First synthesis of (+)- and (-)-elvirol based on an enzymatic function

Article abstract of DOI:10.1016/S0957-4166(01)00447-5

A highly enantioselective synthesis of versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-hydroxy-(2E)-pentenoate 3 was achieved based on the enzymatic reaction of (±)-4 with commercially available lipase 'OF-360' from Cand

Full text of DOI:10.1016/S0957-4166(01)00447-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2597–2604
First synthesis of (+)- and (−)-elvirol based on an enzymatic
function
Machiko Ono, Keiko Suzuki, Shin Tanikawa and Hiroyuki Akita*
School of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Received 14 September 2001; accepted 11 October 2001
Abstract—A highly enantioselective synthesis of versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-
hydroxy-(2E)-pentenoate 3 was achieved based on the enzymatic reaction of ( )-4 with commercially available lipase ‘OF-360’
from Candida rugosa. An application of (S)-3 and (R)-3 to the total syntheses of (S)-elvirol 1 and (R)-elvirol 1, respectively, is
described. © 2001 Published by Elsevier Science Ltd.
1. Introduction
tiomers of elvirol 1 is of significant value from the
standpoint of biological activity. Although racemic syn-
theses of elvirol 1 have been developed in past years,5 a
useful asymmetric synthesis bearing construction of a
benzylic asymmetric center has not been reported so
far.6 We now report that (S)-1 and (R)-1 have been
synthesized based on enzymatic resolution using lipase
in an organic solvent.
In 1969 the isolation of a new bisabolane sesquiterpene
from Elvira biflora (Compositae) was reported and this
phenol was called elvirol 1 whose structure did not
obey the isoprene rule.1 Although this phenol contains
one stereogenic center, no reference was made to any
optical activity in the natural compound. The phenolic
sesquiterpenes of the bisabolane family have been iso-
lated from many different natural sources.2 Among
them, curcuphenol 2 being a structural isomer of elvirol
1 (Scheme 1), was isolated as two optically active
forms. (S)-(+)-Curcuphenol 2, isolated from the marine
sponge Epipolasis sp. inhibits strongly the activity of
gastric H, K-ATPase,3 while (R)-(−)-curcuphenol 2,
isolated from a Caribbean gorgonian Pseudopterogorgia
rigida and Lasianthaea podocephala exhibits antibacte-
rial activities against Staphylcoccus aureus and Vibrio
anguillarum.4 Accordingly, the establishment of an
efficient and general synthetic route to both enan-
2. Results and discussion
The most intriguing point of the present synthesis is the
preparation of the optically active primary alcohols
possessing one stereogenic center of (S)- and (R)-4-
aryl-5-hydroxy-(2E)-pentenoate 3 (Scheme 2). This was
successfully achieved by carrying out an enantioselec-
tive hydrolysis of ( )-acetate 4 derived from ( )-3 using
lipase. The desired ( )-3 was already obtained in the
reaction of methyl (4,5)-epoxy-(2E)-pentenoate and p-
methoxytoluene in the presence of BF3·Et2O by us.7
R2
R2
Initially, ( )-4 was subjected to screening experiments
using several kinds of commercially available lipases.
Among them, lipase ‘OF-360’ from Candida rugosa was
found to be effective. When ( )-4 was subjected to
enantioselective hydrolysis using ‘OF-360’ in water sat-
urated isopropyl ether for a short time (15 h), alcohol
(S)-3 (24%, 76% e.e.) and the unreacted (R)-4 (71%,
24% e.e.) were obtained (entry 1, Table 1). On the other
hand, asymmetric hydrolysis of ( )-4 using ‘OF-360’ for
a prolonged period (240 h) gave (S)-3 (50%, 56% e.e.)
and (R)-4 (49%, 56% e.e.) (entry 4, Table 1). Alcohol
(S)-3 with 76% e.e. was subjected to enantioselective
acetylation using ‘OF-360’ in the presence of isoprop-
R1
R1
OH
Me
OH
Me
Me
Me
Me
Me
R1=Me R2=H : (S)-1
R1=H R2=Me : (S)-2
R1=Me R2=H : (R)-1
R1=H R2=Me : (R)-2
Scheme 1.
* Corresponding author.
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00447-5

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M. Ono et al. / Tetrahedron: Asymmetry 12 (2001) 2597–2604
Me
Me
BF3·Et2O
+
COOMe
OMe
COOMe
O
OMe
RO
R=H (±)-3
R=Ac (±)-4
Ac2O / pyridine
Scheme 2.
Table 1.
Me
RO
Me
RO
Me
RO
lipase "OF-360"
+
H2O
saturated i-Pr2O
OMe
OMe
COOMe
OMe
COOMe
COOMe
35°C
R=H (S)-3
R=Ac (S)-4
R=Ac (R)-4
R=H (R)-3
R=Ac (±)-4
Entry
Substrate
Time (h)
Products (%, % ee)
1
2
3
4
5
(9)-4 (10)
15
48
12
240
240
(S)-3 24 (76) (R)-4 71 (24)
(S)-3 23 (64) (S)-4 70 (80)
(S)-3 40 (92) (S)-4 50 (70)
(S)-3 50 (56) (R)-4 49 (56)
(R)-3 54 (28) (R)-4 36 (96)
(S)-3 (76% ee, 2.03)
(S)-4 (80% ee, 1.66)
(9)-4 (10)
(R)-4 (56% ee, 3.35)
90% e.e.) and a-keto ester (S)-(+)-10 (10% yield, [h]D
+2.4 (c=0.26, CHCl3) corresponding to 90% e.e.). The
spectral data ([h]D, 1H NMR) of (+)-5 derived from
(+)-8 were identical with those of the authentic (S)-(+)-
5 and thence the absolute configurations of (−)-3 and
(+)-4 were determined to be (S) and (R), respectively.
enyl acetate in isopropyl ether to afford (S)-4 (70%,
80% e.e.) and (S)-3 (23%, 64% e.e.) (entry 2, Table 1).
The acetate (S)-4 possessing 80% e.e. was again sub-
jected to enantioselective hydrolysis to afford (S)-3
(40%, 92% e.e., [h]D −9.0 (c=0.5, CHCl3)) and (S)-4
(50%, 70% e.e.) (entry 3, Table 1). The acetate (R)-4
with 56% e.e. was also subjected to enantioselective
hydrolysis to afford (R)-3 (54%, 28% e.e.) and (R)-4
(36%, 96% e.e., [h]D +11.3 (c=0.5, CHCl3)) (entry 5,
Table 1). The enantiomeric purity of the obtained chiral
compounds was determined by HPLC on a Chiralcel
AD (250×4.6 mm) column.
The total syntheses of (S)- and (R)-elvirol 1 were
achieved from (S)-3 (Scheme 4) (92% e.e.) and (R)-3
(Scheme 5) (96% e.e.), respectively. Treatment of (S)-3
with p-toluenesulfonic anhydride (Ts2O) in pyridine
gave tosylate (S)-6 (85% yield) which was subjected to
the following treatment: (1) catalytic hydrogenation, (2)
NaBH4 reduction, (3) LiAlH4 reduction, to afford alco-
hol (S)-9 (70% overall yield from (S)-6, [h]D +8.0
(c=0.5, CHCl3) corresponding to 92% e.e.). Demethyl-
ation of (S)-9 with a combination of AlCl3 and
ethanethiol (EtSH) provided a phenol, which was
treated with 3,5-dinitrobenzoyl chloride to afford the
corresponding 3,5-dinitrobenzoate (S)-12 in 59% over-
all yield from (S)-9. Recrystallization of (S)-12 from
AcOEt gave the enantiomerically pure (S)-12 (mp 120–
122°C, [h]D +10.0 (c=0.5, CHCl3)) which was treated
with methoxymethyl chloride (MOMCl) in the presence
of Hu¨nig’s base to afford the corresponding MOM
ether (S)-13 (Scheme 4) ([h]D +4.6 (c=0.66, CHCl3)) in
88% yield. Alkaline treatment of (S)-13 with K2CO3 in
MeOH provided alcohol (S)-14 ([h]D +9.9 (c=0.51,
CHCl3)) in 93% yield. Pyridinium chlorochromate
(PCC)-oxidation of (S)-14 followed by Wittig reaction
afforded olefin (S)-15 ([h]D +19.6 (c=0.16, CHCl3)) in
19% overall yield from (S)-14. Deprotection of (S)-15
In order to confirm the absolute configuration of the
present (−)-3, it was successfully converted to the opti-
cally active dimethyl 2-methylglutarate 5. Treatment of
(−)-3 (76% e.e.) with tosyl chloride (TsCl) gave tosylate
6 (Scheme 3) in 77% yield. Catalytic hydrogenation of 6
followed by NaBH4 reduction of 7 provided 4-arylpen-
tanoate (+)-8 (43% overall yield, [h]D +8.9 (c=1.45,
CHCl3) corresponding to 76% e.e.) and alcohol (+)-9
(31% overall yield, [h]D +7.4 (c=0.94, CHCl3) corre-
sponding to 76% e.e.). Oxidative cleavage of the aro-
matic ring of (+)-8 with NaIO4 in the presence of a
catalytic amount of RuCl3·3H2O followed by esterifica-
tion with CH2N2 provided (+)-5 (20% yield, [h]D +14.6
(c=1.07, CHCl3) corresponding to 76% e.e.) and h-keto
ester 10 (22% yield). For a comparison, authentic (S)-5
was derived from the reported (S)-4-arylpentanoate
11.8 The same oxidative cleavage of the aromatic ring
of (S)-11 (90% e.e.) as for (+)-8 gave (S)-(+)-5 (33%
yield, [h]D +15.8 (c=0.72, CHCl3) corresponding to

M. Ono et al. / Tetrahedron: Asymmetry 12 (2001) 2597–2604
2599
Me
Me
Me
b
c
OMe
OMe
R4
OMe
COOMe
R3O
a
TsO
COOMe
R3=H (-)-3 (76% ee)
Me
7
R4=COOMe (+)-8
R4=CH2OH (+)-9
R3=Ts
6
COOMe
COCOOMe
d
(+)-8
+
Me
COOMe
Me
COOMe
10
(+)-5
Me
d
(S)-(+)-10
+
(S)-(+)-5
OMe
Me
COOMe
(S)-11 (90% ee)
Scheme 3. (a) TsCl/pyridine, (b) H2/20% Pd(OH)2-C; (c) NaBH4/DMSO; (d) NaIO4/RuCl3·3H2O (2 mol%)/CCl4/MeCN/H2O.
Me
Me
Me
NO2
b
c
OMe
OMe
OR5
R3O
a
O
COOMe
R3=H (S)-3 (92% ee)
Me
CH2OH
Me
d
NO2
O
(S)-9
R5=H (S)-12 (>99% ee)
R5=MOM (S)-13
R3=Ts
Me
(S)-6
Me
e
f
OMOM
CH2OH
OR5 Me
Me
Me
Me
R5=MOM (S)-15
R5=H (S)-1
(S)-14
g
Scheme 4. (a) Ts2O/pyridine; (b) (1) H2/20% Pd(OH)2-C, (2) NaBH4/DMSO, (3) LiAlH4; (c) (1) EtSH/AlCl3, (2) 3,5-dinitroben-
zoyl chloride; (d) MOMCl/(i-Pr)2NEt; (e) K2CO3/MeOH; (f) (1) PCC/CH2Cl2, (2) (iso-Pr)-P+Ph3I−/n-BuLi/THF; (g) 2 M
HCl/i-PrOH.
(R)-12 in 50% overall yield from (R)-9. Recrystalliza-
tion of (R)-12 from AcOEt gave the enantiomerically
pure (R)-12 (mp 120–122°C, [h]D −11.6 (c=0.5,
CHCl3)) which was treated with methoxymethyl chlo-
ride (MOMCl) to afford the corresponding MOM ether
(R)-13 in 86% yield. Alkaline treatment of (R)-13 with
K2CO3 in MeOH gave alcohol (R)-14 ([h]D −10.0 (c=
0.5, CHCl3)) in 74% yield. Pyridinium chlorochromate
(PCC)-oxidation of (R)-14 followed by the Wittig reac-
tion then afforded olefin (R)-15 ([h]D −18.7 (c=0.16,
CHCl3)) in 39% overall yield from (R)-14. Deprotection
of (R)-15 gave (R)-elvirol (1) (58% yield, [h]D −37.1
(c=0.23, CHCl3)), whose NMR data were identical
with those of (S)-1.
gave (S)-elvirol 1 (34% yield, [h]D +36.1 (c=0.46,
CHCl3)), whose NMR data were identical with those of
the natural product 1.1
The synthesis of (R)-elvirol 1 from (R)-4 (96% e.e.) was
carried out fundamentally in the same way as that of
(S)-3. Deprotection of (R)-4 to give alcohol (R)-3 ([h]D
+8.5 (c=0.51, CHCl3)) followed by tosylation gave
tosylate (R)-6 in 85% overall yield. Successive treatment
of (R)-6 in the same way as for (S)-6 afforded alcohol
(R)-9 (82% overall yield from (S)-6, [h]D −9.5 (c=0.5,
CHCl3) corresponding to 96% e.e.). Demethylation of
(R)-9 followed by treatment with 3,5-dinitrobenzoyl
chloride gave the corresponding 3,5-dinitrobenzoate

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M. Ono et al. / Tetrahedron: Asymmetry 12 (2001) 2597–2604
Me
Me
Me
NO2
c
d
OMe
OMe
OR5
R3O
O
COOMe
R3=Ac (R)-4 (96% ee)
Me
CH2OH
Me
e
NO2
O
(R)-9
a
b
R5=H (R)-12 (>99% ee)
R5=MOM (R)-13
R3=H
(R)-3
(R)-6
R3=Ts
Me
Me
f
g
OMOM
OR5 Me
Me
CH2OH
Me
Me
R5=MOM (R)-15
R5=H (R)-1
(R)-14
h
Scheme 5. (a) NaOMe/MeOH; (b) Ts2O/pyridine; (c) (1) H2/20% Pd(OH)2-C, (2) NaBH4/DMSO, (3) LiAlH4; (d) (1) EtSH/AlCl3,
(2) 3,5-dinitrobenzoyl chloride; (e) MOMCl/(i-Pr)2NEt; (f) K2CO3/MeOH; (g) (1) PCC/CH2Cl2, (2) (iso-Pr)-P+Ph3I−/n-BuLi/THF;
(h) 2 M HCl/i-PrOH.
3. Experimental
(1H, dd, J=2, 9 Hz), 7.15 (1H, dd, J=7, 16 Hz).
Anal. calcd for C16H20O5: C, 65.74; H, 6.90%. Found:
C, 65.41; H, 7.29. FAB MS m/z: 293 (M++1).
3.1. General
All melting points were measured on a Yanaco MP-3S
micro melting point apparatus and are uncorrected. H
3.3. Enzymatic resolution of ( )-4
1
and 13C NMR spectra were recorded on JEOL EX 400
spectrometer in CDCl3. Carbon substitution degrees
were established by DEPT pulse sequence. High-resolu-
tion mass spectra (HRMS) and the fast atom bombard-
ment mass spectra (FAB MS) were obtained with JEOL
JMS-DX 303 spectrometer. IR spectra were recorded a
Jasco FT/IR-300 spectrometer. The HPLC system was
composed of two SSC instruments (ultraviolet (UV)
detector 3000B and flow system 3100). Optical rotations
were measured with a Jasco DIP-370 digital polarime-
ter. All evaporations were performed under reduced
pressure. For column chromatography, silica gel
(Kieselgel 60) was employed.
(i) Table 1, entry 1; a suspension of ( )-4 (1 g), lipase
OF-360 (0.2 g) in H2O-saturated-isopropyl ether (20
mL) was incubated at 33°C for 15 h. This scale experi-
ment was simultaneously carried out ten times (total
amount of ( )-4 was 10 g). After the reaction mixture
was filtered, the precipitate was washed with diiso-
propyl ether. The combined organic layer was dried
over MgSO4 and evaporated. The residue was chro-
matographed on silica gel (50 g) to give (R)-4 (7.13 g,
71%, 24% e.e.) from n-hexane:AcOEt=10:1 eluent and
(S)-3 (2.038 g, 24%, 76% e.e.) as a homogeneous oil
from n-hexane:AcOEt=4:1 eluent. The NMR data of
(S)-3 were identical with those of the reported ( )-3.7
3.2. ( )-Methyl 5-acetoxy-4-(2%-methoxy-5%-methyl-
phenyl)-(2E)-pentenoate 4
(ii) Table 1, entry 2; a suspension of (S)-3 (76% e.e., 1
g), lipase OF-360 (0.2 g) and isopropenyl acetate (1 g)
in isopropyl ether (20 mL) was incubated at 33°C for
48 h. This scale experiment was simultaneously carried
out twice (total amount of (S)-3 was 2.03 g). The
reaction mixture was worked up in the same way as
for (i) to give (S)-4 (1.67 g, 70%, 80% e.e.) and (S)-3
(0.467 g, 23%, 64% e.e.).
A solution of ( )-3 (0.99 g, 3.96 mmol) in pyridine (20
mL) was treated with Ac2O (0.93 g, 9.11 mmol) and
the reaction mixture was stirred for 24 h at room
temperature. The reaction mixture was diluted with
H2O and extracted with ether. The ether layer was
washed with 2 M aqueous HCl, 7% aqueous NaHCO3,
saturated brine and dried over MgSO4. Evaporation of
the organic layer gave a crude residue, which was
chromatographed on silica gel (20 g, n-hex-
ane:AcOEt=8:1) to give a colorless oil ( )-4 (0.93 g,
(iii) Table 1, entry 3; a suspension of (S)-4 (80% e.e.,
0.8 g), lipase OF-360 (0.2 g) in H2O-saturated-isopro-
pyl ether (20 mL) was incubated at 33°C for 12 h.
This scale experiment was simultaneously carried out
twice (total amount of (S)-4 was 1.66 g). The reaction
mixture was worked up in the same way as for (i) to
give (S)-4 (0.83 g, 50%, 70% e.e.) and (S)-3 (0.569 g,
40%, [h]2D3 −9.0 (c=0.5, CHCl3) corresponding to 92%
e.e.).
1
80%). ( )-4: IR (neat): 1740 cm−1; H NMR: 2.03 (3H,
s), 2.26 (3H, s), 3.72 (3H, s), 3.80 (3H, s), 4.19 (1H,
br. q, J=7.5 Hz), 4.30 (1H, dd, J=6, 10 Hz), 4.39
(1H, dd, J=9, 10 Hz), 5.87 (1H, dd, J=2, 16 Hz),
6.78 (1H, d, J=9 Hz), 6.90 (1H, d, J=2 Hz), 7.03

M. Ono et al. / Tetrahedron: Asymmetry 12 (2001) 2597–2604
2601
(iv) Table 1, entry 4; a suspension of ( )-4 (1 g), lipase
OF-360 (0.2 g) in H2O-saturated-isopropyl ether (20
mL) was incubated at 33°C for 240 h. This scale
experiment was simultaneously carried out ten times
(total amount of ( )-4 was 10 g). The reaction mixture
was worked up in the same way as for (i) to give (R)-4
(4.9 g, 49%, 56% e.e.) and (S)-3 (4.281 g, 50%, 56% e.e.).
J=7 Hz), 1.88–1.94 (2H, m), 2.14–2.29 (2H, m), 2.29
(3H, s), 3.19 (1H, sextet, J=7 Hz), 3.63 (3H, s), 3.78
(3H, s), 6.74 (1H, d, J=9 Hz), 6.92–7.00 (2H, m). Anal.
calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 70.90;
H, 8.33%. FAB MS m/z: 236 (M+). (+)-9: [h]D24 +7.4
(c=1.45, CHCl3), IR (neat): 3343 cm−1 (OH); 1H
NMR: 1.20 (3H, d, J=8 Hz), 1.40–1.69 (5H, m), 2.28
(3H, s), 3.17 (1H, sextet, J=8 Hz), 3.60 (2H, t, J=6
Hz), 3.78 (3H, s), 6.74 (1H, d, J=8 Hz), 6.94 (1H, dd,
J=2, 8 Hz), 6.96 (1H, s). Anal. calcd for C13H20O2: C,
74.96; H, 9.68. Found: C, 74.49; H, 9.88%. FAB MS
m/z: 208 (M+).
(v) Table 1, entry 5; a suspension of (R)-4 (56% e.e., 1.1
g), lipase OF-360 (0.3 g) in H2O-saturated-isopropyl
ether (20 mL) was incubated at 33°C for 240 h. This
scale experiment was simultaneously carried out three
times (total amount of (R)-4 was 3.35 g). The reaction
mixture was worked up in the same way as for (i) to
give (R)-4 (1.206 g, 36%, [h]2D6 +11.3 (c=0.5, CHCl3)
corresponding to 96% e.e.) and (R)-3 (1.549 g, 54%,
28% e.e.).
3.6. Oxidative cleavage of aromatic ring of (+)-8
To a solution of (+)-8 (0.145 g, 0.61 mmol) in MeCN (1
mL) was added NaIO4 (2.63 g, 12.3 mmol) and H2O
(1.5 mL) at 0°C. A mixture of RuCl3·3H2O (10 mg) in
CCl4 (1 mL) was added to the above reaction mixture,
and the whole mixture was vigorously stirred at room
temperature for 6 h and stood for 12 h. The reaction
mixture was filtered with the aid of Celite and the
precipitate was washed with MeCN. The filtrate and
washing were combined and concentrated to give a
residue which was acidified with 2 M aqueous HCl. The
acidic layer was extracted with ether and the organic
layer was washed with saturated brine, dried over
MgSO4. Evaporation of the organic layer gave a
residue which was treated with an excess of CH2N2–
ether solution to afford a crude oil. It was chro-
matographed on silica gel (10 g) to afford (+)-5 (0.021
g, 20% yield) as a homogeneous oil from n-hex-
ane:AcOEt=40:1 eluent and (+)-10 (0.027 g, 22% yield)
as a homogeneous oil from n-hexane:AcOEt=20:1 elu-
3.4. Methyl 5-tosyloxy-4-(2%-methoxy-5%-methylphenyl)-
(2E)-pentenoate 6
A solution of (−)-3 (76% e.e., 0.46 g, 1.84 mmol) in
pyridine (10 mL) was treated with TsCl (0.53 g, 2.78
mmol), and the mixture was allowed to stand for 12 h
at room temperature. Ether and 7% aqueous NaHCO3
were added to the reaction mixture, and the organic
layer was washed with 2 M aqueous HCl, saturated
brine and dried over MgSO4. The organic layer was
evaporated to give
a residue which was chro-
matographed on silica gel (15 g, n-hexane:AcOEt=
10:1) to afford 6 (0.576 g, 77% yield) as a homogeneous
1
oil. Compound 6: IR (neat): 1725 cm−1; H NMR: 2.22
(3H, s), 2.44 (3H, s), 3.70 (3H, s), 3.71 (3H, s), 4.12
(1H, br. q, J=7 Hz), 4.27 (2H, d, J=7 Hz), 5.80 (1H,
dd, J=2, 16 Hz), 6.70 (1H, d, J=8 Hz), 6.77 (1H, d,
J=2 Hz), 7.01 (1H, dd, J=2, 8 Hz), 7.02 (1H, dd,
J=7, 16 Hz), 7.30 (2H, d, J=8 Hz), 7.70 (2H, d, J=8
Hz). Anal. calcd for C21H24O6S: C, 62.36; H, 5.98.
Found: C, 61.94; H, 5.92%. FAB MS m/z: 404 (M+
+1).
1
ent. (+)-5: [h]2D6 +14.6 (c=1.07, CHCl3), H NMR: 1.18
(3H, d, J=7 Hz), 1.74–1.82 (1H, m), 1.93–2.01 (1H, m),
2.29–2.40 (2H, m), 2.51 (1H, sextet, J=7 Hz), 3.67 (3H,
s), 3.68 (3H, s). 13C NMR: 17.1 (q), 28.6 (t), 31.7 (t),
38.7 (d), 51.6 (q), 51.6 (q), 173.5 (s), 176 (s). FAB MS
1
m/z: 174 (M+). (+)-10: [h]D27 +3.2 (c=1.35, CHCl3), H
NMR: 1.18 (3H, d, J=7 Hz), 1.72–1.82 (1H, m),
2.02–2.11 (1H, m), 2.29–2.40 (2H, m), 3.30 (1H, sextet,
J=7 Hz), 3.68 (3H, s), 3.89 (3H, s). 13C NMR: l 15.4
(q), 26.7 (t), 31.2 (t), 41.3 (d), 51.7 (q), 53.0 (q), 161.8
(s), 173.3 (s), 196.8 (s). Anal. calcd for C9H14O5: C,
53.46; H, 6.98. Found: C, 53.00; H, 6.78%. FAB MS
m/z: 203 (M++1).
3.5. Preparation of methyl 4-(2%-methoxy-5%-methyl-
phenyl)pentanoate (+)-8 and 4-(2%-methoxy-5%-
methylphenyl)pentanol (+)-9
A solution of 6 (76% e.e., 0.576 g, 1.4 mmol) in AcOEt
(10 mL) was hydrogenated over 20% Pd-C (20 mg) at
room temperature under an atmospheric pressure of
hydrogen. After removal of the catalyst by filtration,
the filtrate was evaporated to give (S)-7 as a colorless
oil quantitatively. A solution of (S)-7 and NaBH4 (0.31
g, 8.1 mmol) in DMSO (10 mL) was warmed for 3 h at
80°C, then allowed to cool. Small amounts of acetone,
ether and 7% aqueous NaHCO3 were added to the
reaction mixture and the organic layer was separated.
The organic layer was washed with saturated brine and
dried over MgSO4. The organic layer was evaporated to
give a residue which was chromatographed on silica gel
(17 g) to afford (+)-8 (0.145 g, 43% yield) as a homoge-
neous oil from n-hexane:AcOEt=30:1 eluent and (+)-9
(0.094 g, 31% yield) as a homogeneous oil from n-hex-
ane:AcOEt=15:1 eluent. (+)-8: [h]2D4 +8.9 (c=1.45,
CHCl3), IR (CHCl3): 1735 cm−1; 1H NMR: 1.23 (3H, d,
3.7. Oxidative cleavage of the aromatic ring of methyl
4-(2%-methoxy-4%-methylphenyl)pentanoate (S)-11
To a solution of (S)-11 (90% e.e., 0.289 g, 1.2 mmol) in
MeCN (2 mL) was added NaIO4 (5.23 g, 24 mmol) and
H2O (3 mL) at 0°C. A mixture of RuCl3·3H2O (20 mg)
in CCl4 (2 mL) was added to the above reaction
mixture, and the whole mixture was vigorously stirred
at room temperature for 6 h and stood for 12 h. The
reaction mixture was worked up in the same way as for
(+)-8 to give (S)-5 (0.072 g, 33% yield) and (S)-10
(0.026 g, 10% yield). (S)-5: [h]2D5 +15.8 (c=0.72,
CHCl3). The NMR data of (S)-5 were identical with
those of (+)-5. (S)-10: [h]2D4 +2.4 (c=0.26, CHCl3). The
NMR data of (S)-10 were identical with those of
(+)-10.

2602
M. Ono et al. / Tetrahedron: Asymmetry 12 (2001) 2597–2604
3.8. 4-(2%-Methoxy-5%-methylphenyl)pentanol (S)-9
2.26 (3H, s), 3.12 (1H, sextet, J=7 Hz), 3.70 (2H, t,
J=6 Hz), 6.10 (1H, br. s), 6.67 (1H, d, J=8 Hz), 6.85
(1H, dd, J=2, 8 Hz), 6.94 (1H, d, J=2 Hz). Anal. calcd
for C12H18O2: C, 74.19; H, 9.34. Found: C, 73.89; H,
9.42.%. FAB MS m/z: 194 (M+).
(i) To a solution of (S)-3 (92% e.e., 1.50 g, 6 mmol) in
benzene (20 mL) was added Ts2O (3.91 g, 12 mmol)
and pyridine (0.95 g, 12 mmol) and the mixture was
stirred at 40°C for 12 h at room temperature. The
reaction mixture was worked up in the same way as for
the preparation of 6 to afford (S)-6 (2.056 g, 85% yield)
as a homogeneous oil. The NMR data of (S)-6 were
identical with those of the previous 6.
(ii) A solution of above diol (0.16 g, 0.82 mmol) in
pyridine (2 mL) was treated with 3,5-dinitrobenzoyl
chloride (0.16 g, 0.7 mmol) and the reaction mixture
was stirred for 1 h at room temperature. The reaction
mixture was diluted with H2O and extracted with ether.
The ether layer was washed with 2 M aqueous HCl, 7%
aqueous NaHCO3, saturated brine and dried over
MgSO4. Evaporation of the organic layer gave a crude
residue, which was chromatographed on silica gel (10 g,
n-hexane:AcOEt=20:1) to give a colorless crystal (S)-
12 (0.208 g, 65% yield). Recrystallization of (S)-12 from
AcOEt gave an optically pure (S)-12 (0.18 g). (S)-12:
mp 120–122°C: IR (KBr): 3388, 1710, 1544 cm−1; [h]D23
(ii) A solution of (S)-6 (92% e.e., 2.056 g, 5.08 mmol) in
MeOH (12 mL) was hydrogenated over 20% Pd–C (0.2
g) at room temperature under an atmospheric pressure
of hydrogen. After removal of the catalyst by filtration,
the filtrate was evaporated to give (S)-7 (1.79 g) as a
colorless oil quantitatively. Compound (S)-7: 1H NMR:
1.86–1.95 (1H, m), 2.03–2.11 (1H, m), 2.12–2.18 (2H,
m), 2.22 (3H, s), 2.43 (3H, s), 3.27–3.34 (1H, m), 3.60
(3H, s), 3.67 (3H, s), 4.13 (1H, dd, J=7, 10 Hz), 4.17
(1H, dd, J=7, 10 Hz), 6.67 (1H, d, J=8 Hz), 6.78 (1H,
d, J=2 Hz), 6.97 (1H, dd, J=2, 8 Hz), 7.27 (2H, d,
J=8 Hz), 7.67 (2H, d, J=8 Hz).
1
+10.0 (c=0.5, CHCl3) corresponding to >99% e.e.: H
NMR: 1.28 (3H, d, J=7 Hz), 1.67–1.86 (4H, m), 2.26
(3H, s), 3.16 (1H, sextet, J=7 Hz), 4.42–4.45 (2H, t,
J=6 Hz), 4.91 (1H, s), 6.64 (1H, d, J=8 Hz), 6.85 (1H,
dd, J=2, 8 Hz), 6.95 (1H, s), 9.14 (2H, d, J=2 Hz),
9.21 (1H, t, J=2 Hz). Anal. calcd for C19H20N2O7: C,
58.76; H, 5.19; N, 7.21. Found: C, 58.38; H, 5.16; N,
7.39%. FAB MS m/z: 388 (M+).
(iii) A solution of (S)-7 (1.79 g, 4.4 mmol) and NaBH4
(0.83 g, 21.9 mmol) in DMSO (12 mL) was warmed for
2 h at 80°C, then allowed to cool. The reaction mixture
was worked up in the same way as for the preparation
of (+)-8 and (+)-9 to afford a mixture (2.45 g) of (+)-8
and (+)-9.
3.10. 4-(2%-Methoxymethyloxy-5%-methylphenyl)pentanyl
3,5-dinitrobenzoate (S)-13
(iv) To a suspension of LiAlH4 (0.6 g, 15.8 mmol) in
THF (20 mL) was added a solution of the above
mixture in THF (20 mL) and the whole mixture was
stirred at room temperature for 3 h. Small amounts of
acetone, ether and 7% aqueous NaHCO3 were added to
the reaction mixture and the organic layer was sepa-
rated. The organic layer was washed with saturated
brine and dried over MgSO4. The organic layer was
To a solution of (S)-12 (0.178 g, 0.46 mmol) in MeCN
(1 mL) was added N,N-diisopropylethylamine (1.6 g,
12.4 mmol) and chloromethylmethyl ether (MOMCl;
0.67 g, 8.82 mmol) at 0°C and the mixture was stirred
at 40°C for 12 h. After ether was added to the reaction
mixture, the organic layer was washed with saturated
brine and dried over MgSO4. Evaporation of the
organic solvent gave a crude oil which was chro-
matographed on silica gel (10 g) to afford (S)-13 (0.174
g, 88% yield) as a homogeneous oil from n-hex-
ane:AcOEt=20:1 eluent. (S)-13: [h]2D4 +4.6 (c=0.66,
CHCl3), IR (neat): 1729, 1564 cm−1; 1H NMR: 1.26
(3H, d, J=7 Hz), 1.66–1.85 (4H, m), 2.28 (3H, s), 3.27
(1H, sextet, J=7 Hz), 3.47 (3H, s), 4.42 (2H, t, J=6
Hz), 5.15 (1H, d, J=6 Hz), 5.17 (1H, d, J=6 Hz), 6.94
(1H, dd, J=2, 8 Hz), 6.97 (1H, d, J=8 Hz), 6.99 (1H,
d, J=2 Hz), 9.13 (2H, d, J=2 Hz), 9.21 (1H, t, J=2
Hz). Anal. calcd for C21H24N2O8: C, 58.33; H, 5.59; N,
6.48. Found: C, 58.49; H, 5.74, N, 6.31.%. FAB MS
m/z: 432 (M+).
evaporated to give
a residue which was chro-
matographed on silica gel (60 g) to afford (S)-9 (0.745
g, 70% overall yield from (S)-6) as a homogeneous oil
from n-hexane:AcOEt=10:1 eluent. (S)-9: [h]2D6 +7.97
(c=0.5, CHCl3). The NMR data of (S)-9 were identical
with those of (+)-9.
3.9. 4-(2%-Hydroxy-5%-methylphenyl)pentanyl 3,5-dinitro-
benzoate (S)-12
(i) To a solution of (S)-9 (0.20 g, 0.96 mmol) in EtSH
(3 mL) was added a mixture of AlCl3 (0.64 g, 4.8 mmol)
in EtSH (1 mL) at 0°C, and the mixture was stirred for
0.5 h at the same temperature. After ether and 0.2 M
aqueous HCl were added to the reaction mixture, the
organic layer was washed with saturated brine and
dried over MgSO4. Evaporation of the organic solvent
gave a crude oil which was chromatographed on silica
gel (10 g) to afford (4S)-(2%-hydroxy-5%-methyl-
phenyl)pentanol (0.169 g, 91% yield) as a homogeneous
oil from n-hexane:AcOEt=4:1 eluent. (4S)-(2%-
Hydroxy-5%-methylphenyl)pentanol: [h]2D4 +11.0 (c=
3.11. 4-(2%-Methoxymethyloxy-5%-methylphenyl)pentanol
(S)-14
A mixture of (S)-13 (0.154 g, 0.36 mmol) and K2CO3
(40 mg) in MeOH (2 mL) was stirred at room tempera-
ture for 1 h. The reaction mixture was diluted with
Et2O, washed with saturated brine and the organic
layer was dried over MgSO4. Evaporation of the
organic solvent gave a crude oil which was chro-
matographed on silica gel (10 g) to afford (S)-14 (0.079
g, 93% yield) as a homogeneous oil from n-hex-
1
0.72, CHCl3), IR (neat): 3400 cm−1 (OH); H NMR:
1.24 (3H, d, J=7 Hz), 1.45–1.74 (4H, m), 2.05 (1H, m),

M. Ono et al. / Tetrahedron: Asymmetry 12 (2001) 2597–2604
2603
ane:AcOEt=4:1 eluent. (S)-14: [h]2D2 +9.9 (c=0.51,
3.14. Methyl 5-hydroxy-4-(2%-methoxy-5%-methylphenyl)-
(2E)-pentenoate (R)-3
1
CHCl3), IR (neat): 3353 cm−1; H NMR: 1.22 (3H, d,
J=7 Hz), 1.41–1.71 (4H, m), 2.28 (3H, s), 3.20 (1H,
sextet, J=7 Hz), 3.46 (3H, s), 3.60 (2H, t, J=6 Hz),
5.15 (2H, s), 6.92 (1H, dd, J=2, 8 Hz), 6.95 (1H, d,
J=8 Hz), 6.98 (1H, d, J=2 Hz). Anal. calcd for
C14H22O3: C, 70.56; H, 9.30. Found: C, 70.03; H,
9.50%. FAB MS m/z: 238 (M+).
To a solution of (S)-4 (96% e.e., 0.593 g, 2 mmol) in
MeOH (1 mL) was added 0.5 M MeONa/MeOH (6
mL) at 0°C and the whole mixture was stirred at the
same temperature for 30 min. After 7% aqueous
NaHCO3 and Et2O were added to the reaction mixture,
the organic layer was washed with saturated brine and
dried over MgSO4. The organic layer was evaporated to
give a residue which was chromatographed on silica gel
(30 g, n-hexane:AcOEt=5:1) to afford (R)-3 (0.46 g,
90% yield) as a homogeneous oil. The spectral data of
(R)-3 were identical with those of (S)-3. [h]2D6 +8.5
(c=0.51, CHCl3).
3.12. 2-Methyl-(6S)-(2%-methoxymethyloxy-5%-methyl)-
phenyl-2-heptene (S)-15
(i) Pyridinium chlorochromate (PCC, 0.4 g, 1.86 mmol)
was added to a mixture of (S)-14 (0.077 g, 0.33 mmol)
and Celite 545 (0.2 g) in CH2Cl2 (2 mL) at 0°C. The
reaction mixture was stirred for 2 h at room tempera-
ture and filtered. The filtrate was subjected to short
column chromatography (n-hexane:AcOEt=20:1) to
give an aldehyde (0.06 g). (ii) This was added to a
solution of triphenylisopropylphosphonium iodide (0.22
g, 0.5 mmol) and n-BuLi in hexane (1.6 M, 0.32 mL,
0.5 mmol) in tetrahydrofuran (THF, 3 mL) under
stirring and the whole mixture was stirred for 1.5 h at
room temperature. After ether and aqueous NH4Cl
were added to the reaction mixture, the organic layer
was washed with saturated brine and dried over
MgSO4. The organic layer was evaporated to give a
residue which was chromatographed on silica gel (10 g,
n-hexane:AcOEt=50:1) to afford (S)-15 (0.016 g, 19%
overall yield from (S)-14) as a homogeneous oil. (S)-15:
3.15. 4-(2%-Methoxy-5%-methylphenyl)pentanol (R)-9
(i) Tosylate (R)-6 was prepared in 95% yield in the
same way as for the preparation of (S)-6. The spectral
data of (R)-6 were identical with those of (S)-6. (ii) The
successive treatment of (R)-6 in the same way as for the
conversion of (S)-6 to (S)-9 gave (R)-9 in 78% overall
yield from (R)-3. The spectral data of (R)-9 were
identical with those of (S)-9. [h]2D6 −9.5 (c=0.5, CHCl3).
3.16. 4-(2%-Hydroxy-5%-methylphenyl)pentanyl 3,5-dinitro-
benzoate (R)-12
3,5-Dinitrobenzoate (R)-12 was prepared in 50% over-
all yield from (R)-9 in the same way as for the prepara-
tion of (S)-12. The spectral data of (R)-12 were
identical with those of (S)-12. Mp 120–122°C. [h]D23
−11.6 (c=0.5, CHCl3).
1
[h]2D7 +19.6 (c=0.16, CHCl3). IR (neat): 1011 cm−1; H
NMR: 1.20 (3H, d, J=7 Hz), 1.53 (3H, s), 1.67 (3H, s),
1.50–1.59 (1H, m), 1.59–1.68 (1H, m), 1.86–1.97 (2H,
m), 2.27 (3H, s), 3.17 (1H, sextet, J=7 Hz), 3.47 (3H,
s), 5.12 (1H, br. t, J=7 Hz), 5.14 (2H, s), 6.91 (1H, dd,
J=2, 8 Hz), 6.94 (1H, d, J=8 Hz), 6.97(1H, d, J=2
Hz). FAB MS m/z: 262 (M+).
3.17. 4-(2%-Methoxymethyloxy-5%-methylphenyl)pentanyl
3,5-dinitrobenzoate (R)-13
3.13. (S)-Elvirol 1
The MOM ether (R)-13 was prepared in 86% yield in
the same way as for the preparation of (S)-13. The
spectral data of (R)-13 were identical with those of
(S)-13.
A solution of (S)-15 (0.016 g, 0.06 mmol), 2 M aqueous
HCl (0.5 mL) in isopropanol (1 mL) was warmed at
60°C for 3.5 h. After ether was added to the reaction
mixture, the ether layer was washed with saturated
brine and dried over MgSO4. The organic layer was
3.18. 4-(2%-Methoxymethyloxy-5%-methylphenyl)pentanol
(R)-14
evaporated to give
a residue which was chro-
matographed on silica gel (10 g, n-hexane:AcOEt=
50:1) to afford (S)-1 (0.0046 g, 34%) as a homogeneous
oil. (S)-1: [h]2D0 +36.1 (c=0.46, CHCl3). IR (neat): 3409
The MOM alcohol (R)-14 was prepared in 74% yield in
the same way as for the preparation of (S)-14. The
spectral data of (R)-14 were identical with those of
(S)-14. [h]2D2 −10.0 (c=0.5, CHCl3).
1
cm−1; H NMR (CCl4:CDCl3=5:1): 1.17 (3H, d, J=7
Hz), 1.49 (3H, br.s), 1.48–1.54 (1H, m), 1.61–1.68 (1H,
m), 1.62 (3H, br.s), 1.82–1.95 (2H, m), 2.21 (3H, s), 3.00
(1H, sextet, J=7 Hz), 5.05 (1H, t, J=7 Hz), 6.53 (1H,
d, J=8 Hz), 6.68 (1H, dd, J=2, 8 Hz), 6.80 (1H, d,
J=2 Hz). 13C NMR (CDCl3): 17.67 (q), 20.73 (q),
21.00 (q), 25.73 (q), 26.10 (t), 31.67 (d), 37.28 (t), 115.31
(d), 124.61 (d), 127.05 (d), 127.62 (d), 130.03 (s), 132.06
(s), 132.80 (s), 150.77 (s). Anal. HRMS calcd for
C15H22O (M+, m/z): 218.1677. Found: 218.1670. The
spectral data (1H NMR) were identical with those of
the reported ( )-1.5b
3.19. 2-Methyl-(6R)-(2%-methoxymethyloxy-5%-methyl)-
phenyl-2-heptene (R)-15
The MOM ether of elvirol (R)-15 was prepared in 39%
overall yield from (R)-14 in the same way as for the
preparation of (S)-15. The spectral data of (R)-15 were
identical with those of (S)-15. [h]2D7 −18.7 (c=0.16,
CHCl3).

2604
M. Ono et al. / Tetrahedron: Asymmetry 12 (2001) 2597–2604
Ghisalberti, E. L.; Jefferies, P. R.; Stuart, A. D. Aust. J.
3.20. (R)-Elvirol 1
Chem. 1979, 32, 1627–1630.
The (R)-Elvirol 1 (30 mg) was prepared in 58% yield
from (R)-15 in the same way as for the preparation of
(S)-1. The spectral data of (R)-1 were identical with
those of (S)-1. [h]3D0 −37.1 (c=0.23, CHCl3).
4. McEnroe, F. J.; Fenical, W. Tetrahedron 1978, 34, 1661–
1664.
5. (a) Bohlmann, F.; Ko¨rnig, D. Chem. Ber. 1974, 107,
1777–1779; (b) Dennison, N. R.; Mirrington, R. N.; Stu-
art, A. D. Aust. J. Chem. 1975, 28, 1339–1343; (c) Tanaka,
J.; Adachi, K. Nippon Kagakukaishi 1979, 758–764.
6. Recently, the studies of lipase-catalyzed transesterification
of 2-phenyl-1-propanol with vinyl esters having aromatic
ring in acyl moiety are extensively carried out. (a)
Kawasaki, M.; Goto, M.; Kawabata, S.; Kodama, T.;
Kometani, T. Tetrahedron Lett. 1999, 40, 5223–5226; (b)
Kawasaki, M.; Goto, M.; Kawabata, S.; Kometani, T.
Tetrahedron: Asymmetry, 2001, 12, 585–596.
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