Titanocene(III) chloride mediated radical-induced synthesis of 3,4-dihydroisocoumarins: synthesis of (±)-hydrangenol, (±)-phyllodulcin, (±)-macrophyllol and (±)-thunberginol G

Article abstract of DOI:10.1016/j.tet.2008.09.075

A radical-promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titanocene(III) chloride (Cp₂TiCl) as the radical initiator. The total synthesis of four naturally occurring dihydrocoumarins hydrangenol, phyllodulcin, macrophyllol and thunberginol G has been accomplished using the radical technology. Cp₂TiCl was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and Zn-dust in THF under argon.

Full text of DOI:10.1016/j.tet.2008.09.075

Tetrahedron 64 (2008) 11050–11057
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Titanocene(III) chloride mediated radical-induced synthesis of 3,4-
dihydroisocoumarins: synthesis of (ꢀ)-hydrangenol, (ꢀ)-phyllodulcin,
(ꢀ)-macrophyllol and (ꢀ)-thunberginol G
*
Samir Kumar Mandal, Subhas Chandra Roy
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A radical-promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields
using titanocene(III) chloride (Cp2TiCl) as the radical initiator. The total synthesis of four naturally oc-
curring dihydrocoumarins hydrangenol, phyllodulcin, macrophyllol and thunberginol G has been ac-
complished using the radical technology. Cp2TiCl was prepared in situ from commercially available
titanocene dichloride (Cp2TiCl2) and Zn-dust in THF under argon.
Received 15 July 2008
Received in revised form 22 September
2008
Accepted 25 September 2008
Available online 7 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Titanocene(III) chloride
Dihydroisocoumarins
Radical
Natural products
Synthesis
1. Introduction
and compared the activity of hydrangenol (1) and thunberginol G
(4) for T-lymphocyte suppression and concluded that 30-OH group
The 3-aryl-3,4-dihydroisocoumarins constitute a class of natu-
rally occurring compounds, which exhibit a broad range of signi-
ficant biological activities such as antifungal, antiallergic,
antileukaemic, antiulcer and antimalarial activities.1 Although they
are individually different by the number, and type of substituent on
the aromatic ring, existence of 8-hydroxy group is very frequent at
the core structure in many of them. Hydrangea Dulas Folium
(amacha in Japanese), a natural medicine containing 3-aryl-3,
4-dihydroisocoumarins was isolated from the fermented and dried
leaves of Hydrangea macrophylla Seringe var. thunbergii Makino,
a plant indigenous to Japan.2 This is widely used in confectionary,
drinks, oral refrigerant and a sweetening agent.3 It is also used to
make tea served during the Hanamatsuri (birth of Buddha) cele-
bration. Hydrangenol (1) and phyllodulcin (2) are the chief con-
stituents (Fig. 1) of this natural medicine along with other. Several
biological activities have been shown by phyllodulcin, including
antiallergic effects on the Schultz-Dale reaction,4 inhibition of mi-
crosomal lipid peroxidation induced by NADPH and the Fenton-
type reaction.5 It has been shown by Matsuda that hydrangenol (1)
suppresses T-lymphocyte proliferation induced by concanavalin A
had no effect6 in the same (Fig. 1). The discovery that phyllodulcin
(2) is 600–800 times as sweet as sucrose and its medicinal im-
portance has excited the chemist for structure–taste correlation in
sweet dihydrochalcone and bitter flavone compounds.7 Other
dihydroisocoumarins do not show any sweetness property like
phyllodulcin. A number of methods have been described for the
synthesis of 3-aryl-3,4-dihydroisocoumarin derivatives, but most of
these methods involve either ortho- or lateral-lithiation.8 Other
methods reported for the preparation of 3-aryl-3,4-dihydro-
isocoumarins involve cyclization of stilbene carboxylic acids,9
cycloaddition reactions,10 AlCl3-mediated reaction,11 polyketide-
derived synthesis12 and many others.13 However, many of these
methodologies suffer from harsh reaction conditions, multi-step
procedures and inefficiency due to functional group intolerance.
The mildness and efficiency of radical-mediated reactions have
significantly encouraged synthetic chemists in recent years to uti-
lize radical technology in developing novel methodologies and
their applications in natural product synthesis. In a continuation
of our studies of the synthesis of natural products involving
radical-induced reactions,14 we have developed a mild and novel
radical-mediated methodology to construct C-3 substituted 3,4-
dihydroisocoumarins in a single operation with moderate to good
yields using dicyclopentadienyl titanocene(III) chloride (Cp2TiCl) as
the radical initiator. Cp2TiCl can easily be prepared from the
* Corresponding author. Tel.: þ91 33 2473 4971; fax: þ91 33 2473 2805.
E-mail address: ocscr@iacs.res.in (S.C. Roy).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.075

S.K. Mandal, S.C. Roy / Tetrahedron 64 (2008) 11050–11057
11051
Table 1
OH
O
OH
O
Synthesis of 3,4-dihydrocoumarins
O
O
Entry Aldehyde
Producta
Yieldb (%)
O
O
CHO
OMe
OH
OH
2, Phyllodulcin
1
2
3
62
1, Hydrangenol
OH
6a
7a
OH
O
O
O
O
O
CHO
O
O
O
OMe
OMe
59
51
OH
O
6b
7b
OH
4, Thunberginol G
OMe
3, Macrophyllol
O
O
CHO
CHO
Figure 1.
O
6c
7c
commercially available titanocene dichloride (Cp2TiCl2) and zinc
dust in THF.15 The total synthesis of the four naturally occurring
lactones hydrangenol (1), phyllodulcin (2), macrophyllol (3) and
thunberginol G (4) has been successfully completed using the
radical technology.
O
O
4
60
Me
7d
6d
Me
2. Results and discussion
O
CHO
O
In an initial experiment,
a mixture of ethyl 2-bromo-
5
6
56
48
methylbenzoate (5) and benzaldehyde (6a) was treated with
titanocene(III) chloride in THF at room temperature to afford 3-
phenyl-3,4-dihydroisocoumarin 7 (Scheme 1) in 62% yield.16 The
reaction proceeds via a Barbier type addition17 followed by in situ
lactonization.
Encouraged by this result where various alkyl and aryl alde-
hydes 6a–l were reacted with ethyl 2-bromomethylbenzoate in the
presence of Cp2TiCl and the results are summarized in Table 1. It is
noteworthy that when tri-n-butyltin hydride was used as the rad-
ical mediator, only reduced 5 was obtained without a trace of
dihydroisocoumarins. Reaction of ethyl 2-bromomethylbenzoate
(5) with allyl and propargyl substituted salicylaldehydes 6h and 6i
MeO
7e
6e
OMe
O
CHO
CHO
O
Cl
7f
6f
Cl
O
O
7
8
53
54
MeO
(entries
8 and 9, Table 1) furnished the expected dihy-
OMe
OMe
OMe
6g
droisocoumarins 7h and 7i, respectively, without any intra-
molecular cyclizations, as observed previously in our laboratory.14j
This is probably due to the fact that the formation of radicals from
benzyl bromides by Cp2TiCl is much faster than aldehydes. Cin-
namyl aldehyde (6k) and furfural (6l) underwent radical-induced
reaction with compound 5 to furnish 7k and 7l, respectively, in
moderate yield (entries 11 and 12). 4-Nitrobenzaldehyde remained
unchanged when it was treated with 5 under similar reaction
conditions (entry 13). Ketones, such as cyclohexanone and aceto-
phenone, reacted to generated self-coupling products in the pres-
ence of Cp2TiCl without producing any of the desired
dihydroisocoumarins.
7g
O
CHO
O
O
O
6h
7h
O
CHO
O
O
O
9
56
53
6i
7i
After successful experiments with different types of aldehydes,
our radical technology was applied to the synthesis of
(ꢀ)-hydrangenol (1), a dihydroisocoumarin, isolated from Hy-
drangea opuloides Steud. var. otakusa.8
O
O
O
10
H
6j
7j
O
O
COOEt
Cp TiCl / THF, rt
CHO
CHO
2
O
+
O
then H3O+
62%
Br
11
51
5
6a
7a
6k
7k
Scheme 1.
(continued on next page)

11052
S.K. Mandal, S.C. Roy / Tetrahedron 64 (2008) 11050–11057
Table 1 (continued )
NO2
OH
i) Pd/ C , H2
MeOH , rt
Producta
Yieldb (%)
COOH
Me
COOH
Me
Entry
Aldehyde
O
ii) NaNO2 / H2SO4
-5 to 0 °C then 50 °C
93%
15
14
O
12
47
CHO
O
6l
O
OH
7l
COOMe
Me
TBDMSCl / Et3N
DMAP, DCM, rt
96%
CH2N2 / ether
CHO
0 °C
95%
13
No reaction
O2N
16
6m
OTBDMS
COOMe
OTBDMS
a
Products were characterized by IR, NMR and HRMS studies.
Yields refer to pure isolated products.
COOMe
NBS / AIBN
CCl4, 2 h
96%
b
Br
Me
18
For this purpose, easily accessible18 methyl 2-methyl-6-
17
Scheme 3.
methoxybenzoate (11) was used as the starting material. Com-
pound 11 was prepared from commercially available aldehyde 8
using the standard reaction sequences shown in Scheme 2. Phenol
8 on the treatment with MeI in the presence of K2CO3 gave ether 9,
which on oxidation followed by esterification afforded ester 11.
Compound 11, on bromination with NBS in the presence of a cata-
lytic amount of AIBN yielded 12 in 92% yield. The bromide 12 on
treatment with Cp2TiCl in THF under argon at room temperature in
the presence of 4-methoxybenzaldehyde (6e) followed by de-
composition afforded lactone 13 in 53% yield as a crystalline solid.
Demethylation of 13 with boron tribromide in CH2Cl2 afforded
hydrangenol (1)2a,b in 88% yield as colourless crystals.
15 via hydrogenation followed by diazotization. Compound 15 was
then treated with diazomethane in ether to yield the corresponding
methyl ester 16. It is noteworthy that the phenolic hydroxyl group
remains unaffected during the etherification with diazomethane,
which is probably due to strong intramolecular hydrogen bonding.
Phenol 16 was then protected with TBDMS-Cl to provide methyl
ether 17. Compound 17, on photochemical bromination with NBS in
the presence of a catalytic amount of AIBN yielded bromide 18. This
benzyl bromide was utilized as a common precursor for the syn-
thesis of dihydrocoumarins (ꢀ)-hydrangenol (1), (ꢀ)-phyllodulcin
(2), (ꢀ)-macrophyllol (3) and (ꢀ)-thunberginol G (4), as shown in
Scheme 4. Thus, Cp2TiCl-mediated reaction of compound 18 with
aldehyde 20 followed by acidic workup furnished hydrangenol (1)
in 51% yield. Similarly, reaction of 18 with aldehydes 21 and 22 gave
phyllodulcin (2) and macrophyllol (3), respectively, in 57% and 55%
yields. Radical-mediated reaction of 18 with aldehyde 23 furnished
19 (53%), which on treatment with BBr3 in CH2Cl2 afforded thun-
berginol G (4) in 86% yield.
OMe
OH
CHO
Me
CHO
Me
MeI /K2CO3
Acetone, Reflux
2h, 93%
8
9
OMe
In summary, we have developed a mild and novel radical-in-
duced method for the synthesis of C-3 substituted 3,4-dihy-
droisocoumarins using titanocene(III) chloride as the radical
initiator. This radical technology has also been applied successfully
to the total synthesis of the four naturally occurring dihy-
drocoumarins hydrangenol, phyllodulcin, macrophyllol and thun-
berginol G in racemic forms.
COOH
CH2N2 / Ether
96%
Aqueous Ag2O
Reflux, 1 h
58%
Me
10
OMe
OMe
COOMe
COOMe
Me
NBS / AIBN
CCl4, 92%
CH2Br
3. Experimental section
3.1. General
12
11
OMe O
(i) Cp2 TiCl / THF
MeO
O
The compounds described are all racemates. Melting points
were determined in open capillary tubes and are uncorrected. 1H
NMR and 13C NMR spectra were recorded in CDCl3 with Bruker DPX
300 spectrometer using tetramethyl silane as the internal standard.
IR spectra were recorded on Shimadzu FT IR-8300. Column chro-
matography was performed on silica gel (60–120 mesh) and pre-
parative TLC was performed using pre-coated silica 60 F254 plates
(0.2 mm). High-resolution mass spectra were obtained using a Qtof
Micro YA263 instrument. Diethyl ether and tetrahydrofuran were
freshly distilled from sodium. Methylene chloride was freshly dis-
tilled over calcium hydride. Light petroleum of boiling range 60–
80 ꢁC was used for chromatography.
CHO
(ii)
OMe
53%
13
OH
O
BBr3 / CH2Cl2
-78 °C, 3 h
88%
O
OH
1
Scheme 2.
In a quest for a general method to synthesize all four natural
products 1–4, it was realized that the bromo-compound 18 could
serve as a common precursor. Thus, compound 18 was prepared
from the commercially available nitro-compound 14 in five steps, as
shown in Scheme 3. Thus, compound 14 was transformed to phenol
3.2. Typical experimental procedure
A red solution of Cp2TiCl2 (747 mg, 3.0 mmol) in deoxygenated
THF (40 mL) was stirred with activated zinc dust (393 mg, 6 mmol)

S.K. Mandal, S.C. Roy / Tetrahedron 64 (2008) 11050–11057
11053
OTBDMS
3.4. 3-(1,3-Benzodioxol-5-yl)-3,4-dihydro-1H-isochromen-1-
one (7b)
OH
O
White solid. Mp 138–140 ꢁC. Rf¼0.25 (10% ethyl acetate in light
OTBDMS
COOMe
CHO
20
petroleum); IR (KBr): nmax 1705, 1448, 1255 cmꢃ1
;
1H NMR
O
Cp2TiCl
(300 MHz, CDCl3):
d
3.05 (dd, J¼3.0, 16.4 Hz, 1H), 3.28 (dd, J¼12.0,
Br
THF, rt
16.4 Hz, 1H), 5.42 (dd, J¼3.0, 12.0 Hz, 1H), 5.95 (s, 2H), 6.79 (d,
J¼8.0 Hz,1H), 6.89 (dd, J¼1.0, 8.0 Hz,1H), 6.95 (d, J¼1.0 Hz,1H), 7.25
(d, J¼7.4 Hz, 1H), 7.39 (dd, J¼7.5, 7.6 Hz, 1H), 7.54 (dd, J¼7.4, 7.5 Hz,
then H3O+
1
OH
18
CHO
1H), 8.10 (d, J¼7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 34.5, 78.8,
100.2, 105.7, 107.2, 118.9, 124.0, 126.3, 126.8, 129.3, 131.3, 132.8,
137.8, 146.8, 146.9, 164.2; HRMS (ESI) calcd for C16H13O4 269.0808
[MþH]þ, found 269.0849.
OTBDMS
OH
O
OMe
21
OTBDMS
COOMe
O
Cp2TiCl
THF, rt
Br
3.5. 3-(Naphthalen-2-yl)-3,4-dihydro-1H-isochromen-1-
one (7c)
then H3O+
OMe
18
OH
2
White solid. Mp 135–136 ꢁC. Rf¼0.31 (10% ethyl acetate in light
MeO
MeO
MeO
petroleum); IR (KBr): nmax 1718, 1286, 1128 cmꢃ1
;
1H NMR
CHO
(300 MHz, CDCl3):
d
3.23 (dd, J¼2.5, 16.3 Hz, 1H), 3.43 (dd, J¼11.9,
OH
O
16.3 Hz, 1H), 5.73 (dd, J¼2.5, 11.9 Hz, 1H), 7.30 (d, J¼7.4 Hz, 1H), 7.45
OTBDMS
O
22
(dd, J¼7.4,7.7 Hz, 1H), 7.50–7.61 (m, 4H), 7.86–7.96 (m, 4H), 8.18 (d,
COOMe
OMe
OMe
J¼7.7 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 35.5, 79.9, 123.5, 125.0,
Cp2TiCl
THF, rt
Br
125.1, 126.3, 126.4, 127.2, 127.6, 127.8, 128.0, 128.4, 130.3, 133.0,
133.1, 133.8, 135.8, 138.8, 165.2; HRMS (ESI) calcd for C19H15O2
275.1067 [MþH]þ, found 275.1026.
then H3O+
18
OMe
3
CHO
OH
O
MeO
3.6. 3-(4-Methylphenyl)-3,4-dihydro-1H-isochromen-1-
one (7d)
OMe
23
OTBDMS
COOMe
O
Colourless solid. Mp 92–94 ꢁC. Rf¼0.34 (10% ethyl acetate in light
Cp2TiCl
THF, rt
Br
petroleum); IR (KBr): nmax 1724, 1263, 1118 cmꢃ1
;
1H NMR
OMe
then H3O+
18
(300 MHz, CDCl3):
d
2.38 (s, 3H), 3.11 (dd, J¼3.1, 16.4 Hz, 1H), 3.34
OMe
19
OH
O
(dd, J¼11.9, 16.4 Hz, 1H), 5.53 (dd, J¼3.1, 11.9 Hz, 1H), 7.22 (d,
J¼8.0 Hz, 2H), 7.28 (d, J¼7.6 Hz, 1H), 7.37 (d, J¼8.0 Hz, 2H), 7.43 (dd,
J¼7.5, 7.6 Hz, 1H), 7.57 (t, J¼7.5 Hz, 1H), 8.15 (d, J¼7.5 Hz, 1H); 13C
O
BBr3, CH2Cl2
-78 °C to rt, 3 h
NMR (75 MHz, CDCl3):
d 35.9, 55.7, 80.2, 114.2 (2C), 125.6, 127.8,
128.1 (2C), 128.2, 130.8, 131.1, 134.3, 139.5, 160.3, 165.9; HRMS (ESI)
OH
calcd for C16H14O2Na 261.0891 [MþNa]þ, found 261.0892.
OH
4
Scheme 4.
3.7. 3-(4-Methoxyphenyl)-3,4-dihydro-1H-isochromen-1-
one (7e)
under argon until it turned green. This green solution was trans-
ferred to a dropping funnel by a cannula and was added dropwise
for 9 h to a solution of the bromide 5 (1.5 mmol) and the aldehyde 6
(1.5 mmol) in THF (20 mL). The reaction mixture was then stirred
for an additional 4 h. After completion of the reaction (monitored
by TLC), it was decomposed slowly with 25% aqueous H2SO4. Most
of the THF was removed under reduced pressure and the resulting
residue was extracted with diethyl ether (3ꢂ25 mL). The organic
layer was washed successively with water (2ꢂ10 mL), brine
(2ꢂ10 mL) and finally dried (Na2SO4). Solvent was removed in
vacuo to give the crude product, which was purified by column
chromatography (ethyl acetate in light petroleum) to furnish 7.
White solid. Mp 106–108 ꢁC. Rf¼0.25 (10% ethyl acetate in light
petroleum); IR (KBr): nmax 1716, 1515, 1255, 1110 cmꢃ1 1H NMR
;
(300 MHz, CDCl3):
d
3.08 (dd, J¼3.0, 16.4 Hz, 1H), 3.34 (dd, J¼12.0,
16.4 Hz, 1H), 3.81 (s, 3H), 5.49 (dd, J¼3.0, 12.0 Hz, 1H), 6.92 (d,
J¼8.7 Hz, 2H), 7.27 (d, J¼7.5 Hz, 1H), 7.36–7.44 (m, 3H), 7.55 (t,
J¼7.5 Hz, 1H), 8.13 (d, J¼7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
35.4, 55.3, 79.8, 114.0 (2C), 125.1, 127.3, 127.6 (2C), 127.8, 130.4,
130.6, 133.8, 139.0, 159.8, 165.4; HRMS (ESI) calcd for C16H15O3
255.1016 [MþH]þ, found 255.1004.
3.8. 3-(4-Chlorophenyl)-3,4-dihydro-1H-isochromen-1-
3.3. 3-Phenyl-3,4-dihydro-1H-isochromen-1-one (7a)
one (7f)
Colourless solid. Mp 87–89 ꢁC; Rf¼0.28 (10% ethyl acetate in
Colourless solid. Mp 81–83 ꢁC. Rf¼0.37 (10% ethyl acetate in light
light petroleum); IR (KBr): nmax 1722, 1271, 1118 cmꢃ1
;
1H NMR
petroleum); IR (KBr): nmax 1714, 1083 cmꢃ1 1H NMR (300 MHz,
;
(300 MHz, CDCl3):
d
3.14 (dd, J¼3.2, 16.4 Hz, 1H), 3.35 (dd, J¼11.9,
CDCl3):
d
3.05 (dd, J¼3.3, 16.4 Hz, 1H), 3.23 (dd, J¼11.8, 16.4 Hz, 1H),
16.4 Hz, 1H), 5.57 (dd, J¼3.2, 11.9 Hz, 1H), 7.29 (d, J¼7.5 Hz, 1H),
5.46 (dd, J¼3.3, 11.8 Hz, 1H), 7.20 (d, J¼7.6 Hz, 1H), 7.29–7.39 (m,
7.37–7.50 (m, 6H), 7.58 (dt, J¼1.2, 7.5 Hz, 1H), 8.16 (d, J¼7.8 Hz, 1H);
5H), 7.50 (dd, J¼7.5, 7.6 Hz, 1H), 8.07 (d, J¼7.6 Hz, 1H); 13C NMR
13C NMR (75 MHz, CDCl3):
d
36.0, 80.4, 125.5, 126.5 (2C), 127.8,
(75 MHz, CDCl3): d 35.7, 79.3, 125.9, 127.5, 127.6, 128.2, 128.9, 129.0,
128.3, 129.0, 129.1 (2C), 130.8, 134.3, 139.0, 139.4, 165.8; HRMS (ESI)
130.6, 131.3, 134.2, 137.2, 138.7, 165.2; HRMS (ESI) calcd for
calcd for C15H13O2 225.0915 [MþH]þ, found 225.0886.
C15H12O2Cl 259.0520 [MþH]þ, found 259.0557.

11054
S.K. Mandal, S.C. Roy / Tetrahedron 64 (2008) 11050–11057
3.9. 3-(3,4-Dimethoxyphenyl)-3,4-dihydro-1H-isochromen-1-
3.14. 3-(Furan-2-yl)-3,4-dihydroisochromen-1-one (7l)
one (7g)
Colourless oil. Rf¼0.28 (10% ethyl acetate in light petroleum); IR
Colourless needles. Mp 102–104 ꢁC. Rf¼0.28 (20% ethyl acetate
(neat): nmax 1732, 1606, 1274 cmꢃ1 1H NMR (300 MHz, CDCl3):
;
d
in light petroleum); IR (KBr): nmax 1714, 1278, 1141 cmꢃ1
;
1H NMR
3.21 (dd, J¼3.4, 16.5 Hz, 1H), 3.55 (dd, J¼10.9, 16.5 Hz, 1H), 5.59
(300 MHz, CDCl3):
d
3.11(dd, J¼3.0, 16.4 Hz, 1H), 3.37 (dd, J¼12.0,
(dd, J¼3.4, 10.9 Hz, 1H), 6.37 (d, J¼1.6 Hz, 1H), 6.41 (d, J¼3.1 Hz, 1H),
7.29 (d, J¼7.5 Hz, 1H), 7.39–7.43 (m, 2H), 7.56 (d, J¼7.5 Hz, 1H), 8.11
16.4 Hz, 1H), 3.90 (s, 3H), 3.92 (s, 3H), 5.51 (dd, J¼3.0, 12.0 Hz, 1H),
6.88 (d, J¼8.0 Hz, 1H), 6.99 (d, J¼8.0 Hz, 1H), 7.03 (s, 1H), 7.29 (d,
J¼7.5 Hz, 1H), 7.43 (t, J¼7.5 Hz, 1H), 7.57 (dd, J¼7.5, 7.6 Hz, 1H), 8.15
(d, J¼7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 31.6, 73.1, 109.1, 110.6,
125.0, 127.6, 128.0, 130.5, 134.1, 138.6, 143.2, 150.8, 164.8; HRMS
(d, J¼7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
35.4, 55.9 (2C), 79.9,
(ESI) calcd for C13H10O3Na 237.0528 [MþNa]þ, found 237.0525.
109.4, 110.9, 118.6, 125.0, 127.3, 127.8, 130.3, 131.0, 133.8, 139.0, 149.1,
149.2, 165.4; HRMS (ESI) calcd for C17H17O4 285.1121 [MþH]þ,
found 285.1115.
3.15. 2-Methoxy-6-methyl-benzaldehyde (9)
To a solution of 2-hydroxy-6-methyl-benzaldehyde (340 mg,
2.5 mmol) in dry acetone (15 mL), potassium carbonate (414 mg,
3 mmol) and methyl iodide (529 mg, 3.75 mmol) were added and
refluxed for 2 h. After cooling, the mixture was concentrated under
reduced pressure and then water (20 mL) was added to it. The re-
action mass was extracted with diethyl ether (3ꢂ15 mL). The
combined organic layer was washed with water (10 mL), brine
(10 mL) and finally dried (Na2SO4). The organic layer was concen-
trated under reduced pressure and the residue obtained was pu-
rified by column chromatography over silica gel (5% ethyl acetate in
light petroleum) to give the corresponding methyl ether 9 (93%) as
a colourless solid. Mp 38–40 ꢁC. Rf¼0.50 (7% ethyl acetate in light
3.10. 3-[2-(Prop-2-en-1-yloxy)phenyl]-3,4-dihydro-1H-
isochromen-1-one (7h)
Colourless oil. Rf¼0.34 (10% ethyl acetate in light petroleum); IR
(neat): nmax 1724, 1492, 1272, 1118 cmꢃ1 1H NMR (300 MHz,
;
CDCl3):
d
3.13–3.16 (m, 2H), 4.52 (ddd, J¼1.5, 3.2, 6.5 Hz, 2H), 5.18
(dd, J¼1.5, 10.5 Hz, 1H), 5.29 (dd, J¼1.5, 17.3 Hz, 1H), 5.87–6.02 (m,
2H), 6.84 (d, J¼8.3 Hz, 1H), 6.97 (dd, J¼7.0, 7.6 Hz, 1H), 7.19–7.26 (m,
2H), 7.36 (t, J¼7.5 Hz, 1H), 7.49 (dt, J¼1.4, 7.6 Hz, 1H), 7.55 (dd, J¼1.4,
7.6 Hz, 1H), 8.09 (dd, J¼0.7, 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
34.8, 69.3, 75.6, 112.1, 117.8, 121.5, 125.6, 127.2, 127.7, 127.8, 128.1,
petroleum); IR (KBr): nmax 1683, 1596, 1473, 1271, 1099 cmꢃ1 1H
;
129.7, 130.8, 133.4, 134.2, 140.0, 155.2, 166.2; HRMS (ESI) calcd for
NMR (300 MHz, CDCl3):
d
2.52 (s, 3H), 3.82 (s, 3H), 6.73 (d, J¼7.8 Hz,
C18H17O3 [MþH]þ 281.1172, found 281.1160.
1H), 6.77 (d, J¼7.8 Hz, 1H), 7.31 (t, J¼7.8 Hz, 1H), 10.58 (s, 1H); 13C
NMR (75 MHz, CDCl3):
d 21.4, 55.6, 109.0, 123.2, 124.0, 134.4, 141.8,
163.1, 192.1; HRMS (ESI) calcd for C9H11O2 151.0754 [MþH]þ found
3.11. 3-[2-(Prop-2-yn-1-yloxy)phenyl]-3,4-dihydro-1H-
151.0756.
isochromen-1-one (7i)
3.16. 2-Methoxy-6-methyl-benzoic acid (10)
Colourless oil. Rf¼0.20 (10% ethyl acetate in light petroleum); IR
(neat): nmax 2117, 1720, 1276, 1120 cmꢃ1; 1H NMR (300 MHz, CDCl3):
Fresh silver oxide was prepared by treating aqueous solution of
silver nitrate (680 mg, 4 mmol) in 1 M aqueous sodium hydroxide
solution (8 mL) and the suspension was stirred at room tempera-
ture for 30 min. A solution of 2-methoxy-6-methyl-benzaldehyde 9
(300 mg, 2 mmol) in a 1 M aqueous sodium hydroxide solution
(15 mL) was added to the suspension of silver oxide, and the mix-
ture was refluxed gently for 1 h. After cooling, the mixture was
filtered off and the aqueous alkaline solution was acidified with 20%
hydrochloric acid and extracted with diethyl ether (3ꢂ15 mL). The
combined organic layer was washed successively with water
(10 mL), brine (10 mL) and finally dried (Na2SO4). The organic layer
was concentrated under reduced pressure and the residue obtained
was purified by column chromatography over silica gel (25% ethyl
acetate in light petroleum) to yield the corresponding carboxylic
acid 10 (58%) as a colourless solid. Mp 138–140 ꢁC. Rf¼0.31 (25%
ethyl acetate in light petroleum); IR (KBr): 3012, 2559, 1697, 1587,
d
2.51 (t, J¼2.3 Hz, 1H), 3.19–3.22 (m, 2H), 4.74 (d, J¼2.3 Hz, 2H),
5.95 (m, 1H), 7.04 (d, J¼8.5 Hz, 1H), 7.09 (t, J¼7.6 Hz, 1H), 7.26–7.45
(m, 3H), 7.56 (dt, J¼1.2, 7.4 Hz, 1H), 7.64 (dd, J¼1.2, 7.6 Hz, 1H), 8.16
(d, J¼7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 34.6, 56.2, 75.0, 76.0,
78.4, 112.2, 122.0, 125.3, 127.1, 127.5, 127.8, 128.0, 129.4, 130.4, 133.9,
139.6, 153.9, 165.8; HRMS (ESI) calcd for C18H15O3 [MþH]þ
279.1016, found 279.1008.
3.12. 3-Propyl-3,4-dihydro-1H-isochromen-1-one (7j)
Colourless oil. Rf¼0.56 (10% ethyl acetate in light petroleum); IR
(neat): nmax 1716, 1261, 1076 cmꢃ1 1H NMR (300 MHz, CDCl3):
;
d
0.93 (t, J¼7.1 Hz, 3H), 1.47–1.89 (m, 4H), 2.81–2.97 (m, 2H), 4.44–
4.53 (m, 1H), 7.18 (d, J¼7.5 Hz, 1H), 7.33 (dd, J¼7.4, 7.5 Hz, 1H), 7.48
(dd, J¼7.4, 7.5 Hz, 1H), 8.04 (d, J¼7.5 Hz, 1H); 13C NMR (75 MHz,
1473, 1296, 1089 cmꢃ1 1H NMR (300 MHz, CDCl3):
; d 2.45 (s, 3H),
CDCl3):
d
13.9, 18.3, 33.3, 37.1, 78.6, 125.8, 127.5, 127.7, 130.4, 133.7,
3.88 (s, 3H), 6.81 (d, J¼8.1 Hz, 1H), 6.55 (d, J¼8.1 Hz, 1H), 7.29 (t,
139.3, 165.8; HRMS (ESI) calcd for C12H15O2 [MþH]þ 191.1067,
J¼8.1 Hz, 1H), 10.90 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 20.5, 56.5,
found 191.1073.
109.2, 122.3, 123.5, 131.5, 138.4, 157.3, 173.4. HRMS (ESI) calcd for
C9H10O3 189.0528 [MþNa]þ, found 189.0527.
3.13. 3,4-Dihydro-3-styrylisochromen-1-one (7k)
3.17. Methyl 2-methoxy-6-methylbenzoate (11)
Colourless oil. Rf¼0.27 (10% ethyl acetate in light petroleum); IR
To a solution of 2-methoxy-6-methyl-benzoic acid 10 (415 mg,
2.5 mmol) in ether (10 mL) at 0 ꢁC, diazomethane (5 mmol) in ether
(10 mL) was added dropwise and stirred for 2 h. After removing the
excess diazomethane it was diluted with ether (20 mL). The ether
layer was washed successively with water (10 mL), brine (10 mL)
and finally dried (Na2SO4). The organic layer was concentrated
under reduced pressure and the residue obtained was purified by
column chromatography over silica gel (5% ethyl acetate in light
(neat): nmax 1722, 1606, 1278 cmꢃ1 1H NMR (300 MHz, CDCl3):
;
d
3.08–3.24 (m, 2H), 5.18–5.25 (m, 1H), 6.34 (dd, J¼6.3, 16.0 Hz, 1H),
6.79 (d, J¼16.0 Hz, 1H), 7.27–7.44 (m, 7H), 7.56 (t, J¼7.4 Hz, 1H), 8.13
(d, J¼7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 34.2, 79.1, 125.6,
126.3, 127.1 (2C), 127.8, 128.2, 128.7, 129.1 (2C), 130.8, 133.7, 134.2,
136.2, 139.0, 165.5; HRMS (ESI) calcd for C17H14O2Na 273.0891
[MþNa]þ, found 273.0891.

S.K. Mandal, S.C. Roy / Tetrahedron 64 (2008) 11050–11057
11055
petroleum) to obtain the ester 11 as a colourless oil (96%). Rf¼0.45
(5% ethyl acetate in light petroleum); IR (neat): nmax 1733, 1585,
(2ꢂ10 mL) and finally dried (Na2SO4). Solvent was removed under
reduced pressure and the crude material obtained was purified by
column chromatography over silica gel (30% ethyl acetate in light
petroleum) to furnish hydrangenol (1) (113 mg, 88%) as a white
solid; mp179–181 ꢁC (lit.2c 180–181 ꢁC). Rf¼0.15 (20% ethyl acetate
in light petroleum); IR (KBr): nmax 3354, 1658, 1460, 1230,
1473, 1267, 1091 cmꢃ1 1H NMR (300 MHz, CDCl3):
; d 2.27 (s, 3H),
3.78 (s, 3H), 3.89 (s, 3H), 6.73 (d, J¼8.1 Hz, 1H), 6.77 (d, J¼8.1 Hz,
1H), 7.21 (t, J¼8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 19.1, 52.1,
55.8, 108.4, 122.3, 123.7, 130.3, 136.4, 156.4, 168.8; HRMS (ESI) calcd
for C10H12O3 203.0684 [MþNa]þ, found 203.0667.
1028 cmꢃ1
;
1H NMR (300 MHz, DMSO-d6):
d
3.10 (dd, J¼2.5,
16.4 Hz, 1H), 3.37 (dd, J¼12.0, 16.4 Hz, 1H), 5.63 (dd, J¼2.5, 12.0 Hz,
1H), 6.79 (d, J¼8.2 Hz, 2H), 6.83–6.89 (m, 2H), 7.31 (d, J¼8.2 Hz, 2H),
7.50 (t, J¼7.9 Hz, 1H), 9.62 (s, 1H, phenolic OH), 10.92 (s, 1H, phe-
3.18. Methyl 2-(bromomethyl)-6-methoxybenzoate (12)
N-Bromosuccinamide (356 mg, 2 mmol) was added to a solution
of 11 (360 mg, 2.0 mmol) in carbon tetrachloride (5 mL) and was
heated to reflux in the presence of visible light. Then, a catalytic
amount of AIBN was added and the reflux was continued for 2 h.
After cooling to room temperature the precipitated solid was fil-
tered off and the filtrate was concentrated under reduced pressure
and the residue was extracted with diethyl ether (3ꢂ15 mL). The
organic layer was washed successively with water (2ꢂ10 mL), brine
(2ꢂ10 mL) and finally dried (Na2SO4). After removal of the solvent
in vacuo the residue obtained was purified by column chroma-
tography over silica gel (5% ethyl acetate in light petroleum) to
furnish the benzyl bromide 12 (476 mg, 92%) as a colourless oil.
Rf¼0.42 (5% ethyl acetate in light petroleum); IR (neat): nmax 1730,
nolic OH); 13C NMR (75 MHz, DMSO-d6):
d 34.4, 81.4, 109.3, 116.1
(2C), 116.3, 119.1 (2C), 129.2, 129.3, 137.2, 141.5, 158.7, 161.8, 170.2;
HRMS (ESI) calcd for C15H12O4Na 279.0633 [MþNa]þ, found
279.0649.
3.21. 2-Hydroxy-6-methyl-benzoic acid (15)
To a stirred solution of 2-methyl-6-nitro-benzoic acid 14 (1.0 g,
5.52 mmol) in dry methanol (10 mL), 10% Pd on activated charcoal
(20 mg) was added and then hydrogen gas was purged to it. The
reaction mixture was allowed to stir for overnight. The catalyst was
filtered off and the filtrate was concentrated under reduced pres-
sure. The solid mass obtained was dissolved into 9% aqueous H2SO4
solution (10 mL). The resulting solution was cooled to ꢃ5 ꢁC and
a cold saturated solution of NaNO2 (419 mg, 6.07 mmol) was added
slowly to it with hand shaking. Then, it was left for 20 min at room
temperature and was heated until the temperature reached to
50 ꢁC. Heating was continued until evolution of N2 ceases. The re-
action mass was extracted with diethyl ether (3ꢂ50 ml). The
combined organic extract was washed successively with water
(2ꢂ15 mL), brine (20 mL) and finally dried (Na2SO4). After removal
of the solvent the crude product obtained was purified by column
chromatography over silica gel (15% ethyl acetate in light petro-
leum) to furnish 15 (780 mg, 93%) as colourless needles. Mp 154–
156 ꢁC. Rf¼0.22 (20% ethyl acetate in light petroleum); IR (KBr):
1585, 1471, 1271, 1114, 1074 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d 3.80
(s, 3H), 3.93 (s, 3H), 4.48 (s, 2H), 6.86 (d, J¼8.4 Hz, 1H), 6.98 (d,
J¼7.7 Hz,1H), 7.30 (dd, J¼7.7, 8.4 Hz,1H); 13C NMR (75 MHz, CDCl3):
d
30.0, 52.5, 56.1, 111.6, 122.3, 123.2, 131.1, 136.5, 156.9, 167.5; HRMS
(ESI) calcd for C10H11BrO3Na 280.9790 [MþNa]þ, found 280.9786.
3.19. Preparation of 8-methoxy-3-(4-methoxyphenyl)-3,4-
dihydro-1H-isochromen-1-one (13)
A red solution of Cp2TiCl2 (747 mg, 3.0 mmol) in deoxygenated
THF (40 mL) was stirred with activated zinc dust (393 mg, 6 mmol)
under argon until it turned green. This green solution was trans-
ferred to a dropping funnel by a cannula and was added dropwise
for 9 h to a solution of the bromide 12 (390 mg, 1.5 mmol) and
4-methoxybenzaldehyde (205 mg, 1.5 mmol) in dry deoxygenated
THF (20 mL) under argon. The reaction mixture was stirred for an
additional 8 h and was decomposed slowly with 25% aqueous
H2SO4. Most of THF was removed under reduced pressure and
resulting residue was extracted with diethyl ether (3ꢂ25 mL). The
organic layer was washed successively with water (2ꢂ10 mL), brine
(2ꢂ10 mL) and finally dried (Na2SO4). Solvent was removed under
reduced pressure and the crude material obtained was purified by
column chromatography over silica gel (25% ethyl acetate in light
petroleum) to furnish 13 (227 mg, 53%) as colourless needles. Mp
152–154 ꢁC. Rf¼0.29 (25% ethyl acetate in light petroleum); IR
nmax 3075, 1647, 1444, 1251 cmꢃ1; 1H NMR (300 MHz, CDCl3):
(s, 3H), 6.77 (d, J¼7.4 Hz, 1H), 6.87 (d, J¼8.3 Hz, 1H), 7.34 (dd, J¼8.3,
7.4 Hz, 1H), 11.04 (s, 1H); 13C NMR (75 MHz, CDCl3):
24.2, 111.1,
d 2.63
d
116.0, 123.4, 135.6, 143.1, 163.9, 176.1. Anal. Calcd for C8H8O3: C,
63.15; H, 5.30. Found: C, 63.13; H, 5.28.
3.22. Methyl 2-hydroxy-6-methylbenzoate (16)
To a solution of 15 (760 mg, 5.0 mmol) in diethyl ether (10 ml) at
0 ꢁC, diazomethane (15 mmol) in ether (10 mL) was added drop-
wise and stirred for 2 h. After removing the excess diazomethane
the ether layer was washed with water (10 mL), brine (10 mL) and
finally dried (Na2SO4). After removal of the solvent under reduced
pressure the residue obtained was purified by column chroma-
tography over silica gel (10% ethyl acetate in light petroleum) to
give the corresponding ester 16 (788 mg, 95%) as a colourless oil.
Rf¼0.32 (15% ethyl acetate in light petroleum); IR (KBr): nmax 3039,
;
(KBr): nmax 1728, 1595, 1475, 1240, 1080 cmꢃ1 1H NMR (300 MHz,
CDCl3):
d
2.98 (dd, J¼2.6, 16.2 Hz, 1H), 3.23 (dd, J¼11.9, 16.2 Hz, 1H),
3.78 (s, 3H), 3.92 (s, 3H), 5.32 (dd, J¼2.6, 11.9 Hz, 1H), 6.81 (d,
J¼7.5 Hz, 1H), 6.83–6.93 (m, 3H), 7.35 (d, 8.6 Hz, 2H), 7.45 (dd, J¼7.7,
8.2 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
36.6, 55.3, 56.2, 78.9, 111.1,
1664, 1442, 1215 cmꢃ1 1H NMR (300 MHz, CDCl3):
; d 2.52 (s, 3H),
113.9 (2C), 119.3, 120.2, 127.7 (2C), 130.6, 134.7, 141.8, 159.8, 161.2,
162.5; HRMS (ESI) calcd for C17H16O4Na 307.0946 [MþNa]þ, found
307.0944.
3.93 (s, 3H), 6.69 (d, J¼7.4 Hz, 1H), 6.83 (d, J¼8.3 Hz, 1H), 7.25 (dd,
J¼7.4, 8.3 Hz, 1H), 11.29 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 24.0,
52.1, 112.3, 115.6, 122.9, 134.2, 141.3, 162.9, 172.2. Anal. Calcd for
C9H10O3: C, 65.05; H, 6.07. Found: C, 65.01; H, 6.12.
3.20. Synthesis of hydrangenol (1)
3.23. Methyl 2-(tert-butyldimethylsilyloxy)-6-
A solution of BBr3 (1 M, 2 mL) in CH2Cl2 (2 mL) was added
dropwise to a stirred solution of dimethyl ether 13 (142 mg,
0.5 mmol) in CH2Cl2 (5 mL) at ꢃ78 ꢁC. The reaction mixture was
then allowed to warm to room temperature and was stirred for an
additional 3 h. It was decomposed with saturated aqueous NaHCO3
solution (10 mL) and extracted with CH2Cl2 (3ꢂ25 mL). The organic
layer was washed successively with water (2ꢂ10 mL), brine
methylbenzoate (17)
A solution of 16 (830 mg, 5.0 mmol) in dichloromethane (20 mL)
was stirred with triethylamine (1.02 g, 10 mmol), DMAP (62.5 mg,
0.5 mmol) and TBDMS-Cl (904 mg, 6.0 mmol) for 10 h at room
temperature. Then, the reaction mixture was diluted with diethyl
ether (20 mL). The ether layer was washed successively with water

11056
S.K. Mandal, S.C. Roy / Tetrahedron 64 (2008) 11050–11057
(15 mL), brine (15 mL) and finally dried (Na2SO4). After evaporation
of the solvent the residual mass was chromatographed over silica
gel (5% ethyl acetate in light petroleum) to afford 17 (1.35 g, 96%) as
a colourless oil. Rf¼0.62 (5% ethyl acetate in light petroleum); IR
(KBr): nmax 1735, 1467, 1290, 840 cmꢃ1; 1H NMR (300 MHz, CDCl3):
3.27. Synthesis of hydrangenol (1) from 18
A solution of 18 (537 mg, 1.5 mmol) and 4-(tert-butyldime-
thylsilyloxy)-benzaldehyde 20 (354 mg, 1.5 mmol) in THF (15 mL)
was reacted in the presence of Cp2TiCl in THF followed by acidic
work-up as described for the preparation of 13 to give hydrangenol
(1) as colourless needles (196 mg, 51%).
d
0.22 (s, 6H), 0.97 (s, 9H), 2.28 (s, 3H), 3.87 (s, 3H), 6.67 (d, J¼8.2 Hz,
1H), 6.78 (d, J¼7.5 Hz, 1H), 7.13 (dd, J¼7.5, 8.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3):
126.6, 130.0, 136.7, 152.5, 169.0; HRMS (ESI) calcd for C15H25O3Si
d
ꢃ4.3 (2C), 18.1, 19.4, 25.6 (3C), 52.0, 116.4, 122.7,
3.28. Thunberginol G dimethyl ether (19)
281.1567 [MþH]þ, found 281.1552.
A
solution of 18 (537 mg, 1.5 mmol) and 3,4-dimethoxy-
benzaldehyde 23 (250 mg, 1.5 mmol) in THF (15 mL) was reacted in
the presence of Cp2TiCl in THF followed by acidic work-up as
described for the preparation of 13 to give compound 19 as a col-
ourless needles (238 mg, 53%). Mp 105–107 ꢁC. Rf¼0.27 (25% ethyl
3.24. Methyl 2-(tert-butyldimethylsilyloxy)-6-
(bromomethyl)-benzoate (18)
N-Bromosuccinamide (356 mg, 2 mmol) was added to a solution
of 17 (560 mg, 2 mmol) in CCl4 (10 ml) and heated to reflux under
visible light. A catalytic amount of AIBN (4 mg) was added and the
reflux continued for 2 h. After cooling, the solids were filtered off
and the filtrate concentrated under reduced pressure. It was diluted
with diethyl ether (20 mL) and washed with water (10 mL), brine
(10 mL) and finally dried (Na2SO4). After removal of the solvent in
vacuo the residue obtained was purified by column chromatogra-
phy over silica gel (5% ethyl acetate in light petroleum) to obtain the
benzyl bromide 18 (688 mg, 96%) as a colourless oil. Rf¼0.60 (5%
ethyl acetate in light petroleum); IR (KBr): nmax 1728, 1465, 1296,
acetate in light petroleum); IR (KBr): nmax 1670, 1616, 1232 cmꢃ1
;
1H NMR (300 MHz, CDCl3):
d
2.99 (dd, J¼3.1, 16.5 Hz, 1H), 3.22 (dd,
J¼12.2, 16.5 Hz, 1H), 3.78 (s, 3H), 3.79 (s, 3H), 5.41 (dd, J¼3.1,
12.2 Hz,1H), 6.63 (d, J¼7.3 Hz,1H), 6.76–6.89 (m, 4H), 6.84–6.89 (m,
2H), 7.33 (dd, J¼7.9, 8.0 Hz, 1H), 10.90 (s, 1H); 13C NMR (75 MHz,
CDCl3):
d 35.1, 56.0 (2C), 80.9, 108.4, 109.4, 111.0, 116.3, 118.0, 118.8,
130.4, 136.4, 139.4, 149.2, 149.5, 162.2, 169.9; HRMS (ESI) calcd for
C17H17O5 301.1071 [MþH]þ, found 301.1077.
3.29. Thunberginol G (4)
842 cmꢃ1 1H NMR (300 MHz, CDCl3):
; d 0.22 (s, 6H), 0.97 (s, 9H),
Compound 19 (150 mg, 0.5 mmol) was treated with BBr3 (1 M,
2 mL) in CH2Cl2 (2 mL) following the same procedure described for
1 to give thunberginol (4) (117 mg, 86%) as a white solid. Mp 176–
178 ꢁC. Rf¼0.21 (30% ethyl acetate in light petroleum); IR (KBr): nmax
3.90 (s, 3H), 4.49 (s, 2H), 6.79 (d, J¼7.9 Hz, 1H), 6.98 (d, J¼7.6 Hz,
1H), 7.22 (dd, J¼7.6, 7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
ꢃ4.3
(2C), 18.1, 25.6 (3C), 30.3, 52.3, 119.6, 122.7, 126.0, 130.8, 136.9, 153.2,
167.8; HRMS (ESI) calcd for C15H23O3BrSiNa 381.0497 [MþNa]þ,
found 381.0529.
3303, 1658, 1614, 1203 cmꢃ1; 1H NMR (300 MHz, DMSO-d6):
d 3.12
(dd, J¼2.9, 16.5 Hz, 1H), 3.33 (dd, J¼11.8, 16.5 Hz, 1H), 5.59 (dd,
J¼2.9, 11.8 Hz, 1H), 6.77–6.91 (m, 5H), 7.51 (dd, J¼7.8, 7.9 Hz, 1H),
9.07 (s, 1H), 9.10 (s, 1H), 10.95 (s, 1H); 13C NMR (75 MHz, DMSO-d6):
3.25. Phyllodulcin (2)
d
33.1, 80.0, 108.0, 113.7, 114.9 (2C), 117.3, 117.9, 128.5, 135.8, 140.1,
A solution of 18 (537 mg, 1.5 mmol) and 3-(tert-butyldime-
thylsilyloxy)-4-methoxybenzaldehyde 21 (400 mg, 1.5 mmol) in
THF (15 mL) was reacted in the presence of Cp2TiCl in THF followed
by acidic work-up as described for the preparation of 13 to give
phyllodulcin (2) as a colourless needles (245 mg, 57%). Mp 127–
129 ꢁC (lit. 128–130 ꢁC). Rf¼0.16 (20% ethyl acetate in light petro-
144.7, 145.3, 160.4, 168.9; HRMS (ESI) calcd for C15H12O5Na:
295.0583 [MþNa]þ, found 295.0584.
Acknowledgements
We thank DST, New Delhi for financial support. S.K.M. thanks
CSIR, New Delhi for awarding the research fellowship.
leum); IR (KBr): nmax 3352, 1670, 1618, 1230 cmꢃ1
;
1H NMR
(300 MHz, DMSO-d6):
d
3.16 (dd, J¼3.2, 16.5 Hz, 1H), 3.37 (dd,
J¼11.6, 16.5 Hz, 1H), 3.78 (s, 3H), 5.66 (dd, J¼3.2, 11.6 Hz, 1H), 6.87–
Supplementary data
6.97 (m, 5H), 7.53 (dd, J¼7.9, 8.0 Hz, 1H), 9.12 (s, 1H), 10.92 (s, 1H);
13C NMR (75 MHz, DMSO-d6):
d 33.5, 55.6, 80.1, 108.4, 111.9, 113.9,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.09.075.
115.4, 117.5, 118.4, 130.7, 136.3, 140.4, 146.4, 147.9, 160.9, 169.2;
HRMS (ESI) calcd for C16H14O5Na: 309.0739 [MþNa]þ, found
309.0730.
References and notes
1. (a) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.; Nakajima, S. Chem. Pharm. Bull.
1981, 29, 2689; (b) ShimoJima, Y.; Shirai, T.; Baba, T.; Hayashi, H. J. Med. Chem.
1885, 28, 3; (c) Fusetani, N.; Sugawar, T.; Matsunaga, S.; Hirota, H. J. Org. Chem.
1991, 56, 4971; (d) Yoshikawa, M.; Uchida, E.; Chatani, N.; Kobayashi, H.; Naitoh,
Y.; Okuno, Y.; Matsuda, H.; Yamahara, J.; Murakami, N. Chem. Pharm. Bull. 1992,
40, 3352; (e) Yoshikawa, M.; Ueda, T.; Shimoda, H.; Murakami, T.; Yamahara, J.;
Matsuda, H. Chem. Pharm. Bull. 1999, 47, 383; (f) Umehara, K.; Matsumoto, M.;
Nakamura, M.; Miyase, T.; Kuroyanagi, M.; Noguchi, H. Chem. Pharm. Bull. 2000,
48, 566; (g) Kongsaeree, P.; Prabpai, S.; Sriubolmas, N.; Vongvein, C.; Wiyak-
rutta, S. J. Nat. Prod. 2003, 66, 709; (h) Kokubun, T.; Veitch, N. C.; Bridge, P. D.;
Simmonds, M. S. J. Phytochemistry 2003, 62, 779; (i) Zidorn, C.; Lohwasser, U.;
Pschorr, S.; Salvenmoser, D.; Ongania, K.-H.; Ellmerer, E. P.; Bo¨rner, A.; Stuppner,
H. Phytochemistry 2005, 66, 1691; (j) Jiao, P.; Gloer, J. B.; Campbell, J.; Shearer, C.
A. J. Nat. Prod. 2006, 69, 612.
3.26. Macrophyllol (3)
A solution of 18 (537 mg, 1.5 mmol) and 3,4,5-trimethoxy-
benzaldehyde 22 (294 mg, 1.5 mmol) in THF (15 mL) was reacted in
the presence of Cp2TiCl in THF followed by acidic work-up as de-
scribed for the preparation of 13 to give macrophyllol (3) as a col-
ourless needles (272 mg, 55%). Mp 149–151 ꢁC (lit.2c 151–153 ꢁC).
Rf¼0.22 (25% ethyl acetate in light petroleum); IR (KBr): nmax 3408,
1664,1620,1230 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d
3.12 (dd, J¼2.8,
16.5 Hz, 1H), 3.32 (dd, J¼12.1, 16.5 Hz, 1H), 3.86 (s, 3H), 3.88 (s, 6H),
5.52 (dd, J¼2.8, 12.1 Hz, 1H), 6.67 (s, 2H), 6.75 (d, J¼7.3 Hz, 1H), 6.93
(d, J¼8.4 Hz, 1H), 7.45 (dd, J¼7.8, 8.0 Hz, 1H), 10.96 (s, 1H); 13C NMR
2. (a) Asahina, Y.; Asano, J. Chem. Ber. 1929, 62B, 171; (b) Asahina, Y.; Asano, J.
Chem. Ber. 1930, 63B, 429; (c) Hashimoto, T.; Tori, M.; Asakawa, Y. Phytochem-
istry 1987, 26, 3323; (d) Yoshikawa, M.; Matsuda, H.; Shimoda, H.; Shimada, H.;
Harada, E.; Naitoh, Y.; Miki, A.; Yamahara, J.; Murakami, N. Chem. Pharm. Bull.
1996, 44, 1440.
(75 MHz, CDCl3): d 35.5, 56.4 (2C), 61.0, 81.1, 103.4 (2C), 108.5, 116.6,
118.1, 120.3, 133.7, 136.6, 139.3, 153.6 (2C), 162.5, 169.8; HRMS (ESI)
calcd for C18H18O6Na 353.1001 [MþNa]þ, found 353.1014.
3. Matsuda, H.; Shimoda, H.; Yoshikawa, M. Bioorg. Med. Chem. 1999, 7, 1445.

S.K. Mandal, S.C. Roy / Tetrahedron 64 (2008) 11050–11057
11057
4. Yamahara, J.; Matsuda, H.; Shimoda, H.; Ishikawa, H.; Kawamori, S.; Wariishi, N.;
Harada, E.; Murakami, N.; Yoshikawa, M. Yakugaku Zasshi 1994, 114, 401.
5. Yamahara, J.; Miki, A.; Tsukamoto, K.; Ueno, A.; Murakami, N.; Yoshikawa, M.
Nat. Med. 1995, 49, 84.
6. Matsuda, H.; Shimoda, H.; Yamahara, J.; Yoshikawa, M. Bioorg. Med. Chem. Lett.
1998, 8, 215.
7. Shin, W.; Kim, S. J.; Shin, J. M.; Kim, S. H. J. Med. Chem. 1995, 38, 4325.
8. (a) Watanabe, M.; Sahara, M.; Kubo, M.; Furukawa, S.; Billedeau, R. J.; Snieckus,
V. J. Org. Chem. 1984, 49, 742; (b) Fu, P. P.; Unruh, L. E.; Miller, D. W.; Huang, L.
W.; Yang, D. T. C. J. Org. Chem. 1985, 50, 1259; (c) Regan, A. C.; Staunton, J.
J. Chem. Soc., Chem. Commun. 1987, 520; (d) Broady, S. D.; Rexhausen, J. E.;
Thomas, E. J. J. Chem. Soc., Chem. Commun. 1991, 708; (e) Ward, R. A.; Procter, G.
Tetrahedron 1995, 51, 12301; (f) McNicholas, C.; Simpson, T. J.; Willett, N. J.
Tetrahedron Lett. 1996, 37, 8053; (g) Salvadori, P.; Superchi, S.; Minutolo, F. J. Org.
Chem. 1996, 61, 4190 and references therein; (h) Uchida, K.; Watanabe, H.;
Kitahara, T. Tetrahedron 1998, 54, 8975; (i) Tahara, N.; Fukuda, T.; Iwao, M.
Tetrahedron Lett. 2004, 45, 5117; (j) Clayden, J.; Stimson, C. C.; Helliwell, M.;
Keenan, M. Synlett 2006, 873.
9. Gu¨nes, M.; Speicher, A. Tetrahedron 2003, 59, 8799.
10. Kessar, S. V.; Singh, P.; Vohra, R.; Kour, N. P.; Venugopal, D. J. Org. Chem. 1992, 57,
6716.
11. Mali, R. S.; Babu, K. N. J. Indian Inst. Sci. 2001, 81, 103.
12. Takeuchi, N.; Murase, M.; Ochi, K.; Tobinaga, S. J. Chem. Soc., Chem. Commun.
1976, 820.
13. (a) Takeuchi, N.; Ochi, K.; Murase, M.; Tobinaga, S. J. Chem. Soc., Chem. Commun.
1980, 593; (b) Fitzgerald, J. J.; Pagano, A. R.; Sakoda, V. M.; Olofson, R. A. J. Org.
Chem. 1994, 59, 4117.
14. (a) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem. 1998, 63, 2829; (b) Roy, S. C.;
Rana, K. K.; Guin, C. J. Org. Chem. 2002, 67, 3242; (c) Banerjee, B.; Roy, S. C.
Synthesis 2005, 2913; (d) Banerjee, B.; Roy, S. C. Eur. J. Org. Chem. 2006, 489; (e)
Jana, S.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2004, 45, 6575; (f) Jana, S.; Guin, C.;
Roy, S. C. J. Org. Chem. 2005, 70, 8252; (g) Jana, S.; Guin, C.; Roy, S. C. Tetrahedron
Lett. 2005, 46, 1155; (h) Mandal, S. K.; Jana, S.; Roy, S. C. Tetrahedron Lett. 2005,
46, 6115; (i) Mandal, S. K.; Roy, S. C. Tetrahedron Lett. 2006, 47, 1599; (j) Jana, S.;
Roy, S. C. Tetrahedron Lett. 2006, 47, 5949.
15. (a) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986 and refer-
ences cited therein; (b) Cuerva, J. M.; Justicia, J.; Oller-Lo´ pez, J. L.; Oltra, J. E. Top.
Curr. Chem. 2006, 264, 63; (c) Barrero, A. F.; Quı´lez del Moral, J. F.; Sa´nchez, E.
M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627; (d) Gansa¨uer, A. Synlett 1998, 801;
(e) Gansa¨uer, A.; Bluhm, H. Chem. Commun. 1998, 2143; (f) Gansa¨uer, A.; Lau-
terbach, T.; Bluhm, H.; Noltemeyer, M. Angew. Chem., Int. Ed. 1999, 38, 2909; (g)
Gansa¨uer, A.; Lauterbach, T.; Narayan, S. Angew. Chem., Int. Ed. 2003, 42, 5556;
(h) Journet, M.; Malacria, M. J. Org. Chem. 1994, 59, 718; (i) Devin, P.; Festerbank,
L.; Malacria, M. J. Org. Chem. 1998, 63, 6764.
16. (a) For preliminary communication see: Mandal, S. K.; Roy, S. C. Tetrahedron Lett.
2007, 48, 4131; [Corrigendum: Mandal, S. K.; Roy, S. C. Tetrahedron Lett. 2007, 48,
6225] (b) Cp2TiCl-mediated reaction of activated bromocompounds with alde-
hydes has also been reported at the same time by Barrero, A. F.; Herrador, M. M.;
Quı´lez del Moral, J. F.; Arteaga, P.; Akssira, M.; EI Hanbali, F.; Arteaga, J. F.; Die´guez,
H. R.; Sa´nchez, E. M. J. Org. Chem. 2007, 72, 2251.
17. Rosales, A.; Oller-Lopez, J. L.; Justicia, J.; Gansa¨uer, A.; Oltra, J. E.; Cuerva, J. M.
Chem. Commun. 2004, 2628.
18. Kanakam, C. C.; Mani, N. S.; Ramanathan, H.; Subba Rao, G. S. R. J. Chem. Soc.,
Perkin Trans. 1 1989, 1907.