EDDA-catalyzed rapid synthetic routes for biologically interesting polycycles bearing citrans and chalcones: the first total synthesis of sumadain A

Article abstract of DOI:10.1016/j.tet.2009.10.045

An efficient and concise synthetic route for biologically interesting polycycles bearing citran and chalcone nuclei was developed starting from a variety of trihydroxybenzenes with substituents on the ring. The key strategies involved an ethylenediamine diacetate-catalyzed cyclization by a domino aldol-type/electrocyclization/H-shift/hetero Diels-Alder reaction of trihydroxybenzenes and citral or trans,trans-farnesal. This methodology was applied successfully to the synthesis of three natural products, desbenzylidenerubramin, rubraine, sumadain A, and their unnatural derivatives.

Full text of DOI:10.1016/j.tet.2009.10.045

Tetrahedron 65 (2009) 10125–10133
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
EDDA-catalyzed rapid synthetic routes for biologically interesting polycycles
bearing citrans and chalcones: the first total synthesis of sumadain A
*
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 7 July 2009
Received in revised form 12 October 2009
Accepted 13 October 2009
Available online 15 October 2009
An efficient and concise synthetic route for biologically interesting polycycles bearing citran and chal-
cone nuclei was developed starting from a variety of trihydroxybenzenes with substituents on the ring.
The key strategies involved an ethylenediamine diacetate-catalyzed cyclization by a domino aldol-type/
electrocyclization/H-shift/hetero Diels–Alder reaction of trihydroxybenzenes and citral or trans,trans-
farnesal. This methodology was applied successfully to the synthesis of three natural products, des-
benzylidenerubramin, rubraine, sumadain A, and their unnatural derivatives.
Keywords:
Polycycles
Citran
Ó 2009 Elsevier Ltd. All rights reserved.
Chalcone
Rubraine
Sumadain A
1. Introduction
as marijuana or hashish (Fig. 1).3 This plant contains a group of
more than 60 structurally related terpenophenolic compounds
Polycycles bearing citran or cyclol nuclei are widely distributed
in nature1 and have a range of biological and pharmacological
properties.2 Among these, cannabinoids 1–4 containing a citran or
cyclol moiety have been isolated from Cannabis sativa, also known
and has been used as a psychotomimetic drug since ancient
times.2a It has also been shown to possess analgesic, antiemetic,
psychotropic, and anti-inflammatory properties, and is currently
used in traditional medicines for the treatment of asthma and
H
H
OH
OH
O
H
OH
H
H
CO2H
H
H
H
O
O
O
O
3
4
2
1
cannabicitran
H
cannabicyclol
cannabicyclovarin
cannabicycloic acid
H
H
H
O
HO
OH
H
O
O
O
O
O
H
H
H
H
O
O
O
O
O
O
O
O
O
OH
O
OH
O
9
7
8
6
5
eriobrucinol
bruceol
deoxybruceol
desbenzylidenerubramin
Figure 1. Biologically active and naturally occurring polycycles 1–9 with a citran and a cyclol nucleus.
glaucoma.2a The increased consumption of this plant has caused
worldwide social, legal, and medical problems. However, the
biological importance of this plant was realized only after
the discovery of the endogenous cannabinoid system. With the
* Corresponding author. Tel.: þ82 53 810 2529; fax: þ82 53 810 4631.
E-mail address: yrlee@yu.ac.kr (Y.R. Lee).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.045

10126
X. Wang, Y.R. Lee / Tetrahedron 65 (2009) 10125–10133
discovery of the two cannabinoid receptors, CB1 and CB2, a new
era of research into the pharmacology of these compounds was
ushered in.4 As other polycycles bearing these citran or cyclol
moieties, eriobrucinol (5), bruceol (6), and deoxybruceol (7) were
isolated from Eriostemon brucei and their structures were
determined by spectral and X-ray analysis.5 Desbenzylideneru-
bramin (8) and its isomer 9 of the tetracyclic monoterpenoid were
also isolated from Euodia latifolia.6 This plant has shown to
possess desirable medicinal properties and its decoction has been
used as a remedy for fever and cramps.6
Novel polycycles with unique monoterpene–chalcone conju-
gates have been found in nature. Rubranine (10) was already
isolated from Aniba rosaeodora (Fig. 2).7 Importantly, the essential
oils obtained from the extracts of this plant were shown to have
antifungal and antimicrobial activities.8 Very recently, as part of an
ongoing research program to isolate bioactive compounds from
Chinese medicinal plants, monoterpene–chalcone conjugated
rubraine (or rubranine) (10),9 isorubraine (11),9 and sesquiterpene–
chalcone conjugated sumadains A (12)10 and B (13)10 with citran
and chalcone moieties were isolated from Alpinia katsumadai
(Fig. 2). This plant is traditionally used as an antiemetic agent in
traditional Chinese medicine to treat stomach disorders and has
been coded in the Chinese pharmacopeia.11
reported for a variety of biologically interesting polycycles bearing
these citran and chalcone moieties. As an application of these
methodologies, this paper reports the concise one or two-step
synthesis of desbenzylidenerubramin (8), rubraine (or rubranine)
(10), sumadain A (12), and their unnatural derivatives.
2. Results and discussion
A reaction of 2,4,6-trihydroxyacetophenone (14) with citral in the
presence of 20 mol % ethylenediamine diacetate was first examined
(Scheme 1). Treatment of 14 with 1.2 equiv of citral at 100 ꢀC for 10 h
in DMF afforded tetracyclic monoterpenoid desbenzylidenerubramin
(8) in 66% yield, without any formation of its regioisomer 9. The as-
signment of 8 was easily defined by observing the chemical shifts of
the characteristic protons and by comparison with reported data and
known X-ray structure in the literature.6 The 1H NMR spectrum of 8
showed an aromatic peak at
proton of the benzylic position at
d
¼6.04 ppm as a singlet and a methine
d
¼2.73 ppm as a broad singlet.
H
HO
OH
O
O
citral
O
EDDA
(20 mol%)
DMF
OH
OH
O
14
8
100 °C
66%
Scheme 1.
H
H
H
H
O
O
O
O
O
O
O
O
OH
O
13
OH
O
12
OH
O
OH
O
11
10
isorubraine
sumadain A
rubraine
sumadain B
(or rubranine)
Figure 2. Naturally occurring polycycles 10–13 with a citran, cyclol, and chalcone nucleus.
The range of biological activities and properties has stimulated
interest in the synthesis of naturally occurring desbenzylideneru-
bramin (8), rubraine (10), sumadain A (12), and their unnatural
derivatives. The structures of desbenzylidenerubramin (8),
rubraine (10), isorubraine (11), and sumadains A (12) and B (13)
were established by NMR spectroscopy and X-ray crystallogra-
phy.6,9,10 However, no synthetic approaches to isorubraine (11) and
sumadains A (12) and B (13) have been reported.
Although a few syntheses of these types of polycycles have been
reported, the known protocol was determined from a reaction of
phloroglucinol with citral in pyridine as a catalyst and solvent.12
Nevertheless, there are the limitations of low yields and capricious
product isolation.12 The necessity for overcoming these problems
has prompted research for the development of a new synthetic
methodologies for polycycles bearing the citran and chalcone
moieties.
Further reactions of several types of substituted trihydroxy-
benzenes 15–23 and others 24–25 with citral or trans,trans-farnesal
were examined (Table 1). Reaction of 2,4,6-trihydroxybenzaldehyde
(15) with citral in the presence of 20 mol % of ethylenediamine
diacetate at 100 ꢀC for 12 h in DMF provided adduct 26 in 45% yield
(entry 1). Reactions of 2,4,6-trihydroxypropiophenone (16) and 2-
phenyl-20,40,60-trihydroxyacetophenone (17) with citral afforded
adducts 27 and 29 in 65 and 62% yields (entries 2 and 4), whereas
thosewith trans,trans-farnesal gave desired compounds 28 and 30 in
53 and 52% yields, respectively (entries 3 and 5). With 20,40,60-tri-
hydroxydihydrochalcone (18) isolated from Boesenbergia pandur-
ata,16 the cycloaddition reaction was successful. Reaction of 18 with
citral for 10 h gave cycloadduct 31 in 55% yield (entry 6). Similarly,
treatment of trihydroxydihydrochalcones 19–20 with citral for 12 h
afforded adducts 32–33 in 50 and 57% yield, respectively (entries
7–8). Moreover, reactions of 2,4,6-trihydroxybenzophenones 21–22
were also successful. Treatment of 21 with citral provided desired
adduct 34 in 45% yield (entry 9), whereas that of 22 gave 35 in 40%
yield (entry 10). These reactions provide a rapid route for the syn-
thesis of polycycles with a variety of substituents on the benzopyran
ring. To examine further reactions, the commercially available
phloroglucinol and pyrogallol were condensed with citral. In-
terestingly, reaction of phloroglucinol with citral afforded the triple
condensation product 36 (22%) as a single C3-symmetric compound.
The structure of 36 was confirmed by comparison with spectral data
of the authenticsample, whichwas producedbyphenylboronic acid/
Brønsted acid–base combined salt catalyzed reactions are one of
the most promising catalysts in organic synthesis.13 Recently, this
lab reported a new methodology for synthesizing a variety of
benzopyrans by ethylenediamine diacetate-catalyzed reactions of
1,3-dicarboyls and resorcinols with a,b
-unsaturated aldehydes.14 In
the original work, a methodology for the preparation of polycycles
using ethylenediamine diacetate (EDDA) as a catalyst was de-
veloped.15 Further work and new methodologies for the synthesis
of a variety of polycycles with citran and chalcone moieties were
attempted. In this paper, efficient and facile synthetic routes are

X. Wang, Y.R. Lee / Tetrahedron 65 (2009) 10125–10133
10127
Table 1
Reactions of several substituted trihydroxybenzenes and others with citral or trans,trans-farnesal
Entry
Starting material
Unsaturated aldehyde
Time (h)
Product
Yield (%)
H
HO
HO
HO
OH
H
O
O
26
1
Citral
12
45
65
53
62
H
15
OH
OH
OH
O
OH
O
H
OH
O
O
O
2
3
4
Citral
12
12
10
27
16
OH
O
H
OH
O
O
O
trans,trans-Farnesal
16
28
OH
H
O
HO
OH
O
O
Citral
OH
O
17
OH
O
O
29
H
HO
OH
O
O
5
trans,trans-Farnesal
10
52
OH
OH
H
O
17
30
HO
OH
O
O
6
Citral
10
55
OH
O
18
31
OH
O
H
HO
OH
O
O
O
7
Citral
12
50
19
OH
32
OH
O
(continued on next page)

10128
X. Wang, Y.R. Lee / Tetrahedron 65 (2009) 10125–10133
Table 1 (continued)
Entry
Starting material
Unsaturated aldehyde
Time (h)
Product
Yield (%)
H
HO
OH
OCH3
O
O
OCH3
8
Citral
12
57
20
OH
O
33
OH
O
H
HO
OH
O
O
9
Citral
12
45
OCH3
21
OCH3
OH
O
OH
H
O
34
HO
OH
O
OCH3
22
O
O
OCH3
10
Citral
12
40
OH
35
OH
O
HO
OH
O
O
11
Citral
12
22
23
OH
O
36
HO
OH
O
OH
24
12
Citral
12
43
OCH3
37
OCH3
HO
OH
O
13
Citral
12
62
O
OH
25
OCH3
O
38
OCH3
propionic acid promoted cycloaddition.17 However, reaction of
pyrogallol with citral provided only polymeric gummy materials
without the isolation of any cycloadducts. Next, we employed other
compounds 24–25 containing two hydroxyl groups on the benzene
ring for a cyclization. In these cases, benzopyrans 37 and 38 were
produced in 43 and 62% yield, respectively, instead of the formation
of the desired polycycles. The structural assignment of 38 was done
on the base of 1H NMR data. The 1H NMR spectrum of 38 showed two
group in the benzene ring was observed as a singlet associated with
a hydrogen bond to a carbonyl group at 14.30 ppm.
d
The mechanism for regio- and stereochemistry of synthesized
28 in Table 1 can be explained as shown in Scheme 2. trans,trans-
Farnesal is first protonated by EDDA to give protonated aldehyde,
which is then attacked by 2,4,6-trihydroxypropiophenone (16) in
the presence of EDDA to yield intermediate 39. Such a process for
producing aldol-type products by a Ca(OH)2-mediated reaction of
resorcinol to enals was suggested by Shigemasa.18 The dehydration
of 39 in the presence of EDDA gives two possible o-quinone
vinylic protons on the pyranyl ring at
d
6.67 (J¼9.9 Hz) and 5.37
(J¼9.9 Hz). In particular, the signal for the proton of one hydroxyl

X. Wang, Y.R. Lee / Tetrahedron 65 (2009) 10125–10133
10129
H
O
O
hetero Diels-Alder
H-shift
O
O
O
O
OH
O
OH
28
O
OH
43
42
OH
pathway A
electrocyclization
HO
OH
trans,trans-farnesal
-H2O
OH
OH
O
EDDA
O
HO
O
O
O
OH
16
H
O
O
O
39
40
41
OH
OH
OH
more stable
electrocyclization
pathway B
H
O
O
O
O
hetero Diels-Alder
O
O
H-shift
HO
O
O
OH
45
OH
28a
OH
44
Scheme 2. The mechanism for the formation and stereochemistry of compound 28.
methides 40 and 41 through a tautomerism. Intermediate 40 with
intramolecular hydrogen bonding is probably more stable than 41
with dipole–dipole repulsions. It is at this stage that the observed
regioselectivity of 28 can be determined. Electrocyclization of much
more stable intermediate 40 gives benzopyran 42 that undergoes
a H-shift to furnish another quinine methide 43 by pathway A in-
stead of pathway B.19 The stereochemistry of 28 can be explained by
the pseudoequatorial conformation of methyl group of o-quinone
methide 43 in the chair-like transition state.20 In the process of the
hetero Diels–Alder reaction of 43, 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 using the intramolecular hetero Diels–Alder
cycloaddition of o-quinone methide.21
To extend the utility of this methodology, further reaction with
pinosylvin (46) was examined (Scheme 3). Reaction of pinosylvin
(46) with citral using 20 mol % ethylenediamine diacetate in
refluxing p-xylene for 10 h provided both benzopyran 47 (23%) and
tetracycle 48 (40%). The two compounds were easily separated by
column chromatography and assigned by spectroscopic analyses
based on reported data in the literature.22 The 1H NMR spectrum of
47 showed two vinyl protons on pyranyl ring at
d
6.59 (1H, d,
J¼10.0 Hz) and 5.49 (1H, d, J¼10.0 Hz) ppm, whereas that of com-
pound 48 showed a benzylic methine proton at 2.83 ppm as
d
a broad singlet. Further support for the structural assignment of 48
was obtained from its 13C NMR spectrum, which clearly showed the
expected two quaternary carbons on two tetrahydropyranyl rings
at
d
83.8 and 74.7 ppm.
A one-step synthesis of natural product rubraine (10) and its
derivatives 52–53 was next investigated (Scheme 4). This lab has
already reported on the synthesis of rubranine (10) starting from
desbenzylidenerubramin (8), described above through a two-step
aldol reaction. As another synthetic approach, reaction of 20,40,60-
trihydroxychalcone (49) with citral in the presence of 20 mol %
ethylenediamine diacetate in DMF at 100 ꢀC for 10 h produced
rubraine (10) in 36% yield. The spectroscopic data of synthetic
material 10 were identical to the values reported in the litera-
ture.7,9,23 Similarly, treatment of 50 and 51 with citral gave
unnatural rubraine derivatives 52 and 53 in 40 and 49% yields,
respectively.
H
HO
OH
O
R
citral
O
R
O
H
EDDA
(20 mol%)
DMF
HO
OH
OH
49 R=H
100 °C
O
O
OH
OH
O
10 R=H
36%
O
50 R=CH3
51 R=OCH3
52 R=CH3 40%
53 R=OCH3 49%
citral
+
EDDA (20 mol %)
p-xylene
Scheme 4.
reflux
46
47
48
23%
40%
As other applications of this methodology, first total synthesis of
sumadain A (12) was investigated. Scheme 5 shows a concise
synthetic approach to sumadain A (12) and its derivatives 55–57. A
Scheme 3. Reaction of pinosylvin (46) with citral in the presence of EDDA.

10130
X. Wang, Y.R. Lee / Tetrahedron 65 (2009) 10125–10133
H
H
R2
O
HO
OH
O
R1
O
O
trans,trans-farnesal
O
R2
R1
O
H
EDDA (20 mmol%)
DMF
KOH
EtOH
OH
100 °C
55%
OH
54
O
OH
O
12 R1=R2=H
95%
14
55 R1=H, R2=CH3 98%
56 R1=H, R2=OCH3 93%
57 R1=R2=OCH3
90%
Scheme 5. Synthesis of sumadain A (12) and its derivatives 55–57.
reaction of 2,4,6-trihydroxyacetophenone (14) with trans,trans-
farnesal using 20 mol % ethylenediamine diacetate in DMF at 100 ꢀC
for 10 h afforded adduct 54 in 55% yield. The conversion of 54 to
sumadain A (12) and its derivatives 55–57 was attempted by aldol
condensation. Reaction of 54 with benzaldehyde in the presence of
KOH in ethanol at room temperature for 48 h gave sumadain A (12)
in 95% yield. The spectroscopic data of synthetic material 12 were
the same as the values reported in the literature.10 Similarly,
treatment of 54 with 4-methylbenzaldehyde, 4-methoxy-
benzaldehyde, and 3,4-dimethoxy benzaldehyde in the presence of
ethanolic KOH for 48 h gave 55–57 in 98, 93, and 90% yields,
respectively.
In conclusion, an efficient and concise synthetic route for
biologically interesting polycycles with citran dihydrochalcone, and
chalcone nuclei was developed starting from substituted trihy-
droxybenzenes. Using this methodology, polycycles with a variety
of substituents on the pyranyl rings were synthesized. The key
strategy in these synthetic routes was the domino aldol-type re-
action/electrocyclization/H-migration/hetero Diels–Alder reaction,
which led to the successful synthesis of three natural products,
desbenzylidenerubramin (8), rubraine (10) and sumadain A (12),
and their unnatural derivatives.
2.65 (3H, s), 2.22–2.06 (2H, m), 1.90 (2H, d, J¼13.5 Hz), 1.62 (3H, s),
1.56–1.42 (1H, m), 1.41 (3H, s), 1.39–1.23 (1H, m), 1.15 (3H, s), 0.94–
0.76 (1H, m); IR (KBr) 2976, 2932, 1612, 1427, 1366, 1292, 1219, 1163,
1084, 1047, 1026, 1010, 974, 893, 825, 734 cmꢂ1; HRMS m/z (Mþ)
calcd for C18H22O4: 302.1518. Found: 302.1520; EIMS m/z 302 (Mþ,
23), 287 (7), 259 (5), 221 (11), 220 (12), 219 (100), 201 (5), 69 (5).
3.2.2. Compound 26. Reaction of 15 (154 mg, 1.0 mmol) with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 26
(130 mg, 45%) as a solid: mp 66–67 ꢀC; 1H NMR (300 MHz, CDCl3)
d
11.69 (1H, s), 9.96 (1H, s), 5.97 (1H, s), 2.77 (1H, br s), 2.25–2.14
(1H, m), 2.08–2.03 (1H, m), 1.84 (2H, d, J¼13.5 Hz), 1.55 (3H, s),
1.49–1.42 (1H, m) 1.37 (3H, s), 1.34–1.23 (1H, m), 1.10 (3H, s), 0.86–
0.73 (1H, m); 13C NMR (75 MHz, CDCl3)
d 190.8, 164.8, 162.9, 160.8,
108.0, 107.4, 96.3, 86.6, 76.6, 45.8, 37.4, 34.6, 29.4, 28.6, 27.2, 24.0,
21.8; IR (KBr) 2934, 1640, 1443, 1370, 1294, 1163, 1140, 1076, 909,
797 cmꢂ1; HRMS m/z (Mþ) calcd for C17H20O4: 288.1362. Found:
288.1364.
3.2.3. Compound 27. Reaction of 16 (182 mg, 1.0 mmol) with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 27
(205 mg, 65%) as a solid: mp 100–101 ꢀC; 1H NMR (300 MHz, CDCl3)
d
13.42 (1H, s), 6.01 (1H, s), 3.15–3.06 (1H, m), 3.04–2.87 (1H, m),
3. Experimental section
3.1. General
2.69 (1H, br s), 2.18–2.11 (1H, m), 2.08–2.05 (1H, m), 1.82 (2H, d,
J¼13.2 Hz), 1.55 (3H, s), 1.50–1.34 (1H, m), 1.35 (3H, s), 1.31–1.20
(1H, m), 1.13 (3H, t, J¼7.2 Hz), 1.08 (3H, s), 0.87–0.73 (1H, m); 13C
NMR (75 MHz, CDCl3)
d 205.5, 164.2, 162.3, 159.3, 107.5, 107.1, 96.9,
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 Bruker Model ARX (300 and
75 MHz, respectively) spectrometer in CDCl3 as the solvent
chemical shift. IR spectra were recorded on a Jasco FTIR 5300
spectrophotometer. The HRMS and MS (EI) spectra were carried
out at the Korea Basic Science Institute on a Jeol JMS 700
spectrometer.
86.6, 76.0, 46.1, 37.4, 36.5, 34.8, 29.9, 28.7, 27.5, 24.4, 21.8, 8.4; IR
(KBr) 3455, 2976, 2932, 1637, 1583, 1485, 1458, 1356, 1263, 1236,
1163,1140,1071,1010, 889, 825, 733 cmꢂ1; HRMS m/z (Mþ) calcd for
C19H24O4: 316.1675. Found: 316.1675.
3.2.4. Compound 28. Reaction of 16 (182 mg, 1.0 mmol) with
trans,trans-farnesal (264 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC
for 12 h afforded 28 (204 mg, 53%) as a solid: mp 102–103 ꢀC; 1H
NMR (300 MHz, CDCl3)
d 13.39 (1H, s), 6.00 (1H, s), 5.16 (1H, t,
J¼6.9 Hz), 3.17–3.04 (1H, m), 2.97–2.84 (1H, m), 2.71 (1H, br s),
2.28–1.95 (5H, m), 1.81 (2H, d, J¼13.2 Hz), 1.73–1.63 (1H, m), 1.69
(3H, s), 1.63 (3H, s), 1.49–1.37 (1H, m), 1.35 (3H, s), 1.29–1.22 (1H,
m), 1.13 (3H, t, J¼7.5 Hz), 1.04 (3H, s), 0.92–0.77 (1H, m); 13C NMR
3.2. Typical procedure for compounds 8 and 26–30
To a solution of trihydroxybenzenes (1.0 mmol) and citral or
trans,trans-farnesal (1.2 mmol) in DMF (10 mL) was added ethyl-
enediamine diacetate (36 mg, 0.2 mmol) at room temperature. The
reaction mixture was stirred at 100 ꢀC for 10–12 h and then cooled
to room temperature. Water (30 mL) was added and the solution
was extracted with ethyl acetate (30 mLꢁ3). Evaporation of solvent
and purification by column chromatography on silica gel gave
products.
(75 MHz, CDCl3) d 205.4, 164.1, 162.3, 158.9, 132.2, 123.7, 108.0,
107.2, 96.9, 88.8, 76.0, 45.4, 42.0, 37.5, 36.6, 34.7, 28.6, 27.4, 25.7,
22.6, 21.8, 21.2, 17.7, 8.5; IR (KBr) 3484, 2924, 1611, 1482, 1352,
1429, 1379, 1352, 1230, 1153, 1081, 1040, 1000, 893, 819, 762,
709 cmꢂ1; HRMS m/z (Mþ) calcd for C24H32O4: 384.2301. Found:
384.2302.
3.2.5. Compound 29. Reaction of 17 (244 mg, 1.0 mmol) with citral
(183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for 10 h afforded 29
(234 mg, 62%) as a solid: mp 138–139 ꢀC; 1H NMR (300 MHz, CDCl3)
3.2.1. Desbenzylidenerubramin (8). Reaction of 14 (168 mg,
1.0 mmol) with citral (183 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC
for 10 h afforded 8 (200 mg, 66%) as a solid: mp 138–140 ꢀC; 1H
d
13.25 (1H, s), 7.35–7.23 (5H, m), 6.05 (1H, s), 4.54 (1H, d,
J¼16.5 Hz), 4.22 (1H, d, J¼16.5 Hz), 2.74 (1H, br s), 2.21–2.05 (2H,
NMR (300 MHz, CDCl3)
d 13.42 (1H, s), 6.04 (1H, s), 2.73 (1H, br s),
m), 1.85 (2H, d, J¼13.5 Hz), 1.65 (3H, s), 1.51–1.38 (1H, m), 1.38

X. Wang, Y.R. Lee / Tetrahedron 65 (2009) 10125–10133
10131
(3H, s), 1.35–1.25 (1H, m), 1.08 (3H, s), 0.93–0.79 (1H, m); 13C NMR
(75 MHz, CDCl3) 201.8, 164.5, 162.8, 159.2, 135.4, 129.7, 128.3,
126.6, 107.7, 107.1, 97.0, 87.1, 76.2, 49.3, 46.1, 37.4, 34.7, 29.9, 28.6,
27.5, 24.3, 21.8; IR (KBr) 3418, 2976, 1622, 1479, 1429, 1350, 1258,
1163, 1140, 1073, 1009, 893, 824, 770 cmꢂ1; HRMS m/z (Mþ) calcd
for C24H26O4: 378.1831. Found: 378.1834.
(1H, s), 3.77 (3H, s), 3.51–3.40 (1H, m), 3.24–3.14 (1H, m), 2.94 (2H,
t, J¼7.6 Hz), 2.71 (1H, br s), 2.20–2.12 (1H, m), 2.09–2.02 (1H, m),
1.84 (2H, d, J¼13.2 Hz), 1.55 (3H, s), 1.50–1.40 (1H, m), 1.37 (3H, s),
1.33–1.24 (1H, m), 1.07 (3H, s), 0.88–0.76 (1H, m); 13C NMR
d
(75 MHz, CDCl3) d 203.8, 164.4, 162.5, 159.2, 157.7, 1337, 129.2, 113.7,
107.6, 107.2, 97.0, 86.8, 76.0, 55.2, 46.2, 44.8, 37.4, 34.8, 30.0, 29.6,
28.6, 27.5, 24.4, 21.8; IR (KBr) 3454, 2932, 1614, 1466, 1442, 1359,
1310, 1247, 1156, 1039, 828, 723 cmꢂ1; HRMS m/z (Mþ) calcd for
C26H30O5: 422.2093. Found: 422.2090; EIMS m/z 422 (Mþ, 44), 340
(22), 339 (100), 219 (48), 177 (14), 129 (21), 121 (30), 69 (20).
3.2.6. Compound 30. Reaction of 17 (244 mg, 1.0 mmol) with
trans,trans-farnesal (264 mg, 1.2 mmol) in DMF (10 ml) at 100 ꢀC for
10 h afforded 30 (232 mg, 52%) as a solid: mp 147–148 ꢀC; 1H NMR
(300 MHz, CDCl3)
d 13.22 (1H, s), 7.35–7.22 (5H, m), 6.06 (1H, s),
5.17 (1H, t, J¼6.9 Hz), 4.54 (1H, d, J¼16.8 Hz), 4.23 (1H, d,
J¼16.8 Hz), 2.78 (1H, br s), 2.29–2.14 (3H, m), 2.04–1.99 (2H, m),
1.85 (2H, d, J¼13.5 Hz), 1.80–1.67 (1H, m), 1.70 (3H, s), 1.62 (3H, s),
1.53–1.44 (1H, m), 1.39 (3H, s), 1.34–1.26 (1H, m), 1.07 (3H, s), 0.97–
3.3.4. Compound 34. Reaction of 21 (130 mg, 0.5 mmol) with citral
(92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 34
(89 mg, 45%) as a solid: mp 149–150 ꢀC; 1H NMR (300 MHz, CDCl3)
d
12.59 (1H, s), 7.26 (1H, t, J¼7.5 Hz), 7.09 (1H, d, J¼7.5 Hz), 7.04 (1H,
0.82 (1H, m); 13C NMR (75 MHz, CDCl3)
d
201.7, 164.5, 162.7, 158.8,
s), 6.98 (1H, d, J¼7.5 Hz), 6.10 (1H, s), 3.92 (3H, s), 2.65 (1H, br s),
2.21–2.14 (1H, m), 1.93–1.87 (1H, m), 1.80 (2H, d, J¼13.2 Hz), 1.45–
1.33 (1H, m), 1.37 (3H, s), 1.22–1.08 (1H, m), 1.08 (3H, s), 0.78–0.65
135.3, 132.2, 129.8, 128.3, 126.6, 123.6, 108.2, 107.4, 97.1, 89.4, 76.2,
49.2, 45.2, 42.1, 37.5, 34.6, 28.6, 27.4, 25.7, 22.8, 21.8, 21.3, 17.7; IR
(KBr) 3032, 2927, 1615, 1483, 1451, 1380, 1262, 1155, 1084, 999, 896,
844, 712 cmꢂ1; HRMS m/z (Mþ) calcd for C29H34O4: 446.2457.
Found: 446.2459.
(1H, m), 0.62 (3H, s); 13C NMR (75 MHz, CDCl3)
d 198.5, 164.3, 163.4,
159.3, 158.8, 143.3, 128.4, 120.4, 116.6, 112.4, 107.9, 107.3, 97.3, 85.6,
76.3, 55.4, 45.8, 37.6, 34.8, 29.1, 28.6, 27.5, 23.5, 21.7; IR (KBr) 3446,
2931, 1615, 1581, 1466, 1305, 1250, 1156, 1067, 982, 894, 819,
786 cmꢂ1; HRMS m/z (Mþ) calcd for C24H26O5: 394.1780. Found:
394.1778; EIMS m/z 394 (Mþ, 24), 379 (6), 313 (8), 312 (19), 311
(100), 203 (14), 135 (7), 69 (5).
3.3. Typical procedure for compounds 10, 31–38, and 52–53
To a solution of trihydroxybenzenes (0.5 mmol) or resorcinols
(0.5 mmol) and citral (0.6 mmol) in DMF (10 mL) was added eth-
ylenediamine diacetate (18 mg, 0.1 mmol) at room temperature.
The reaction mixture was stirred at 100 ꢀC for 10–12 h and then
cooled to room temperature. Water (30 mL) was added and the
solution was extracted with ethyl acetate (30 mLꢁ3). Evaporation
of solvent and purification by column chromatography on silica gel
gave products.
3.3.5. Compound 35. Reaction of 22 (130 mg, 0.5 mmol) with citral
(92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 35
(79 mg, 40%) as a solid: mp 155–156 ꢀC; 1H NMR (300 MHz, CDCl3)
d
12.43 (1H, s), 7.59 (2H, d, J¼8.0 Hz), 6.85 (2H, d, J¼8.0 Hz), 6.11
(1H, s), 3.85 (3H, s), 2.70 (1H, br s), 2.22–2.16 (1H, m), 1.95–1.87 (1H,
m), 1.82 (2H, d, J¼13.2 Hz), 1.45–1.37 (1H, m), 1.37 (3H, s), 1.25–1.15
(1H, m), 1.14 (3H, s), 0.78–0.65 (1H, m), 0.63 (3H, s); 13C NMR
3.3.1. Compound 31. Reaction of 18 (129 mg, 0.5 mmol) with citral
(92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 10 h afforded 31
(108 mg, 55%) as a solid: mp 74–75 ꢀC; 1H NMR (300 MHz, CDCl3)
(75 MHz, CDCl3) d 197.3, 163.9, 162.7, 162.1, 158.8, 134.2, 130.8, 112.5,
108.0, 107.6, 97.6, 85.6, 76.1, 55.4, 46.1, 37.6, 34.9, 29.2, 28.7, 27.7,
23.6, 21.8; IR (KBr) 3497, 2932, 1604, 1454, 1303, 1253, 1156, 1037,
952, 877, 825 cmꢂ1; HRMS m/z (Mþ) calcd for C24H26O5: 394.1780.
Found: 394.1777; EIMS m/z 394 (Mþ, 40), 313 (9), 312 (21), 311
(100), 203 (34), 148 (10), 135 (11), 69 (18).
d
13.37 (1H, s), 7.26–7.16 (5H, m), 6.04 (1H, s), 3.55–3.44 (1H, m),
3.30–3.12 (1H, m), 3.01 (2H, t, J¼7.6 Hz), 2.72 (1H, br s), 2.20–2.13
(1H, m), 2.10–2.03 (1H, m), 1.85 (2H, d, J¼13.2 Hz),1.55 (3H, s), 1.50–
1.41 (1H, m), 1.38 (3H, s), 1.32–1.25 (1H, m), 1.07 (3H, s), 0.89–0.74
(1H, m); 13C NMR (75 MHz, CDCl3)
d
203.6, 164.3, 162.2, 159.2, 141.6,
3.3.6. Compound 3617. Reaction of 23 (63 mg, 0.5 mmol) with citral
(92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 36
128.3, 128.2, 125.8, 107.7, 107.1, 97.0, 86.8, 76.1, 46.1, 44.5, 37.4, 34.7,
30.4, 29.9, 28.6, 27.5, 24.4, 21.7; IR (KBr) 3447, 2974, 2934, 1601,
1481, 1448, 1360, 1301, 1258, 1219, 1160, 1140, 1071, 975, 894,
822 cmꢂ1; HRMS m/z (Mþ) calcd for C25H28O4: 392.1988. Found:
392.1990.
(58 mg, 22%) as an oil: 1H NMR (300 MHz, CDCl3)
d 6.59 (3H, d,
J¼9.9 Hz), 5.35 (3H, d, J¼9.9 Hz, 5.07) (3H, t, J¼6.8 Hz), 2.20–2.10
(6H, m), 1.80–1.55 (6H, m), 1.64 (9H, s), 1.48 (9H, s), 1.35 (9H, s); 13C
NMR (75 MHz, CDCl3)
40.7, 26.0, 25.5, 22.4, 17.4; IR (neat) 2921, 1631, 1596, 1447, 1370,
1140, 1009, 905, 821, 724 cmꢂ1
d 149.0, 131.4, 124.6, 124.0, 117.0, 102.8, 78.4,
3.3.2. Compound 32. Reaction of 19 (136 mg, 0.5 mmol) with citral
(92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 32
(102 mg, 50%) as an solid: mp 105–106 ꢀC; 1H NMR (300 MHz,
.
3.3.7. 7-Methoxy-2-methyl-2-(methylpent-3-enyl)-2H-chromen-5-ol
(37). Reaction of 24 (70 mg, 0.5 mmol) with citral (92 mg,
0.6 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 37 (59 mg,
CDCl3)
d
13.37 (1H, s), 7.14 (2H, d, J¼8.1 Hz), 7.09 (2H, d, J¼8.1 Hz),
6.04 (1H, s), 3.53–3.42 (1H, m), 3.26–3.15 (1H, m), 2.96 (2H, t,
J¼7.6 Hz), 2.72 (1H, br s), 2.31 (3H, s), 2.21–2.16 (1H, m), 2.10–2.03
(1H, m), 1.84 (2H, d, J¼13.2 Hz), 1.55 (3H, s), 1.50–1.41 (1H, m), 1.37
(3H, s), 1.33–1.24 (1H, m), 1.07 (3H, s), 0.89–0.74 (1H, m); 13C NMR
43%) as an oil: 1H NMR (300 MHz, CDCl3)
d
6.55 (1H, d, J¼9.9 Hz),
5.99 (1H, s), 5.87 (1H, s), 5.39 (1H, d, J¼9.9 Hz), 5.08 (1H, t,
J¼6.8 Hz), 3.70 (3H, s), 2.15–2.03 (2H, m), 1.82–1.63 (2H, m), 1.64
(75 MHz, CDCl3)
d
203.8, 164.4, 162.5, 159.2, 138.5, 135.3, 128.9,
(3H, s), 1.56 (3H, s), 1.36 (3H, s); 13C NMR (75 MHz, CDCl3)
d 160.6,
128.2, 107.7, 107.1, 97.0, 86.8, 76.0, 46.2, 44.6, 37.4, 34.8, 30.0, 29.9,
28.7, 27.5, 24.5, 21.8, 21.0; IR (KBr) 3443, 2971, 1618, 1473, 1438,
1363, 1225, 1219, 1150, 1066, 817, 717 cmꢂ1; HRMS m/z (Mþ) calcd
for C26H30O4: 406.2144. Found: 406.2142; EIMS m/z 406 (Mþ, 7),
323 (19), 302 (22), 220 (14), 219 (100), 201 (5), 69 (5).
155.2, 152.1, 131.7, 125.3, 124.1, 116.6, 103.1, 94.7, 94.6, 78.6, 55.3,
41.0, 26.2, 25.7, 22.7, 17.6; IR (neat) 3415, 2957, 1620, 1490, 1449,
1364,1262,1197,1140, 971, 819, 779 cmꢂ1; HRMS m/z (Mþ) calcd for
C17H22O3: 274.1569. Found: 274.1572; EIMS m/z 274 (Mþ, 11), 259
(5), 192 (12), 191 (100), 148 (3), 69 (3).
3.3.3. Compound 33. Reaction of 20 (144 mg, 0.5 mmol) with citral
(92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 33
(120 mg, 57%) as a solid: mp 109–110 ꢀC; 1H NMR (300 MHz, CDCl3)
3.3.8. 6-Acetyl-7-methoxy-2-methyl-2-(methylpent-3-enyl)-2H-
chromen-5-ol (38). Reaction of 25 (91 mg, 0.5 mmol) with citral
(92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 12 h afforded 38
(98 mg, 62%) as a solid: mp 79–80 ꢀC; 1H NMR (300 MHz, CDCl3)
d
13.36 (1H, s), 7.15 (2H, d, J¼8.7 Hz), 6.82 (2H, d, J¼8.7 Hz), 6.03

10132
X. Wang, Y.R. Lee / Tetrahedron 65 (2009) 10125–10133
d
14.30 (1H, s), 6.67 (1H, d, J¼9.9 Hz), 5.85 (1H, s), 5.37 (1H, d, J¼9.9 Hz),
CDCl3)
d
14.04 (1H, s), 8.13 (1H, d, J¼15.6 Hz), 7.74 (1H, d,
5.06 (1H, t, J¼6.8 Hz), 3.83 (3H, s), 2.57 (3H, s), 2.10–2.02 (2H, m),1.80–
J¼15.6 Hz), 7.56 (2H, d, J¼8.7 Hz), 6.92 (2H, d, J¼8.7 Hz), 6.08 (1H,
s), 3.83 (3H, s), 2.77 (1H, br s), 2.22–2.05 (2H, m), 1.86 (2H, d,
J¼13.2 Hz), 1.64 (3H, s), 1.56–1.40 (1H, m), 1.38 (3H, s), 1.32–1.23
(1H, m), 1.05 (3H, s), 0.91–0.80 (1H, m); 13C NMR (75 MHz, CDCl3)
1.64 (2H, m), 1.64 (3H, s), 1.55 (3H, s), 1.38 (3H, s); 13C NMR (75 MHz,
CDCl3) d 203.0, 162.9, 161.7, 160.5, 131.8, 124.0, 123.8, 116.4, 105.5, 102.4,
90.8, 80.6, 55.5, 41.6, 32.9, 27.1, 25.6, 22.6,17.6; IR (KBr) 3476, 2919,1615,
1438,1379,1268,1213,1123,1034, 988, 881, 822 cmꢂ1; HRMS m/z (Mþ)
calcd for C19H24O4: 316.1675. Found: 316.1672; EIMS m/z 316 (Mþ, 10),
234 (14), 233 (100), 215 (12), 191 (16), 69 (6).
d
191.9, 165.5, 162.7, 161.2, 159.0, 142.0, 130.0, 128.4, 124.9, 114.4,
108.3, 108.1, 97.5, 86.8, 76.1, 55.4, 46.2, 37.6, 34.8, 30.2, 28.7, 27.7,
24.4, 21.8; IR (KBr) 3445, 1622, 1553, 1510, 1480, 1422, 1352, 1233,
1171, 1022, 829 cmꢂ1; HRMS m/z (Mþ) calcd for C26H28O5: 420.1937.
Found: 420.1938.
3.3.9. 2-Methyl-2-(4-methylpent-3-enyl)-7-(E)-styryl-2H-chromen-
5-ol (47) and compound 48. A reaction of 46 (106 mg, 0.5 mmol)
with citral (91 mg, 0.6 mmol) in refluxing p-xylene (10 mL) for 10 h
afforded compounds 47 (40 mg, 23%) and 48 (69 mg, 40%) as an oil.
3.3.13. Compound 54. To a solution of 2,4,6-trihydroxyacetophenone
(14) (168 mg, 1.0 mmol) with trans,trans-farnesal (264 mg,
1.2 mmol) in DMF (10 ml) at 100 ꢀC. The reaction mixture was
stirred at 100 ꢀC for 10 h and then cooled to room temperature.
Water was added and the solution was extracted with ethyl acetate.
Evaporation of solvent and purification by column chromatography
on silica gel gave product 54 (204 mg, 55%) as a solid: mp 68–69 ꢀC;
Compound47: 1H NMR (300 MHz, CDCl3)
d
7.40 (2H, d, J¼8.6 Hz), 7.26
(2H, dd, J¼8.6, 8.4 Hz), 7.18 (1H, d, J¼8.4 Hz), 6.96 (1H, d, J¼16.3 Hz),
6.83 (1H, d, J¼16.3 Hz), 6.59 (1H, d, J¼10.0 Hz), 6.55 (1H, s), 6.39 (1H,
s), 5.49 (1H, J¼10.0 Hz), 5.10–4.98 (2H, m), 2.18–1.99 (2H, m), 1.75–
1.63 (2H, m), 1.60 (3H, s), 1.53 (3H, s), 1.34 (3H, s); 13C NMR (75 MHz,
CDCl3)
d
154.4,151.4,138.3,137.2,131.7,128.9,128.7,128.2,128.1,127.7,
1H NMR (300 MHz, CDCl3)
d 13.29 (1H, s), 6.01 (1H, s), 5.18–5.12
126.5,124.1,116.8,109.2,107.1,106.1, 78.4, 41.1, 26.3, 25.7, 22.7,17.6; IR
(neat) 3409, 2970, 2921,1613,1567,1429,1343,1263,1198,1143,1083,
1058, 960, 824, 749 cmꢂ1; HRMS m/z (Mþ) calcd for C24H26O2:
346.1933. Found: 346.1936;EIMS m/z 346(Mþ, 9), 264(19), 263 (100),
150 (3), 107 (3), 77 (3), 69 (9), 58 (5). Compound 48: 1H NMR
(1H, m), 2.72 (1H, br s), 2.58 (3H, s), 2.26–1.94 (5H, m), 1.82 (2H, br
d, J¼13.4 Hz), 1.76–1.69 (1H, m), 1.69 (3H, s), 1.63 (3H, s), 1.50–1.40
(1H, m), 1.36 (3H, s), 1.32–1.23 (1H, m) 1.05 (3H, s), 0.94–0.79 (1H,
m); 13C NMR (75 MHz, CDCl3)
d 202.1, 164.2, 162.6, 159.1, 132.1,
123.7, 108.0, 107.7, 96.9, 88.9, 76.1, 45.4, 42.1, 37.5, 34.7, 32.1, 28.6,
27.4, 25.6, 22.7, 21.8, 21.1, 17.7; IR (neat) 2928, 1622, 1485, 1433,
1364, 1294, 1161, 1061, 961, 824, 772, 735 cmꢂ1; HRMS m/z (Mþ)
calcd for C23H30O4: 370.2144. Found: 370.2142; EIMS m/z 370 (Mþ,
23), 261 (8), 221 (31), 220 (13), 219 (100), 181 (5), 69 (10).
(300 MHz, CDCl3)
d
7.41 (2H, d, J¼7.8 Hz), 7.27 (2H, dd, J¼7.8, 7.5 Hz),
7.17 (1H, d, J¼7.5 Hz), 6.94 (2H, s), 6.60 (1H, s), 6.57 (1H, s), 2.83(1H, br
s), 2.20–2.15 (1H, m), 2.02–1.98 (1H, m),1.878 (2H, d, J¼13.2 Hz),1.48
(3H, s), 1.41–1.36 (1H, m), 1.33 (3H, s), 1.25–1.18 (1H, m), 0.98 (3H, s),
0.74–0.61 (1H, m); 13C NMR (75 MHz, CDCl3)
d 157.3, 156.9, 137.4,
136.8, 129.2, 128.6, 128.2, 127.3, 126.4, 116.9, 107.8, 107.4, 83.8, 74.7,
46.7, 37.3, 35.2, 29.7, 29.0, 28.3, 23.8, 22.1; IR (neat) 3026, 2975, 2930,
1610, 1578, 1449, 1424, 1352, 1314, 1130, 1065, 997, 963, 909, 883, 827,
733 cmꢂ1; HRMS m/z (Mþ) calcd for C24H26O2: 346.1933. Found:
346.1929; EIMS m/z 346 (Mþ, 30), 331 (7), 303 (5), 265 (10), 264 (22),
263 (100), 151 (10), 123 (7), 109 (5), 91 (7), 69 (31).
3.4. Typical procedure for compounds 12 and 55–57
To a solution of 54 (0.5 mmol) in ethanol (5 ml) were added
potassium hydroxide (2.5 mmol) and corresponding aldehyde
(0.5 mmol) at room temperature. The reaction mixture was stirred
for 48 h at room temperature. Addition of water (30 mL) and ex-
traction with ethyl acetate (3ꢁ50 mL), washing with 2 N-HCl so-
lution and brine, drying over MgSO4, and removal of the solvent
followed by flash column chromatography on silica gel gave
products.
3.3.10. Rubraine (10)7,9,23. To
a
solution of 20,40,60-trihydroxy-
chalcone 49 (126 mg, 0.5 mmol) with citral (92 mg, 0.6 mmol) in
DMF (10 ml) at 100 ꢀC for 10 h afforded rubraine 10 (70 mg, 36%) as
a solid: mp 172–173 ꢀC; 1H NMR (300 MHz, CDCl3)
d 14.02 (1H, s),
8.29 (1H, d, J¼15.7 Hz), 7.80 (1H, d, J¼15.7 Hz), 7.66–7.57 (2H, d,
J¼7.5 Hz), 7.50–7.40 (3H, m), 6.13 (1H, s), 2.79 (1H, br s), 2.25–2.09
(2H, m), 1.90 (2H, d, J¼13.2 Hz), 1.68 (3H, s), 1.58–1.45 (1H, m) 1.42
(3H, s), 1.35–1.22 (1H, m), 1.09 (3H, s), 0.93–0.79 (1H, m); 13C NMR
3.4.1. Sumadain A (12). To a solution of 54 (185 mg, 0.5 mmol) in
ethanol (5 ml) were added KOH (140 mg, 2.5 mmol) and benzal-
dehyde (53 mg, 0.5 mmol) at room temperature for 48 h afforded
12 (218 mg, 95%) as a solid: mp 172–173 ꢀC; 1H NMR (300 MHz,
(75 MHz, CDCl3)
d
191.7,165.4,162.9,159.0,141.8,135.5,129.9,128.8,
CDCl3)
d
13.95 (1H, s), 8.16 (1H, d, J¼15.6 Hz), 7.78 (1H, d,
128.1, 127.1, 108.3, 107.9, 97.4, 86.9, 76.2, 46.0, 37.4, 34.6, 30.0, 28.5,
27.6, 24.2, 21.7; IR (KBr) 3445, 1631, 1479, 1339, 1231, 1163, 1142,
J¼15.6 Hz), 7.63–7.60 (2H, m), 7.37–7.35 (3H, m), 6.09 (1H, s), 5.22–
5.18 (1H, m), 2.79 (1H, br s), 2.41–2.29 (1H, m), 2.29–2.02 (4H, m),
1.85 (2H, br d, J¼13.5 Hz),1.79–1.69 (1H, m),1.73 (3H, s),1.64 (3H, s),
1.51–1.41 (1H, m), 1.38 (3H, s), 1.30–1.24 (1H, m), 1.01 (3H, s), 0.94–
1074, 1017, 826, 731 cmꢂ1
.
3.3.11. Compound 52. To a solution of 50 (135 mg, 0.5 mmol) with
citral (92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 10 h afforded
52 (81 mg, 40%) as a solid: mp 216–217 ꢀC; 1H NMR (300 MHz,
0.79 (1H, m); 13C NMR (75 MHz, CDCl3)
d 191.7, 165.6, 162.9, 158.7,
142.3, 135.5, 132.2, 130.0, 128.8, 128.4, 127.1, 123.6, 108.8, 108.3, 97.6,
89.2, 76.2, 45.6, 42.4, 37.6, 34.7, 28.6, 27.6, 25.7, 23.0, 21.8, 21.1, 17.7;
IR (KBr) 3452, 2972, 2925, 1626, 1552, 1478, 1340, 1234, 1161, 1080,
1022, 982, 909, 827, 763, 726 cmꢂ1; HRMS m/z (Mþ) calcd for
C30H34O4: 458.2457. Found: 458.2458; EIMS m/z 458 (Mþ, 31), 309
(27), 308 (22), 307 (100), 203 (38), 69 (12).
CDCl3)
d
13.95 (1H, s), 8.19 (1H, d, J¼15.7 Hz), 7.74 (1H, d,
J¼15.7 Hz), 7.51 (2H, d, J¼8.1 Hz), 7.17 (2H, d, J¼8.1 Hz), 6.08 (1H, s),
2.77 (1H, br s), 2.37 (3H, s), 2.24–2.06 (2H, m), 1.86 (2H, d,
J¼13.5 Hz), 1.64 (3H, s), 1.53–1.41 (1H, m), 1.38 (3H, s), 1.32–1.23
(1H, m), 1.05 (3H, s), 0.92–0.77 (1H, m); 13C NMR (75 MHz, CDCl3)
d
191.9, 165.5, 162.8, 159.0, 142.1, 140.4, 132.8, 129.6, 128.2, 126.2,
3.4.2. Compound 55. To a solution of 54 (185 mg, 0.5 mmol) in
ethanol (5 ml) were added KOH (140 mg, 2.5 mmol) and p-tolu-
aldehyde (60 mg, 0.5 mmol) at room temperature for 48 h afforded
55 (232 mg, 98%) as a solid: mp 160–161 ꢀC; 1H NMR (300 MHz,
108.3, 108.0, 97.4, 86.8, 76.2, 46.1, 37.5, 34.7, 30.1, 28.6, 27.6, 24.3,
21.8, 21.5; IR (KBr) 3449, 2924, 1618, 1549, 1478, 1235, 1181, 1163,
1142, 1078, 1020, 988, 881, 823 cmꢂ1; HRMS m/z (Mþ) calcd for
C26H28O4: 404.1988. Found: 404.1985.
CDCl3)
d
13.98 (1H, s), 8.12 (1H, d, J¼15.6 Hz), 7.77 (1H, d,
J¼15.6 Hz), 7.51 (2H, d, J¼8.1 Hz), 7.16 (2H, d, J¼8.1 Hz), 6.09 (1H, s),
5.23–5.18 (1H, m), 2.79 (1H, br s), 2.44–2.32 (1H, m), 2.36 (3H, s),
2.28–2.01 (4H, m), 1.84 (2H, d, J¼13.5 Hz), 1.81–1.69 (1H, m), 1.74
(3H, s),1.65 (3H, s), 1.50–1.41 (1H, m), 1.38 (3H, s), 1.30–1.21 (1H, m),
3.3.12. Compound 53. To a solution of 51 (143 mg, 0.5 mmol) with
citral (92 mg, 0.6 mmol) in DMF (10 ml) at 100 ꢀC for 10 h afforded
53 (103 mg, 49%) as a solid: mp 208–209 ꢀC; 1H NMR (300 MHz,

X. Wang, Y.R. Lee / Tetrahedron 65 (2009) 10125–10133
10133
1.01 (3H, s), 0.94–0.79 (1H, m); 13C NMR (75 MHz, CDCl3)
d
191.9,
Supplementary data
165.6, 162.8, 158.7, 142.5, 140.4, 132.9, 132.3, 129.6, 128.4, 126.1,
123.7, 108.8, 108.4, 97.6, 89.2, 76.2, 45.6, 42.5, 37.7, 34.7, 28.7, 27.7,
25.8, 23.0, 21.9, 21.5, 21.2, 17.7; IR (KBr) 3453, 2928, 2856, 1737,
1624, 1547, 1473, 1342, 1238, 1159, 1079, 1016, 986, 912, 876, 818,
712 cmꢂ1; HRMS m/z (Mþ) calcd for C31H36O4: 472.2614. Found:
472.2617; EIMS m/z 472 (Mþ, 32), 323 (28), 322 (23), 321 (100), 203
(40), 69 (19).
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.10.045.
References and notes
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3.4.3. Compound 56. To a solution of 54 (185 mg, 0.5 mmol) in
ethanol (5 ml) were added KOH (140 mg, 2.5 mmol) and p-ani-
saldehyde (68 mg, 0.5 mmol) at room temperature for 48 h affor-
ded 56 (227 mg, 93%) as a solid: mp 175–176 ꢀC; 1H NMR (300 MHz,
CDCl3)
d
13.98 (1H, s), 8.05 (1H, d, J¼15.6 Hz), 7.76 (1H, d,
J¼15.6 Hz), 7.56 (2H, d, J¼8.7 Hz), 6.87 (2H, d, J¼8.7 Hz), 6.08 (1H,
s), 5.23–5.18 (1H, m), 3.82 (3H, s), 2.78 (1H, br s), 2.44–2.32 (1H, m),
2.30–2.02 (4H, m), 1.85 (2H, d, J¼13.5 Hz), 1.82–1.70 (1H, m), 1.73
(3H, s),1.65 (3H, s),1.52–1.40 (1H, m),1.37 (3H, s), 1.29–1.21 (1H, m),
1.01 (3H, s), 0.94–0.79 (1H, m); 13C NMR (75 MHz, CDCl3)
d 191.8,
165.6, 162.7, 161.3, 158.6, 142.3, 132.2, 130.1, 128.4, 124.8, 123.7,
114.3, 108.7, 108.4, 97.6, 89.1, 76.1, 55.3, 45.7, 42.5, 37.7, 34.7, 28.6,
27.7, 25.7, 23.0, 21.9, 21.1, 17.8; IR (KBr) 3463, 2930, 1624, 1547, 1510,
1474, 1421, 1348, 1290, 1235, 1166, 1021, 1084, 984, 911, 876, 824,
731 cmꢂ1; HRMS m/z (Mþ) calcd for C31H36O5: 488.2563. Found:
488.2562; EIMS m/z 488 (Mþ, 40), 340 (5), 339 (25), 338 (23), 337
(100), 205 (5), 204 (5), 203 (41), 161 (5), 69 (7).
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3.4.4. Compound 57. To a solution of 54 (185 mg, 0.5 mmol) in
ethanol (5 ml) were added KOH (140 mg, 2.5 mmol) and 3,4-
dimethoxy benzaldehyde (83 mg, 0.5 mmol) at room temperature
for 48 h afforded 57 (233 mg, 90%) as a solid: mp 158–159 ꢀC; 1H
NMR (300 MHz, CDCl3)
d
14.05 (1H, s), 8.03 (1H, d, J¼15.6 Hz), 7.76
(1H, d, J¼15.6 Hz), 7.17 (1H, d, J¼7.8 Hz), 7.16 (1H, s), 6.94 (1H, d,
J¼7.8 Hz), 6.09 (1H, s), 5.18–5.5.13 (1H, m), 3.91 (3H, s), 3.87 (3H, s),
2.79 (1H, br s), 2.34–1.98 (5H, m), 1.84 (2H, d, J¼13.5 Hz), 1.84–1.78
(1H, m),1.71 (3H, s),1.60 (3H, s),1.51–1.40 (1H, m),1.38 (3H, s),1.29–
1.23 (1H, m), 1.02 (3H, s), 0.93–0.78 (1H, m); 13C NMR (75 MHz,
CDCl3)
d 191.7, 165.6, 162.7, 158.6, 151.0, 149.2, 142.6, 132.5, 128.7,
124.9, 123.5, 111.0, 109.5, 108.7, 108.4, 97.7, 89.1, 76.1, 56.0, 55.7, 45.3,
42.6, 37.7, 34.7, 28.6, 27.7, 25.7, 23.1, 21.9, 21.4, 17.7; IR (KBr) 3410,
2930, 1621, 1547, 1511, 1474, 1420, 1353,1319, 1260, 1160, 1024,1083,
1160, 1024, 980, 905, 818, 771 cmꢂ1; HRMS m/z (Mþ) calcd for
C32H38O6: 518.2668. Found: 518.2665; EIMS m/z 518 (Mþ, 17), 369
(21), 368 (23), 367 (100), 205 (5), 204 (6), 203 (41), 191 (6), 165 (5),
69 (7).
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J. Org. Chem. 1996, 61, 6768.
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631.
Acknowledgements
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This work was supported by grant no. RTI04-01-04 from the
Regional Technology Innovation Program of the Ministry of
Knowledge Economy (MKE).