Asymmetric synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins from (S)-4-isopropyl-2-(2-methoxy-6-methylphenyl)oxazoline

Article abstract of DOI:10.1016/j.tet.2007.04.092

Reaction of the laterally lithiated (S)-4-isopropyl-2-(2-methoxy-6-methylphenyl)oxazoline with p-tolualdehyde gave an inseparable mixture of the addition products in low diastereoselectivity. However, the (S,S)-product cyclized to the corresponding 3,4-di

Full text of DOI:10.1016/j.tet.2007.04.092

Tetrahedron 63 (2007) 7178–7186
Asymmetric synthesis of 3-substituted 8-hydroxy-3,4-
dihydroisocoumarins from (S)-4-isopropyl-2-(2-methoxy-6-
methylphenyl)oxazoline
Katsuya Uchida,a Tsutomu Fukudaa and Masatomo Iwaob,
*
aGraduate School of Science and Technology, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
bDepartment of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 13 March 2007; revised 25 April 2007; accepted 26 April 2007
Available online 3 May 2007
Abstract—Reaction of the laterally lithiated (S)-4-isopropyl-2-(2-methoxy-6-methylphenyl)oxazoline with p-tolualdehyde gave an
inseparable mixture of the addition products in low diastereoselectivity. However, the (S,S)-product cyclized to the corresponding 3,4-di-
hydroisocoumarin faster than the (S,R)-product on silica gel, which allowed to be produced both enantiomers of 8-methoxy-3-(p-tolyl)-3,4-
dihydroisocoumarin in moderate to good optical purity [S-enantiomer: 75% ee; R-enantiomer: 96% ee]. This procedure was applied to the
short-step synthesis of optically active 3,4-dihydroisocoumarin natural products such as (R)-8-hydroxy-3-(1-tridecyl)-3,4-dihydroisocou-
marin and (R)-phyllodulcin.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
reaction has been successfully applied to the short-step syn-
thesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins,
including (ꢀ)-hydrangenol and (ꢀ)-phyllodulcin.5 Re-
cently, we also investigated an asymmetric synthesis of
3-substituted 3,4-dihydroisocoumarins via stereoselective
addition of laterally lithiated chiral 2-(o-tolyl)oxazoline 1
to aldehydes.6 In the research, we disclosed the addition re-
actions proceeded in good stereoselectivities (up to 84% de)
in diethyl ether in the presence of TMEDA. In addition, we
found the major diastereomers 2 lactonized to 3,4-dihydro-
isocoumarins 3 faster than the minor diastereomers under
acidic conditions. By combination of these matched stereo-
selective reactions, we obtained 3-substituted 3,4-dihydro-
isocoumarins 3 in good optical purity (up to 97% ee)
(Scheme 1).
The 3,4-dihydroisocoumarins constitute a class of natural
products, which exhibit a wide range of biological activities
such as antifungal,1a antiulcer,1b antileukemic,1c antialler-
gic,1d differentiation-inducing,1e and antimalarial1f activi-
ties. Structurally, these natural products generally possess
an aryl or alkyl substituent at C-3 and a hydroxy group at
C-8 of the dihydroisocoumarin core. In addition, most of
them are optically active due to the stereocenter at C-3
(Fig. 1).
Although a variety of synthetic approaches to this class of
compounds have been developed,2 the most straightforward
route may be the reaction of laterally lithiated o-toluic acid
derivatives with aldehydes.3 In 2002, we reported unprece-
dented reagent-controlled optional ortho- and lateral lithia-
tions of 4,4-dimethyl-2-(o-tolyl)oxazolines.4 This unique
Herein, we report an application of this method for
asymmetric synthesis of 3-substituted 8-hydroxy-3,4-
dihydroisocoumarins including natural products by using
2-(2-methoxy-6-methylphenyl)oxazoline 4 as the starting
material.
HO
8
O
O
3
R
*
2. Results and discussion
R = aryl or alkyl
2.1. Addition of the laterally lithiated oxazoline 4
to p-tolualdehyde
Figure 1. Common scaffold of 3,4-dihydroisocoumarin natural products.
Keywords: Asymmetric synthesis; 3,4-Dihydroisocoumarin; Oxazoline;
Lateral lithiation; Diastereomer-selective lactonization; Silica gel.
* Corresponding author. Tel./fax: +81 95 819 2681; e-mail: iwao@
nagasaki-u.ac.jp
Treatment of the oxazoline 4 with sec-BuLi in diethyl ether
or THF at ꢁ78 ꢂC resulted in the corresponding lateral lithio
species as a characteristic burgundy red solution, which
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.092

K. Uchida et al. / Tetrahedron 63 (2007) 7178–7186
7179
O
i-Pr
O
1. sec-BuLi, Et2O, -78 °C
2. TMEDA
3. R-CHO
O
i-Pr
N
TFA, THF, water
N
O
0 °C, 24 h
R
up to 97% ee
HO
R
1
2
3
up to 84% de
Scheme 1.
Table 1. Addition of laterally lithiated oxazoline 4 to p-tolualdehyde
MeO
O
MeO
O
S
S
i-Pr
i-Pr
N
N
MeO
O
S
i-Pr 1. sec-BuLi (1.2 eq), solvent, -78 °C, 1 h
+
N
2. additive (1.5 eq), -78 °C, 1 h
3. p-tolualdehyde (1.0 eq), -78 °C, 1 h then r.t.
S
R
HO
HO
5b (S,R)
4
5a (S,S)
Entry
Solvent
Additive
Yielda (%)
dr (5a/5b)b
1
2
3
4
5
Et2O
THF
Et2O
Et2O
THF
None
None
TMEDA
PMDTAc
tert-BuOK
80
78
70
56
75
1:1.3
1.1:1
1:1.1
1:1.2
1:1
a
Isolated yield.
Determined by HPLC analysis (Daicel Chiralpak AD-H).
N,N,N0,N00,N00-Pentamethyldiethylenetriamine.
b
c
upon treatment with p-tolualdehyde afforded the addition
product 5 after chromatographic purification over Chroma-
torex NH-DM1020 silica gel. Purification over normal silica
gel caused considerable decomposition of 5 to the corre-
sponding 3,4-dihydroisocoumarin (vide infra). The diaste-
reomer ratio 5a:5b was determined by HPLC analysis. As
shown in Table 1, the stereoselectivities of this reaction are
disappointingly low even in the presence of Lewis basic
ligands including TMEDA. This is in sharp contrast to the
results observed in a similar reaction of the parental oxazo-
line 1. Although the reason for the low selectivity is not
clear, it is reasonable to assume that the methoxy group ad-
jacent to the oxazoline ring in the lithiated 4 interferes to
keep 4 from taking the rigid eight-membered ring transition
state for the stereoselective addition proposed by us.6
HPLC analysis of the supernatant. It was found that (S,S)-dia-
stereomer 5a cyclized to the corresponding 3,4-dihydroiso-
coumarin 6a faster than (S,R)-diastereomer 5b. The time
dependence of ee of the cyclized 6a and that of de of the
unreacted 5b is shown in Figure 2. The ee of 6a was quite
high at the initial stage of the reaction such as 90% ee
after 9 h. On the other hand, de of 5b increased up to
100% after 36 h. These results suggested both enantiomers
of 3-substituted 8-methoxy-3,4-dihydroisocoumarins could
be produced in good optical purity by means of this dia-
stereomer-selective lactonization technique even if the
diastereomer ratio of the starting adduct is low. The
selectivity can be accounted for by the gauche interaction
between two aromatic rings in the transition state of the
cyclization. A similar rationale has been proposed in the
previous paper.6
2.2. Diastereomer-selective lactonization of the addition
product 5
In practice, both enantiomers of the 3,4-dihydroisocoumar-
ins 6a and 6b were prepared as follows (Scheme 2). The
addition product 5 was treated with silica gel in dichloro-
methane at 0 ꢂC for 30 h. After column chromatography,
(S)-3,4-dihydroisocoumarin 6a (75% ee) and unreacted
(S,R)-adduct 5b (98% de) were isolated in 43% and 42%
yields, respectively. The recovered 5b was converted to the
corresponding (R)-3,4-dihydroisocoumarin 6b (96% ee) by
treatment with silica gel in dichloromethane at 30 ꢂC for
4 days in 93% yield.
In order to produce an enantiomerically enriched 8-me-
thoxy-3,4-dihydroisocoumarin 6, we next pursued the dia-
stereomer-selective lactonization of the addition product 5.
Thus, 5 was treated with trifluoroacetic acid in aqueous
THF at 0 ꢂC for 24 h to effect lactonization. Under these
previously established conditions,6 the cyclization was ex-
tremely slow and the unreacted starting material 5 was re-
covered. The slow cyclization may be accounted for by
stabilization of the N-protonated oxazoline through intramo-
lecular hydrogen bonding to the ortho-methoxy group. As
mentioned briefly in Section 2.1, we observed considerable
lactonization took place during the chromatographic purifi-
cation of 5 on silica gel. Thus, we examined the silica gel-
catalyzed cyclization of 5. The mixture of 5 (5a/5b¼1:1.3)
and silica gel (Merck Silica gel 60) in dichloromethane
was stirred at 0 ꢂC and the reaction was monitored by
2.3. Determination of the absolute configuration
of 3,4-dihydroisocoumarin 6b
The absolute configuration of 3,4-dihydroisocoumarin 6b
was determined by the sequence shown in Scheme 3. The
compound 6b was treated with 1 equiv of BBr3 to give de-
methylated compound 7 in 87% yield. The hydroxy group

7180
K. Uchida et al. / Tetrahedron 63 (2007) 7178–7186
Figure 2. Silica gel-catalyzed lactonization of 5.
MeO
O
S
MeO
O
S
i-Pr
i-Pr
MeO
O
MeO
O
N
N
silica gel, CH2Cl2
0 °C, 30 h
silica gel, CH2Cl2
30 °C, 4 d
O
O
+
R
S
R
HO
HO
5
6a
6b
5b
42%, 98% de
5a:5b= 1:1.3
Scheme 2. Diastereomer-selective lactonization of 5.
43%, 75% ee
93%, 96% ee
MeO
O
HO
O
TfO
O
O
O
O
O
O
(a)
(b)
(c)
6b
7
8
9
[ ]23 +124 (c 1.15, methanol)
D
Scheme 3. Reagents and conditions: (a) BBr3 (1.0 equiv), CH2Cl2, ꢁ78 ꢂC, 3 h then 0 ꢂC, 1 h (87%, 96% ee); (b) (1) Tf2O (1.5 equiv), pyridine, 0 ꢂC, 1 h then
rt, 19 h, (2) Tf2O (1.5 equiv), rt, 24 h (77%, 96% ee); (c) Pd(OAc)2 (5 mol %), dppf (5 mol %), Et3SiH (2.5 equiv), DMF, 60 ꢂC, 30 min (97%, 96% ee).
of 7 was trifluoromethanesulfonated with Tf2O in pyridine to
generate 8. Finally, the trifluoromethanesulfonyloxy group
of 8 was removed by hydrogenolysis using Et3SiH in the
presence of Pd(OAc)2 and 1,10-bis(diphenylphosphino)fer-
rocene (dppf)7 to give 9. The absolute configuration of 9
was found to be R by chiroptical comparison with previously
reported data.6 Thus, the absolute configuration of 6b was
determined to be R.
at ꢁ78 ꢂC in diethyl ether followed by quenching with 1-tet-
radecanal produced the addition product 10 in 65% yield.
The diastereomer ratio was determined to be 1.1:1 by
HPLC analysis. The addition product 10 was treated with sil-
ica gel in dichloromethane at 0 ꢂC for 30 h to give 11a (64%
ee) and 10b (99% de) in 64% and 34%, respectively. Further
treatment of 10b with silica gel in dichloromethane at 30 ꢂC
for 4 days afforded 11b (98% ee) in 98% yield. Final de-
methylation of 11a and 11b with BBr3 gave the desired
products 12a and 12b, respectively, without loss of optical
purity. The absolute configurations of these products were
determined by chiroptical comparison with previously
established data.8
2.4. Asymmetric synthesis of the natural products 12
and 16
Next, we applied the aforementioned method for asymmet-
ric synthesis of 3,4-dihydroisocoumarin natural products
having an alkyl or aryl substituent at C-3. At first, 8-
hydroxy-3-(1-tridecyl)-3,4-dihydroisocoumarin (12), which
was isolated from Ginkgo biloba L., was selected as a target.8
The synthesis of both enantiomers of 12 is shown in
Scheme 4. Lateral lithiation of oxazoline 4 using sec-BuLi
Phyllodulcin (16) is a sweet component of Amacha (Hydran-
gea Dulcis Folium), a natural medicine indigenous to Japan,
produced from the leaves of Hydrangea macrophylla Ser-
inge var. thumbergii Makino.9 It has been reported that
(R)-enantiomer 16b exhibits an intensely sweet taste, while

K. Uchida et al. / Tetrahedron 63 (2007) 7178–7186
MeO
7181
MeO
O
S
O
S
MeO
O
MeO
O
i-Pr
i-Pr
N
N
(b)
(c)
(a)
O
+
O
4
S
(CH2)12CH3
(CH2)12CH3
R
S
HO
10
(CH2)12CH3
HO
(CH2)12CH3
10b
11a
(d)
11b
(d)
HO
O
HO
O
O
O
(CH2)12CH3
(CH2)12CH3
R
S
12a
12b
Scheme 4. Synthesis of (R)- and (S)-8-hydroxy-3-(1-tridecyl)-3,4-dihydroisocoumarins 12a,b. Reagents and conditions: (a) (1) sec-BuLi (1.2 equiv), Et2O,
ꢁ78 ꢂC, 1 h, (2) 1-tetradecanal, ꢁ78 ꢂC, 1 h then rt [65%, (S,R):(S,S)¼1.1:1]; (b) silica gel, CH2Cl2, 0 ꢂC, 30 h (11a: 64%, 64% ee; 10b: 34%, 99% de);
(c) silica gel, CH2Cl2, 30 ꢂC, 4 days (98%, 98% ee); (d) BBr3, CH2Cl2, ꢁ78 ꢂC, 10 min then 0 ꢂC, 15 min (12a: 87%, 64% ee; 12b: 95%, 98% ee).
the (S)-enantiomer 16a is completely tasteless.10 In spite of
its simple structure, asymmetric synthesis of phyllodulcin is
rather problematic due to easy epimerization at C-3. The first
enantioselective synthesis was reported by Napolitano in
1996.11 Our synthesis of optically active phyllodulcin is
shown in Scheme 5. The laterally lithiated 4 was reacted
with O-methoxymethylisovanillin in a similar manner as
described above to give 13 in 78% yield as a 1:1.2 dia-
stereomeric mixture. Treatment of 13 with silica gel in
dichloromethane at 0 ꢂC for 30 h produced (S)-3,4-dihydro-
isocoumarin 14a (49% ee) and unreacted (S,R)-adduct 13b
(97% de) in 57% and 31% yields, respectively. Treatment
of 13b with silica gel in dichloromethane at 30 ꢂC for 4
days gave (R)-3,4-dihydroisocoumarin 14b (91% ee) in
73% yield. An attempted simultaneous deprotection of
methyl and methoxymethyl groups of 14b with BBr3
afforded only completely racemized (ꢀ)-phyllodulcin even
at ꢁ78 ꢂC. After an extensive survey for deprotection condi-
tions (BCl3, TMSI, TMSBr, Me2NCH2CH2SNa/DMF12), we
found that the methyl group of 14b could be removed by
heating with lithium chloride in dry DMF13 with minimum
racemization to produce 15b (83% ee). Final deprotection
of the methoxymethyl group with HCl in methanol produced
(R)-phyllodulcin (16b) (83% ee) in quantitative yield. The
(S)-phyllodulcin 16a was also prepared in a similar manner
from 14a albeit in low optical purity.14
3. Conclusion
The addition of the laterally lithiated 2-(2-methoxy-6-methyl-
phenyl)oxazoline 4 to aldehydes proceeded non-stereose-
lectively. However, lactonization of the addition products
over silica gel proceeded diastereomer-selectively. The com-
bination of these reactions allowed both enantiomers of
3-substituted 8-hydroxy-3,4-dihydroisocoumarins to be pro-
duced including natural products in modest to good optical
purity.
MeO
O
S
MeO
O
S
MeO
O
MeO
O
i-Pr
i-Pr
N
N
(a)
(b)
OMOM
OMe
(c)
OMOM
OMe
O
+
O
4
OMOM
OMOM
OMe
R
R
S
HO
13
HO
13b
14a
(d)
14b
(d)
OMe
HO
O
HO
O
O
O
OMOM
OMe
OMOM
OMe
R
S
15a
15b
(e)
(e)
HO
O
HO
O
O
O
OH
OH
S
R
16a
16b
OMe
OMe
Scheme 5. Synthesis of (S)- and (R)-phyllodulcins 16a,b. Reagents and conditions: (a) (1) sec-BuLi (1.2 equiv), Et2O, ꢁ78 ꢂC, 1 h, (2) O-methoxymethyliso-
vanillin, ꢁ78 ꢂC, 1 h then rt [78%, (S,S):(S,R)¼1:1.2]; (b) silica gel, CH2Cl2, 0 ꢂC, 30 h (14a: 57%, 49% ee; 13b: 31%, 97% de); (c) silica gel, CH2Cl2, 30 ꢂC, 4
days (73%, 91% ee); (d) LiCl (3 equiv), DMF, 150 ꢂC, 17 h (15a: 41%, 43% ee; 15b: 39%, 83% ee); (e) concd HCl, MeOH, rt, 3 h (16a: 98%, 42% ee; 16b:
quant., 83% ee).

7182
K. Uchida et al. / Tetrahedron 63 (2007) 7178–7186
4. Experimental
4.2.1. 2-{2-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-3-
methoxyphenyl}-1-(p-tolyl)ethanol (5). Under an argon
atmosphere, a hexane–cyclohexane solution of sec-butyl-
lithium (4.8 mmol) was added dropwise to a solution of
the oxazoline 4 (933 mg, 4.0 mmol) in diethyl ether
(20 mL) at ꢁ78 ꢂC. After being stirred for 1 h, a solution
of p-tolualdehyde (481 mg, 4.0 mmol) in diethyl ether
(10 mL) was added and the mixture was stirred for an addi-
tional 1 h at ꢁ78 ꢂC. The reaction mixture was allowed to
warm to room temperature and quenched with water. The
products were extracted with diethyl ether and the extract
was washed successively with water and brine, dried over
Na2SO4, and evaporated. The residue was purified by flash
chromatography over Chromatorex NH-DM1020 silica gel
(hexane–ethyl acetate¼3:1) to give 1.13 g (80%) of 5 (5a/
5b¼1:1.3). The diastereomer ratio was determined by
HPLC analysis (Daicel Chiralpak AD-H, hexane–i-PrOH¼
1H NMR (400 MHz, CDCl3): d 1.00 (d, J¼6.7 Hz, 1.31H,
(S,S)-isomer), 1.01 (d, J¼6.6 Hz, 1.69H, (S,R)-isomer),
1.12 (d, J¼6.6 Hz, 1.69H, (S,R)-isomer), 1.13 (d, J¼
6.7 Hz, 1.31H, (S,S)-isomer), 1.83–1.97 (m, 1H, both iso-
mers), 2.34 (s, 3H, both isomers), 2.92–3.10 (m, 2H, both
isomers), 3.83 (s, 3H, both isomers), 4.08–4.22 (m, 2H,
both isomers), 4.46–4.56 (m, 1H, both isomers), 4.83 (dd,
J¼3.6 and 9.0 Hz, 0.56H, (S,R)-isomer), 4.90 (dd, J¼4.3
and 8.1 Hz, 0.44H, (S,S)-isomer), 6.02 (br s, 0.44H, (S,S)-
isomer), 6.62 (br s, 0.56H, (S,R)-isomer), 6.77 (d, J¼
7.7 Hz, 0.44H, (S,S)-isomer), 6.81 (d, J¼8.3 Hz, 0.44H,
(S,S)-isomer), 6.81 (d, J¼8.3 Hz, 0.56H, (S,R)-isomer),
6.87 (d, J¼7.7 Hz, 0.56H, (S,R)-isomer), 7.14 (d, J¼
7.4 Hz, 0.87H, (S,S)-isomer), 7.16 (d, J¼7.4 Hz, 1.13H,
(S,R)-isomer), 7.26–7.36 (m, 3H, both isomers). HREIMS
m/z calcd for C22H27NO3 (M+): 353.1991; found: 353.1972.
4.1. General
Melting points were determined with a Yanagimoto micro
melting points apparatus and are uncorrected. IR spectra
were obtained with a Perkin–Elmer System 2000 instru-
ment. NMR spectra were recorded on a JEOL JNM-
AL400 instrument (400 MHz for 1H and 100 MHz for 13C)
using tetramethylsilane as an internal standard. High-resolu-
tion mass spectra were recorded on a JEOL JMS-700N spec-
trometer. HPLC analyses were performed on a Shimadzu
LC-6A apparatus. Optical rotations were measured on
a JASCO DPI-1000 digital polarimeter at ambient tempera-
ture. Column chromatography was conducted on Silica Gel
60N, 63–210 mm (Kanto Chemical Co., Inc.) or Chroma-
torex NH-DM1020 silica gel (Fuji Silysia Chemical Ltd.).
sec-Butyllithium was purchased from Kanto Chemical
Co., Inc. and used after titration with 2,5-dimethoxybenzyl
alcohol. Dry diethyl ether and THF were distilled from
Na-benzophenone ketyl under argon immediately before
use.
8:2). IR (KBr): 3222, 1655, 1583, 1467, 1268, 1081 cmꢁ1
;
4.1.1. (S)-4-Isopropyl-2-(2-methoxy-6-methylphenyl)-
4,5-dihydrooxazole (4). Thionyl chloride (9.2 mL, ca.
126 mmol) was added as a neat liquid to 2-methoxy-6-
methylbenzoic acid15 (3.00 g, 18.1 mmol) at 0 ꢂC. After
being stirred for 10 min, the mixture was allowed to warm
to room temperature, stirred for 8 h, and evaporated. The
residual thionyl chloride was removed by azeotropic treat-
ment with toluene to give 2-methoxy-6-methylbenzoyl
chloride. The crude acid chloride was dissolved in dichloro-
methane (10 mL) and the solution was added dropwise to
a mixture of (S)-valinol (1.86 g, 18.1 mmol) and triethyl-
amine (8.81 mL, 63.2 mmol) in dichloromethane (80 mL)
at 0 ꢂC. After being stirred for 2 h, the mixture was allowed
to warm to room temperature, stirred for 1 h, and cooled
to 0 ꢂC again. Methanesulfonyl chloride (1.54 mL,
19.9 mmol) was added as a neat liquid to the reaction mix-
ture. After being stirred for 1 h, the mixture was allowed to
warm to room temperature and stirred for 15 h. The mixture
was quenched with 10% aqueous NaOH and the product was
extracted with dichloromethane. The extract was washed
successively with 10% aqueous NaOH and brine, dried
over Na2SO4, and evaporated. The residue was purified by
bulb-to-bulb distillation (115–120 ꢂC/0.6 mmHg) to give 4
as colorless oil (3.80 g, 90%). IR (neat): 1671, 1586, 1472,
1270, 1087, 1052, 954 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 1.00 (d, J¼6.8 Hz, 3H), 1.05 (d, J¼6.8 Hz, 3H), 1.84–
1.96 (m, 1H), 2.32 (s, 3H), 3.79 (s, 3H), 4.10–4.20 (m, 2H),
4.41 (dd, J¼7.4 and 8.9 Hz, 1H), 6.73 (d, J¼8.0 Hz, 1H),
6.80 (d, J¼8.0 Hz, 1H), 7.22 (t, J¼8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 18.35, 18.83, 19.39, 32.61, 55.81,
69.76, 72.82, 108.18, 118.78, 122.11, 130.14, 138.51,
157.68, 161.58; [a]2D6 ꢁ64.3 (c 1.00, MeOH). HREIMS m/z
calcd for C14H19NO2 (M+): 233.1416; found: 233.1399.
4.3. Silica gel-catalyzed lactonization of 5:
HPLC analysis
The results shown in Figure 2 were obtained as follows. The
addition product 5 (5a/5b¼1:1.3) (50 mg, 0.141 mmol) and
2,3-dimethylnaphthalene (20.0 mg, 0.128 mmol: an internal
standard) were dissolved in dichloromethane (5.0 mL) and
the mixture was cooled to 0 ꢂC. Silica gel (Merck Silica
gel 60) (200 mg) was added portionwise to this mixture
and the progress of the lactonization was monitored by
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH¼8:2). An
aliquot of 1 mL of the supernatant was used for each analysis.
Retention times of the reactants and the products are as fol-
lows: 5a: 8.7 min; 5b: 19.8 min; 6a: 18.2 min; 6b: 22.5 min.
The absolute yields could not be estimated because consider-
able amounts of these compounds were absorbed on silica
gel. Figure 2 shows only de of 5 and ee of 6 dissolved in
supernatant.
4.4. Diastereomer-selective lactonization of 5
The addition product 5 (5a/5b¼1:1.3) (342 mg, 0.967
mmol) was dissolved in dichloromethane (35 mL) and the
mixture was cooled to 0 ꢂC. Silica gel (Merck Silica gel
60) (1.40 g) was added portionwise to this mixture. After
being stirred for 30 h at 0 ꢂC, the reaction mixture was
quenched with triethylamine (3.5 mL). Silica gel was re-
moved by filtration over a pad of Celite and washed with
4.2. Addition of the laterally lithiated oxazoline 4
to p-tolualdehyde
The reactions summarized in Table 1 were conducted in
a similar manner as described in the previous paper.6
Preparation of 5 is shown below.

K. Uchida et al. / Tetrahedron 63 (2007) 7178–7186
7183
ethyl acetate. The filtrate was evaporated under reduced
pressure and the residue was purified by flash chromato-
graphy over silica gel 60N (dichloromethane–ethyl
acetate¼20:1 to ethyl acetate containing 1% triethylamine)
to give 3,4-dihydroisocoumarin 6a (111 mg, 43%) and un-
cyclized 5b (143 mg, 42%).
0 ꢂC and stirred for an additional 1 h. The mixture was
quenched with saturated aqueous NaHCO3 and extracted
with dichloromethane. The extract was washed with brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography over
Silica Gel 60N (hexane–ethyl acetate¼3:1–1:1) to give 7
as colorless solid (41.0 mg, 87%). HPLC (Daicel Chiralcel
OD-H, hexane–i-PrOH¼9:1): 96% ee. Mp 104.0–
106.0 ꢂC; IR (KBr): 3123, 1671, 1620, 1463, 1226, 1208,
4.4.1. (S)-8-Methoxy-3-(p-tolyl)-3,4-dihydroisocoumarin
(6a). Colorless solid. HPLC (Daicel Chiralpak AD-H, hex-
ane–i-PrOH¼8:2): 75% ee. Mp 116.0–119.0 ꢂC; IR (KBr):
1
1115, 1036 cmꢁ1; H NMR (400 MHz, CDCl3): d 2.37 (s,
1732, 1596, 1477, 1239, 1075, 1056 cmꢁ1
;
1H NMR
3H), 3.10 (dd, J¼3.2 and 16.5 Hz, 1H), 3.30 (dd, J¼12.1
and 16.5 Hz, 1H), 5.55 (dd, J¼3.2 and 12.1 Hz, 1H), 6.73
(d, J¼7.4 Hz, 1H), 6.92 (d, J¼8.3 Hz, 1H), 7.22 (d, J¼
8.1 Hz, 2H), 7.34 (d, J¼8.1 Hz, 2H), 7.43 (dd, J¼7.4 and
8.3 Hz, 1H), 11.01 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 21.20, 35.12, 80.83, 108.50, 116.40, 117.94, 126.13,
129.43, 134.99, 136.31, 138.81, 139.39, 162.29, 169.83;
[a]2D4 +95.0 (c 0.730, MeOH). HREIMS m/z calcd for
C16H14O3 (M+): 254.0943; found: 254.0930.
(400 MHz, CDCl3): d 2.36 (s, 3H), 3.03 (dd, J¼2.8 and
16.2 Hz, 1H), 3.25 (dd, J¼12.0 and 16.2 Hz, 1H), 3.96 (s,
3H), 5.38 (dd, J¼2.8 and 12.0 Hz, 1H), 6.83 (d, J¼7.5 Hz,
1H), 6.94 (d, J¼8.5 Hz, 1H), 7.19 (d, J¼8.0 Hz, 2H), 7.35
(d, J¼8.0 Hz, 2H), 7.47 (dd, J¼7.5 and 8.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d 21.17, 36.72, 56.21, 79.02,
111.09, 113.90, 119.22, 126.19, 129.25, 134.59, 135.61,
138.33, 141.81, 161.30, 162.34; [a]2D5 ꢁ140 (c 1.00,
MeOH). HREIMS m/z calcd for C17H16O3 (M+):
268.1099; found: 268.1090.
4.5.2. (R)-3-(p-Tolyl)-8-trifluoromethanesulfonyloxy-3,4-
dihydroisocoumarin (8). Under an argon atmosphere, tri-
fluoromethanesulfonic anhydride (37.7 mL, 0.224 mmol)
was added as a neat liquid to a solution of 7 (38.0 mg,
0.149 mmol) in pyridine (3.0 mL) at 0 ꢂC. After being
stirred for 1 h, the reaction mixture was allowed to warm
to room temperature and stirred for 19 h. Additionaltrifluoro-
methanesulfonic anhydride (37.7 mL, 0.224 mmol) was
added and the mixture was stirred for further 24 h at room
temperature. The mixture was quenched with 2 M aqueous
HCl and the product was extracted with ethyl acetate. The
extract was washed successively with 2 M aqueous HCl, wa-
ter, and brine, and dried over Na2SO4, and evaporated under
reduced pressure. The residue was purified by column chro-
matography over Silica Gel 60N (toluene to toluene–ethyl
acetate¼20:1) to give 8 as colorless solid (44.7 mg, 77%).
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH¼8:2):
96% ee. Mp 159.5–161.0 ꢂC; IR (KBr): 1723, 1614, 1431,
4.4.2. (R)-2-{2-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-
3-methoxyphenyl}-1-(p-tolyl)ethanol (5b). Colorless
solid. HPLC (Daicel Chiralpak AD-H, hexane–i-
PrOH¼8:2): 98% de. Mp 118.0–122.0 ꢂC; IR (KBr): 3129,
1
1651, 1583, 1470, 1269, 1087 cmꢁ1; H NMR (400 MHz,
CDCl3): d 1.01 (d, J¼6.7 Hz, 3H), 1.12 (d, J¼6.7 Hz, 3H),
1.83–1.95 (m, 1H), 2.34 (s, 3H), 2.95 (dd, J¼9.3 and
13.7 Hz, 1H), 3.02 (dd, J¼3.9 and 13.7 Hz, 1H), 3.83 (s,
3H), 4.12 (ddd, J¼6.7, 9.0 and 9.0 Hz, 1H), 4.19 (dd,
J¼8.0 and 9.0 Hz, 1H), 4.49 (dd, J¼8.0 and 9.0 Hz, 1H),
4.83 (dd, J¼3.9 and 9.3 Hz, 1H), 6.62 (br s, 1H), 6.81 (d,
J¼8.4 Hz, 1H), 6.87 (d, J¼7.7 Hz, 1H), 7.16 (d, J¼7.9 Hz,
2H), 7.28 (d, J¼7.9 Hz, 2H), 7.33 (dd, J¼7.7 and 8.4 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 18.72, 19.07, 21.11,
32.89, 43.82, 56.05, 71.38, 72.03, 75.19, 109.28, 118.46,
122.50, 125.44, 128.92, 131.19, 136.38, 140.44, 143.33,
158.35, 164.03; [a]2D5 ꢁ57.7 (c 1.00, MeOH). HREIMS
m/z calcd for C22H27NO3 (M+): 353.1991; found: 353.1980.
1267, 1224, 1141, 1012 cmꢁ1
;
1H NMR (400 MHz,
CDCl3): d 2.37 (s, 3H), 3.18 (dd, J¼3.0 and 16.6 Hz, 1H),
3.35 (dd, J¼11.7 and 16.6 Hz, 1H), 5.51 (dd, J¼3.0 and
11.7 Hz, 1H), 7.21 (d, J¼8.1 Hz, 2H), 7.29 (d, J¼7.9 Hz,
1H), 7.33 (d, J¼8.1 Hz, 2H), 7.35 (d, J¼7.9 Hz, 1H), 7.63
(t, J¼7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.19,
35.98, 79.54, 118.80 (q, J¼321 Hz), 119.11, 122.24,
126.08, 127.79, 129.45, 134.65, 134.72, 138.84, 142.25,
149.42, 160.75; [a]D23 +144 (c 0.500, CHCl3). HREIMS
m/z calcd for C17H13F3O5S (M+): 386.0436; found:
386.0429.
4.4.3. (R)-8-Methoxy-3-(p-tolyl)-3,4-dihydroisocoumarin
(6b). A mixture of the 98% de sample of 5b (120 mg,
0.340 mmol), silica gel (Merck Silica gel 60) (982 mg),
and dichloromethane (12.3 mL) was stirred for 4 days at
30 ꢂC. Silica gel was removed by filtration over a pad of
Celite and washed with ethyl acetate. The filtrate was evap-
orated under reduced pressure and the residue was purified
by column chromatography over silica gel 60N (dichlorome-
thane–ethyl acetate¼20:1) to give 3,4-dihydroisocoumarin
6b (85.0 mg, 93%) as colorless solid. HPLC (Daicel Chiral-
pak AD-H, hexane–i-PrOH¼8:2): 96% ee. Mp 126.0–
128.0 ꢂC; [a]2D5 +185 (c 1.00, MeOH). HREIMS m/z calcd
for C17H16O3 (M+): 268.1099; found: 268.1091.
4.5.3. (R)-3-(p-Tolyl)-3,4-dihydroisocoumarin (9). Under
an argon atmosphere, triethylsilane (40.3 mL, 0.252 mmol)
was added as a neat liquid to a solution of 8 (39.0 mg,
0.100 mmol), Pd(OAc)2 (1.1 mg, 5.1 mmol), and 1,10-bis(di-
phenylphosphino)ferrocene (2.8 mg, 5.1 mmol) in DMF
(2.0 mL) at 60 ꢂC. After being stirred for 30 min, the reac-
tion mixture was cooled to room temperature and diluted
with diethyl ether. The product was washed successively
with water, saturated aqueous NaHCO3, and brine, dried
over Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography over Silica
Gel 60N (hexane–ethyl acetate¼3:1) to give 9 as colorless
solid (23.0 mg, 97%). HPLC (Daicel Chiralpak AD-H,
4.5. Determination of the absolute configuration of 6b
4.5.1. (R)-8-Hydroxy-3-(p-tolyl)-3,4-dihydroisocoumarin
(7). Under an argon atmosphere, a dichloromethane solution
of BBr3 (1.0 M, 186 mL, 0.186 mmol) was added dropwise
to a solution of 6b (50.0 mg, 0.186 mmol) in dichloro-
methane (10 mL) at ꢁ78 ꢂC. After being stirred for 3 h at this
temperature, the reaction mixture was allowed to warm to

7184
K. Uchida et al. / Tetrahedron 63 (2007) 7178–7186
hexane–i-PrOH¼7:3): 96% ee. Mp 93.5–94.5 ꢂC; IR (KBr):
1720, 1605, 1463, 1275, 1121, 1066, 1006 cmꢁ1; 1H NMR
(400 MHz, CDCl3): d 2.37 (s, 3H), 3.11 (dd, J¼3.1 and
16.4 Hz, 1H), 3.33 (dd, J¼12.0 and 16.4 Hz, 1H), 5.52
(dd, J¼3.1 and 12.0 Hz, 1H), 7.21 (d, J¼8.1 Hz, 2H), 7.28
(d, J¼7.6 Hz, 1H), 7.36 (d, J¼8.1 Hz, 2H), 7.42 (t,
J¼7.6 Hz, 1H), 7.56 (dt, J¼1.3 and 7.6 Hz, 1H), 8.15 (d,
J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.19,
35.55, 79.93, 125.22, 126.11, 127.36, 127.83, 129.33,
130.41, 133.85, 135.64, 138.49, 139.05, 165.42; [a]D23
+124 (c 1.15, MeOH) {lit.6 [a]D26 ꢁ132 (c 1.02, MeOH,
>99% ee, (S)-isomer)}. HREIMS m/z calcd for C16H14O2
(M+): 238.0994; found: 238.0972.
3H), 4.33–4.41 (m, 1H), 6.79 (d, J¼7.6 Hz, 1H), 6.90 (d,
J¼8.3 Hz, 1H), 7.43 (dd, J¼7.6 and 8.3 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d 14.09, 22.66, 24.94, 29.32,
29.37, 29.48, 29.54, 29.60, 29.62, 29.62, 29.65, 31.89,
34.44, 34.68, 56.10, 77.73, 110.74, 113.90, 119.08,
134.13, 141.92, 160.94, 162.51; [a]2D6 ꢁ55.0 (c 1.00,
MeOH). HREIMS m/z calcd for C23H36O3 (M+):
360.2664; found: 360.2664.
4.6.2.2. (S)-1-{2-[(S)-4-Isopropyl-4,5-dihydrooxazol-
2-yl]-3-methoxyphenyl}-2-pentadecanol (10b). Colorless
oil. HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH¼30:1):
99% de. IR (KBr): 3277, 1655, 1584, 1467, 1268,
1086 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 0.88 (t,
4.6. Synthesis of (R)- and (S)-8-hydroxy-3-(1-tridecyl)-
3,4-dihydroisocoumarins (12a,b)
J¼6.7 Hz, 3H), 0.97 (d, J¼6.7 Hz, 3H), 1.06 (d, J¼6.7 Hz,
3H), 1.22–1.60 (m, 24H), 1.79–1.91 (m, 1H), 2.68 (dd,
J¼8.9 and 13.5 Hz, 1H), 2.83 (dd, J¼3.5 and 13.5 Hz,
1H), 3.71–3.81 (m, 1H), 3.81 (s, 3H), 4.09 (ddd, J¼6.7,
8.0 and 9.0 Hz, 1H), 4.16 (t, J¼8.0 Hz, 1H), 4.46 (dd, J¼
8.0 and 9.0 Hz, 1H), 5.17 (br s, 1H), 6.79 (d, J¼8.4 Hz,
1H), 6.87 (d, J¼7.7 Hz, 1H), 7.32 (dd, J¼7.7 and 8.4 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 14.12, 18.52, 19.02,
22.70, 25.60, 29.37, 29.67, 29.71, 29.73, 29.83, 31.94,
32.78, 38.47, 40.69, 55.99, 70.93, 72.11, 72.74, 109.00,
118.57, 122.52, 130.97, 140.93, 158.23, 163.45; [a]D26
ꢁ14.5 (c 1.00, MeOH). HREIMS m/z calcd for
C28H47NO3 (M+): 445.3556; found: 445.3549.
4.6.1. 1-{2-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-3-
methoxyphenyl}-2-pentadecanol (10). This compound
was prepared from 4 (700 mg, 3.0 mmol) and 1-tetradeca-
nal16 (637 mg, 3.0 mmol) in a similar manner as described
for 5 in Section 4.2.1. After chromatographic purification
over Chromatorex NH-DM1020 silica gel (hexane–ethyl
acetate¼5:1–3:1), 10 was obtained as colorless semi-solid
(871 mg, 65%). HPLC (Daicel Chiralpak AD-H, hexane–i-
PrOH¼30:1): (S,R):(S,S)¼1.1:1. IR (KBr): 3344, 1669,
1582, 1467, 1273, 1088 cmꢁ1
;
1H NMR (400 MHz,
CDCl3): d 0.88 (t, J¼6.8 Hz, 3H, both isomers), 0.97 (d,
J¼6.7 Hz, 1.44H, (S,S)-isomer), 1.00 (d, J¼6.7 Hz, 1.56H,
(S,R)-isomer), 1.06 (d, J¼6.7 Hz, 1.44H, (S,S)-isomer),
1.10 (d, J¼6.7 Hz, 1.56H, (S,R)-isomer), 1.20–1.60 (m,
24H, both isomers), 1.79–1.91 (m, 1H, both isomers), 2.68
(dd, J¼8.9 and 13.4 Hz, 0.48H, (S,S)-isomer), 2.73 (dd,
J¼8.6 and 13.4 Hz, 0.52H, (S,R)-isomer), 2.83 (dd, J¼3.6
and 13.4 Hz, 0.48H, (S,S)-isomer), 2.86 (dd, J¼3.8 and
13.4 Hz, 0.52H, (S,R)-isomer), 3.70–3.80 (m, 1H, both iso-
mers), 3.81 (s, 3H, both isomers), 4.05–4.19 (m, 2H, both
isomers), 4.47 (dd, J¼8.1 and 9.3 Hz, 0.48H, (S,S)-isomer),
4.49 (dd, J¼7.8 and 9.2 Hz, 0.52H, (S,R)-isomer), 5.08 (br s,
0.52H, (S,R)-isomer), 5.16 (br s, 0.48H, (S,S)-isomer), 6.79
(d, J¼8.4 Hz, 1H, both isomers), 6.86 (d, J¼7.8 Hz,
0.48H, (S,S)-isomer), 6.87 (d, J¼7.8 Hz, 0.52H, (S,R)-iso-
mer), 7.32 (dd, J¼7.8 and 8.4 Hz, 1H, both isomers).
HREIMS m/z calcd for C28H47NO3 (M+): 445.3556; found:
445.3547.
4.6.3. (S)-8-Methoxy-3-(1-tridecyl)-3,4-dihydroisocou-
marin (11b). This compound was prepared from 10b
(91.2 mg, 0.205 mmol) in a similar manner as described
for 6b in Section 4.4.3. After chromatographic purification
over Silica Gel 60N (hexane–ethyl acetate¼3:1), 11b was
obtained as colorless solid (72.2 mg, 98%). HPLC (Daicel
Chiralpak AD-H, hexane–i-PrOH¼9:1): 98% ee. Mp 78.0–
79.0 ꢂC; [a]2D5 +87.2 (c 1.00, MeOH). HREIMS m/z calcd
for C23H36O3 (M+): 360.2664; found: 360.2661.
4.6.4. (R)-8-Hydroxy-3-(1-tridecyl)-3,4-dihydroisocou-
marin (12a). Under an argon atmosphere, a dichloromethane
solution of BBr3 (1.0 M, 624 mL, 0.624 mmol) was added
dropwise to a solution of 11a (150 mg, 0.416 mmol) in di-
chloromethane (10 mL) at ꢁ78 ꢂC. After being stirred for
10 min at this temperature, the reaction mixture was allowed
to warm to 0 ꢂC and stirred for an additional 15 min. The
mixture was quenched with water and extracted with di-
chloromethane. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography over Silica
Gel 60N (hexane–ethyl acetate¼3:1) to give 12a as colorless
solid (126 mg, 87%). HPLC (Daicel Chiralcel OD-H, hex-
ane–i-PrOH¼200:1): 64% ee. Recrystallization from diethyl
ether–hexane gave an optically pure sample as colorless nee-
dles. Mp 91.0–92.0 ꢂC; IR (KBr): 1655, 1618, 1465,
4.6.2. Diastereomer-selective lactonization of 10. A mix-
ture of 10 (504 mg, 1.13 mmol), silica gel (Merck Silica
gel 60) (1.60 g), and dichloromethane (40 mL) was stirred
for 30 h at 0 ꢂC and worked up in a similar manner as de-
scribed in Section 4.4. After chromatographic purification
over Silica Gel 60N (toluene–ethyl acetate¼5:1 to ethyl ace-
tate containing 1% triethylamine), 11a (261 mg, 64%) and
10b (173 mg, 34%) were isolated.
1
1242 cmꢁ1; H NMR (400 MHz, CDCl3): d 0.88 (t, J¼
4.6.2.1. (R)-8-Methoxy-3-(1-tridecyl)-3,4-dihydroiso-
coumarin (11a). Colorless solid. HPLC (Daicel Chiralpak
AD-H, hexane–i-PrOH¼9:1): 64% ee. Mp 73.0–75.0 ꢂC;
6.8 Hz, 3H), 1.21–1.39 (m, 20H), 1.39–1.60 (m, 2H),
1.66–1.77 (m, 1H), 1.83–1.93 (m, 1H), 2.88–2.99 (m, 2H),
4.53–4.61 (m, 1H), 6.69 (d, J¼7.4 Hz, 1H), 6.88 (d, J¼
8.4 Hz, 1H), 7.40 (dd, J¼7.4 and 8.4 Hz, 1H), 11.04 (s,
1H); 13C NMR (100 MHz, CDCl3): d 14.12, 22.70, 24.84,
29.36, 29.47, 29.55, 29.64, 29.66, 29.69, 31.93, 32.95,
34.81, 79.77, 108.55, 116.17, 117.92, 136.07, 139.55,
162.18, 170.00; [a]D25 ꢁ34.4 (c 1.00, CHCl3, >99% ee)
1
IR (KBr): 1733, 1596, 1484, 1220, 1091 cmꢁ1; H NMR
(400 MHz, CDCl3): d 0.88 (t, J¼6.7 Hz, 3H), 1.23–1.37
(m, 20H), 1.37–1.48 (m, 1H), 1.48–1.60 (m, 1H), 1.60–
1.71 (m, 1H), 1.71–1.89 (m, 1H), 2.83 (dd, J¼3.5 and
16.0 Hz, 1H), 2.90 (dd, J¼10.7 and 16.0 Hz, 1H), 3.94 (s,

K. Uchida et al. / Tetrahedron 63 (2007) 7178–7186
7185
{lit.8 [a]D23 ꢁ31 (c 1, CHCl3): (R)-isomer}. HREIMS m/z
solid. HPLC (Daicel Chiralcel OD-H, hexane–EtOH¼7:3):
calcd for C22H34O3 (M+): 346.2508; found: 346.2494.
49% ee. Mp 97.5–99.0 ꢂC; IR (KBr): 1719, 1596, 1521,
1476, 1237, 1082, 997 cmꢁ1
;
1H NMR (400 MHz,
4.6.5. (S)-8-Hydroxy-3-(1-tridecyl)-3,4-dihydroisocou-
marin (12b). This compound was prepared from 11b
(50 mg, 0.139 mmol) in a similar manner as described for
12a. After chromatographic purification over Silica Gel
60N (hexane–ethyl acetate¼3:1), 12b was obtained as color-
less solid (45.6 mg, 95%). HPLC (Daicel Chiralcel OD-H,
hexane–i-PrOH¼200:1): 98% ee. Recrystallization from di-
ethyl ether–hexane gave an optically pure sample as color-
less needles. Mp 91.0–92.0 ꢂC; [a]D25 +34.7 (c 0.705,
CHCl3, >99% ee) {lit.8 [a]D23 +32 (c 1, CHCl3): (S)-isomer}.
HREIMS m/z calcd for C22H34O3 (M+): 346.2508; found:
346.2496.
CDCl3): d 3.04 (dd, J¼2.7 and 16.2 Hz, 1H), 3.30 (dd,
J¼12.0 and 16.2 Hz, 1H), 3.53 (s, 3H), 3.90 (s, 3H), 3.97
(s, 3H), 5.24 (d, J¼6.8 Hz, 1H), 5.27 (d, J¼6.8 Hz, 1H),
5.35 (dd, J¼2.7 and 12.0 Hz, 1H), 6.85 (d, J¼7.5 Hz, 1H),
6.92 (d, J¼8.3 Hz, 1H), 6.96 (d, J¼8.6 Hz, 1H), 7.11 (dd,
J¼2.1 and 8.3 Hz, 1H), 7.25 (d, J¼2.1 Hz, 1H), 7.47 (dd,
J¼7.5 and 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 36.58, 56.00, 56.21, 56.31, 78.94, 95.66, 111.08, 111.66,
113.83, 114.81, 119.23, 120.64, 131.14, 134.62, 141.81,
146.55, 150.03, 161.30, 162.39; [a]2D6 ꢁ68.8 (c 1.00,
MeOH). HREIMS m/z calcd for C19H20O6 (M+):
344.1260; found: 344.1257.
4.7. Synthesis of (S)- and (R)-phyllodulcins (16a,b)
4.7.2.2. (R)-2-{2-[(S)-4-Isopropyl-4,5-dihydrooxazol-
2-yl]-3-methoxyphenyl}-1-(4-methoxy-3-methoxymeth-
oxyphenyl)ethanol (13b). Colorless semi-solid. HPLC
(Daicel Chiralpak AD-H, hexane–i-PrOH¼1:1): 97% de.
IR (KBr): 3387, 1655, 1584, 1509, 1467, 1265, 1080,
4.7.1. 2-{2-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-3-
methoxyphenyl}-1-(4-methoxy-3-methoxymethoxyphe-
nyl)ethanol (13). This compound was prepared from 4 (933
mg, 4.0 mmol) and O-methoxymethylisovanillin17 (785 mg,
4.0 mmol) in a similar manner as described for 5 in Section
4.2.1. After chromatographic purification over Chromatorex
NH-DM1020 silica gel (hexane–ethyl acetate¼1:1), 13 was
obtained as colorless semi-solid (1.35 g, 78%). HPLC (Dai-
cel Chiralpak AD-H, hexane–i-PrOH¼1:1): (S,S):(S,R)¼
1:1.2. IR (KBr): 3172, 1649, 1583, 1515, 1475, 1270,
1010 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.01 (d,
;
J¼6.7 Hz, 3H), 1.12 (d, J¼6.7 Hz, 3H), 1.83–1.94 (m,
1H), 2.93–3.04 (m, 2H), 3.53 (s, 3H), 3.83 (s, 3H), 3.87 (s,
3H), 4.13–4.23 (m, 2H), 4.47–4.57 (m, 1H), 4.80 (dd,
J¼4.7 and 9.0 Hz, 1H), 5.22 (d, J¼6.7 Hz, 1H), 5.27 (d,
J¼6.7 Hz, 1H), 6.80 (br s, 1H), 6.82 (d, J¼8.4 Hz, 1H),
6.87 (d, J¼7.7 Hz, 1H), 6.87 (d, J¼8.3 Hz, 1H), 7.00 (dd,
J¼1.9 and 8.3 Hz, 1H), 7.20 (d, J¼1.9 Hz, 1H), 7.33 (dd,
J¼7.7 and 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 18.73, 18.99, 32.96, 43.75, 56.02, 56.05, 56.20, 71.48,
71.88, 74.97, 95.61, 109.29, 111.54, 113.88, 118.43,
119.38, 122.50, 131.19, 139.24, 140.26, 146.57, 148.68,
158.34, 164.05; [a]2D6 ꢁ32.1 (c 1.00, MeOH). HREIMS
m/z calcd for C24H31NO6 (M+): 429.2151; found: 429.2154.
1
1083 cmꢁ1; H NMR (400 MHz, CDCl3): d 1.00 (d, J¼
6.7 Hz, 1.33H, (S,S)-isomer), 1.02 (d, J¼6.5 Hz, 1.67H,
(S,R)-isomer), 1.13 (d, J¼6.5 Hz, 1.67H, (S,R)-isomer),
1.14 (d, J¼6.7 Hz, 1.33H, (S,S)-isomer), 1.84–1.98 (m, 1H,
both isomers), 2.93–3.10 (m, 2H, both isomers), 3.52 (s,
1.33H, (S,S)-isomer), 3.53 (s, 1.67H, (S,R)-isomer), 3.84 (s,
3H, both isomers), 3.88 (s, 3H, both isomers), 4.12–4.24
(m, 2H, both isomers), 4.48–4.58 (m, 1H, both isomers),
4.80 (dd, J¼4.9 and 8.6 Hz, 0.56H, (S,R)-isomer), 4.88 (dd,
J¼4.1 and 8.3 Hz, 0.44H, (S,S)-isomer), 5.21 (d, J¼6.7 Hz,
0.44H, (S,S)-isomer), 5.23 (d, J¼6.8 Hz, 0.56H, (S,R)-iso-
mer), 5.24 (d, J¼6.7 Hz, 0.44H, (S,S)-isomer), 5.28 (d, J¼
6.8 Hz, 0.56H, (S,R)-isomer), 6.15 (br s, 1H, both isomers),
6.76 (d, J¼7.7 Hz, 0.44H, (S,S)-isomer), 6.81 (d, J¼
8.4 Hz, 0.44H, (S,S)-isomer), 6.82 (d, J¼8.4 Hz, 0.56H,
(S,R)-isomer), 6.87 (d, J¼8.2 Hz, 0.56H, (S,R)-isomer),
6.88 (d, J¼8.2 Hz, 1H, both isomers), 7.00 (dd, J¼2.0 and
8.2 Hz, 0.56H, (S,R)-isomer), 7.02 (dd, J¼2.0 and 8.2 Hz,
0.44H, (S,S)-isomer), 7.18 (d, J¼2.0 Hz, 0.44H, (S,S)-
isomer), 7.21 (d, J¼2.0 Hz, 0.56H, (S,R)-isomer), 7.30 (dd,
J¼7.7 and 8.4 Hz, 0.44H, (S,S)-isomer), 7.34 (dd, J¼7.7
and 8.4 Hz, 0.56H, (S,R)-isomer). HREIMS m/z calcd for
C24H31NO6 (M+): 429.2151; found: 429.2136.
4.7.3. (R)-8-Methoxy-3-(4-methoxy-3-methoxymethoxy-
phenyl)-3,4-dihydroisocoumarin (14b). This compound
was prepared from 13b (238 mg, 0.553 mmol) in a similar
manner as described for 6b in Section 4.4.3. After chroma-
tographic purification over Silica Gel 60N (hexane–ethyl
acetate¼1:1), 14b was obtained as colorless solid (139 mg,
73%). HPLC (Daicel Chiralcel OD-H, hexane–EtOH¼7:3):
91% ee. Mp 98.5–101.0 ꢂC; [a]2D5 +122 (c 1.00, MeOH).
HREIMS m/z calcd for C19H20O6 (M+): 344.1260; found:
344.1247.
4.7.4. (S)-8-Hydroxy-3-(4-methoxy-3-methoxymethoxy-
phenyl)-3,4-dihydroisocoumarin (15a). Under an argon at-
mosphere, a solution of 14a (50 mg, 0.145 mmol) and LiCl
(18.5 mg, 0.435 mmol) in DMF (4.0 mL) was heated at
150 ꢂC for 17 h. The reaction mixture was allowed to cool
to room temperature and quenched with saturated aqueous
NH4Cl. The product was extracted with ethyl acetate and
the extract was washed successively with water and brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography over
Silica Gel 60N (toluene–ethyl acetate¼20:1) to give 15a
as colorless solid (19.8 mg, 41%). HPLC (Daicel Chiralpak
AS, hexane–i-PrOH¼1:1): 43% ee. Mp 93.0–95.0 ꢂC; IR
(KBr): 3431, 1671, 1615, 1514, 1463, 1235, 1159,
4.7.2. Diastereomer-selective lactonization of 13. A mix-
ture of 13 (950 mg, 2.21 mmol), silica gel (Merck Silica
gel 60) (3.20 g), and dichloromethane (80 mL) was stirred
for 30 h at 0 ꢂC and worked up in a similar manner as de-
scribed in Section 4.4. After chromatographic purification
over Silica Gel 60N (dichloromethane–ethyl acetate¼10:1
containing 1% triethylamine), 14a (436 mg, 57%) and 13b
(293 mg, 31%) were isolated.
4.7.2.1. (S)-8-Methoxy-3-(4-methoxy-3-methoxymeth-
oxyphenyl)-3,4-dihydroisocoumarin (14a). Colorless
1000 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 3.10 (dd,
J¼3.2 and 16.5 Hz, 1H), 3.33 (dd, J¼12.2 and 16.5 Hz,

7186
K. Uchida et al. / Tetrahedron 63 (2007) 7178–7186
1H), 3.52 (s, 3H), 3.90 (s, 3H), 5.24 (d, J¼6.8 Hz, 1H), 5.26
(d, J¼6.8 Hz, 1H), 5.52 (dd, J¼3.2 and 12.2 Hz, 1H), 6.74
(d, J¼7.4 Hz, 1H), 6.92 (d, J¼8.4 Hz, 2H), 7.09 (dd,
J¼2.1 and 8.4 Hz, 1H), 7.25 (d, J¼2.1 Hz, 1H), 7.44 (dd,
J¼7.4 and 8.4 Hz, 1H), 11.00 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 35.03, 56.02, 56.32, 80.74, 95.69,
108.47, 111.73, 114.76, 116.41, 117.94, 120.59, 130.51,
136.32, 139.39, 146.74, 150.30, 162.31, 169.82; [a]D25
ꢁ30.8 (c 0.980, MeOH). HREIMS m/z calcd for C18H18O6
(M+): 330.1103; found: 330.1103.
References and notes
1. (a) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.; Nakajima,
S. Chem. Pharm. Bull. 1981, 29, 2689–2691; (b) Shimojima,
Y.; Shirai, T.; Baba, T.; Hayashi, H. J. Med. Chem. 1985, 28,
3–9; (c) Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota,
H. J. Org. Chem. 1991, 56, 4971–4974; (d) Yoshikawa, M.;
Uchida, E.; Chatani, N.; Kobayashi, H.; Naitoh, Y.; Okuno,
Y.; Matsuda, H.; Yamahara, J.; Murakami, N. Chem. Pharm.
Bull. 1992, 40, 3352–3354; (e) Umehara, K.; Matsumoto, M.;
Nakamura, M.; Miyase, T.; Kuroyanagi, M.; Noguchi, H.
Chem. Pharm. Bull. 2000, 48, 566–567; (f) Kongsaeree, P.;
Prabpai, S.; Sriubolmas, N.; Vongvein, C.; Wiyakrutta, S.
J. Nat. Prod. 2003, 66, 709–711.
2. For reviews, see: (a) Barry, R. D. Chem. Rev. 1964, 64, 229–
260; (b) Hill, R. A. Prog. Chem. Org. Nat. Prod. 1986, 49, 1–
78; (c) Mc Inerney, B. V.; Taylor, W. C. Studies in Natural
Products Chemistry; Rahman, A., Ed.; Elsevier: Amsterdam,
1995; Vol. 15, pp 381–422; (d) Napolitano, E. Org. Prep.
Proced. Int. 1997, 29, 631–664.
3. (a) Regan, A. C.; Staunton, J. J. Chem. Soc., Chem. Commun.
1983, 764–765; (b) Watanabe, M.; Sahara, M.; Kubo, M.;
Furukawa, S.; Billedeau, R. J.; Snieckus, V. J. Org. Chem.
1984, 49, 742–747; (c) Fu, P. P.; Unruh, L. E.; Miller, D. W.;
Huang, L. W.; Yang, D. T. C. J. Org. Chem. 1985, 50, 1259–
1261; (d) Hamada, Y.; Kawai, A.; Kohno, Y.; Hara, O.;
Shioiri, T. J. Am. Chem. Soc. 1989, 111, 1524–1525; (e)
Hamada, Y.; Hara, O.; Kawai, A.; Kohno, Y.; Shioiri, T.
Tetrahedron 1991, 47, 8635–8652; (f) Broady, S. D.;
Rexhausen, J. E.; Thomas, E. J. J. Chem. Soc., Chem.
Commun. 1991, 708–710; (g) Broady, S. D.; Rexhausen, J. E.;
Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1999, 1083–1094.
4. Tahara, N.; Fukuda, T.; Iwao, M. Tetrahedron Lett. 2002, 43,
9069–9072.
5. Tahara, N.; Fukuda, T.; Iwao, M. Tetrahedron Lett. 2004, 45,
5117–5120.
6. Kurosaki, Y.; Fukuda, T.; Iwao, M. Tetrahedron 2005, 61,
3289–3303.
7. Kotsuki, H.; Datta, P. K.; Hayakawa, H.; Suenaga, H. Synthesis
1995, 1348–1350.
8. Choukchou-Braham, N.; Asakawa, Y.; Lepoittevin, J.-P.
Tetrahedron Lett. 1994, 35, 3949–3952.
9. (a) Asahina, Y.; Ueno, M. Yakugaku Zasshi 1916, 408, 146–
159; (b) Asahina, Y.; Asano, J. Yakugaku Zasshi 1931, 51,
749–753.
10. Zehnter, R.; Gerlach, H. Tetrahedron: Asymmetry 1995, 6,
2779–2786.
4.7.5. (R)-8-Hydroxy-3-(4-methoxy-3-methoxymethoxy-
phenyl)-3,4-dihydroisocoumarin (15b). This compound
was prepared from 14b (50.0 mg, 0.145 mmol) in a similar
manner as described for 15a. After chromatographic purifi-
cation over Silica Gel 60N (toluene–ethyl acetate¼20:1),
15b was obtained as colorless solid (18.6 mg, 39%).
HPLC (Daicel Chiralpak AS, hexane–i-PrOH¼1:1): 83%
ee. Mp 92.0–94.0 ꢂC; [a]2D5 +56.8 (c 0.835, MeOH).
HREIMS m/z calcd for C18H18O6 (M+): 330.1103; found:
330.1105.
4.7.6. (S)-Phyllodulcin (16a). To a solution of 15a
(17.1 mg, 51.7 mmol) in methanol (3.0 mL) was added cata-
lytic amount of concd HCl (two drops). After being stirred
for 3 h at room temperature, the mixture was evaporated
under reduced pressure. The product was dissolved in di-
chloromethane and the solution was washed with brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography over
Silica Gel 60N (hexane–ethyl acetate¼1:1) to give 16a as
colorless solid (14.5 mg, 98%). HPLC (Daicel Chiralpak
AD, hexane–EtOH¼1:1): 42% ee. Mp 103.0–107.0 ꢂC; IR
(KBr): 3346, 1675, 1622, 1587, 1520, 1467, 1282, 1231,
1208, 1113 cmꢁ1 1H NMR (400 MHz, CDCl3): d 3.09
;
(dd, J¼3.2 and 16.5 Hz, 1H), 3.30 (dd, J¼12.1 and
16.5 Hz, 1H), 3.91 (s, 3H), 5.50 (dd, J¼3.2 and 12.1 Hz,
1H), 5.70 (br s, 1H), 6.73 (d, J¼7.4 Hz, 1H), 6.87 (d,
J¼8.3 Hz, 1H), 6.92 (d, J¼8.4 Hz, 1H), 6.95 (dd, J¼2.1
and 8.3 Hz, 1H), 7.02 (d, J¼2.1 Hz, 1H), 7.43 (dd, J¼7.4
and 8.4 Hz, 1H), 11.01 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 35.02, 56.05, 80.66, 108.49, 110.62, 112.63,
116.40, 117.95, 118.23, 131.13, 136.31, 139.38, 145.85,
147.00, 162.30, 169.79; [a]2D2 ꢁ29.8 (c 0.725, acetone)
{lit.10 [a]2D0 ꢁ77.6 (c 1.02, acetone): (S)-isomer}. HREIMS
m/z calcd for C16H14O5 (M+): 286.0841; found: 286.0825.
4.7.7. (R)-Phyllodulcin (16b). This compound was prepared
from 15b (13.6 mg, 41.2 mmol) in a similar manner as de-
scribed for 16a. After chromatographic purification over
Silica Gel 60N (hexane–ethyl acetate¼1:1), 16b was ob-
tained as colorless solid (11.7 mg, quant.). HPLC (Daicel
Chiralpak AD, hexane–EtOH¼1:1): 83% ee. Mp 110.0–
112.0 ꢂC; [a]D23 +56.1 (c 0.585, acetone) {lit.10 [a]2D0 +78.8
(c 1.01, acetone): (R)-isomer)}. HREIMS m/z calcd for
C16H14O5 (M+): 286.0841; found: 286.0819.
11. Ramacciotti, A.; Fiaschi, R.; Napolitano, E. J. Org. Chem.
1996, 61, 5371–5374.
12. Magano, J.; Chen, M. H.; Clark, J. D.; Nussbaumer, T. J. Org.
Chem. 2006, 71, 7103–7105.
13. Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A.
Synthesis 1989, 287–289.
14. Recrystallization of 16a from two different solvent systems
(diethyl ether–hexane or ethanol) has been attempted.
Unfortunately, however, the enantiomeric purity of 16a was
not improved.
15. Hauser, F. M.; Ellenberger, S. R. Synthesis 1987, 723–724.
16. Baldwin, J. E.; Adlington, R. M.; Sham, V. W.-W.; Marquez,
R.; Bulger, P. G. Tetrahedron 2005, 61, 2353–2363.
17. Romanelli, G.; Autino, J. C.; Baronetti, G.; Thomas, H.
Molecules 2001, 6, 1006–1011.
Acknowledgements
This research was supported by the president’s discretionary
fund of Nagasaki University, Japan.