Enzyme-mediated preparation of optically active 1,2-diols bearing a long chain: Enantioselective hydrolysis of cyclic carbonates

Article abstract of DOI:10.1016/S0040-4020(00)00904-2

A new entry for the efficient preparation of optically active 1,2-diols having a long aliphatic chain via an enzymatic reaction is disclosed. PPL catalyzes the hydrolysis of a racemic five-membered cyclic carbonate, 4-(%benzyloxy)heptyl-1,3-dioxolan-2-one (2a), with high enantioselectivity to produce the optically active (R)-2a and (S)-9-benzyloxynonane-1,2-diol (3a) in excellent yields. The reaction is applicable to the substrates with a longer chain (10-benzyloxydecyl (3b) and 13-benzyloxytridecyl group (3c)). Optically pure (S)-(+)-8hydroxyhexadecanoic acid (1), a biologically active natural compound with a chiral long aliphatic part, is effectively synthesized starting from (R)-3-(7-benzyloxy)heptyl-2-oxirane (9), which is converted from both enantiomers of 3a. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00904-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9281±9288
Enzyme-Mediated Preparation of Optically Active
1,2-Diols Bearing a Long Chain: Enantioselective Hydrolysis of
Cyclic Carbonates
*
Megumi Shimojo, Kazutsugu Matsumoto and Minoru Hatanaka
Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Fukui University, Bunkyo 3-9-1, Fukui 910-8507, Japan
Received 23 August 2000; accepted 29 September 2000
AbstractÐA new entry for the ef®cient preparation of optically active 1,2-diols having a long aliphatic chain via an enzymatic reaction is
disclosed. PPL catalyzes the hydrolysis of a racemic ®ve-membered cyclic carbonate, 4-(7-benzyloxy)heptyl-1,3-dioxolan-2-one (2a), with
high enantioselectivity to produce the optically active (R)-2a and (S)-9-benzyloxynonane-1,2-diol (3a) in excellent yields. The reaction is
applicable to the substrates with a longer chain (10-benzyloxydecyl (3b) and 13-benzyloxytridecyl group (3c)). Optically pure (S)-(1)-8-
hydroxyhexadecanoic acid (1), a biologically active natural compound with a chiral long aliphatic part, is effectively synthesized starting
from (R)-3-(7-benzyloxy)heptyl-2-oxirane (9), which is converted from both enantiomers of 3a. q 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
hydrolysis of various kinds of ®ve-membered cyclic carbon-
ates, resulting in the formation of a variety of optically
active 1,2-diols.12 Scheme 1 shows the proposed reaction
mechanism. In the ®rst step, the enzyme attacks the carbon-
yl group of the substrate, and water molecules attack the
acyl-enzyme intermediates in the second step. While the
®rst step is reversible, the second step is not reversible
because the acyl moiety of the substrate leaves the reaction
system as carbon dioxide. When the enzyme recognizes the
stereochemistry of the substrate, the unreacted (R)-cyclic
carbonate and the resulting (S)-diol are obtained in optically
active forms. These products are easily separated because
their physical properties, such as boiling point and polarity,
are quite different. Interestingly, the increment in the carbon
number of the substituents in the substrates leads to a drastic
increase in enantioselectivity. These facts indicate that this
enzymatic method can be useful for the preparation of
optically active 1,2-diols bearing a long aliphatic chain,
the diols of which are important precursors to natural
products including part of the chiral secondary alcohol. In
this report, we have established the enantioselective
enzymatic hydrolysis of the substrates with a long carbon
chain, and a new entry for an ef®cient synthesis of (S)-1 via
the enzymatic reaction as the key step.12d
Many biologically active compounds, such as sphingo-
fungins,1,2 lipid A,3 coriolic acid,4,5 and so on, have a long
chiral aliphatic part. (S)-(1)-8-Hydroxyhexadecanoic acid (1)
is a hydroxy-fatty acid, which is an endogeneous inhibitor for
spore germination in Lycopodium complanatum and
Lygodium japonicum.6,7 The compound is also known as a
component of the resin produced by the insect genus
Laccifer.8 In spite of its simple structure, it is dif®cult to
synthesize 1 in an optically pure form because the asymmetric
carbon is located at a remote position from the terminus. Such
structures have been generally constructed by several tedious
steps starting from an optically active C3- or C4-unit (Fig. 1).
The enzymatic reaction is one of the attractive methods for
the preparation of optically active compounds.9 Recently,
the enzymatic enantioselective hydrolysis of cyclic carbo-
nates has been disclosed as a useful procedure for the
preparation of optically active diols (Scheme 1).10±13 We
also reported that Porcine Pancreas Lipase (PPL, EC
3.1.1.3, Type II from Sigma) ef®ciently catalyzed the
Results and Discussion
Figure 1.
Enzymatic hydrolysis of cyclic carbonates bearing a long
chain dl-2
Keywords: cyclic carbonates; enzymes and enzyme reactions; diols;
hydrolysis.
* Corresponding author. Fax: 181-776-27-8747;
e-mail: mkazu@acbio2.acbio.fukui-u.ac.jp
In order to prepare useful chiral building blocks, it is
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00904-2

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M. Shimojo et al. / Tetrahedron 56 (2000) 9281±9288
Scheme 1.
Scheme 2. (i) BnBr, NaH/THF, re¯ux (5a: 54% (recovery of 4a, 35%); 5b: 51% (recovery of 4b, 35%);5c: 48% (recovery of 4c, 33%)); (ii) TsCl, py/CH2Cl2,
rt; (iii) NaI/acetone, rt (7a: 86% from 5a; 7b: 79% from 5b; 7c: 60% from 5c); (iv) CH2vCHCH2MgBr, cat. Li2CuCl4/THF, 08C (8a: 83%; 8b: 76%; 8c: 98%);
(v) cat. OsO4, NMO/acetone±H2O, rt (3a: 88%; 3b: 79%; 3c: 60%); (vi) triphosgene, py/CH2Cl2, 278!08C (2a: 84%; 2b: 91%; 2c: 97%).
desirable that the substrate has a functional group protected
by an appropriate group at the terminus. We have already
tried the PPL-mediated reaction for the substrates having
benzyloxymethyl, (2-benzyloxy)ethyl, and (3-benzyloxy)-
propyl group.12a,b Herein, we focused on the compounds
bearing longer substituents. The racemic 4-(7-benzyloxy)-
heptyl-(dl-2a, nˆ7), 4-(10-benzyloxy)decyl-(dl-2b, nˆ10),
and 4-(13-benzyloxy)tridecyl-1,3-dioxolan-2-one (dl-2c,
nˆ13) were then selected as the substrates. The substrates
dl-2 were readily prepared according to Scheme 2. Mono-
hydroxyl groups of commercially available 1,6-hexane-
(4a), 1,9-nonane-(4b), and 1,12-dodecanediol (4c) were
protected with benzyl groups using benzyl bromide and
sodium hydride, and the following by tosylations and
iodinations gave the corresponding 7a, 7b, and 7c, respec-
tively. The iodides 7 were transformed into ole®ns 8 by
coupling with allylmagnesium bromide in the presence of
Li2CuCl4.14 The osmium tetraoxide oxidations of 8 gave
racemic 9-benzyloxynonane-(3a), 12-benzyloxydodecane-
(3b), and 15-benzyloxypentadecane-1,2-diol (3c), respec-
tively. Cyclic carbonates 2 were readily synthesized by
the treatments of the corresponding 3 with pyridine and
bis(trichloromethyl)carbonate (triphosgene).15
First, we examined the PPL-catalyzed reactions of dl-2a
(Scheme 3 and Table 1). In all cases, i-Pr2O was used as
the co-solvent of the reaction medium (0.1 M phosphate
buffer (pH 6.5)) because the hydrolyses without i-Pr2O
were very slow.12 As expected, the hydrolysis of dl-2a
smoothly proceeded with high enantioselectivity. Under
the conditions of 108C for 6 h (Entry 1), the reaction
proceeded to afford optically active (R)-2a (46% ee) and
(S)-3a (87% ee) in 61 and 32% yields, respectively
(conv.16ˆ0.35, E value16ˆ23). The ee of (R)-2a was deter-
mined by HPLC analysis with CHIRALCEL OB-H (Daicel
Chemical Industries, Ltd.) and a similar analysis of (S)-2a
derived from (S)-3a was also performed. When the reaction
was continued to 24 h, the enantiomerically pure (R)-2a,
[a]2D2ˆ111.3 (c 1.01, CHCl3), was produced (Entry 2).
Scheme 3.
Table 1. Enantioselective hydrolysis of cyclic carbonate dl-2a with PPL (incubation was performed using 10 mM of dl-2a with PPL in 0.1 M phosphate
buffer (pH 6.5) at 108C containing i-Pr2O as the co-solvent)
Entry
Time (h)
Conc. of i-Pr2O (% v/v)
Carbonate (R)-2a
Diol (S)-3a
Yield (%)
Conv.a
Eb
Yield (%)
Ee (%)
Ee (%)
1
2
3
6
24
24
10
10
50
61
40
51
46
.99
66
32
52
41
87
66
85
0.35
0.60
0.44
23
24
24
a Calculated by ee(2)/[ee(2)1ee(3)].
b Calculated by ln[(12Conv.)(12ee(2))]/ln[(12Conv.)(11ee(2))].

M. Shimojo et al. / Tetrahedron 56 (2000) 9281±9288
9283
Table 2. Enantioselective hydrolysis of cyclic carbonate dl-2b and 2c with PPL (incubation was performed using 10 mM of dl-2 with PPL in 0.1 M phosphate
buffer (pH 6.5) at 108C containing 10% i-Pr2O as the co-solvent)
Entry
Substrate
Time (h)
Carbonate (R)-2
Diol (S)-3
Yield (%)
Conv.
E
Yield (%)
Eea (%)
Eeb (%)
1
2
3
4
2b
2b
2c
2c
6
24
6
72
38
66
49
28
.99
9
23
55
17
39
91
68
78
71
0.24
0.59
0.10
0.41
28
27
9
24
50
10
a Determined by HPLC analysis with CHIRALCEL OJ (2b) and OB-H (2c).
b Determined by HPLC analysis after the transformation into the corresponding cyclic carbonate 2.
Although the amount of the co-solvent could improve the
enantioselectivity in our previous case,12c the addition of
more i-Pr2O (50% in the reaction medium, Entry 3) did
not change the enantioselectivity (E valueˆ24) but
decreased the reactivity.
ate 2b is most suitable for the active site of PPL and longer
chains than that of 2b do not favorably ®t.
Synthesis of (S)-(1)-8-hydroxyhexadecanoic acid (1)
As an example of demonstrating the validity of this
enzymatic reaction, we planned the ef®cient synthesis of
the naturally occurring (S)-1 in the optically pure form
(Schemes 4 and 5). First, we examined the optically active
epoxide 9 as an important intermediate for the target
molecule. Optically pure (R)-2a obtained by the enzymatic
hydrolysis as mentioned above was hydrolyzed with K2CO3
to afford (R)-3a, [a]2D2ˆ17.8 (c 0.97, MeOH). The treat-
ment of (R)-3a with p-toluenesulfonyl chloride produced
considerable amounts of the bis-tosylated product, which
was useless for the synthesis. After several trials, selective
protection of the primary hydroxyl group of (R)-3a was
achieved using 2,4,6-triisopropylbenzenesulfonyl chloride
and pyridine to afford the alcohol 10. Successive treatment
of the product 10 with K2CO3 in MeOH resulted in the
intermediate (R)-epoxide 9, [a]2D2ˆ14.5 (c 0.92, CHCl3),
in 67% yield (2 steps) and the starting material (R)-3a in
26% yield.
Next, we examined the substrates bearing a much longer
chain (dl-2b and 2c, Table 2). Changing the substituent
from the 7-benzyloxyheptyl group (2a) to the 10-benzyl-
oxydecyl group (2b) apparently increased the E value up
to 28 and 27 (Entries 1 and 2), and optically active (R)-2b
and (S)-3b were obtained. The reaction for 24 h gave opti-
cally pure (R)-2b in 38% yield. These optically active
products can be potentially useful for preparing optically
active 11-hydroxyhexadecanoic acid, which is an important
intermediate for the synthesis of biologically active macro-
cyclic glycolipids, such as calonyctin A17,18 and tricolorin
A.19,20 On the other hand, the reaction of dl-2c also
proceeded to afford the corresponding optically active
compounds (Entries 3 and 4). However, the elongation of
the side chain to the 13-benzyloxytridecyl group caused a
drastic decrease in the reactivity and enantioselectivity. In
the reaction of dl-2c for even 24 h, the conversion and E
values were only 0.41 and 10, respectively. These results
suggest that the length of substituents of the cyclic carbon-
An alternative route to 9 was also examined starting from
Scheme 4. (i) K2CO3/MeOH, rt (94%); (ii) 2,4,6-triisopropylbenzenesulfonyl chloride/py, rt; (iii) K2CO3/MeOH, rt (67% from (R)-3a; recovery of (R)-3a,
26%); (iv) triphosgene, py/CH2Cl2, 278!08C ((S)-2a, 90%, 66% ee); (v) PPL, 10% i-Pr2O in buffer, 108C, 24h ((S)-3a, 72%, 89% ee; recovery of (R)-2a,
13%, .99% ee); (vi) triphosgene, py/CH2Cl2, 278!08C ((S)-2a, 97%, 89% ee); (vii) PPL, 10% i-Pr2O in buffer, 108C, 6 h (73%); (viii) TBDMSCl, Et3N, cat.
DMAP/CH2Cl2, rt; (ix) TsCl, cat. DMAP/py, rt; (x) TBAF/THF, rt (55% from (S)-3a).
Scheme 5. (i) CH3(CH2)6MgBr/THF, 2108C; (ii) Ac2O, cat. DMAP/py, rt; (iii) H2, 5% Pd-C/EtOH, rt (67% from 9); (iv) Jones reagent/acetone, rt; (v) KOH/
MeOH±H2O, rt (68% from 15).

9284
M. Shimojo et al. / Tetrahedron 56 (2000) 9281±9288
(S)-3a obtained by the enzymatic reaction. In order to
improve the ee of (S)-3a (66% ee), we tried repeating
enzymatic reaction in the following manner. First, (S)-3a
was converted to (S)-2a, which was hydrolyzed again with
PPL to afford (S)-3a of 89% ee. In this step, optically
pure (R)-2a was also obtained in 13% yield. Second,
re-conversion to the carbonate 2a and the enzymatic
hydrolysis for 6 h gave the optically pure (S)-3a,
[a]2D4ˆ28.4 (c 0.97, MeOH). In total, an optically pure
(R)-2a of 46% and (S)-3a of 24% were obtained from
racemic 2a. The primary hydroxyl group of the resulting
optically pure (S)-3a was ef®ciently protected with t-butyl-
dimethylsilyl group to afford the alcohol 11. Inversion of the
stereochemistry was accomplished by tosylation and
deprotection to give the desired (R)-epoxide 9,
[a]1D6ˆ15.5 (c 1.21, CHCl3). Finally, optically pure 10
was synthesized in 41% yield based on racemic 2a.
Column chromatography was performed with Merck
Kieselgel 60 Art.7734. Melting points were obtained on a
Yanako melting point apparatus and were not corrected.
Porcine Pancreas Lipase (PPL, EC 3.1.1.3, Type II) was
purchased from Sigma Chemical Co. All other chemicals
were also obtained from commercial sources.
Preparation of racemic diols dl-3
6-Benzyloxy-1-hexanol (5a). Under an argon atmosphere,
to a suspension of NaH (60% in oil, 2.03 g, 50.8 mmol) in
THF (30 mL) were added a solution of 1,6-hexanediol (4a,
5.00 g, 42.4 mmol) in THF (30 mL) and benzyl bromide
(3.5 g, 50.8 mmol) at 08C. The mixture was stirred for 2 h
under re¯ux and the reaction was quenched with 0.2 M
phosphate buffer (pH 6.5). The products were extracted
with AcOEt (£4), and the organic layer was washed with
brine and dried over Na2SO4. After evaporation under
reduced pressure, the residue was puri®ed by ¯ash column
chromatography on silica gel (hexane/AcOEtˆ5/1!2/1) to
give 5a as a colorless oil (4.75 g, 54%). Diol 4a was
Next, the sequential steps consisting of alkylation with
heptylmagnesium bromide, protection with acetic
anhydride, and deprotection of the benzyl group converted
from the epoxide 9 into the primary alcohol 15 in 67% yield
(3 steps), which was the same precursor of 1 as already
reported (Scheme 5).7 Lastly, Jones oxidation and hydroly-
sis of the acetyl group gave the desired 1 in 46% yield based
on 15; mp 76±778C (lit.7a 77±79.58C), [a]2D2ˆ10.15 (c
1.73, CHCl3) (lit.7a [a]D22ˆ10.34 (c 2.2, CHCl3)). The
spectral data of 1 are identical with those reported in the
literature.6,7²
1
recovered in 35%. H NMR (500 MHz, CDCl3) d 1.31±
1.74 (m, 8H), 3.47 (t, Jˆ6.5 Hz, 2H), 3.62 (t, Jˆ6.5 Hz,
2H), 4.50 (s, 2H), 7.24±7.38 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 25.5, 26.0, 29.7, 32.7, 62.9, 70.3,
72.9, 127.5, 127.6, 128.3, 138.6; IR (neat) 3392, 2932,
2856, 1454, 1364, 1100, 1078, 1065, 1028, 736 cm21; MS
m/z (rel. intensities) 208 (M1, 26), 117 (32), 107 (85), 91
(100); HRMS m/z 208.1459 (208.1463 calcd for C13H20O2,
M1).
Conclusion
6-Benzyloxy-1-iodohexane (7a). Under an argon atmos-
phere, to a solution of alcohol (5a, 4.00 g, 19.3 mmol) in
CH2Cl2 (80 mL) was added pyridine (5.50 g, 39.0 mmol)
and p-TsCl (2.3 ml, 29.0 mmol) at 08C. The mixture was
stirred for 3 days at room temperature. The reaction was
stopped with sat. NH4Cl aqueous solution and the products
were extracted with AcOEt (£4). The organic layer was
washed with 1 M HCl (£2), brine, sat. NaHCO3 aqueous
solution, and brine and dried over Na2SO4. After evapora-
tion, the residue 6a was used the following reaction without
puri®cation. To a solution of 6a in acetone (120 mL) were
added NaI (5.78 g, 38.6 mmol) and NaHCO3 (2.43 g,
29.0 mmol) at 08C. The mixture was stirred for 3 days at
room temperature, and the reaction was stopped with sat.
Na2S2O5 aqueous solution. The products were extracted
with AcOEt (£5), and the organic layer was washed with
sat. Na2S2O5 aqueous solution and brine, and dried over
Na2SO4. After evaporation, the residue was puri®ed by
column chromatography on silica gel (hexane/AcOEtˆ10/
In this paper, we established a facile chemoenzymatic
procedure for the preparation of optically active 1,2-diols
bearing a long aliphatic chain, which are useful inter-
mediates in the synthesis of natural products. The PPL-
mediated enzymatic hydrolysis of dl-2a followed by several
steps afforded both enantiomers of 1,2-diol 3a.The diols
were successfully transformed into (S)-(1)-8-hydroxy-
hexadecanoic acid (1). Further investigations for the applica-
tion of the enzymatic reaction are now in progress.
Experimental
General
1H (500 MHz) and 13C (125 MHz) NMR spectra were
measured on a JEOL Lambda 500 with tetramethylsilane
(TMS) as the internal standard. IR spectra were recorded
with a Hitachi 270-30 spectrometer. Mass spectra were
obtained with a JEOL JMS-700T by the EI method. Optical
rotations were measured with a Jasco DIP-181 and DIP-
1030 polarimeter. HPLC data were obtained on a Jasco
TRI ROTAR-VI and UVIDEC-100-VI. Merck Kieselgel
60 F254 Art.5715 was used for analytical TLC. Preparative
TLC was performed on Merck Kieselgel 60 F254 Art.5744.
1
1) to give 7a as a colorless oil (5.10 g, 86% from 5a). H
NMR (500 MHz, CDCl3) d 1.36±1.45 (m, 4H), 1.58±1.65
(m, 2H), 1.79±1.86 (m, 2H), 3.18 (t, Jˆ7.0 Hz, 2H), 3.47 (t,
Jˆ6.5 Hz, 2H), 4.50 (s, 2H), 7.26±7.37 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 7.03, 25.5, 30.3, 33.5, 70.2, 72.9,
127.5, 127.6, 128.3, 138.6; IR (neat) 3020, 2928, 2852,
1454, 1366, 1206, 1168, 1104, 734, 698 cm21; MS m/z
(rel. intensities) 318 (M1, 19), 173 (100), 155 (43), 131
(59), 107 (69); HRMS m/z 318.0467 (318.0481 calcd for
C13H19OI, M1).
²
The optical rotations of the intermediates including 1 showed low values.
However, the compound 1 must be obtained in an optically pure form
because the preparation of the epoxide 9 from the diols (R)- and (S)-3a
and the following sequential steps to 1 are the chemically established
methods.
8-Benzyloxy-1-nonene (8a). Under an argon atmosphere,
allylmagnesium bromide (1.0 M in Et2O, 47.2 mL) was

M. Shimojo et al. / Tetrahedron 56 (2000) 9281±9288
9285
added to a solution of 7a (5.01 g, 0.016 mol) in THF
(30 mL) at 08C, followed by addition of a solution of
Li2CuCl4 (1.74 g, 7.9 mmol)14 in THF (10 mL) at 08C.
The mixture was stirred for 2 h. The reaction was quenched
with sat. NH4Cl aqueous solution and the products were
extracted with Et2O (£4). The organic layer was washed
with brine and dried over Na2SO4. After evaporation, the
residue was puri®ed by column chromatography on silica
gel (hexane/AcOEtˆ50/1) to give 8a as a colorless oil
(t, Jˆ7.0 Hz, 2H), 3.46 (t, Jˆ6.5 Hz, 2H), 4.50 (s, 2H),
7.18±7.42 (m, 5H); 13C NMR (125 MHz, CDCl3) d 7.26,
26.1, 28.4, 29.3, 29.7, 30.4, 33.5, 70.4, 72.8, 127.4, 127.6, 128.3,
138,6; IR (neat) 2924, 2848, 1738, 1454, 1368, 1240, 1102,
cm21; MS m/z (rel. intensities) 360 (M1, 12), 269 (14), 155
(24), 141 (4.0), 123 (24), 107 (15), 91 (100); HRMS m/z
360.0954 (360.0951 calcd for C16H25OI, M1).
1-Benzyloxy-11-dodecene (8b). According to the pro-
cedure for the preparation of 8a described above, 7b
(4.2 g, 11.6 mmol) was converted to 8b (2.4 g, 76%) as a
colorless oil. 1H NMR (500 MHz, CDCl3) d 1.22±1.43 (m,
14H), 1.61 (tt, Jˆ7.0 Hz, 2H), 2.04 (dt, Jˆ7.0 Hz, 2H), 3.46
(t, Jˆ6.5 Hz, 2H), 4.50 (s, 2H), 4.93 (dd, Jˆ1.0, 10.0 Hz,
1H), 4.99 (dd, Jˆ1.0, 17.0 Hz, 1H), 5.81 (tdd, Jˆ4.5, 10.0,
17.0 Hz, 1H), 7.24±7.37 (m, 5H); 13C NMR (125 MHz,
CDCl3) d 26.2, 28.9, 29.1, 29.3, 29.46, 29.53, 29.56, 29.8,
33.8, 70.5, 72.8, 114.1, 127.4, 127.6, 128.3, 138.8, 139.2; IR
(neat) 3060, 3024, 2924, 2852, 1454, 1362, 1104, 1026, 994,
1
(3.03 g, 83%). H NMR (500 MHz, CDCl3) d 1.25±1.40
(m, 8H), 1.61 (tt, Jˆ7.5, 7.0 Hz, 2H), 2.03 (td, Jˆ7.5,
7.0 Hz, 2H), 3.46 (t, Jˆ6.5 Hz, 2H), 4.50 (s, 2H), 4.92
(dd, Jˆ10.0, 1.0 Hz, 1H), 4.99 (dd, Jˆ17.0, 1.5 Hz, 1H),
5.80 (tdd, Jˆ17.0, 10.5, 5.0 Hz, 1H), 7.25±7.34 (m, 5H);
13C NMR (125 MHz, CDCl3) d 26.1, 28.9, 29.0, 29.3, 29.8,
33.8, 70.5, 72.9, 114.1, 127.4, 127.6, 128.3, 138.7, 139.2; IR
(neat) 3524, 3064, 3020, 2924, 2848, 1640, 1454, 1360,
1102, 910, 734, 698 cm21; MS m/z (rel. intensities) 232
(M1, 59), 161 (24), 141 (28), 107 (100); HRMS m/z
232.1770 (232.1827 calcd for C16H24O, M1).
910, 734, 698 cm21
.
dl-9-Benzyloxy-1,2-nonandiol (3a). To a solution of 8a
(2.84 g, 12.0 mmol) in acetone (150 mL) and H2O
(105 mL) were added 4-methylmorpholine N-oxide (6.0 g,
48.0 mmol), tert-butanol (10 mL), and a catalytic amount of
OsO4, and the mixture was stirred for 2 h at room tempera-
ture. After addition of Na2S2O4 and stirring for 30 min, the
mixture was ®ltrated through a celite pad, and the products
were extracted with AcOEt (£3) from the ®ltrate, washed
with brine, and dried over Na2SO4. After evaporation, the
residue was puri®ed by column chromatography on silica
gel (hexane/AcOEtˆ1/1) to give dl-3a as a colorless oil
dl-12-Benzyloxy-1,2-dodecandiol (3b). According to the
procedure for the preparation of 3a described above, 8b
(1.5 g, 5.4 mmol) was converted to 3b (728.5 mg, 79%) as
a white crystal. This was further recrystallized from
1
hexane±Et2O. Mp 56±588C; H NMR (500 MHz, CDCl3)
d 1.22±1.47 (m, 16H), 1.61 (tdd, Jˆ6.5, 7.0 Hz, 2H), 2.78
(brs, 2H), 3.46 (t, Jˆ6.5 Hz, 2H), 3.61±3.66 (m, 1H), 3.66±
3.73 (m, 1H), 4.50 (s, 2H), 7.18±7.39 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 25.5, 26.1, 29.42, 29.51, 29.58, 29.7,
33.1, 66.7, 70.5, 72.3, 72.8, 127.4, 127.6, 128.3, 138.6; IR
(KBr) 3500, 3224, 2912, 2844, 1468, 1126, 872, 734 cm21
;
1
(2.86 g, 88%). H NMR (500 MHz, CDCl3) d 1.26±1.42
MS m/z (rel. intensities) 256 (M12H2O, 2.7), 149 (3.5), 107
(8.6), 91 (100); HRMS m/z 274.2321 (274.2296 calcd for
C19H30O3, M1).
(m, 10H), 1.61 (dt, Jˆ13.5, 7.0 Hz, 2H), 2.33 (br.s, 2H),
3.41 (dd, Jˆ10.5, 7.0 Hz, 1H), 3.46 (t, Jˆ6.5 Hz, 2H),
3.63 (dd, Jˆ11.0, 2.5 Hz, 1H), 3.63±3.73 (m, 1H), 4.50
(s, 2H), 7.25±7.37 (m, 5H); 13C NMR (125 MHz, CDCl3)
d 25.4, 26.1, 29.3, 29.5, 29.7, 33.1, 66.7, 70.4, 72.3, 72.8,
127.5, 127.6, 128.3, 138.6; IR (neat) 3368, 2928, 2852,
1542, 1545, 1366, 1096, 1076, 736, 700 cm21; MS m/z
(rel. intensities) 266 (M1, 23), 249 (100), 141 (15), 91
(100); HRMS m/z 266.1826 (266.1882 calcd for C16H26O3,
M1). Anal. Calcd for C16H26O3: C, 72.14; H, 9.84%. Found:
C, 71.55; H, 9.72%.
12-Benzyloxy-1-dodecanol (5c). According to the pro-
cedure for the preparation of 5a described above, 4c
(2.02 g, 9.9 mmol) was converted to 5c (1.41 g, 48%) as a
1
colorless oil. Diol 4c was recovered in 33%. H NMR
(500 MHz, CDCl3) d 1.21±1.39 (m, 16H), 1.46±1.50 (brs,
1H), 1.52±1.64 (m, 4H), 3.46 (t, Jˆ6.5 Hz, 2H), 3.63 (t,
Jˆ6.5 Hz, 2H), 4.50 (s, 2H), 7.23±7.39 (m, 5H); 13C
NMR (125 MHz, CDCl3) d 25.7, 26.2, 29.4, 29.5, 29.6,
29.8, 32.8, 63.1, 70.5, 72.8, 127.4, 127.6, 128.3, 138.7; IR
(neat) 3412, 2924, 2852, 1454, 1364, 1102, 1076, 1028, 736,
698 cm21; MS m/z (rel. intensities) 292 (M1, 34), 274 (2.5),
201 (0.5), 185 (0.5), 107 (81), 91 (100); HRMS m/z
292.2439 (292.2402 calcd for C19H32O2, M1).
9-Benzyloxy-1-nonanol (5b). According to the procedure
for the preparation of 5a described above, 4b (5.0 g,
31.3 mmol) was converted to 5b (4.0 g, 51%) as a colorless
1
oil. Diol 4b was recovered in 35%. H NMR (500 MHz,
CDCl3) d 1.21±1.45 (m, 10H), 1.45±1.68 (m, 4H), 2.78
(brs, 1H), 3.46 (t, Jˆ6.5 Hz, 2H), 3.61 (t, Jˆ6.5 Hz, 2H),
4.50 (s, 2H), 7.22±7.38 (m, 5H); 13C NMR (125 MHz,
CDCl3) d 25.6, 26.1, 29.29, 29.32, 29.5, 29.7, 32.6, 62.9,
70.4, 72.8, 127.4, 127.6, 128.3, 138.6; IR (neat) 3426, 2924,
2848, 1718, 1454, 1368, 1102 cm21; MS m/z (rel. intensi-
ties) 250 (M1, 42), 232(0.9), 107 (79), 91, (100); HRMS m/z
250.1915 (250.933 calcd for C16H26O2, M1).
12-Benzyloxy-1-iodododecane (7c). According to the
sequential procedure for the preparation of 7a described
above, 5c (1.36 g, 4.6 mmol) was converted to 7c (1.12 g,
60% from 5c) as a colorless oil. 1H NMR (500 MHz, CDCl3)
d 1.22±1.41 (m, 16H), 1.61 (tt, Jˆ7.0 Hz, 2H), 1.81 (tt,
Jˆ7.0 Hz, 2H), 3.18 (t, Jˆ7.0 Hz, 2H), 3.46 (t, Jˆ6.5 Hz,
2H), 4.50 (s, 2H), 7.24±7.39 (m, 5H); 13C NMR (125 MHz,
CDCl3) d 7.31, 26.2, 28.5, 29.37, 29.44, 29.48, 28.49, 29.5,
29.7, 30.5, 33.5, 70.5, 72.8, 127.4, 127.6, 128.3, 138,7; IR
(neat) 2924, 2852, 1454, 1362, 1204, 1176, 1104, 1026, 734,
698, 602 cm21; MS m/z (rel. intensities) 402 (M1, 13), 311
(16), 246 (29), 123 (34), 91 (100); HRMS m/z 402.1395
(402.1420 calcd for C19H31OI, M1).
1-Benzyloxy-9-iodononane (7b). According to the sequen-
tial procedure for the preparation of 7a described above, 5b
(3.86 g, 15.4 mmol) was converted to 7b (4.2 g, 79% from
5b) as a colorless oil. 1H NMR (500 MHz, CDCl3) d 1.22±
1.45 (m, 10H), 1.56±1.65 (m, 2H), 1.76±1.86 (m, 2H), 3.18

9286
M. Shimojo et al. / Tetrahedron 56 (2000) 9281±9288
15-Benzyloxy-1-pentadecene (8c). According to the pro-
cedure for the preparation of 8a described above, 7c
(1.04 g, 2.6 mmol) was converted to 8c (0.80 g, 98%) as a
colorless oil. 1H NMR (500 MHz, CDCl3) d 1.21±1.40 (m,
20H), 1.60 (tt, Jˆ7.0 Hz, 2H), 2.04 (dt, Jˆ7.0 Hz, 2H), 3.46
(t, Jˆ6.5 Hz, 2H), 4.50 (s, 2H), 4.92 (dd, Jˆ10.0, 1.0 Hz,
1H), 4.99 (dd, Jˆ17.0, 1.5 Hz, 1H), 5.81 (tdd, Jˆ17.0, 10.5,
5.0 Hz, 1H), 7.24±7.35 (m, 5H); 13C NMR (125 MHz,
CDCl3) d 26.2, 28.9, 29.2, 29.5, 29.59, 29.63, 29.8, 33.8,
70.5, 72.8, 114.0, 127.4, 127.6, 128.3, 138.7, 139.3; IR
(neat) 2924, 2852, 1454, 1362, 1104, 1026, 994, 910, 734,
648 cm21; MS m/z (rel. intensities) 317 (M11H, 25), 226
(0.6), 207 (2.0), 107 (34), 91 (100); HRMS m/z 316.2776
(316.2766 calcd for C22H36O, M1).
1H), 4.50 (s, 2H), 4.51 (dd, Jˆ8.0, 8.5 Hz, 1H), 4.68 (tdd,
Jˆ5.5, 8.0, 8.5 Hz, 1H), 7.22±7.42 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 24.3, 26.1, 29.1, 29.26, 29.31, 29.37,
29.42, 29.7, 33.8, 69.3, 70.5, 72.8, 77.0, 127.4, 127.6, 128.3,
138.7, 155.0; IR (neat) 3472, 2924, 2848, 1802, 1168,
1064 cm21; MS m/z (rel. intensities) 316 (M1, 4.0), 255
(0.3), 228 (0.6),138 (3.8), 107 (18), 91 (100), 87 (10);
HRMS m/z 316.2023 (316.2038 calcd for C20H28O3, M1).
dl-4-(13-Benzyloxy)tridecyl-1,3-dioxolan-2-one
(2c).
According to the procedure for the preparation of dl-2a
described above, dl-3c (476.9 mg, 1.4 mmol) was converted
to dl-2c (497.5 mg, 97%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) d 1.22±1.41 (m, 18H), 1.53±1.85 (m,
2H), 3.46 (t, Jˆ6.5 Hz, 2H), 4.06 (t, Jˆ7.5 Hz, 1H), 4.50 (s,
2H), 4.53 (dd, Jˆ8.0 Hz, 1H), 4.69 (tt, Jˆ7.0 Hz, 1H),
7.24±7.35 (m, 5H); 13C NMR (125 MHz, CDCl3) d 24.3,
26.1, 29.1, 29.3, 29.40, 29.45, 29.5, 29.8, 33.9, 69.3, 70.5,
72.8, 127.4, 127.6, 128.3, 138.8, 155.0; IR (neat) 2924,
2852, 1802, 1454, 1384, 1366, 1170, 1102, 1068, 1028,
776, 736, 700 cm21; MS m/z (rel. intensities) 376 (M1,
17), 285 (4), 107 (58), 91 (100); HRMS m/z 376.2576
(376.2613 calcd for C17H24O4, M1).
dl-15-Benzyloxy-1,2-pentadecandiol (3c). According to
the procedure for the preparation of dl-3a described
above, 8c (0.77 g, 2.4 mmol) was converted to dl-3c
1
(0.50 g, 60%) as a white crystal. Mp 65±668C; H NMR
(500 MHz, CDCl3) d 1.20±1.37 (m, 22H), 1.39±1.45 (m,
2H), 1.61 (tt, Jˆ7.0 Hz, 2H), 2.16±2.38 (brs, 2H), 3.38±
3.49 (m, 2H), 3.61±3.72 (m, 1H), 4.50 (s, 2H), 7.24±7.37
(m, 5H); 13C NMR (125 MHz, CDCl3) d 25.5, 26.2, 29.4,
29.51, 29.56, 29.58, 29.6, 29.7, 33.2, 66.8, 70.5, 72.3, 72.8,
127.4, 127.6, 128.3, 138.7; IR (KBr) 3380, 2916, 2848,
2792, 1470, 1370, 1122, 1094, 1078, 1058, 1044, 1020,
736, 698 cm21; MS m/z (rel. intensities) 350 (M1, 33),
333 (9.3), 320 (29), 227 (20), 123 (17), 107 (100), 91
(100); HRMS m/z 350.2803 (350.2821 calcd for C22H38O3,
M1).
Typical procedure for the hydrolysis of cyclic carbonates
dl-2 with PPL
To a solution of 114 mg (0.39 mmol, 10 mM) of dl-2a in
i-Pr2O (4 mL) were added 0.1 M sodium phosphate buffer
(pH 6.5, 36 mL) and 500 mg of PPL, and the mixture was
incubated for 24 h at 108C. The products were extracted
with AcOEt and puri®ed using ¯ash column chromato-
graphy on silica gel (hexane/AcOEtˆ3/1!2/1!AcOEt)
to afford (R)-2a (45.5 mg, 40%, .99% ee) and (S)-3a
(53.4 mg, 52%, 66% ee).
Preparation of racemic cyclic carbonates dl-2
dl-4-(7-Benzyloxy)heptyl-1,3-dioxolan-2-one (2a). Under
an argon atmosphere, pyridine (4.9 g, 62 mmol) was added
to a solution of dl-3a (2.75 g, 0.01 mol) in CH2Cl2 (100 mL)
at 08C, followed by addition of a solution of triphosgene
(1.85 g, 6.2 mmol) in CH2Cl2 (30 mL) at 2788C. The
mixture was then slowly warmed to 08C and stirred for
1 h. The reaction was stopped with sat. NH4Cl aqueous
solution and the products were extracted with CH2Cl2
(£3). The organic layer was washed with 1 M HCl (£2),
brine and sat. NaHCO3 aqueous solution, and dried over
Na2SO4. After evaporation, the residue was puri®ed by
column chromatography on silica gel to give dl-2a
(2.14 g, 84%) as a colorless oil. 1H NMR (500 MHz,
CDCl3) d 1.26±1.79 (m, 14H), 3.46 (t, Jˆ6.5 Hz, 2H),
4.05 (dd, Jˆ8.0 Hz, 1H), 4.50 (dd, Jˆ8.0 Hz, 2H), 4.67
(tdd, Jˆ13.5, 8.5, 2.0 Hz, 1H), 7.26±7.35 (m, 5H); 13C
NMR (125 MHz, CDCl3) d 24.0, 25.8, 27.6, 28.9, 29.0,
33.5, 69.2, 70.1, 72.6, 76.9, 127.0, 127.3, 127.4, 128.1,
128.7, 138.5, 155.0; IR (neat) 2928, 2852, 1804, 1454,
1386, 1168, 1102, 1070, 776, 738, 700 cm21; MS m/z (rel.
intensities) 292 (M1, 18), 274 (8.5), 236 (7.2), 124 (24), 107
(97), 91 (100); HRMS m/z 292.1660 (292.1675 calcd for
C17H24O4, M1).
Enantioselective hydrolysis of the other substrates were
carried out by means of the same procedure. All the spectral
data (1H and 13C NMR, IR, and MS) of cyclic carbonates
and diols were in full agreement with those of the racemates.
Properties of the products and the determination methods of
the ees are as follows.
Compound (R)-2a. [a]D22ˆ111.3 (c 1.01, CHCl3), .99%
ee. The ee of (R)-2a was analyzed by HPLC. The conditions
were as follows: column, CHIRALCEL OB-H (Daicel
Chemical Industries, Ltd); Eluent, hexane/i-PrOHˆ50/50;
¯ow rate, 0.5 ml/min; retention time, 62 (R) and 74 (S) min.
Compound (S)-3a. [a]2D4ˆ28.4 (c 0.97, MeOH), .99% ee.
The ee of (S)-3a was determined by similar analysis of the
corresponding cyclic carbonate.
Compound (R)-2b. [a]D21ˆ113.2 (c 1.37, CHCl3), .99%
ee. The products were analyzed by HPLC. The conditions
were as follows: column, CHIRALCEL OJ (Daicel Chemi-
cal Industries, Ltd); Eluent, hexane/i-PrOHˆ80/20; ¯ow
rate, 0.5 ml/min; retention time, 53 (R) and 56 (S) min.
dl-4-(10-Benzyloxy)decyl-1,3-dioxolan-2-one (2b). Accord-
ing to the procedure for the preparation of dl-2a described
above, dl-3b (1.29 g, 4.2 mmol) was converted to dl-2b
(1.27 g, 91%) as a colorless oil. 1H NMR (500 MHz,
CDCl3) d 1.20±1.40 (m, 13H), 1.54±1.73 (m, 3H), 1.73±
1.85 (m, 1H), 3.46 (t, Jˆ6.5 Hz, 2H), 4.05 (dd, Jˆ8.0 Hz,
Compound (S)-3b. [a]2D1ˆ24.8 (c 1.06, MeOH), 68% ee.
The ee of (S)-3b was determined by similar analysis of the
corresponding cyclic carbonate.

M. Shimojo et al. / Tetrahedron 56 (2000) 9281±9288
9287
Compound (R)-2c. [a]D28ˆ17.6 (c 0.46, CHCl3), 50% ee.
The products were analyzed by HPLC. The conditions were
as follows: column, CHIRALCEL OB-H (Daicel Chemical
Industries, Ltd); Eluent, hexane/i-PrOHˆ80/20; ¯ow rate,
0.5 ml/min; retention time, 48 (R) and 55 (S) min.
was added p-TsCl (115 mg, 0.60 mmol) and a catalytic
amount of DMAP at 08C. The mixture was then warmed
to room temperature and stirred overnight. The reaction was
stopped with pH 6.5 buffer and the products were extracted
with AcOEt (£3). The organic layer was washed with 2 M
HCl (£2), brine, sat. NaHCO3 aqueous solution, and brine
and dried over Na2SO4. After evaporation, the residue was
used in the following reaction without puri®cation. To a
solution of 12 in THF (4 mL) was added Bn4NF´xH2O
(88 mg, 0.27 mmol) at 08C. The mixture was then warmed
to room temperature and stirred overnight. The reaction was
stopped with H2O and the products were extracted with
AcOEt (£3). The organic layer was washed with sat.
NH4Cl aqueous solution, sat. NaHCO3 aqueous solution,
and brine and dried over Na2SO4. After evaporation, the
residue was puri®ed by preparative TLC (hexane/
AcOEtˆ10/1) to afford 9 as a colorless oil (24.9 mg,
0.10 mmol). [a]1D6ˆ15.5 (c 1.21, CHCl3). All the spectral
data (1H and 13C NMR, IR, and MS) of the resulting 9 were
in full agreement with those of 9 derived from (R)-2a.
Compound (S)-3c. [a]3D2ˆ26.5 (c 0.77, MeOH), 78% ee.
The ee of (S)-3c was determined by similar analysis of the
corresponding cyclic carbonate.
Synthesis of (S)-(1)-8-hydroxyhexadecanoic acid (1)
(R)-2-(7-Benzyloxy)heptyloxirane (9) from (R)-2a. K2CO3
was added to a solution of optically pure (R)-2a in MeOH
(3 mL) at 08C, and stirred for 2 h. The reaction was stopped
with brine, and the mixture was saturated with NaCl, the
products were extracted with Et2O (£3), and the organic
layer was dried over Na2SO4. After evaporation under
reduced pressure, the residue was puri®ed by ¯ash column
chromatography on silica gel (hexane/AcOEtˆ1/1) to give
(R)-3a as a colorless oil (147.4 mg, 94%), [a]2D2ˆ17.8 (c
0.97, MeOH). 2,4,6-Triisopropylbenzenesulfonyl chloride
(210 mg, 0.35 mmol) was added to a solution of optically
pure (R)-3a in pyridine (6 mL) at 08C, and stirred for 3 days.
The reaction was stopped with H2O, and the mixture was
extracted with AcOEt (£4), and washed with 1 M HCl (£2),
brine, sat. NaHCO3 aqueous solution and brine. The organic
layer was dried over Na2SO4. After evaporation, the residue
10 was used in the following reaction without puri®cation.
K2CO3 was added to a solution of 10 in MeOH (12 mL) at
08C, and stirred for 2 h. The reaction was stopped with H2O,
and the mixture was extracted with Et2O (£3), and washed
with H2O (£2), brine, and dried over Na2SO4. After
evaporation, the residue was puri®ed by column chromato-
graphy on silica gel (hexane/AcOEtˆ5/1!2/1!1/
1!AcOEt) to afford 9 as a colorless oil (58.1 mg, 67%).
(R)-diol 3a (23.8 mg) of 26% was recovered. [a]2D2ˆ14.5 (c
0.92, CHCl3); 1H NMR (500 MHz, CDCl3) d 1.34±1.58 (m,
12H), 2.46 (dd, Jˆ5.0, 2.5 Hz, 1H), 2.74 (dd, Jˆ5.0, 4.0 Hz,
1H), 2.86±2.93 (m, 1H), 3.46 (t, Jˆ6.5 Hz, 2H), 4.50 (s, 2H),
7.25±7.38 (m, 5H); 13C NMR (125 MHz, CDCl3) d 24.7,
25.9, 26.1, 29.4, 29.7, 32.5, 47.1, 52.4, 70.4, 72.9, 127.5,
127.6, 128.3, 138.7; IR (neat) 3900, 3536, 3024, 2924,
2848, 1454, 1362, 1102, 736, 698 cm21; MS m/z (rel.
intensities) 248 (M1, 5.5), 187 (9.2), 107 (59), 91 (100);
HRMS m/z 248.1750 (248.1777 calcd for C16H24O2, M1).
(S)-8-Acetoxy-1-hexadecanoic acid (15). Under an argon
atmosphere, to a solution of 9 in THF (5 mL) was added a
solution of 0.58 M n-heptylmagnatium bromide at 08C, and
stirred for 3 h. The reaction was quenched with sat. NH4Cl
aqueous solution, and the products were extracted with Et2O
(£4), washed with brine, and dried over Na2SO4. After
evaporation, the residue 13 was used in the following reac-
tion without puri®cation. To a solution of 13 in pyridine
(2 mL) was added 137 mL of acetic anhydride and a
catalytic amount of DMAP at 08C and stirred overnight.
The reaction was stopped with H2O and the products were
extracted with AcOEt (£3), washed with 2 M HCl (£2),
brine, sat. NaHCO3 aqueous solution, and brine and dried
over Na2SO4. After evaporation, the residue 14 was used in
the following reaction without puri®cation. To a solution of
14 in EtOH (10 mL) was added 120 mg of 5% Pd-C, and the
solution was degassed under reduced pressure. The reaction
was carried out in an atmosphere of hydrogen and stirred
overnight. After the mixture was ®ltrated and evaporated in
vacuo, the residue was puri®ed by ¯ash column chromato-
graphy (hexane/AcOEtˆ5/1) to give 15 as a colorless oil
1
(63.7 mg, 69%). [a]D26ˆ21.83 (c 2.07, CHCl3); H NMR
(500 MHz, CDCl3) d 0.88 (t, Jˆ7.0 Hz, 3H), 1.21±1.34
(m, 19H), 1.48±1.59 (m, 8H), 2.04 (s, 3H), 3.64 (t,
Jˆ6.5 Hz, 2H), 4.86 (ttt, Jˆ6.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 14.1, 21.3, 22.6, 25.2, 25.3, 25.6,
29.2, 29.3, 29.4, 29.47, 29.52, 31.8, 32.7, 34.07, 34.11,
63.0, 74.4, 171.0; IR (neat) 3452, 2924, 2852, 1738, 1464,
1376, 1244, 1052, 1022, 612 cm21; MS m/z (rel. intensities)
257 (M12Ac), 239 (16), 222 (58), 187 (32), 127 (46), 109
(100); HRMS m/z 301.2739 (301.2743 calcd for C18H37O3,
M11H).
Preparation of 9 from (S)-3a
Under an argon atmosphere, to a solution of optically pure
(S)-3a (56.8 mg, 0.21 mmol) in CH2Cl2 (3 mL) was added
Et3N (178 mL, 1.28 mmol), 194 mL (0.64 mmol) of
TBDMSCl in toluene (3.3 M) and a catalytic amount of
DMAP at 08C. The mixture was then warmed to room
temperature, and stirred overnight. The reaction was
stopped with 0.2 M phosphate buffer (pH 6.5) and the
products were extracted with AcOEt (£3). The organic
layer was washed with brine and dried over Na2SO4. After
evaporation, the residue was puri®ed by column chromato-
graphy on silica gel (hexane/AcOEtˆ10/1) to give 11 as a
colorless oil. This was used in the following reaction with-
out further puri®cation. Under an argon atmosphere, to a
solution of 11 (69.4 mg, 0.18 mmol) in pyridine (2 mL)
Compound 1. To a solution of 15 (54.2 mg, 0.18 mmol) in
acetone (6 mL) was added 3 M Jones reagent (3 mL) and
stirred for 10 min at 08C. The mixture was added MeOH
(3 mL) and diluted with H2O. The products were extracted
with Et2O (£4) and dried over Na2SO4. After evaporation,
the residue 16 was used in the following reaction without
puri®cation. To a solution of 16 in MeOH (5 mL) was added
10% KOH aqueous solution at 08C and stirred for 2 h. The
reaction was stopped with H2O. The mixture was acidi®ed

9288
M. Shimojo et al. / Tetrahedron 56 (2000) 9281±9288
Legoy, M. D. J. Am. Oil Chem. Soc. 1997, 74, 641±645.
(d) Johnson, D. V.; Griengl, H. Tetrahedron 1997, 53, 617±624.
(e) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron 2000, 56, 327±331.
by the addition of 2 M HCl, and the products were extracted
with Et2O and washed with brine. After evaporation, the
residue was puri®ed by column chromatography on silica
gel (hexane/AcOEtˆ1/1!AcOEt) to afford 1 as a white
crystal (34.1 mg, 69%). Mp 76±778C; [a]2D2ˆ10.15 (c
1.73, CHCl3); 1H NMR (500 MHz, CDCl3) d 0.88 (t,
Jˆ7.0 Hz, 3H), 1.19±1.52 (m, 22H), 1.52±1.61 (m, 2H),
2.35 (t, Jˆ7.5 Hz, 2H), 3.53±3.69 (m, 1H), 5.00 (brs, 2H);
13C NMR (125 MHz, CDCl3) d 57.3, 65.9, 67.8, 68.6, 68.9,
72.2, 72.5, 72.8, 72.9, 80.7, 115.3, 120.0, 120.2, 120.4,
120.5, 222.3; IR (KBr) 3314, 3200, 2924, 2815, 1698,
1470, 1439, 1412, 1343, 1291, 1235, 1130, 1100, 1019,
901, 721 cm21; MS m/z (rel. intensities) 254 (M1, 9.4),
236 (39), 192 (9.6), 159 (100), 95 (100); HRMS m/z
254.2192 (254.2246 calcd for C16H32O3, M1). Anal. Calcd
for C16H32O3: C, 70.54; H, 11.84%. Found: C, 70.89; H,
11.74%.
6. For isolations, see: (a) Tulloch, A. P. Can. J. Chem. 1965, 43,
415±420. (b) Yamane, H.; Sato, Y.; Takahashi, N.; Takeno, K.;
Furuya, M. Agric. Biol. Chem. 1980, 44, 1697±1699.
7. For syntheses, see: (a) Masaoka, Y.; Sakakibara, M.; Mori, K.
Agric. Biol. Chem. 1982, 46, 2319±2324. (b) Sugai, T.; Mori, K.
Agric. Biol. Chem. 1984, 48, 2155±2156.
8. (a) Ichikawa, A.; Yasuda, T.; Wakamura, S. J. Chem. Ecol.
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