS: 303.9948 (Mþ, C11H13BrO5þ ; calc. 303.9946).
[3-Bromo-4,5-bis(methoxymethoxy)phenyl]methanol (11). To a stirred soln. of 10 (1.0 g, 3.3 mmol)
in MeOH at 08 was added NaBH4 (0.186 g, 4.9 mmol) in small portions, and the reaction was run for 1 h.
The reaction was quenched by the addition of H2O (30 ml), and the mixture was extracted with AcOEt
(3 ꢀ 40 ml). The org. layer was washed with sat. NH4Cl soln. (40 ml), dried (anh. Na2SO4), and
concentrated under reduced pressure to afford a crude residue. FCC (SiO2; hexane/AcOEt 3 :1) afforded
1
11 (0.90 g, 90%). Liquid. IR (neat): 3430, 2935, 1569, 1481, 1275, 1157, 1006, 949, 852, 676. H-NMR
(CDCl3, 300 MHz): 7.17 (s, 1 H); 7.05 (s, 1 H); 5.15 (s, 2 H); 5.13 (s, 2 H); 4.54 (s, 2 H); 3.62 (s, 3 H); 3.45
(s, 3 H). 13C-NMR (CDCl3, 75 MHz): 150.9; 143.2; 138.4; 124.5; 117.8; 114.2; 98.8; 95.2; 64.1; 57.9; 56.4.
HR-MS: 306.0103 (Mþ, C11H15BrOþ5 ; calc. 306.0103).
{[3-Bromo-4,5-bis(methoxymethoxy)benzyl]oxy}(tert-butyl)dimethylsilane (12). To a stirred soln. of
11 (0.80 g, 2.6 mmol) in dry DMF (10 ml) at 08 was added 1H-imidazole (0.443 g, 6.5 mmol), and the
mixture was stirred for 10 – 15 min. TBSCl (0.471 g, 3.1 mmol) was added carefully, and the mixture was
allowed to stirred at r.t. for 10 h. The reaction was quenched by the addition of H2O (30 ml), and the
mixture was extracted with AcOEt (3 ꢀ 30 ml). The org. layer was washed with sat. NH4Cl soln. (30 ml),
dried (anh. Na2SO4), and concentrated under reduced pressure to give a crude residue. FCC (SiO2;
hexane/AcOEt 4 :1) afforded 12 (0.932 g, 85%). Liquid. IR (neat): 2952, 1570, 1479, 1262, 1158, 1093,
1011, 954, 842, 675. 1H-NMR (CDCl3, 300 MHz): 7.14 (s, 1 H); 7.06 (s, 1 H); 5.15 (s, 2 H); 5.14 (s, 2 H);
4.61 (s, 2 H); 3.63 (s, 3 H); 3.46 (s, 3 H); 0.92 (s, 9 H); 0.07 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 150.8;
142.7; 138.9; 123.6; 117.5; 113.5; 98.8; 95.2; 63.9; 57.9; 56.2; 25.9; 18.3; ꢁ 5.3. HR-MS: 420.0970 (Mþ,
C17H29BrO5Siþ; calc. 420.0968).
{3-[(2E)-3,7-Dimethylocta-2,6-dien-1-yl]-4,5-bis(methoxymethoxy)phenyl}methanol (13). To a soln.
of 12 (0.80 g, 1.9 mmol) in dry THF (10 ml) at ꢁ 788 was added BuLi (0.9 ml, 2.5m in hexane, 2.3 mmol),
and the mixture was stirred for 1 h. To the mixture was added geranyl bromide (0.618 g, 2.85 mmol)
slowly via syringe, and the reaction was run at the same temp. for 2 h. Then, the mixture was stirred at 08
for 12 h, and the reaction was quenched by the addition of H2O (30 ml), and the mixture was extracted
with AcOEt (3 ꢀ 30 ml). The org. layer was washed with sat. NH4Cl soln. (30 ml), dried (anh. Na2SO4),
and concentrated under reduced pressure to afford a crude residue. To the soln. of the crude residue in
THF (10 ml) was added TBAF (1.9 ml, 1.9 mmol, 1.0m in THF) at 08, and the soln. was stirred at r.t. for
3 h. The reaction was quenched by the addition of sat. NH4Cl soln. (30 ml), and the mixture was
extracted with AcOEt (3 ꢀ 30 ml). The org. layer was washed with H2O (30 ml), dried (anh. Na2SO4),
and concentrated under reduced pressure to give a crude residue, which was purified by CC (hexane/
AcOEt 4 :1) to afforded 13 (0.423 g, 61%). Liquid. IR (neat): 3456, 2924, 1597, 1447, 1297, 1155, 1042.
1H-NMR (CDCl3, 300 MHz): 6.98 (s, 1 H); 6.81 (s, 1 H); 5.28 (t, J ¼ 7.2, 1 H); 5.16 (s, 2 H); 5.07 (s, 3 H);
4.55 (s, 2 H); 3.57 (s, 3 H); 3.47 (s, 3 H); 3.40 (d, J ¼ 7.2, 2 H); 2.14 – 1.98 (m, 4 H); 1.69 (s, 3 H); 1.65 (s,
3 H); 1.57 (s, 3 H). 13C-NMR (CDCl3, 75 MHz): 149.6; 143.9; 137.0; 136.1; 135.9; 131.2; 124.1; 122.4;
121.4; 112.6; 98.9; 94.9; 64.8; 57.3; 56.0; 39.6; 28.3; 26.5; 25.5; 17.5; 16.0. HR-MS: 364.2252 (Mþ,
C21H32Oþ5 ; calc. 364.2250).
1-[(2E)-3,7-Dimethylocta-2,6-dien-1-yl]-5-(iodomethyl)-2,3-bis(methoxymethoxy)benzene (14). To
a soln. of 13 (0.75 g, 2.1 mmol) in CH2Cl2 (10 ml) at 08 was added DIPEA (1.329 g, 10.3 mmol), and the
soln. was stirred for few min. To the mixture was added MsCl (0.934 g, 8.2 mmol) slowly, and the reaction
was continued for 4 h. The reaction was quenched by the addition of H2O (30 ml), and the mixture was
extracted with CH2Cl2 (3 ꢀ 30 ml). The org. layer was washed with sat. NH4Cl soln. (30 ml), dried (anh.
Na2SO4), and concentrated under reduced pressure to afford a crude residue. To the soln. of crude
residue in dry acetone (10 ml) was added NaI (1.54 g, 10.3 mmol), and the mixture was stirred at r.t. for
further 24 h. The reaction was quenched by the addition of H2O (30 ml), and the mixture was extracted
with AcOEt (3 ꢀ 30 ml). The org. layer was washed with sat. NaHSO3 soln. (30 ml), dried (anh.
Na2SO4), and concentrated under reduced pressure to afford a crude residue. The resulting residue was
purified by CC (SiO2; hexane/AcOEt 10 :1) to afford 14 (0.78 g, 80%). Liquid. IR (neat): 2920, 1587,
1481, 1295, 1157, 1036, 968, 652. 1H-NMR (CDCl3, 300 MHz): 6.98 (d, J ¼ 2.0, 1 H); 6.83 (d, J ¼ 2.0 Hz,
1 H); 5.27 (t, J ¼ 7.0, 1 H); 5.15 (s, 2 H); 5.09 (t, J ¼ 6.9, 1 H); 5.07 (s, 2 H), 4.37 (s, 2 H); 3.57 (s, 3 H);

Helvetica Chimica Acta – Vol. 93 (2010)
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3.50 (s, 3 H); 3.36 (d, J ¼ 7.0, 2 H); 2.11 – 2.01 (m, 4 H); 1.68 (s, 3 H), 1.67 (s, 3 H), 1.59 (s, 3 H). 13C-NMR
(CDCl3, 75 MHz): 149.6; 144.4; 136.6; 136.3; 134.9; 131.4; 124.2; 123.4; 122.1; 114.5; 98.9; 95.1; 57.4; 56.2;
39.7; 28.3; 26.6; 25.7; 17.7; 16.1; 6.2.
Diethyl {3-[(2E)-3,7-Dimethylocta-2,6-dien-1-yl]-4,5-bis(methoxymethoxy)benzyl}phosphonate (3).
To a soln. of 14 (0.50 g, 1.1 mmol) in xylene was added P(OEt)3 (0.266 g, 1.6 mmol), and the mixture was
refluxed for 12 h. After the mixture was allowed to cool to r.t., the extra P(OEt)3 was removed under high
vacuum. The crude yellow oil was purified by CC (SiO2; hexane/AcOEt 1:2) to afford 3 (0.50 g, 98%).
1
Liquid. IR (neat): 2948, 1590, 1484, 1254, 1158, 1035, 968.5, 799.5, 674.6. H-NMR (CDCl3, 300 MHz):
6.90 (t, J ¼ 2.4, 1 H); 6.71 (t, J ¼ 2.4, 1 H); 5.25 (t, J ¼ 7.0, 1 H); 5.13 (s, 2 H); 5.08 – 5.03 (m, 1 H); 5.03 (m,
2 H); 4.04 – 3.93 (m, 4 H); 3.55 (s, 3 H); 3.45 (s, 3 H); 3.35 (d, J ¼ 7.0, 2 H); 2.98 (d, J ¼ 21.3, 2 H); 2.07 –
1.97 (m, 4 H); 1.66 (s, 3 H); 1.63 (s, 3 H); 1.55 (s, 3 H); 1.23 – 1.18 (m, 6 H). 13C-NMR (CDCl3, 75 MHz):
149.3; 143.4; 135.9; 135.8; 130.9; 127.1; 124.1; 123.9; 122.2; 115.3; 98.7; 94.8; 61.7; 61.6; 57.0; 55.8; 39.4;
33.9; 32.1; 28.0; 26.3; 25.3; 17.3; 16.0; 15.8. HR-MS: 484.2593 (Mþ, C25H41O7Pþ; calc. 484.2590).
5-{(E)-2-[3,5-Bis(methoxymethoxy)-4-(3-methylbut-2-en-1-yl)phenyl]ethenyl}-1-[(2E)-3,7-dimethy-
locta-2,6-dien-1-yl]-2,3-bis(methoxymethoxy)benzene; 15). To a soln. of 2 (0.191 g, 0.4 mmol) in dry THF
(10 ml), t-BuOK (0.219 g, 2.0 mmol) was added in one portion, and the mixture was stirred for few min at
08. To the mixture was added 3 (0.127 g, 0.4 mmol) in THF (1 ml) slowly, and the mixture was stirred at
r.t. for 10 h. The reaction was quenched by the addition of H2O (30 ml), and the mixture was extracted
with AcOEt (3 ꢀ 30 ml). The org. layers were washed with sat. NH4Cl soln. (30 ml), dried (anh.
Na2SO4), and concentrated under reduced pressure. The resulting residue was purified by CC (SiO2;
hexane/AcOEt 1:1) to give 15 (0.097 g, 66%). Liquid. IR (neat): 2921, 1583, 1673, 1444, 1158, 1049, 1099,
970, 856, 740. 1H-NMR (CDCl3, 300 MHz): 7.13 (s, 1 H,); 6.95 – 6.89 (m, 5 H); 5.32 (t, J ¼ 6.9, 1 H); 5.21
(s, 6 H); 5.20 – 5.15 (m, 2 H); 5.10 (s, 2 H); 3.55 (s, 3 H); 3.51 (s, 3 H); 3.49 (s, 6 H); 3.41 (d, J ¼ 6.9, 2 H);
3.37 (d, J ¼ 6.9, 2 H); 2.11 – 2.03 (m, 4 H); 1.76 (s, 3 H); 1.73 (s, 3 H); 1.66 (s, 3 H); 1.65 (s, 3 H); 1.59 (s,
3 H). 13C-NMR (CDCl3, 75 MHz): 155.7; 149.9; 144.3; 136.4; 136.1; 133.5; 131.4; 131.0; 128.0; 127.9;
124.2; 122.7; 122.5; 121.7; 119.7; 111.6; 108.0; 106.1; 99.0; 95.0; 94.4; 57.5; 56.2; 55.9; 39.7; 29.2; 26.6; 25.8;
25.7; 22.7; 17.7; 17.6; 16.2. HR-MS: 624.3660 (Mþ, C37H52O8þ ; calc. 624.3662).
Mappain (¼ 5-{(E)-2-[3,5-Dihydroxy-4-(3-methylbut-2-en-1-yl)phenyl]ethenyl}-3-[(2E)-3,7-dime-
thylocta-2,6-dien-1-yl]benzene-1,2-diol; 1). To a stirred soln. of 15 (0.058 g, 0.1 mmol) in MeOH (5 ml)
were added 5 drops of conc. HCl at 08, and the mixture was stirred at r.t. for 12 h. The mixture was diluted
with sat. NaHCO3 soln. (30 ml) and extracted with AcOEt (3 ꢀ 30 ml). Removal of solvent at reduced
pressure left an oily residue, which was then purified by CC (SiO2; hexane/AcOEt 3 :1) to give 1 (0.025 g,
1
62%). Solid. M.p. 99 – 1018. IR (KBr): 3461, 2923, 1611, 1505, 1441, 1044, 852, 740. H-NMR (CDCl3,
300 MHz): 6.91 (d, J ¼ 1.8, 1 H); 6.83 (d, J ¼16.2, 1 H); 6.75 (d, J ¼ 1.8, 1 H); 6.71 (d, J ¼ 16.2, 1 H); 6.51
(s, 2 H); 5.48 (s, 1 H); 5.33 – 5.23 (br. s, 2 H), 5.05 – 5.01 (m, 1 H), 3.39 (d, J ¼ 7.0, 2 H); 3.36 (d, J ¼ 7.0,
2 H); 2.14 – 2.06 (m, 4 H); 1.81 (s, 3 H); 1.77 (s, 3 H); 1.74 (s, 3 H); 1.67 (s, 3 H); 1.59 (s, 3 H). 13C-NMR
(CDCl3, 75 MHz,): 155.1; 144.3; 142.0; 138.6; 137.1; 135.2; 132.0; 130.0; 128.4; 127.5; 126.1; 123.8; 121.5;
121.4; 120.5; 112.9; 110.6; 106.1; 39.6; 29.6; 26.4; 25.8; 25.7; 22.5; 17.8; 17.7; 16.2. HR-MS: 448.2617 (Mþ,
C29H36Oþ4 ; calc. 448.2614).
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Received September 3, 2009