A concise route for the synthesis of biologically interesting pyranocoumarins - Seselin, (±)-cis-khellactone, (±)- quianhucoumarin D, and the (±)-5-deoxyprotobruceol-I regioisomer

Article abstract of DOI:10.1055/s-2006-926329

An efficient synthesis of pyranocoumarins is achieved starting from 2H-pyrans. This process provides naturally occurring seselin, cis-khellactone, quianhucoumarin D, and the 5-deoxyprotobruceol-I regioisomer. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926329

PAPER
853
A Concise Route for the Synthesis of Biologically Interesting Pyranocoumarins
– Seselin, ( )-cis-Khellactone, ( )-Quianhucoumarin D, and the ( )-5-Deoxy-
protobruceol-I Regioisomer
S
ynthesis of Biolo
o
gically Intere
n
sting Pyrano
g
coumarins Rok Lee,*a Won Kyong Lee,a Seok Kyun Noh,a Won Seok Lyoob
a
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Korea
School of Textiles, Yeungnam University, Gyeongsan 712-749, Korea
Fax +82(53)8104631; E-mail: yrlee@yu.ac.kr
b
Received 20 July 2005; revised 12 September 2005
and Citrus grandis.15 Clinically they are used as photoac-
tive drugs in skin photochemotheraphy, to treat vitiligo
and to prevent sun-burning.16 Also they have been report-
ed to act as DNA-damaging agents17 and have been used
as starting materials for the synthesis of various naturally
occurring compounds.18 (+)-cis-Khellactone (5) and its
derivatives 6–11 are isolated from Prionosciadium watso-
ni.19 They are known to act as a potent anti-AIDS agent in
H9 lymphocytes.7 This range of important biological
properties and activities has stimulated interest in the syn-
thesis of naturally occurring seselin, cis-khellactone, and
their derivatives. Although several synthetic approaches
to pyranocoumarin derivatives including seselin and cis-
khellactone have been reported from resorcinol,7c,16,20
there is still a demand for general methods which can ef-
ficiently provide variously substituted pyranocoumarin
derivatives. In particular, no convergent synthetic routes
to pyranocoumarin derivatives starting from 2H-pyrans
are known.
Abstract: An efficient synthesis of pyranocoumarins is achieved
starting from 2H-pyrans. This process provides naturally occurring
seselin, cis-khellactone, quianhucoumarin D, and the 5-deoxyproto-
bruceol-I regioisomer.
Key words: ring-opening, epoxides, nucleophiles, formylations,
pyranocoumarin derivatives
Pyranocoumarins are widely distributed in nature in both
linear and angular forms (Figure 1).1 Members of both
groups have a variety of interesting biological properties
and potential pharmacological activities such as antima-
larial,2 antibacterial,3 antifungal,4 antiulcer,5 calcium an-
tagonistic,6 and anti-HIV activities.7 They show great
promise in cancer therapy8 and are used to promote
smooth muscle relaxation.9 They have also shown potent
acetylcholinesterase (AChE) inhibitory activity.10 They
have been found in traditional medicines, examples in-
clude Bai-Hua Qian-Hu, which was used for the treatment
of certain respiratory diseases and pulmonary hyperten-
sion in China;9 Aegle marmelos Correa, an Indian medic-
inal plant, was used to treat various ailments;5 and
Angellica gigas Nakai was used not only used to treat ane-
mia, but also as a sedative, an anodyne, and a tonic agent
in Korea.11 Pyranocoumarins, seselin (1), and 5-methoxy-
seselin (2) are primarily isolated from Plumbago zeylani-
ca,12 Naucleopsis caloneura,13 Carum roxburghianum,14
We have recently reported that Yb(OTf)3- or InCl3-cata-
lyzed reactions of 1,3-dicarbonyls with enals provide a
rapid route to 2H-pyrans.21 2H-Pyrans seemed an ideal
starting material for the synthesis of naturally occurring
pyranocoumarin derivatives. We report herein a conve-
nient and efficient synthesis of seselin, ( )-cis-khellac-
tone, and their derivatives, as well as the first total
synthesis of the 5-deoxyprotobruceol-I regioisomer.
O
R2
O
O
O
OR4
OR3
O
O
O
R
O
3 R2 = H xanthyletin
O
1 R = H seselin
2 R = OMe 5-methoxyseselin
4 R2 = OMe xanthoxyletin
5 R3 = H, R4 = H (+)-cis-khellactone
6 R3 = H, R4 = COCH(CH3)2
O
7 R3 = COCH3, R4 = COCH2CH3
O
OR6
8 R3 = (z)-COC(CH3)CHCH3, R4 = H
OR5
9 R3 = COCH3, R4 = COCH(CH3)2 seravshanin
10 R3 = R4 = COCH3 quianhucoumarin D
11 R3 = COCH3, R4 = COCH2CH(CH3)2 suksdorfin
O
O
O
O
12 R5 = (Z)-COC(CH3)CHCH3 jatamansin
13 R5 = COCH(CH3)2
14 R6 = H
15 R6 = COCHC(CH3)2
Figure 1 Naturally occurring pyranocoumarins
SYNTHESIS 2006, No. 5, pp 0853–0859
x
x
.
x
x
.2
0
0
6
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926329; Art ID: F12305SS
© Georg Thieme Verlag Stuttgart · New York

854
Y. R. Lee et al.
PAPER
O
O
O
O
O
OH
LiHMDS, Et3N
DDQ
benzene
H
H
O
ethyl formate
toluene
O
O
O
69%
16
78%
17
OsO4
18
O
OH
O
N-methylmorpholine N-oxide
Ph3P=CHCO2Et
xylene
OH
t-BuOH, THF, H2O
O
60%
O
cis-khellactone (5)
75%
seselin (1)
O
Ac2O
O
OAc
pyridine
r.t.
OAc
85%
O
quianhucoumarin D (10)
Scheme 1
The total syntheses of seselin (1), ( )-cis-khellactone (5), the synthesis of pyranocoumarin derivatives with cis-sub-
and ( )-quianhucoumarin D (10) was recently examined stituents on the dihydropyran ring.
(Scheme 1). Formylation of 2H-pyran 1621b with ethyl
Further conversion of seselin (1) to a variety of pyrano-
formate was attempted under basic conditions. Reaction
of 16 with ethyl formate in the presence of LDA in THF
was extremely slow, with only a 20% yield of the desired
product 17 after a reaction time of 12 hours at –78 °C. The
yield was improved to 35% when the mixture was stirred
in the presence of LiHMDS in THF at –78 °C for 12
hours. Very recently, it was found that the LiHMDS and
coumarin derivatives with trans-substituents on the dihy-
dropyran ring was carried out by the ring-opening of
epoxide 19 with several nucleophiles promoted by a
Lewis acid catalyst (Table 1). Treatment of 1 with
MCPBA at 0 °C for 12 hours gave epoxide 19 in 62%
yield. The epoxide 19 was then reacted with an oxygen,
nitrogen, or sulfur nucleophile at room temperature, either
neat or in a suitable solvent. Reaction of 19 with methanol
triethylamine-mediated reaction of the ketone can acceler-
ate enolization via a dimer-based mechanism.22 As ex-
in the presence of 10 mol% InCl3 at room temperature for
pected, a much faster reaction was observed when 16 was
two hours afforded trans-product 20 as the sole product in
treated with ethyl formate in the presence of LiHMDS and
92% yield, whereas treatment with ethanol at room tem-
triethylamine in toluene. After only three hours at –78 °C,
perature for two hours afforded both trans-product 21 and
cis-product 22 in 88% and 5% yields, respectively
(Table 1, entries 1 and 2). Compound 20 was identified as
compound 17 was isolated in 78% yield. The structure of
17 was assigned to be predominantly the enol form by 1H
NMR spectral analysis. Oxidation of 17 by DDQ in re-
the trans-product by spectroscopic analysis and by com-
fluxing benzene for three hours afforded compound 18 in
parison with the literature.24 Compounds 21 and 22 were
69% yield. In order to build the pyrone ring, we attempted
easily separated by silica gel column chromatography and
the condensation of aldehyde 18 with the Horner–Em-
their structures were assigned on the basis of their spectral
mons reagent, triethyl phosphonoacetate and a base, how-
ever, this reaction was unsuccessful, probably because of
the presence of the acidic phenol group. Fortunately, we
1
data. The H NMR spectrum of trans-adduct 21 showed
two characteristic methine signals on the pyran ring at
4.61 (1 H, d, J = 3.3 Hz) and 3.88 (1 H, d, J = 3.3 Hz) ppm.
The cis-adduct 22 showed two methine protons at 4.79 (1
H, d, J = 5.0 Hz) and 3.83 (1 H, d, J = 5.0 Hz) ppm. With
were able to introduce the pyrone ring by the one-pot Wit-
tig reaction followed by intramolecular cyclization.23
Treatment of 18 with (carbethoxymethylene)triphenyl-
isopropanol, trans-product 23 was produced in 94% yield
phosphorane in refluxing xylene for ten hours afforded se-
(Table 1, entry 3). To further expand the utility of this re-
selin (1) in 75% yield. The physical and spectroscopic
action, other nucleophiles were investigated in the pres-
ence of 10 mol% InCl3. When 19 was treated with
ethanethiol at room temperature for one hour, product 24
was obtained in 92% yield (Table 1, entry 4). Finally, an
properties of our synthetic material 1 was in good agree-
ment with those reported in the literature.20a Conversion
of seselin to ( )-cis-khellactone (5) was carried out by cat-
alytic osmium oxidation using NMO in 60% yield.18b The
aromatic thiol and amine were investigated. Treatment of
spectral data of our synthetic material 5 was in good
19 with thiophenol at room temperature for two hours in
agreement with those reported in the literature.18b Treat-
dichloromethane resulted in products 25 and 26 in 66%
and 32% yields, respectively (Table 1, entry 5). In this
ment of 5 with excess acetic anhydride in pyridine afford-
ed ( )-quianhucoumarin D (10) in 85% yield. The spectral
case, the trans-product was obtained as the major compo-
data of 10 were in agreement with those reported in the lit-
nent. On the other hand, reaction with aniline in dichlo-
romethane afforded the corresponding product 27 in 87%
erature.18d These synthetic routes provide a rapid entry to
yield (Table 1, entry 6). In view of this result, InCl3-cata-
Synthesis 2006, No. 5, 853–859 © Thieme Stuttgart · New York

PAPER
Synthesis of Biologically Interesting Pyranocoumarins
855
Table 1 Ring-Opening of Epoxide 19 with Nucleophiles
O
O
O
O
O
Nu
O
MCPBA
NuH
InCl3
O
OH
CH2Cl2
62%
O
O
20–27
O
1
19
Entry
1
NuH
Time (h)
Solvent
MeOH
Product (yield)
MeOH
2
O
O
OMe
OH
OH
92%
O
20
2
3
4
5
EtOH
i-PrOH
EtSH
2
2
1
2
EtOH
O
O
O
O
O
O
OEt
O
O
OEt
O
OH
5%
88%
21
22
i-PrOH
EtSH
O
O
O
Oi-Pr
O
OH
OH
OH
94%
23
SEt
O
92%
24
25
27
PhSH
CH2Cl2
O
SPh
O
O
SPh
OH
O
66%
32%
26
6
Aniline
2
CH2Cl2
O
O
NHPh
OH
87%
O
O
lyzed reactions of epoxide 19 with several nucleophiles
provided trans-adducts as the major component. The ste-
reochemistry of 23–27 was determined by comparison
with reported data.20b These transformations provided a
rapid entry to the synthesis of biologically interesting pyr-
anocoumarin derivatives with trans-substituents on the
dihydropyran rings.
O
O
O
OOH
O
O
28
29
O
O
This methodology was applied to the first total synthesis
of naturally occurring 5-deoxyprotobruceol-I regioisomer
28. The 5-deoxyprotobruceol-I regioisomer 28, 5-deoxy-
protobruceol-II hydroperoxide regioisomer 29, and 5-
deoxyprotobruceol-III hydroperoxide regioisomer 30
OOH
O
30
Figure 2 Natural products isolated from Boronia lanceolata
Synthesis 2006, No. 5, 853–859 © Thieme Stuttgart · New York

856
Y. R. Lee et al.
PAPER
duced pressure. The residue was purified by flash column chroma-
tography (hexane–EtOAc, 5:1) to give 17 (0.515 g, 78%).
were isolated from Boronia lanceolata, a tall shrub with
tomentose branches found in Australia (Figure 2).25 Start-
ing material 31 was readily prepared from 1,3-cyclohex- IR (neat): 2978, 1637, 1586, 1433, 1358, 1273, 1225, 1208, 1134,
1088, 972, 899 cm–1.
anedione and citral in the presence of 10 mol%
ethylenediamine diacetate in 66% yield.26 The formyla-
tion of 31 by ethyl formate with LiHMDS and triethyl-
amine at –78 °C gave product 32 in 79% yield after three
hours.22 Compound 32 also exists primarily in the enol
form. Oxidation of 32 with DDQ in refluxing benzene for
five hours afforded the aromatic compound 33 in 67%
yield. Reaction of 33 with (carbethoxymethylene)triphen-
ylphosphorane in refluxing xylene gave 28 in 76% yield
(Scheme 2).23 The spectral data of our synthetic material
28 agreed well with those reported in the literature.25
1H NMR (300 MHz, CDCl3): d = 13.78 (1 H, d, J = 11.0 Hz), 7.12
(1 H, d, J = 11.0 Hz), 6.40 (1 H, d, J = 10.0 Hz), 5.27 (1 H, d,
J = 10.0 Hz), 2.57–2.35 (4 H, m), 1.40 (6 H, s).
HRMS: m/z calcd for C12H14O3 (M+): 206.0943; found: 206.0941.
5-Hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde (18)
A mixture of 17 (0.455 g, 2.2 mmol) and DDQ (0.749 g, 3.3 mmol)
in benzene (30 mL) was heated under reflux for 3 h. The resulting
mixture was cooled in an ice-bath and the solids were removed by
filtration through Celite. The filtrate was concentrated under re-
duced pressure and purified by flash column chromatography (hex-
ane–EtOAc, 10:1) to give 18 (0.310 g, 69%) as a solid; mp 45–
47 °C.
In conclusion, a new synthetic route to pyranocoumarins
has been accomplished from 2H-pyrans, which were pre-
pared by the methodology developed by our group. The
process afforded a rapid synthetic route to naturally occur-
ring seselin, cis-khellactone, and quianhucoumarin D.
This synthetic route also provided the biologically inter-
esting cis- or trans-khellactone derivatives and the 5-
deoxyprotobruceol-I regioisomer.
IR (KBr): 2974, 1657, 1580, 1489, 1433, 1375, 1335, 1300, 1256,
1217, 1181, 1111, 1088, 974, 937, 900, 845 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.63 (1 H, s), 9.64 (1 H, s), 7.27
(1 H, d, J = 8.5 Hz), 6.67 (1 H, d, J = 10. 1 Hz), 6.40 (1 H, d, J = 8.5
Hz), 5.59 (1 H, d, J = 10.0 Hz), 1.54 (3 H, s), 1.44 (3 H, s).
13C NMR (75 MHz, CDCl3): d = 194.9, 161.0, 159.1, 135.1, 129.0,
115.6, 115.5, 109.8, 109.2, 78.6, 29.8, 28.8.
HRMS: m/z calcd for C12H12O3 (M+): 204.0786; found: 204.0788.
All experiments were carried out under a nitrogen atmosphere.
Merck precoated silica gel plates (Art. 5554) with a fluorescent in-
dicator were used for analytical TLC. Flash column chromatogra-
phy was performed using silica gel 9385 (Merck). Mps were
determined with microcover glasses on a Fisher-Johns apparatus
Seselin (1)
To aldehyde 18 (0.408 g, 2.0 mmol) in anhyd xylene (10 mL) was
added carbethoxymethylenetriphenylphosphorane (0.836 g, 2.4
mmol) and the mixture was heated under reflux for 10 h. The mix-
ture was concentrated and purified by silica gel column chromatog-
raphy (hexane–EtOAc, 5:1)to give 1 (0.342 g, 75%).
1
and are uncorrected. H NMR spectra were recorded on a Bruker
Model ARX (300 MHz) spectrometer. 13C NMR spectra were re-
corded on a Bruker Model ARX (75 MHz) spectrometer in CDCl3
referenced to the solvent peak at 77.0 ppm. IR spectra were record-
ed on a JASCO FTIR 5300 spectrophotometer. HRMS were ob-
tained with a JEOL JMS-700 spectrometer at the Korea Basic
Science Institute.
IR (neat): 2978, 1736, 1639, 1597, 1485, 1404, 1373, 1292, 1260,
1213, 1157, 1115, 1076, 1011, 837 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.58 (1 H, d, J = 9.5 Hz), 7.19 (1
H, d, J = 8.5 Hz), 6.86 (1 H, d, J = 10.0 Hz), 6.70 (1 H, d, J = 8.5
Hz), 6.21 (1 H, d, J = 9.5 Hz), 5.71 (1 H, d, J = 10.0 Hz), 1.45 (6 H,
s).
2,2-Dimethyl-5-oxo-5,6,7,8-tetrahydro-2H-chromene-6-carb-
aldehyde (17)
To a stirred solution of HMDS (1.162 g, 7.2 mmol) in anhyd toluene
(30 mL) was added a solution of n-BuLi (2.5 M, 2.6 mL) in hexane
at –78 °C. After stirring at the same temperature for 30 min, com-
pound 16 (0.570 g, 3.2 mmol) in toluene (2 mL) and Et3N (3.290 g,
32.5 mmol) were added via cannula. The reaction mixture was
stirred at the same temperature for 3 h, warmed to r.t., quenched by
the addition of an aq solution of NH4Cl (40 mL), and extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed
with brine (50 mL), dried over MgSO4, and concentrated under re-
cis-Khellactone (5)
Seselin (1) (0.115 g, 0.5 mmol) was added to a solution of OsO4 (10
mg, 0.04 mmol) and NMO (0.07 g, 0.6 mmol) in t-BuOH–THF–
H2O (10:3:1, 10 mL) and the reaction mixture was stirred at r.t. for
24 h. A sat. solution of NaHSO3 (30 mL) was added and extracted
with CH2Cl2 (3 × 30 mL). The combined organic layers were
washed with brine (30 mL), dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash column
O
O
O
DDQ
benzene
reflux
LiHMDS, Et3N
H
ethyl formate
O
31
O
79%
toluene
–78 °C
32
O
O
OH
O
Ph3P=CHCO2Et
xylene
H
O
O
76%
33 67%
5-deoxyprotobruceol-I regioisomer (28)
Scheme 2
Synthesis 2006, No. 5, 853–859 © Thieme Stuttgart · New York

PAPER
Synthesis of Biologically Interesting Pyranocoumarins
857
chromatography (hexane–EtOAc, 1:1) to give 5 (0.079 g, 60%) as a
solid; mp 158–160 °C.
4.53 (1 H, d, J = 3.2 Hz), 3.90 (1 H, d, J = 3.2 Hz), 3.73 (3 H, s),
1.47 (3 H, s), 1.42 (3 H, s).
IR (KBr): 3400, 3001, 2928, 2820, 1720, 1680, 1600, 1223, 1020
cm–1.
13C NMR (75 MHz, CDCl3): d = 161.3, 156.5, 155.5, 144.0, 129.0,
115.0, 113.2, 112.9, 109.3, 78.8, 74.5, 71.1, 59.1, 24.5, 23.8.
1H NMR (300 MHz, CDCl3): d = 7.64 (1 H, d, J = 10.0 Hz), 7.29 (1
H, d, J = 8.5 Hz), 6.77 (1 H, d, J = 8.5 Hz), 6.22 (1 H, d, J = 10.0
Hz), 5.16 (1 H, d, J = 5.0 Hz), 3.88 (1 H, d, J = 5.0 Hz), 1.46 (3 H,
s), 1.42 (3 H, s).
13C NMR (75 MHz, CDCl3): d = 160.2, 155.6, 153.8, 144.4, 128.7,
113.8, 111.7, 111.6, 111.2, 78.8, 71.0, 60.1, 26.8, 21.1.
HRMS: m/z calcd for C15H16O5 (M+): 276.0998; found: 276.0997.
trans-10-Ethoxy-9-hydroxy-8,8-dimethyl-9,10-dihydro-8H-
pyrano[2,3-f]chromen-2-one (21) and cis-10-Ethoxy-9-hy-
droxy-8,8-dimethyl-9,10-dihydro-8H-pyrano[2,3-f]chromen-2-
one (22)
Reaction of 19 (0.09 g, 0.4 mmol) with EtOH (3 mL) catalyzed by
InCl3 afforded 21 (0.094 g, 88%) and 22 (5 mg, 5%).
Quianhucoumarin D (10)
To a solution of seselin (1) (0.072 g, 0.3 mmol) in anhyd pyridine
(2 mL) was added Ac2O (2 mL, 21.2 mmol). The reaction mixture
was stirred for 20 h at r.t., H2O (30 mL) was added, and extracted
with CH2Cl2 (3 × 30 mL). The combined organic layers were
washed with HCl (2 N, 30 mL), H2O (30 mL), dried over MgSO4,
and concentrated under reduced pressure. The residue was purified
by flash column chromatography (hexane–EtOAc, 3:1) to give 10
(0.093 g, 85%).
21
Mp 160–162 °C.
IR (KBr): 3472, 1730, 1604, 1489, 1466, 1404, 1372, 1246, 1117,
910 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59 (1 H, d, J = 9.5 Hz), 7.29 (1
H, d, J = 8.6 Hz), 6.75 (1 H, d, J = 8.6 Hz), 6.23 (1 H, d, J = 9.5 Hz),
4.61 (1 H, d, J = 3.3 Hz), 4.11–3.89 (2 H, m), 3.88 (1 H, d, J = 3.3
Hz), 1.46 (3 H, s), 1.44 (3 H, s), 1.28 (3 H, t, J = 7.0 Hz).
IR (neat): 3096, 2979, 1745, 1605, 1224, 1022 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57 (1 H, d, J = 9.5 Hz), 7.31 (1
H, d, J = 8.5 Hz), 6.73 (1 H, d, J = 8.5 Hz), 6.45 (1 H, d, J = 5.0 Hz),
6.15 (1 H, d, J = 9.5 Hz), 5.22 (1 H, d, J = 5.0 Hz), 2.07 (3 H, s),
2.05 (3 H, s), 1.38 (3 H, s), 1.34 (3 H, s).
13C NMR (75 MHz, CDCl3): d = 161.3, 156.6, 155.4, 144.1, 128.9,
115.0, 113.1, 113.0, 109.6, 78.8, 73.0, 71.7, 67.1, 24.5, 24.1, 16.1.
HRMS: m/z calcd for C16H18O5 (M+): 290.1154; found: 290.1155.
13C NMR (75 MHz, CDCl3): d = 169.8, 169.7, 159.8, 156.4, 153.7,
143.3, 129.1, 114.3, 112.9, 112.3, 106.5, 77.3, 70.0, 60.7, 24.6,
22.4, 20.5, 20.4.
22
Mp 149–151 °C.
IR (KBr): 3468, 2924, 2855, 1715, 1605, 1406, 1281, 1240, 1117,
1063, 839 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.60 (1 H, d, J = 9.5 Hz), 7.28 (1
H, d, J = 8.6 Hz), 6.74 (1 H, d, J = 8.6 Hz), 6.23 (1 H, d, J = 9.5 Hz),
4.79 (1 H, d, J = 5.0 Hz), 4.30–4.10 (2 H, m), 3.83 (1 H, d, J = 5.0
Hz), 1.44 (3 H, s), 1.37 (3 H, s), 1.27 (3 H, t, J = 7.0 Hz).
Epoxide 19
To a solution of 1 (0.456 g, 2 mmol) in anhyd CH2Cl2 (20 mL) was
added MCPBA (77%; 0.493 g, 2.2 mmol) and NaHCO3 (0.840 g, 10
mmol) at 0 °C. After stirring at r.t. for 5 h, an aq solution of Na2CO3
(5%; 30 mL) was added, and extracted with CH2Cl2 (3 × 30 mL).
The combined organic layers were washed with brine (30 mL),
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (hexane–
EtOAc, 5:1) to give 19 (0.303 g, 62%) as a solid; mp 116–118 °C.
HRMS: m/z calcd for C16H18O5 (M+): 290.1154; found: 290.1157.
trans-9-Hydroxy-10-isopropoxy-8,8-dimethyl-9,10-dihydro-
8H-pyrano[2,3-f]chromen-2-one (23)
Reaction of 19 (0.09 g, 0.4 mmol) with i-PrOH (3 mL) catalyzed by
InCl3 afforded 23 (0.105 g, 94%) as a solid; mp 134–136 °C.
IR (KBr): 2982, 1732, 1606, 1495, 1464, 1406, 1290, 1256, 1206,
1161, 1121, 1078, 1039, 1011, 943, 916 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.61 (1 H, d, J = 9.5 Hz), 7.30 (1
H, d, J = 8.6 Hz), 6.72 (1 H, d, J = 8.6 Hz), 6.26 (1 H, d, J = 9.5 Hz),
4.60 (1 H, d, J = 4.5 Hz), 3.55 (1 H, d, J = 4.5 Hz), 1.59 (3 H, s),
1.30 (3 H, s).
IR (KBr): 3449, 2976, 2932, 1707, 1607, 1491, 1408, 1360, 1292,
1242, 1123, 1051, 941, 833 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57 (1 H, d, J = 9.5 Hz), 7.27 (1
H, d, J = 8.6 Hz), 6.74 (1 H, d, J = 8.6 Hz), 6.20 (1 H, d, J = 9.5 Hz),
4.70 (1 H, d, J = 2.6 Hz), 4.23–4.15 (1 H, m), 3.82 (1 H, dd, J = 7.2,
2.6 Hz), 1.49 (3 H, s), 1.43 (3 H, s), 1.38 (3 H, d, J = 6.1 Hz), 1.22
(3 H, d, J = 6.1 Hz).
13C NMR (75 MHz, CDCl3): d = 161.4, 156.7, 155.5, 144.1, 128.8,
115.1, 113.0, 112.9, 109.4, 78.5, 72.8, 71.8, 70.8, 25.5, 24.0, 23.8,
22.8.
HRMS: m/z calcd for C14H12O (M+): 244.0736; found: 244.0733.
Ring-Opening of Epoxide 19 with Nucleophiles; General Proce-
dure
To a solution of epoxide 19 (0.09 g, 0.4 mmol) and nucleophile neat
or in CH2Cl2 (3 mL) was added InCl3 (9 mg, 0.04 mmol). The reac-
tion mixture was stirred at r.t. for 1–2 h and then concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (hexane–EtOAc, 2:1).
HRMS: m/z calcd for C17H20O5 (M+): 304.1311; found: 340.1310.
trans-10-Ethylsulfanyl-9-hydroxy-8,8-dimethyl-9,10-dihydro-
8H-pyrano[2,3-f]chromen-2-one (24)
Reaction of 19 (0.09 g, 0.4 mmol) with ethanethiol (3 mL) catalyzed
by InCl3 afforded 24 (0.104 g, 92%) as a solid; mp 166–168 °C.
trans-9-Hydroxy-10-methoxy-8,8-dimethyl-9,10-dihydro-8H-
pyrano[2,3-f]chromen-2-one (20)
Reaction of 19 (0.09 g, 0.4 mmol) with MeOH (3 mL) catalyzed by
InCl3 afforded 20 (0.094 g, 92%) as a solid; mp 202–203 °C.
IR (KBr): 3464, 2976, 2928, 1705, 1603, 1491, 1408, 1277, 1238,
1127, 1055, 941, 839 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59 (1 H, d, J = 9.5 Hz), 7.24 (1
H, d, J = 8.6 Hz), 6.73 (1 H, d, J = 8.6 Hz), 6.23 (1 H, d, J = 9.5 Hz),
3.89 (1 H, d, J = 5.7 Hz), 3.83 (1 H, d, J = 5.7 Hz), 3.12–3.03 (2 H,
m), 1.48 (3 H, s), 1.34 (3 H, d, J = 7.4 Hz), 1.32 (3 H, s).
IR (KBr): 3405, 2928, 2820, 1705, 1607, 1491, 1410, 1364, 1246,
1142, 1126, 1092, 1063, 968 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59 (1 H, d, J = 9.5 Hz), 7.30 (1
H, d, J = 8.6 Hz), 6.76 (1 H, d, J = 8.6 Hz), 6.24 (1 H, d, J = 9.5 Hz),
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Y. R. Lee et al.
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13C NMR (75 MHz, CDCl3): d = 161.3, 156.4, 154.4, 144.1, 128.0,
115.0, 113.2, 113.1, 111.7, 78.9, 75.9, 44.1, 29.4, 26.1, 21.7, 15.6.
IR (neat): 2968, 2926, 2853, 1638, 1589, 1431, 1329, 1223, 1159,
1067, 970 cm–1.
HRMS: m/z calcd for C16H18O4S (M+): 306.0926; found: 306.0928.
1H NMR (300 MHz, CDCl3): d = 13.79 (1 H, d, J = 9.7 Hz), 7.10 (1
H, d, J = 9.7 Hz), 6.43 (1 H, d, J = 10.1 Hz), 5.20 (1 H, d, J = 10.1
Hz), 5.07–5.03 (1 H, m), 2.49–2.35 (4 H, m), 2.09–1.98 (2 H, m),
1.77–1.69 (2 H, m), 1.65 (3 H, s), 1.56 (3 H, s), 1.36 (3 H, s).
13C NMR (75 MHz, CDCl3): d = 189.3, 171.8, 160.1, 132.4, 124.0,
122.5, 116.3, 109.4, 106.5, 83.6, 42.2, 28.7, 28.1, 26.1, 23.0, 22.4,
14.4.
trans-9-Hydroxy-8,8-dimethyl-10-phenylsulfanyl-9,10-dihy-
dro-8H-pyrano[2,3-f]chromen-2-one (25) and cis-9-Hydroxy-
8,8-dimethyl-10-phenylsulfanyl-9,10-dihydro-8H-pyrano[2,3-
f]chromen-2-one (26)
Reaction of 19 (0.09 g, 0.4 mmol) with thiophenol (0.441 g, 4.0
mmol) catalyzed by InCl3 in CH2Cl2 (5 mL) afforded 25 (0.086 g,
66%) and 26 (0.042 g, 32%).
HRMS: m/z calcd for C17H22O3 (M+): 274.1569; found: 274.1566.
5-Hydroxy-2-methyl-2-(4-methylpent-3-enyl)-2H-chromene-6-
carbaldehyde (33)
25
Mp 177–179 °C.
A mixture of 32 (0.563 g, 2.1 mmol) and DDQ (0.699 g, 3.1 mmol)
in benzene (30 mL) was heated under reflux for 3 h. The resulting
mixture was cooled in an ice bath and the solids were removed by
filtration through Celite. The filtrate was concentrated under re-
duced pressure and purified by flash column chromatography (hex-
ane–EtOAc, 10:1) to give 33 (0.374 g, 67%).
IR (KBr): 3493, 2978, 1715, 1603, 1489, 1406, 1354, 1271, 1231,
1123, 1049, 937, 843 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.62–7.58 (3 H, m), 7.31–7.23 (4
H, m), 6.74 (1 H, d, J = 8.6 Hz), 6.26 (1 H, d, J = 9.5 Hz), 4.32 (1
H, d, J = 5.0 Hz), 4.00 (1 H, d, J = 5.0 Hz), 1.54 (3 H, s), 1.35 (3 H,
s).
13C NMR (75 MHz, CDCl3): d = 161.0, 156.9, 154.3, 144.0, 134.6,
134.2, 129.6, 128.7, 128.4, 115.1, 113.3, 113.2, 109.5, 79.1, 74.5,
47.8, 26.5, 22.5.
IR (neat): 2971, 2926, 2855, 1649, 1622, 1578, 1485, 1375, 1329,
1252, 1181, 1094, 960, 908 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.6 (1 H, s), 9.6 (1 H, s), 7.25 (1
H, d, J = 8.6 Hz), 6.70 (1 H, d, J = 10.2 Hz), 6.39 (1 H, d, J = 8.6
Hz), 5.53 (1 H, d, J = 10.2 Hz), 5.09–5.03 (1 H, m), 2.11–2.03 (2 H,
m), 1.81–1.71 (2 H, m), 1.63 (3 H, s), 1.54 (3 H, s), 1.40 (3 H, s).
HRMS: m/z calcd for C20H18O4S (M+): 354.0926; found: 354.0927.
26
13C NMR (75 MHz, CDCl3): d = 194.8, 161.3, 159.0, 135.1, 132.4,
127.8, 124.1, 116.2, 115.4, 109.6, 109.0, 81.1, 42.1, 27.7, 26.1,
23.1, 18.0.
Mp 168–170 °C.
IR (KBr): 3460, 2970, 1701, 1605, 1489, 1404, 1360, 1231, 1142,
1121, 1103, 1078, 835 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.84–7.82 (2 H, m), 7.58 (1 H, d,
J = 9.5 Hz), 7.43–7.34 (3 H, m), 7.27 (1 H, d, J = 8.5 Hz), 6.73 (1
H, d, J = 8.6 Hz), 6.21 (1 H, d, J = 8.6 Hz), 4.70 (1 H, d, J = 6.0 Hz),
4.04 (1 H, d, J = 6.0 Hz), 1.47 (3 H, s), 1.39 (3 H, s).
HRMS: m/z calcd for C17H20O3 (M+): 272.1412; found: 272.1414.
8-Methyl-8-(4-methylpent-3-en-1-yl)-2H,8H-pyrano[2,3-
f]chromen-2-one (28, 5-Deoxyprotobruceol-I Regioisomer)
To aldehyde 33 (0.325 g, 1.2 mmol) in anhyd xylene (10 mL) was
added carbethoxymethylenetriphenylphosphorane (0.499 g, 1.4
mmol) and the mixture was heated under reflux for 10 h. The filtrate
was evaporated under reduced pressure and purified by flash col-
umn chromatography (hexane–EtOAc, 5:1) to give 28 (0.269,
76%).
HRMS: m/z calcd for C20H18O4S (M+): 354.0926; found: 354.0929.
trans-9-Hydroxy-8,8-dimethyl-10-phenylamino-9,10-dihydro-
8H-pyrano[2,3-f]chromen-2-one (27)
Reaction of 19 (0.09 g, 0.4 mmol) with aniline (0.377 g, 4.0 mmol)
catalyzed by InCl3 in CH2Cl2 (5 mL) afforded 27 (0.108g, 87%) as
a solid; mp 169–171 °C.
IR (neat): 2969, 2924, 2854, 1734, 1598, 1481, 1444, 1404, 1377,
1288, 1254, 1158, 1114, 1086, 1008, 835 cm–1.
IR (KBr): 3393, 2976, 1701, 1603, 1514, 1495, 1406, 1319, 1240,
1130, 1053, 941, 837 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57 (1 H, d, J = 9.5 Hz), 7.17 (1
H, d, J = 8.5 Hz), 6.89 (1 H, d, J = 10.0 Hz), 6.68 (1 H, d, J = 8.5
Hz), 6.19 (1 H, d, J = 9.5 Hz), 5.66 (1 H, d, J = 10.0 Hz), 5.08–5.02
(1 H, m), 2.11–2.02 (2 H, m), 1.83–1.66 (2 H, m), 1.62 (3 H, s), 1.53
(3 H, s), 1.41 (3 H, s).
1H NMR (300 MHz, CDCl3): d = 7.52 (1 H, d, J = 9.5 Hz), 7.27 (1
H, d, J = 8.6 Hz), 7.12–7.07 (2 H, m), 6.81 (1 H, d, J = 8.6 Hz), 6.71
(1 H, d, J = 7.4 Hz), 6.63 (1 H, d, J = 7.8 Hz), 6.13 (1 H, d, J = 9.5
Hz), 4.64 (1 H, d, J = 5.0 Hz), 6.12 (1 H, d, J = 5.0 Hz), 4.64 (1 H,
d, J = 5.0 Hz), 4.12 (1 H, d, J = 5.0 Hz), 1.52 (3 H, s), 1.36 (3 H, s).
EIMS: m/z (%) = 296 (10), 283 (3), 253 (3), 213 (100), 185 (7), 128
(3), 69 (2).
HRMS: m/z calcd for C20H19NO4 (M+): 337.1314; found: 337.1312.
HRMS: m/z calcd for C19H20O3 (M+): 296.1413; found: 296.1412.
2-Methyl-2-(4-methylpent-3-enyl)-5-oxo-5,6,7,8-tetrahydro-
2H-chromene-6-carbaldehyde (32)
Acknowledgment
To a stirred solution of HMDS (1.162 g, 7.2 mmol) in anhyd toluene
(30 mL) was added a solution of n-BuLi (2.5 M, 2.6 mL) in hexane
at –78 °C. After stirring at the same temperature for 30 min, com-
pound 31 (0.788 g, 3.2 mmol) in toluene (2 mL) and Et3N (3.290 g,
32.5 mmol) were added via cannula. The reaction mixture was
stirred at the same temperature for 3 h, warmed to r.t., quenched by
the addition of an aq solution of NH4Cl (50 mL), and extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed
with brine (50 mL), dried over MgSO4, and concentrated under re-
duced pressure. The residue was purified by flash column chroma-
tography (hexane–EtOAc, 10:1) to give 33 (0.693 g, 79%).
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).
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Synthesis 2006, No. 5, 853–859 © Thieme Stuttgart · New York