Efficient synthesis of polycycles bearing prenylated, geranylated, and farnesylated citrans: Application to 3′-prenylrubranine and petiolin D regioisomer

Article abstract of DOI:10.1016/j.tet.2011.09.075

Efficient synthetic routes for biologically interesting polycycles with prenylated, geranylated, and farnesylated citrans were developed from several trihydroxybenzenes with prenyl, geranyl, and farnesyl groups on the benzene rings. Ethylenediamine diacet

Full text of DOI:10.1016/j.tet.2011.09.075

Tetrahedron 67 (2011) 9179e9184
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Efficient synthesis of polycycles bearing prenylated, geranylated, and farnesylated
citrans: application to 30-prenylrubranine and petiolin D regioisomer
*
Xue Wang, Yong Rok Lee
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2011
Received in revised form 17 September 2011
Accepted 18 September 2011
Available online 22 September 2011
Efficient synthetic routes for biologically interesting polycycles with prenylated, geranylated, and far-
nesylated citrans were developed from several trihydroxybenzenes with prenyl, geranyl, and farnesyl
groups on the benzene rings. Ethylenediamine diacetate-catalyzed cyclization by a domino aldol-type/
electrocyclization/H-shift/hetero DielseAlder reaction of prenylated, geranylated, and farnesylated tri-
hydroxybenzenes with citral or trans,trans-farnesal provided a variety of tetracycles bearing prenylated,
geranylated, and farnesylated citrans. The mechanistic pathway for regio- and stereochemistry of syn-
thesized polycycles was described. As an application of this methodology, 30-prenylrubranine and pe-
tiolin D regioisomer were first synthesized.
Keywords:
Polycycles
Citran
30-Prenylrubranine
Petiolin D
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
(Fig. 1).3 This plant has shown desirable medicinal properties and
its decoction has been used to treat fever and cramps.3 Other
polycycles with citran and chalcone moieties have been found in
nature. Rubranine (3) has been isolated from Aniba rosaeodora.4
Essential oils from the extracts of this plant were shown to have
antifungal and antimicrobial activities.5 A pair of monoterpene-
Polycycles bearing citrans are common in nature1 and have
a range of biological and pharmacological activities.2 A pair of tet-
racyclic monoterpenoid polycycles, desbenzylidenerubramin (1)
and its regioisomer 2, have been isolated from Euodia latifolia
H
H
H
H
O
O
O
O
O
O
O
O
1
2
3
4
OH O
OH O
isorubraine
OH O
OH O
rubraine
desbenzylidenerubramin
(or rubranine)
H
H
O
O
O
O
OH O
6
OH O
sumadain A
5
sumadain B
Fig. 1. Naturally occurring polycycles 1e6 with citrans.
chalcone conjugated polycycles, rubraine (or rubranine) (3)6 and
isorubraine (4),6 and a pair of sesquiterpene-chalcone conjugated
sumadains A (5)7 and B7 (6), with both citran and chalcone moieties
were isolated from Alpinia katsumadai (Fig. 1). This plant is
* Corresponding author. Tel.: þ82 53 810 2529; fax: þ82 53 810 4631; e-mail
address: yrlee@yu.ac.kr (Y.R. Lee).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.075

9180
X. Wang, Y.R. Lee / Tetrahedron 67 (2011) 9179e9184
traditionally used as an antiemetic agent in traditional Chinese
medicine to treat stomach disorders and has been coded in the
Chinese pharmacopeia.8
with prenyl bromide in methanolic KOH at room temperature for
24 h. Treatment of 11 with 1.2 equiv citral at 100 ꢀC for 10 h in DMF
afforded tetracyclic adduct 12 in 85% yield, which was easily
assigned by observing the chemical shifts of a benzylic methine
Their wide range of biological activities had promoted research
into the development of convenient and efficient syntheses of
polycycles with citrans. Recently, we reported a new methodology
for synthesizing a variety of benzopyrans by ethylenediamine
diacetate-catalyzed reactions of 1,3-dicarbonyls and resorcinols
proton at
group at
d
2.69 ppm as a broad singlet, and a methyl peak of acetyl
2.59 ppm, and a vinyl peak of prenyl groups at
d
d
5.20e5.25 ppm as multiplets. The exact structure and stereo-
chemistry of 12 were also confirmed by X-ray single crystal analysis
(Fig. 3).
with
a
,b
-unsaturated aldehydes.9 We also reported a new and
useful methodology for preparing a number of polycycles bearing
citrans by ethylenediamine diacetate-catalyzed reactions of 2,4,6-
H
trihydroxybenzenes with a,b
-unsaturated aldehydes.10 For exam-
HO
OH
O
citral
ple, treatment of 2,4,6-trihydroxyacetophenone (7) with citral in
the presence of 20 mol % ethylenediamine diacetate at 100 ꢀC for
10 h in DMF afforded tetracyclic monoterpenoid desbenzylidener-
ubramin (1) in 66% yield (Scheme 1).10
O
O
EDDA
(20 mol%)
DMF
OH
11
100 oC
12
OH
O
85%
Scheme 2. Reaction of 3-prenyl-2,4,6-trihydroxyacetophenone (11) and citral for the
synthesis of tetracycle 12.
H
OH
O
HO
citral
O
O
EDDA
(20 mol%)
DMF
OH
100 oC
66%
1
7
O
H
O
Scheme 1. Reaction of 2,4,6-trihydroxyacetophenone (7) and citral for the synthesis of
desbenzylidenerubramin (1).
Biologically interesting 30-prenylrubranine (8) and petiolin D (9)
with prenyl or geranyl groups on citran rings were isolated from
Mallotus philippinensis11 and Hypericum pseudopetiolatum var. kiu-
sianum,12 respectively (Fig. 2). The extract of Mallotus philippinensis
exhibited bacterial activity.11b Members the genus Hypericum are
traditional medicines for the treatment of burns, bruises, swelling,
inflammation, and bacterial and viral infections.13 Importantly, it
was reported that the presence of the prenyl, geranyl or farnesyl
group in the natural products leads to a remarkable increase of
biological activities.14 In view of their importance of prenyl, geranyl,
and farnesyl groups, further novel work for the synthesis of poly-
cycles with prenylated, geranylated, and farnesylated citrans was
attempted. We report herein an efficient and facile synthesis of
a variety of biologically interesting polycycles with prenylated,
geranylated, and farnesylated citrans. The synthetic methodologies
are also employed in the first concise synthesis of 30-prenylru-
branine (8) and petiolin D regioisomer (10).
Fig. 3. X-ray structure of compound 12.
Further reactions of several substituted trihydroxybenzenes
13e17 containing prenyl, geranyl, and farnesyl groups with citral or
trans,trans-farnesal were examined in the presence of 20 mol % of
EDDA in DMF (Table 1). Reactions of 3-geranyl-2,4,6-trihydrox-
yacetophenone (13) with citral or trans,trans-farnesal gave adducts
18 and 19 in 83 and 75% yields, respectively. Similarly, treatment of 3-
farnesyl-2,4,6-trihydroxyacetophenone (14) with citral or trans,-
trans-farnesal afforded adducts 20 and 21 in 86 and 76% yields,
respectively. The reactions of 3-prenyl-2,4,6-trihydroxybenzo-
pheneone (15), 3-geranyl-2,4,6-trihydroxybenzophenone (16), and
3-farnesyl-2,4,6-trihydroxybenzophenone (17) were also successful.
With 3-prenyl-2,4,6-trihydroxybenzopheneone (15), the desired
adduct 22wasproduced in88%yield. Similarly, reaction of3-geranyl-
2. Results and discussion
The reaction of 3-prenyl-2,4,6-trihydroxyacetophenone (11)
with citral in the presence of 20 mol % ethylenediamine diacetate
was first examined (Scheme 2). The starting material 11 was pre-
pared with 65% yield by reacting 2,4,6-trihydroxyacetophenone
H
H
H
O
O
O
O
O
O
8
OH O
OH O
9
petiolin D
OH O
10
3'-prenylrubranine
Fig. 2. Naturally occurring 30-prenylrubranine (8), petiolin D (9), and unnatural petiolin D regioisomer (10).

X. Wang, Y.R. Lee / Tetrahedron 67 (2011) 9179e9184
9181
Table 1
Reactions of several substituted trihydroxybenzenes with citral or trans,trans-farnesal
Starting material
a
,
b
-Unsaturated aldehyde
Time (h)
Product
Yield (%)
H
HO
OH
O
O
Citral
10
83
OH
OH
O
18
13
OH
O
H
HO
OH
O
O
O
trans,trans-Farnesal
12
12
12
75
19
13
OH
O
H
HO
OH
O
O
O
Citral
86
76
88
14
OH
OH
20
OH
O
H
HO
OH
O
O
O
O
trans,trans-Farnesal
14
21
OH
H
HO
OH
O
O
O
Citral
12
15 OH
22
OH
O
H
HO
OH
O
O
Citral
12
86
85
16
OH
O
23
OH
O
O
H
HO
OH
O
O
Citral
10
17
OH
OH
O
24
2,4,6-trihydroxybenzophenone (16) with citral in the presence of
20 mol % ofEDDA at100 ꢀC for 12 h inDMF providedadduct 23in86%
yield, whereas that of 3-farnesyl-2,4,6-trihydroxybenzophenone
(17) afforded tetracyclic compound 24 in 85% yield. These reactions
provide a rapid route for the synthesis of polycycles with prenyl,
geranyl, and farnesyl groups on the benzopyran ring.
The mechanism for regio- and stereochemistry of synthesized
12 can be explained as shown in Scheme 3. Citral is first protonated
by EDDA to give protonated aldehyde, which is then attacked by 3-
prenyl-2,4,6-trihydroxypropiophenone (11) in the presence of
EDDA to yield intermediate 25. The method of producing aldol-type
products by the Ca(OH)2-mediated reaction of resorcinol to enals
was already suggested by Shigemasa.15 Dehydration of 25 in the
presence of EDDA gives two possible o-quinone methides 26 and
27. Intermediate 26, with intramolecular hydrogen bonding, is
probably more stable than 27, with dipoleedipole repulsions. It is at
this stage that the observed regioselectivity of 12 can be de-
termined. Electrocyclization of the more stable intermediate 26

9182
X. Wang, Y.R. Lee / Tetrahedron 67 (2011) 9179e9184
H
H-shift
hetero Diels-Alder
O
O
O
O
O
O
OH
O
OH
12
OH
O
29
28
OH
pathway A electrocyclization
OH
OH
HO
OH
citral
-H2O
HO
O
O
O
O
O
H
O
EDDA
O
O
OH
11
25
27
26
OH
OH
OH
more stable
pathway B
electrocyclization
H
O
hetero Diels-Alder
O
O
O
O
HO
O
O
H-shift
12a
OH
31
OH
O
30
OH
Scheme 3. The mechanism for the formation of compound 12.
gives benzopyran 28 that undergoes H-shift to produce another
quinine methide 29 by pathway A instead of by pathway B.16 The
stereochemistry of 12 can be explained by the pseudoequatorial
conformation of the methyl group of o-quinone methide 29 in the
chair-like transition state.17 During the hetero DielseAlder reaction
of 29, the exo-transition state must be more energetically favorable
than the endo-transition state. This is in good agreement with
Marino, who reported the synthesis of hexahydrocannabinol
through the intramolecular hetero DielseAlder cycloaddition of o-
quinone methide.18
This methodology was applied in one-step synthesis of natural
30-prenylrubraine (8) from synthesized adduct 12 by aldol con-
densation (Scheme 4). The reaction of 12 with benzaldehyde in the
presence of KOH in ethanol at 50 ꢀC for 48 h gave 30-prenylrubraine
(8) in 95% yield. The exact structure and stereochemistry of 8 was
confirmed by X-ray analysis (Fig. 4).
This methodology was also applied in the first synthesis of un-
natural petiolin D regioisomer (10) (Scheme 5). Reaction of 32 with
geranyl bromide in the presence of N,N-diisopropylethylamine in
DMFat room temperature for 48 h gave 33 in 55% yield. Treatmentof
33 with citral in the presence of 20 mol % ethylenediamine diacetate
in DMF at 100 ꢀC for 12 h afforded adduct 10 in 81% yield. The
structure and stereochemistry of 10 were confirmed by comparison
of its spectral data with those previously reported for petiolin D.12
A new synthetic route for biologically interesting polycycles
bearing prenylated, geranylated, and farnesylated citrans was de-
veloped starting from substituted trihydroxybenzenes with prenyl,
geranyl, and farnesyl groups on the benzene ring. The strategy re-
lied on domino aldol-type reaction/electrocyclization/H-migration/
hetero DielseAlder reaction. This methodology was applied to the
synthesis of biologically interesting 30-prenylrubranine (8) and
petiolin D regioisomer (10).
3. Experimental section
3.1. General
H
O
H
H
O
O
O
O
KOH
MeOH
95%
All experiments were carried out in a nitrogen atmosphere.
Merck, pre-coated silica gel plates (Art. 5554) with a fluorescent
indicator were used for analytical TLC. Flash column chromatog-
raphy was performed using silica gel 9385 (Merck). 1H and 13C NMR
spectra were recorded on a Varian-VNS (300 and 75 MHz, re-
spectively) spectrometer in CDCl3 as the solvent chemical shift. IR
spectra were recorded on a Jasco FTIR 5300 spectrophotometer.
HRMS and MS spectra were carried out at the Korea Basic Science
Institute. The HRMS were carried out at the Korea Basic Science
Institute on a Jeol JMS 700 spectrometer.
OH
O
8
12
OH
O
Scheme 4. Synthesis of 30-prenylrubranine (8).
3.2. Typical procedure for compounds 12 and 18e24
To a solution of substituted trihydroxybenzenes (1.0 mmol) and
citral or trans,trans-farnesal (1.2 mmol) in DMF (10 mL) was added
ethylenediamine diacetate (36 mg, 0.2 mmol) at room temperature.
The reaction mixture was stirred at 100 ꢀC for 10e12 h and then
cooled to room temperature. After completion of reaction as in-
dicated by TLC, the reaction mixture was quenched with water
Fig. 4. X-ray structure of synthesized 30-prenylrubranine (8).

X. Wang, Y.R. Lee / Tetrahedron 67 (2011) 9179e9184
9183
H
HO
OH
O
citral
geranyl bromide
HO
OH
O
O
O
EDDA
DIPEA
DMF
55%
DMF
100 oC
81%
OH
32
OH
OH
O
33
10
Scheme 5. Synthesis of petiolin D regioisomer (10).
(30 mL) and extracted with ethyl acetate (50 mLꢁ3). The combined
organic layer was dried over MgSO4 and concentrated, and the
crude product was purified by column chromatography on silica gel
(hexane/ethyl acetate, 20:1) to afford products.
39.8, 39.7, 37.6, 34.8, 32.1, 29.9, 28.8, 27.7, 26.7, 26.6, 25.7, 24.2, 21.9,
21.1, 17.6, 16.1, 15.9; IR (neat) 3436, 2923, 2358, 1610, 1427, 1370,
1293, 1218, 1177, 1116, 1085, 1017, 984, 855, 737 cmꢂ1; HRMS m/z
(Mþ) calcd for C33H46O4: 506.3396. Found: 506.3398.
3.2.1. Compound 12. Reaction of 11 (236 mg, 1.0 mmol) with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 10 h afforded 12
(315 mg, 85%) as a solid: mp 180e181 ꢀC; 1H NMR (300 MHz, CDCl3)
3.2.5. Compound 21. Reaction of 14 (372 mg, 1.0 mmol) with
trans,trans-farnesal (264 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for
12 h afforded 21 (436 mg, 76%) as a solid: mp 62e64 ꢀC; 1H NMR
d
13.57 (1H, s), 5.25e5.20 (1H, m), 3.23 (2H, d, J¼7.2 Hz), 2.69 (1H,
(300 MHz, CDCl3) d 13.55 (1H, s), 5.26e5.21 (1H, m), 5.16e5.14 (1H,
br s), 2.59 (3H, s), 2.19e2.05 (2H, m), 1.82 (2H, d, J¼13.5 Hz), 1.75
(3H, s), 1.65 (3H, s), 1.54 (3H, s), 1.48e1.41 (1H, m), 1.38 (3H, s),
1.33e1.21 (1H, m), 1.07 (3H, s), 0.86e0.69 (1H, m); 13C NMR
m), 5.08e5.04 (1H, m), 3.25 (2H, d, J¼6.9 Hz), 2.72 (1H, br s), 2.59
(3H, s), 2.29e2.20 (1H, m), 2.16e2.08 (3H, m), 2.04e1.89 (11H, m),
1.80 (2H, br d, J¼13.2 Hz), 1.75 (3H, s), 1.70 (3H, s), 1.63 (6H, s), 1.56
(6H, s), 1.49e1.42 (1H, m), 1.38 (3H, s), 1.27e1.19 (1H, m), 1.03 (3H,
(75 MHz, CDCl3)
d 202.3, 161.3, 160.3, 157.2, 130.8, 122.9, 108.9,
107.2, 107.1, 86.1, 75.7, 46.4, 37.6, 34.8, 32.1, 29.9, 28.8, 27.7, 25.8,
24.3, 21.9, 21.2, 17.8; IR (KBr) 3457, 2973, 2917, 1604, 1463, 1423,
1370, 1292, 1223, 1173, 1081, 854, 731 cmꢂ1; HRMS m/z (Mþ) calcd
for C23H30O4: 370.2144. Found: 370.2146.
s), 0.86e0.71 (1H, m); 13C NMR (75 MHz, CDCl3)
d 202.2, 161.3,
160.3,156.8,134.7,134.3,132.1,131.1,124.4,124.3,123.8,122.7,109.0,
107.5, 107.4, 88.3, 75.7, 45.7, 42.1, 39.8, 39.7, 37.7, 34.7, 32.2, 28.8,
27.6, 26.7, 26.6, 25.7, 22.7, 21.9, 21.1, 21.0,17.7,17.6,16.1, 16.0; IR (KBr)
2923, 2357, 1611, 1428, 1373, 1294, 1228, 1176, 1110, 1019, 982, 842,
737 cmꢂ1; HRMS m/z (Mþ) calcd for C38H54O4: 574.4022. Found:
574.4025.
3.2.2. Compound 18. Reaction of 13 (304 mg, 1.0 mmol) with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 10 h afforded 18
(364 mg, 83%) as a solid: mp 158e159 ꢀC; 1H NMR (300 MHz,
CDCl3)
d
13.59 (1H, s), 5.26e5.21 (1H, m), 5.08e5.03 (1H, m), 3.24
3.2.6. Compound 22. Reaction of 15 (298 mg, 1.0 mmol), with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 22
(380 mg, 88%) as a solid: mp 115e116 ꢀC; 1H NMR (300 MHz, CDCl3)
(2H, d, J¼6.9 Hz), 2.70 (1H, br s), 2.60 (3H, s), 2.18e2.12 (1H, m),
2.02e1.94 (4H, m), 1.82 (2H, d, J¼13.5 Hz), 1.75 (3H, s), 1.66e1.60
(1H, m), 1.62 (3H, s), 1.55 (6H, s), 1.49e1.44 (1H, m), 1.38 (3H, s),
1.34e1.17 (1H, m), 1.08 (3H, s), 0.86e0.71 (1H, m); 13C NMR
d
12.87 (1H, s), 7.49e7.47 (2H, m), 7.43e7.33 (3H, m), 5.31e5.26 (1H,
m), 3.31 (2H, d, J¼6.9 Hz), 2.65 (1H, br s), 2.21e2.14 (1H, m),
1.88e1.84 (2H, m), 1.78 (3H, s), 1.68 (3H, s), 1.60e1.52 (1H, m),
1.44e1.32 (1H, m), 1.38 (3H, s), 1.18e1.10 (1H, m), 1.02 (3H, s),
(75 MHz, CDCl3) d 202.3,161.3, 160.4, 157.2, 134.3, 131.0,124.5,122.7,
109.0, 107.2, 107.1, 86.1, 75.6, 46.4, 39.8, 37.6, 34.8, 32.1, 29.9, 28.8,
27.7, 26.7, 25.7, 24.3, 21.9, 21.1, 17.6, 16.1; IR (KBr) 3544, 2924, 1608,
1435, 1375, 1291, 1175, 1106, 856 cmꢂ1; HRMS m/z (Mþ) calcd for
C28H38O4: 438.2770. Found: 438.2768.
0.72e0.59 (1H, m), 0.56 (3H, s); 13C NMR (75 MHz, CDCl3)
d 199.1,
161.4, 161.1, 157.1, 142.5, 131.0, 130.0, 127.7, 127.2, 122.9, 109.6, 107.5,
107.1, 85.1, 75.9, 46.1, 37.8, 34.8, 29.0, 28.8, 27.8, 25.9, 23.4, 21.9, 21.4,
17.8; IR (KBr) 3449, 2976, 2926, 1600, 1567, 1451, 1422, 1367, 1307,
1219,1113,1083,1048, 909, 830, 741 cmꢂ1; HRMS m/z (Mþ) calcd for
C28H32O4: 432.2301. Found: 432.2303.
3.2.3. Compound 19. Reaction of 13 (304 mg, 1.0 mmol) with
trans,trans-farnesal (264 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for
12 h afforded 19 (380 mg, 75%) as a solid: mp 96e97 ꢀC; 1H NMR
(300 MHz, CDCl3)
d
13.55 (1H, s), 5.25e5.21 (1H, m), 5.20e5.14 (1H,
3.2.7. Compound 23. Reaction of 16 (366 mg, 1.0 mmol) with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 23
(430 mg, 86%) as a solid: mp 103e104 ꢀC; 1H NMR (300 MHz,
m), 5.08e5.04 (1H, m), 3.25 (2H, d, J¼7.2 Hz), 2.73 (1H, br s), 2.59
(3H, s), 2.28e2.20 (1H, m), 2.16e2.08 (3H, m), 2.04e1.92 (6H, m),
1.80 (2H, br d, J¼13.2 Hz), 1.75 (3H, s), 1.70 (3H, s), 1.63 (6H, s), 1.56
(3H, s), 1.49e1.42 (1H, m), 1.38 (3H, s), 1.29e1.19 (1H, m), 1.03 (3H,
CDCl3)
d 12.87 (1H, s), 7.51e7.48 (2H, m), 7.44e7.31 (3H, m),
5.31e5.26 (1H, m), 5.10e5.06 (1H, m), 3.31 (2H, d, J¼6.9 Hz), 2.65
(1H, br s), 2.21e2.14 (1H, m), 2.07e1.95 (4H, m), 1.88e1.85 (2H, m),
1.78 (3H, s), 1.71e1.66 (1H, m), 1.64 (3H, s), 1.57 (3H, s), 1.44e1.32
(1H, m), 1.38 (3H, s), 1.17e1.10 (1H, m), 1.02 (3H, s), 0.71e0.59 (1H,
s), 0.86e0.72 (1H, m); 13C NMR (75 MHz, CDCl3)
d 202.2, 161.3,
160.3, 156.8, 134.3, 132.1, 131.0, 124.5, 123.8, 122.7, 109.0, 107.5,
107.4, 88.3, 75.7, 45.7, 42.1, 39.8, 37.7, 34.7, 32.2, 28.8, 27.6, 26.7, 25.7,
22.7, 21.9, 21.1, 21.0, 17.7, 17.6, 16.1; IR (KBr) 3481, 2926, 2368, 1613,
1465, 1430, 1376, 1296, 1227, 1176, 1108, 1022, 981, 862, 832, 802,
733 cmꢂ1; HRMS m/z (Mþ) calcd for C33H46O4: 506.3396. Found:
506.3395.
m), 0.56 (3H, s); 13C NMR (75 MHz, CDCl3)
d 199.1, 161.4, 161.2, 157.1,
142.5, 134.4, 131.1, 130.0, 127.7, 127.2, 124.5, 122.8, 109.6, 107.5, 107.1,
85.1, 75.9, 46.1, 39.8, 37.8, 34.9, 29.0, 28.8, 27.8, 26.8, 25.7, 23.3, 21.8,
21.3, 17.7, 16.1; IR (KBr) 3446, 2975, 2928, 2368, 1606, 1553, 1452,
1421, 1366, 1301, 1142, 1118, 1082, 1051, 910, 853, 818 cmꢂ1; HRMS
m/z (Mþ) calcd for C33H40O4: 500.2927. Found: 500.2925.
3.2.4. Compound 20. Reaction of 14 (372 mg, 1.0 mmol) with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 20
(436 mg, 86%) as an oil: 1H NMR (300 MHz, CDCl3)
d
13.57 (1H, s),
3.2.8. Compound 24. Reaction of 17 (434 mg, 1.0 mmol) with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 10 h afforded 24
(484 mg, 85%) as a solid: mp 72e73 ꢀC; 1H NMR (300 MHz, CDCl3)
5.26e5.21 (1H, m), 5.10e5.02 (2H, m), 3.25 (2H, d, J¼7.5 Hz), 2.70
(1H, br s), 2.60 (3H, s), 2.20e2.12 (1H, m), 2.06e1.88 (9H, m), 1.82
(2H, d, J¼13.2 Hz), 1.75 (3H, s), 1.65 (3H, s), 1.55 (9H, s), 1.48e1.40
(1H, m), 1.38 (3H, s), 1.32e1.20 (1H, m), 1.07 (3H, s), 0.86e0.69 (1H,
d
12.89 (1H, s), 7.50e7.48 (2H, m), 7.41e7.31 (3H, m), 5.31e5.27 (1H,
m), 5.11e5.04 (2H, m), 3.31 (2H, d, J¼7.2 Hz), 2.65 (1H, br s),
2.20e2.13 (1H, m), 2.08e1.93 (9H, m), 1.89e1.84 (2H, m), 1.81 (3H,
s), 1.66 (3H, s), 1.57 (6H, s), 1.44e1.32 (1H, m), 1.38 (3H, s), 1.17e1.09
m); 13C NMR (75 MHz, CDCl3)
d
202.2, 161.3, 160.4, 157.1, 134.7,
134.2, 131.1, 124.4, 124.3, 122.7, 109.0, 107.1, 107.0, 86.0, 75.6, 46.4,

9184
X. Wang, Y.R. Lee / Tetrahedron 67 (2011) 9179e9184
(1H, m), 1.02 (3H, s), 0.71e0.61 (1H, m), 0.56 (3H, s); 13C NMR
(75 MHz, CDCl3) 199.0, 161.3, 161.2, 157.0, 142.4, 134.7, 134.4, 131.2,
30.0, 28.9, 27.9, 26.8, 25.6, 24.3, 22.0, 21.2, 20.3, 18.6, 17.7, 16.1; IR
(KBr) 2974, 2928,1612,1455, 1418,1381, 1367,1252,1179, 1143,1112,
1080, 1051, 1010, 987, 897, 818, 731 cmꢂ1; HRMS m/z (Mþ) calcd for
C30H42O4: 466.3083. Found: 466.3079.
d
130.0, 127.7, 127.2, 124.4, 124.3, 122.7, 109.6, 107.5, 107.0, 85.1, 75.9,
46.1, 39.9, 39.7, 37.7, 34.8, 29.0, 28.8, 27.7, 26.7, 26.6, 25.7, 23.3, 21.8,
21.3, 17.7, 16.1, 16.0; IR (KBr) 3471, 2919, 2369, 1715, 1590, 1450,
1430, 1420, 1367, 1268, 1222, 1165, 1142, 1080, 1050, 950, 823,
735 cmꢂ1; HRMS m/z (Mþ) calcd for C38H48O4: 568.3553. Found:
568.3554.
Acknowledgements
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science, and Technology
(2009-0064779).
3.3. 3-Prenylrubranine (8)
To a solution of 12 (370 mg, 1.0 mmol) in ethanol (10 mL) were
added potassium hydroxide (280 mg, 5.0 mmol) and benzaldehyde
(212 mg, 1.0 mmol) at room temperature. The reaction mixture was
stirred at 50 ꢀC for 48 h. Addition of water (30 mL) and extraction
with ethyl acetate (3ꢁ50 mL), washing with 2 N HCl solution and
brine, dried over MgSO4, and removal of the solvent followed by
flash column chromatography on silica gel gave 8 (462 mg, 95%) as
Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.09.075.
a solid: mp 79e80 ꢀC; 1H NMR (300 MHz, CDCl3)
d 14.20 (1H, s),
References and notes
8.27 (1H, d, J¼15.6 Hz), 7.74 (1H, d, J¼15.6 Hz), 7.61 (2H, d,
J¼7.8 Hz), 7.42e7.33 (3H, m), 5.30e5.25 (1H, m), 3.29 (2H, d,
J¼6.9 Hz), 2.76 (1H, br s), 2.21e2.05 (2H, m), 1.85 (2H, d, J¼13.2 Hz),
1.78 (3H, s), 1.67 (3H, s), 1.63 (3H, s), 1.54e1.45 (1H, m), 1.40 (3H, s),
1.29e1.21 (1H, m), 1.03 (3H, s), 0.86e0.76 (1H, m); 13C NMR
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2003, 59, 5905; (b) Begley, M. J.; Crombie, L.; King, R. W.; Slack, D. A.; Whiting,
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(75 MHz, CDCl3) d 191.9, 162.7, 162.3, 160.7, 156.8, 141.4, 135.8, 130.9,
129.8, 128.9, 128.2, 127.7, 122.8, 109.6, 107.9, 107.8, 86.4, 75.8, 46.4,
37.7, 34.7, 30.2, 28.8, 27.9, 25.9, 24.2, 21.9, 21.3, 17.8; IR (KBr) 3461,
2924, 2672, 1987, 1612, 1447, 1350, 1168, 998, 882, 727 cmꢂ1; HRMS
m/z (Mþ) calcd for C30H34O4: 458.2457. Found: 458.2461.
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(2.33 g, 3.1 mL, 18.0 mmol) in DMF (25 mL) was stirred at room
temperature for 48 h. Addition of 2 N HCl solution (30 mL), ex-
traction with EtOAc (3ꢁ50 mL), and removal of the solvent fol-
lowed by flash column chromatography on silica gel using hexane/
EtOAc (3:1) gave 33 (1.10 g, 55%) as an oil: 1H NMR (300 MHz,
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CDCl3)
d 12.32 (1H, s), 5.95 (1H, s), 5.30e5.20 (1H, m), 5.10e4.95
(1H, m), 3.30 (2H, d, J¼6.6 Hz), 2.07e1.95 (4H, m), 1.76 (3H, s), 1.63
(3H, s), 1.55 (6H, s), 1.13 (6H, d, J¼6.6 Hz); 13C NMR (75 MHz, CDCl3)
d
210.8, 163.0, 161.3, 160.1, 138.1, 131.8, 123.9, 122.0, 106.0, 104.0,
95.3, 39.7, 30.0, 26.4, 25.6, 21.5, 19.3, 17.6, 16.1; IR (neat) 3360, 2968,
10. Wang, X.; Lee, Y. R. Tetrahedron 2009, 65, 10125.
2925, 1620, 1432, 1382, 1236, 1171, 1132, 1097, 1066, 884, 821 cmꢂ1
;
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3.5. Compound 10
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A mixture of 33 (332 mg, 1.0 mmol), citral (183 mg, 1.2 mmol),
and ethylenediamine diacetate (36 mg, 0.2 mmol) in DMF (10 ml)
was stirred at 100 ꢀC for 12 h afforded 10 (378 mg, 81%) as a solid:
mp 73e74 ꢀC; 1H NMR (300 MHz, CDCl3)
d 13.71 (1H, s), 5.27e5.22
(1H, m), 5.08e5.04 (1H, m), 4.00e3.91 (1H, m), 3.25 (2H, d,
J¼7.2 Hz), 2.73 (1H, br s), 2.19e2.12 (1H, m), 2.07e1.93 (5H, m), 1.83
(2H, dd, J¼13.2, 1.5 Hz), 1.75 (3H, s), 1.62 (3H, s), 1.56 (3H, s), 1.54
(3H, s), 1.49e1.40 (1H, m), 1.38 (3H, m), 1.30e1.21 (1H, m), 1.15 (3H,
d, J¼6.3 Hz), 1.13 (3H, d, J¼6.3 Hz), 1.04 (3H, s), 0.90e0.75 (1H, m);
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630.
13C NMR (75 MHz, CDCl3)
d 209.7, 162.1, 160.0, 156.8, 134.2, 131.0,
17. Talley, J. J. J. Org. Chem. 1985, 50, 1695.
124.6,122.9, 109.4, 107.0, 106.3, 85.8, 75.5, 46.6, 39.8, 38.1, 37.7, 35.0,
18. Marino, J. P.; Dax, S. L. J. Org. Chem. 1984, 49, 3671.