Synthesis of (-)-(5R,6S)-6-acetoxyhexadecanolide based on L-proline-catalyzed asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tet.2005.08.111

A convenient method for proline-catalyzed asymmetric aldol reactions using synthons of straight-chain aliphatic aldehydes, and aldehydes bearing a 1,3-dithiane moiety at the β-position, has been developed. This method was successfully applied to the synthesis of (-)-(5R,6S)-6-acetoxyhexadecanolide, an oviposition attractant pheromone of the female Culex mosquito.

Full text of DOI:10.1016/j.tet.2005.08.111

Tetrahedron 62 (2006) 311–316
Synthesis of (K)-(5R,6S)-6-acetoxyhexadecanolide based on
L-proline-catalyzed asymmetric aldol reactions
Hideaki Ikishima, Yusuke Sekiguchi, Yoshiyasu Ichikawa and Hiyoshizo Kotsuki
*
Laboratory of Natural Products Synthesis, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Received 1 June 2005; revised 8 August 2005; accepted 31 August 2005
Available online 3 October 2005
Abstract—A convenient method for proline-catalyzed asymmetric aldol reactions using synthons of straight-chain aliphatic aldehydes, and
aldehydes bearing a 1,3-dithiane moiety at the b-position, has been developed. This method was successfully applied to the synthesis of (K)-
(5R,6S)-6-acetoxyhexadecanolide, an oviposition attractant pheromone of the female Culex mosquito.
q 2005 Elsevier Ltd. All rights reserved.
8
1
. Introduction
attracted considerable attention from synthetic chemists
9
because of its ability to transmit the West Nile virus. In this
lab we reported the short synthesis of this compound based
on a chiral triflate technology starting from D-tartrate as the
chiral source. In recent years, with the increasing demand
for catalytic asymmetric transformations, major studies on
the synthesis of 1 have focused on demonstrating of the
power of newly discovered techniques. Unfortunately,
however, there are no reports on the use of organocatalytic
systems to construct this fascinating molecule, except for
the recent work of Sun et al. We describe here our own
Recent advances in the field of organocatalytic asymmetric
synthesis have provided several new methods for obtaining
chiral compounds in an environmentally benign manner.
Most attention has been focused on the use of proline due to
its ready availability in either L- or D-form and the highly
versatile nature of its reactivity. In particular, proline-
catalyzed asymmetric aldol reactions have been extensively
studied from the viewpoint of their synthetic value as well
1
10
1
,2
11
1
–3
6
as mechanistic considerations.
However, there is still a
significant limitation on the use of unsubstituted aliphatic
approach using proline-catalyzed asymmetric aldol
reactions as a key step along with straight-chain aliphatic
aldehyde synthons.
4
aldehydes as an aldol component. Initially, we thought that
this problem could be solved by applying a high-pressure
technique, but all attempts failed due to the formation of a
5
rather complex mixture. Very recently, Sun et al. reported
the use of undecanal itself for asymmetric aldol reactions of
this type and applied it in their synthesis of (K)-(5R,6S)-6-
2
. Results and discussion
6
acetoxyhexadecanolide (1). This result prompted us to
2.1. Model studies for L-proline-catalyzed asymmetric
aldol reactions
report our independent investigation on the development of
new synthons of straight-chain aliphatic aldehydes and their
application to the enantioselective synthesis of 1.
7
To survey the possible candidates for straight-chain
aliphatic aldehyde synthons, we designed three different
types of substrates, that is, thiophenecarboxaldehydes A and
aldehydes bearing a 1,3-dithiane moiety at the a- or
b-position (B and C), because of the ease at which they
are converted to the naked unbranched side chain structures
1
2
after desulfurization (Fig. 1). Thus, compounds A and B
were chosen as representative aldehydes having no
enolizable a-hydrogens, while with C it can be expected
that the 1,3-dithiane function can act effectively as steric
(K)-(5R,6S)-6-Acetoxyhexadecanolide (1), an oviposition
attractant pheromone of the female Culex mosquito, has
1
3
bulk to impede the undesired side reactions.
Keywords: Proline; Aldol; Aldehydes; Oviposition attractant pheromone.
*
Corresponding author. Tel.: C81 888 44 8298; fax: C81 888 44 8359;
e-mail: kotsuki@cc.kochi-u.ac.jp
To confirm the feasibility of our synthetic strategy, we then
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.111

312
H. Ikishima et al. / Tetrahedron 62 (2006) 311–316
aldehyde carbonyl center (runs 4–6). Fortunately, we found
that the use of aldehyde 5 led to the preferential formation of
syn-adduct 6 with high enantioselectivity (runs 7–9).
Apparently, in 5 the b-dithiane functionality exerts a
remarkable effect in determining the reaction course with
favorable diastereo- and enantioselective control. With
these results in hand, we proceeded with the asymmetric
synthesis of 1.
2.2. Total synthesis of (K)-(5R,6S)-6-acetoxyhexa-
decanolide (1)
Figure 1. Straight-chain aliphatic aldehyde synthons.
The required aldehyde 11 was readily prepared from ethyl
Table 1. L-Proline-catalyzed asymmetric aldol reactions of cyclopentanone (2) with aldehydes 3–5
a
b
c
Run
Aldehyde
Conditions
Yield (%)
dr 6/7
ee (%)
6
7
d
1
2
3
4
5
6
7
8
9
3
3
3
4
4
4
5
5
5
DMSO, rt, 30 h
Solvent-free, rt, 84 h
82
79
48:52
47:53
41:59
31
43
15
34
48
22
Solvent-free, 0.2 GPa, rt, 60 h
d
DMSO, rt, 72 h
Solvent-free, rt, 72 h
Solvent-free, 0.2 GPa, rt, 24 h
d
DMSO, rt, 9 h
Solvent-free, rt, 6 h
Solvent-free, 0.2 GPa, rt, 12 h
77
No reaction
No reaction
No reaction
75
81
86
80:20
80:20
73:27
93
93
90
86
85
88
a
Compound 2:aldehyde 34:1, except in DMSO (6.5 equiv of 2).
Determined by H NMR.
Determined by chiral HPLC (Chiralpak AD).
Compound 2:DMSO 1:4 (vol%).
b
c
d
1
1
7
examined the asymmetric aldol reactions of cyclopentanone
acetoacetate (8) after chain elongation as illustrated in
Scheme 1. We then proceeded to complete the total
synthesis of 1 according to our original idea (Scheme 2).
(
(
2) with thiophenecarboxaldehyde 3 (A, RZH), aldehydes 4
B, RZC H ) and 5 (C, RZH) under the catalysis of
2
5
L-proline. The starting aldehydes 4 and 5 were prepared
1
4
from 2-pentyl-1,3-dithiane via well-known lithiation/
formylation or by the sequential treatment of ethyl
acetoacetate according to the literature procedure.
15
All reactions were examined under three different con-
ditions: (1) in DMSO as a solvent at room temperature; (2)
solvent-free at room temperature; and (3) solvent-free at
Scheme 1.
0
.2 GPa pressure and room temperature. As can be seen
1
6
from the results summarized in Table 1, there is a
significant difference in reactivity and stereoselectivity
between 3–5.
The aldol reaction of 11 with cyclopentanone (2, ca.
30 equiv) in the presence of 30 mol% of L-proline under
solvent-free conditions at 13 8C for 20 h proceeded quite
smoothly to give syn- and anti-adducts, 12 and 13, as a
1
8,19
Thus, thiophenecarboxaldehyde (3) gave the desired
adducts 6 and 7 in good yields, but diastereo- and
enantioselectivity were only moderate under either con-
dition (runs 1–3). Aldehyde 4 was inert under these
conditions, indicating severe steric hindrance around the
75:25 mixture in a combined yield of 85%.
The
enantiomeric purities of 12 and 13 were determined to be
83 and 90%, respectively, by chiral HPLC analysis
(Chiralpak AD, elution with hexane/2-propanol 90:10).
After chromatographic separation, careful treatment of the

H. Ikishima et al. / Tetrahedron 62 (2006) 311–316
313
or cannula through a rubber septum. All high-pressure
reactions were performed in a piston-cylinder type
apparatus (Hikari Koatsu HR-15-B3).
All melting points were measured on Yanagimoto MP-S3
micro-melting point apparatus and were uncorrected. The
NMR spectra were recorded on a JEOL LA 400 (400 MHz
1
13
for H NMR analysis and 100 MHz for C NMR analysis).
All NMR spectra were taken in CDCl solution and were
3
reported in part per millions (d) downfield from TMS as an
internal standard. The infrared spectra were measured with a
JASCO FTIR-460plus Fourier Transform Infrared Spectro-
K1
photometer and were reported in wavenumbers (cm ).
Optical rotations were measured on a JASCO DIP-370
polarimeter. HPLC analysis was carried out using a Hitachi
L-6200 HPLC system.
Thin-layer chromatography (TLC) was conducted by using
Merck Kieselgel 60F-254 plates (0.25 mm). For column
chromatography, Fuji silicia BW-300 and, for flash
chromatography, Merck Kieselgel (230–400 mesh) was
employed.
4.1.1. 2-Pentyl-1,3-dithiane-2-carbaldehyde (3). To a
stirred solution of 2-pentyl-1,3-dithiane (1.82 g,
9
1
.6 mmol) in dry THF (43 mL) at K78 8C was added
4
Scheme 2.
n-BuLi (7.1 mL, 11.2 mmol; 1.58 M in hexanes) and the
mixture was stirred for 2 h. To this light yellow solution was
then added dry DMF (0.77 mL, 10 mmol) and the mixture
was stirred at K78 8C for 1 h. The mixture was quenched
with H O and extracted with CHCl . The combined extracts
2
0
syn-adduct 12 with Raney-Ni (W-4) in ethyl acetate as a
solvent gave the desired b-hydroxy ketone 14 in 62% yield
as a somewhat unstable product. Therefore, this was
immediately subjected to Baeyer–Villiger oxidation by
exposure to 3 equiv of m-CPBA and 3 equiv of NaHCO3,
and the hydroxy-lactone 15 was obtained in 90% yield as a
highly crystalline substance. Recrystallization from ether/
2
3
were dried (MgSO ), concentrated, and purified by silica gel
4
column chromatography (hexane/AcOEt 9:1) to give 3
(1.3 g, 62%) as a colorless oil. R 0.47 (hexane/Et O 4:1);
2
D
0
f 2
hexane gave optically pure 15; mp 67–68 8C, [a] K12.7 (c
1.0, CHCl ) (lit. mp 66.5–68 8C, [a] K11.0 (c 1.5,
3 D
CHCl )), which was finally converted into 1 by acetylation
under normal conditions in quantitative yield. This
compound, [a] K36.8 (c 1.55, CHCl ) (lit. [a] K36.8
c 1.0, CHCl )), was identical in all respects to the authentic
3
1
FTIR (neat) 1715, 1465, 1424; H NMR: 0.88 (3H, t, JZ
.1 Hz), 1.22–1.36 (4H, m), 1.42–1.50 (2H, m), 1.74–1.86
3H, m), 2.10 (1H, dtt, JZ14.2, 4.1, 2.4 Hz), 2.60 (2H, ddd,
6
7
(
3
JZ14.6, 4.1, 3.2 Hz), 3.02 (2H, ddd, JZ14.6, 12.9, 2.4 Hz);
C NMR: 13.8, 22.2, 23.4, 24.5, 26.7 (!2), 31.9, 35.9,
2
D
1
10
24
D
13
3
(
sample.
58.1, 189.6. Anal. Calcd for C H OS : C, 55.00; H, 8.31.
Found: C, 55.08; H, 8.50.
1
0
10 18 2
4.2. General procedure for the L-proline-catalyzed
asymmetric aldol reactions
3. Conclusions
In conclusion, we have developed a convenient method for
the asymmetric aldol reactions of ketones with aldehydes
bearing a 1,3-dithiane moiety at the b-position as
convenient synthons of straight-chain aliphatic aldehydes.
The reaction was successfully applied to the synthesis of 1.
This approach might be useful for preparing a variety of
enantiomerically enriched b-hydroxy ketone derivatives,
and further studies to extend the scope of this method are
now in progress.
Method A (in DMSO at 1 atm and room temperature). A
mixture of aldehyde (0.5 mmol), cyclopentanone (2,
0.3 mL, 3.4 mmol) and L-proline (17 mg, 0.15 mmol) in
dry DMSO (1.2 mL) was stirred at room temperature under
Ar. After completion of the reaction, the mixture was
quenched with water and the aqueous phase was extracted
with CHCl . The combined extracts were dried (MgSO ),
3
4
concentrated, and purified by silica gel column chromato-
graphy to give the pure syn- and anti-aldol adducts.
Method B (solvent-free at 1 atm and room temperature). A
mixture of aldehyde (0.5 mmol), cyclopentanone (2,
4
. Experimental
1
.5 mL, 17.0 mmol) and L-proline (17 mg, 0.15 mmol)
4
.1. General
was stirred at room temperature under Ar, and then treated
as above.
All reactions were performed in an oven-dried glassware
under a positive pressure of nitrogen or argon. Air- and
moisture-sensitive compounds were introduced via syringe
Method C (solvent-free at 0.2 GPa and room temperature).
A mixture of aldehyde (0.5 mmol), cyclopentanone (2,

314
H. Ikishima et al. / Tetrahedron 62 (2006) 311–316
1
.5 mL, 17.0 mmol) and L-proline (17 mg, 0.15 mmol) was
53.9, 69.5, 221.7. Anal. Calcd for C H O S : C, 55.35; H,
12 20 2 2
placed in a Teflon reaction vessel, and the mixture was
allowed to react at 0.2 GPa and room temperature. After
completion of the reaction, the mixture was treated as
above.
7.74. Found: C, 55.28; H, 7.98.
The ee was determined by chiral HPLC (Chiralpak AD,
hexane/2-propanol 85:15, 0.7 mL/min): tR 13.4 and
1
6.4 min.
4
6
[
.2.1. syn-Adduct 6 from 3. Colorless needles; mp 64–
7 8C (from Et O/hexane); R 0.32 (cyclohexane/Et O 1:1);
a] C62.2 (c 1.75, CHCl ; 30% ee); FTIR (KBr): 3366,
4.2.5. Ethyl 3-oxoundecanoate (9). To a solution of LDA,
prepared from i-Pr NH (9.12 mL, 65.1 mmol) and n-BuLi
2
f
2
2
D
6
3
2
1
1
1
2
3
719, 1450, 1401, 1161, 1029; H NMR: 1.70–1.83 (1H, m),
.98–2.10 (3H, m), 2.10–2.22 (1H, m), 2.33–2.41 (1H, m),
.56 (1H, m), 2.71 (1H, d, JZ5.6 Hz), 5.50 (1H, dd, JZ5.1,
.2 Hz), 6.95–6.99 (2H, m), 7.24 (1H, dd, JZ4.6, 1.7 Hz);
C NMR: 20.5, 23.4, 39.1, 55.7, 68.8, 123.9, 124.6, 126.7,
46.3, 220.1. Anal. Calcd for C H O S: C, 61.20; H, 6.16.
(44 mL, 65.08 mmol; 1.48 M in hexanes), in dry THF
(60 mL) at K78 8C was added dropwise ethyl acetoacetate
(3.32 mL, 26.0 mmol) and the mixture was stirred at
K78 8C for 1 h. After warming to 0 8C, to this light yellow
solution was added dropwise 1-bromoheptane (4.5 mL,
28.64 mmol) and the mixture was stirred at room
temperature for 1 h. The mixture was quenched with ice-
1
3
1
1
0 12 2
Found: C, 61.36; H, 6.26.
cold 2 M HCl and extracted with Et O. The combined
2
The ee was determined by chiral HPLC (Chiralpak AD,
hexane/2-propanol 90:10, 0.5 mL/min): tR 17.2 and
extracts were washed with satd NaCl, dried (Na SO ),
4
2
concentrated, and purified by silica gel column chromato-
graphy (hexane/Et O 2:1) to give 9 (3.58 g, 60%) as a
1
9.1 min.
2
colorless oil; R 0.47 (hexane/Et O 2:1); FTIR (neat): 1747,
f
2
1
4
.2.2. anti-Adduct 7 from 3. Colorless oil; R 0.25
f
1718, 1466, 1234, 1031; H NMR: 0.88 (3H, t, JZ7.2 Hz),
1.27 (9H, m), 1.28 (3H, t, JZ7.3 Hz), 1.60 (3H, m), 2.53
(2H, t, JZ7.4 Hz), 3.43 (2H, s), 4.20 (2H, q, JZ7.3 Hz);
C NMR: 14.0(5), 14.0(7), 22.6, 23.4, 29.0, 29.1, 29.3,
31.8, 43.0, 49.3, 61.3, 167.3, 203.0. Anal. Calcd for
1
6
(cyclohexane/Et O 1:1); [a] K88.2 (c 1.05, CHCl ; 48%
2 D 3
ee); FTIR (neat): 3450, 1719, 1449, 1402, 1358, 1222, 1157;
1
13
H NMR: 1.51–1.62 (1H, m), 1.70–1.85 (1H, m), 1.87–2.04
2H, m), 2.25 (1H, ddd, JZ19.3, 11.0, 8.8 Hz), 2.40–2.55
(
(
(
2H, m), 4.65 (1H, s), 5.02 (1H, d, JZ9.3 Hz), 6.94–6.97
C H O : C, 68.38; H, 10.59. Found: C, 68.47; H, 10.56.
13 24 3
1
3
2H, m), 7.28 (1H, dd, JZ4.9, 1.4 Hz); C NMR: 20.3,
7.0, 38.7, 55.8, 71.3, 124.4, 125.1, 126.4, 145.2, 222.4.
Anal. Calcd for C H O S: C, 61.20; H, 6.16. Found: C,
2
4.2.6. Ethyl (2-octyl-1,3-dithian-2-yl)acetate (10). To a
solution of 9 (3.5 g, 15 mmol) in AcOH at room temperature
were added BF $Et O (1 g, 7.05 mmol) and 1,3-propane-
1
0 12 2
6
0.88; H, 6.12.
3
2
dithiol (1.8 g, 16.6 mmol) and the mixture was stirred for
3 h. After cooling to 0 8C, the mixture was quenched with
H O, neutralized with aq NaHCO , and extracted with
The ee was determined by chiral HPLC (Chiralpak AD,
hexane/2-propanol 90:10, 0.5 mL/min): tR 22.3 and
2
3
2
3.7 min.
CH Cl . The combined extracts were dried (MgSO ),
2 2 4
concentrated, and purified by silica gel column chromato-
graphy (hexane/AcOEt 2:1) to give 10 (4.7 g, 98%) as a
4
.2.3. syn-Adduct 6 from 5. Colorless oil; R 0.20
f
1
8
(
cyclohexane/AcOEt 2:1); [a] C61.4 (c 1.40, CHCl ;
3
colorless oil; R 0.58 (hexane/AcOEt 2:1); FTIR (neat):
f
D
1
2% ee); FTIR (neat): 3449, 1732, 1449, 1421, 1403; H
1
8
NMR: 1.68 (3H, s), 1.69–1.83 (1H, m), 1.83–1.96 (1H, m),
1
1735, 1185; H NMR: 0.88 (3H, t, JZ7.3 Hz), 1.27 (3H, t,
JZ7.1 Hz), 1.30 (9H, m), 1.55 (3H, m), 1.87 (1H, ddt, JZ
14.0, 11.2, 3.2 Hz), 2.02–2.12 (3H, m), 2.73 (2H, ddd, JZ
14.2, 5.4, 3.4 Hz), 3.04 (2H, ddd, JZ14.2, 11.2, 2.8 Hz),
.97 (1H, dd, JZ15.0, 1.6 Hz), 2.00–2.20 (6H, m), 2.28–
.36 (1H, m), 2.39 (1H, dd, JZ15.0, 9.8 Hz), 2.78 (1H, dt,
2
1
3
JZ14.4, 3.2 Hz), 2.80 (1H, dt, JZ14.4, 3.2 Hz), 2.97 (1H,
ddd, JZ14.4, 5.8, 2.9 Hz), 3.00 (1H, ddd, JZ14.4, 5.8,
3.05 (2H, s), 4.15 (2H, q, JZ7.1 Hz); C NMR: 14.1, 14.2,
22.6, 23.7, 25.0, 26.4 (!2), 29.2, 29.4, 29.7, 31.8, 39.5,
42.7, 50.3, 60.5, 168.9. HRMS calcd for C H O S
6 30 2 2
2
1
4
1
.9 Hz), 3.21 (1H, d, JZ2.9 Hz), 4.43 (1H, dd, JZ9.8,
.6 Hz); C NMR: 20.7, 23.4, 24.6, 26.6, 26.8, 28.5, 39.0,
1
13
318.1687, found 318.1678.
5.4, 47.6, 54.9, 67.2, 219.8. Anal. Calcd for C H O S $
2 20 2 2
1
/8H O: C, 54.87; H, 7.77. Found: C, 54.85; H, 7.66.
2
4.2.7. (2-Octyl-1,3-dithian-2-yl)acetaldehyde (11). To a
solution of 10 (2.75 g, 8.6 mmol) in dry CH Cl (70 mL) at
2
2
The ee was determined by chiral HPLC (Chiralpak AD,
hexane/2-propanol 80:20, 0.7 mL/min): tR 12.8 and
K78 8C was added a solution of DIBAL-H in toluene
(1.0 M; 10.8 mL, 10.8 mmol) over 0.5 h and the mixture
was placed in a freezer at K78 8C for 0.5 h. The excess of
DIBAL-H was quenched with AcOH (0.45 mL) and
warmed to room temperature. The mixture was then stirred
with satd Rochelle’s salt until the suspension disappeared
and a clear two-phase solution was obtained. The aqueous
phase was extracted with CH Cl and the extracts were
1
3.8 min.
4
.2.4. anti-Adduct 7 from 5. Colorless oil; R 0.24
f
1
9
(
9
cyclohexane/AcOEt 2:1); [a] K85.8 (c 1.79, CHCl ;
D 3
1
3% ee); FTIR (neat): 3481, 1723, 1448, 1421; H NMR:
.70 (3H, s), 1.68–1.84 (2H, m), 1.85–1.96 (1H, m), 1.98
1
2
2
(
2
(
1H, d, JZ15.1 Hz), 1.99–2.12 (2H, m), 2.13–2.27 (3H, m),
.32–2.39 (1H, m), 2.40 (1H, dd, JZ14.9, 9.3 Hz), 2.79
1H, ddd, JZ14.4, 7.4, 3.4 Hz), 2.81 (1H, ddd, JZ14.4, 7.4,
washed with satd NaHCO and satd NaCl, dried (Na SO ),
3 2 4
and concentrated. Purification by silica gel column
chromatography (hexane/AcOEt 2:1) gave 11 (2.33 g,
3
.4 Hz), 2.91 (1H, ddd, JZ14.4, 9.8, 2.9 Hz), 2.96 (1H, ddd,
99%) as a colorless oil; R 0.56 (hexane/AcOEt 2:1);
f
FTIR (neat): 1718, 1465, 1423; H NMR: 0.88 (3H, t, JZ
7.1 Hz), 1.27 (10H, m), 1.50 (2H, m), 1.90–2.09 (4H, m),
1
3
1
JZ14.4, 9.8, 2.9 Hz), 4.06 (1H, br s), 4.13 (1H, m); C
NMR: 20.5, 24.8, 26.5, 26.7, 26.8, 28.3, 39.0, 45.5, 47.9,

H. Ikishima et al. / Tetrahedron 62 (2006) 311–316
315
1
4.10 (1H, br); C NMR: 14.1, 20.6, 22.7, 22.9, 26.0, 29.3,
29.5, 29.6 (!3), 31.9, 34.8, 39.1, 54.4, 69.7, 221.5.
3
2
2
.83 (2H, ddd, JZ14.6, 6.8, 3.7 Hz), 2.91 (2H, d, JZ
.7 Hz), 2.91 (2H, ddd, JZ14.6, 9.5, 3.4 Hz), 9.78 (1H, t,
1
3
JZ2.7 Hz); C NMR: 13.9, 22.4, 23.8, 24.5, 26.0 (!2),
9.0, 29.1, 29.5, 31.6, 40.2, 49.1, 49.9, 199.53. HRMS calcd
for C H OS 274.1425, found 274.1407.
2
This sample was used immediately for the next reaction.
14
26
2
4.2.12. (5R,6S)-6-Hydroxy-5-hexadecanolide (15). To a
solution of 14 (517 mg, 2.03 mmol) in dry CH Cl (30 mL)
4
.2.8. L-Proline-catalyzed asymmetric aldol reaction of
cyclopentanone (2) with aldehyde (11). The mixture of 11
6.82 g, 24.8 mmol), cyclopentanone (2, 74.73 mL,
45 mmol) and L-proline (858 mg, 7.45 mmol) was stirred
2
2
at 0 8C were added m-CPBA (98% activity; 700 mg,
4 mmol) and NaHCO (340 mg, 4 mmol), and the mixture
(
8
3
was stirred at room temperature for 4 h. To this mixture was
added another portion of m-CPBA (98% activity; 350 mg,
2 mmol) and NaHCO (170 mg, 2 mmol) and the mixture
3
at 13 8C for 20 h under Ar. The mixture was quenched with
H O and extracted with CHCl . The combined extracts were
2
3
dried (MgSO ), concentrated, and purified by silica gel
4
was stirred for 5 h. After completion of the reaction, the
excess of m-CPBA was quenched with aq Na S O . The
column chromatography (hexane/AcOEt 2:1) to give 12
5.64 g, 63% yield; 83% ee) and 13 (1.91 g, 22% yield; 90%
2
2 3
(
insoluble material was removed by filtration and washed
with CH Cl . The aqueous phase was extracted with
CH Cl . The combined extracts were washed with satd
ee) as a colorless oil, respectively. The ee of these adducts
were determined by chiral HPLC (254 nm, flow rate:
2
2
2
2
0.7 mL/min) carried out with Chiralpak AD (hexane/2-
propanol 90:10; product 12 t 9.5 and 11.5 min, product 13
tR 11.7 and 13.3 min).
NaHCO and satd NaCl, dried (MgSO ), concentrated, and
3 4
purified by silica gel column chromatography (hexane/
AcOEt 1:1) to give 15 (493 mg, 90%) as a colorless solid.
R
Analytically pure 15 was obtained by recrystallization from
Et O/hexane. Colorless needles; mp 67–68 8C (lit. mp
6
4.2.9. (2R)-2-[(1S)-1-Hydroxy-2-(2-octyl-1,3-dithian-2-
yl)ethyl]cyclopentanone (12). R 0.36 (hexane/AcOEt
2
2
0
6
6.5–68 8C); R 0.25 (hexane/AcOEt 1:1); [a] K12.7 (c
f D
6
f
2
2
1.0, CHCl ) (lit. [a] K11.0 (c 1.5, CHCl )); FTIR (KBr)
3 D 3
1
2
:1); [a] C45.6 (c 1.6, CHCl ); FTIR (neat): 3446, 1736,
3
457, 1421; H NMR: 0.88 (3H, t, JZ7.3 Hz), 1.29 (10H,
D
1
3421, 1714, 1267, 1054; H NMR: 0.88 (3H, t, JZ7.1 Hz),
.26 (15H, s), 1.40–1.65 (4H, m), 1.71–2.02 (3H, m), 2.04
1H, br), 2.45 (1H, ddd, JZ17.6, 9.0, 7.1 Hz), 2.61 (1H,
ddd, JZ17.6, 7.1, 5.6 Hz), 3.83 (1H, m), 4.25 (1H, dt, JZ
1
m), 1.41 (1H, m), 1.53 (1H, m), 1.70–1.80 (1H, m), 1.85–
1
(
2
2
2
2
2
3
.18 (10H, m), 2.31 (1H, m), 2.37 (1H, dd, JZ15.1, 9.8 Hz),
.73–2.81 (2H, m), 2.93 (1H, ddd, JZ13.4, 10.2, 2.9 Hz),
.99 (1H, ddd, JZ13.4, 10.2, 2.9 Hz), 3.34 (1H, d, JZ
.7 Hz), 4.42 (1H, d, JZ9.5 Hz); C NMR: 14.1, 20.7,
2.6, 23.3, 23.9, 24.9, 26.0, 26.4, 29.2, 29.4, 29.8, 31.8,
9.0, 39.7, 42.4, 52.1, 54.9, 66.9, 219.7. Anal. Calcd for
1
3
10.7, 3.4 Hz); C NMR: 14.1, 18.3, 21.2, 22.7, 25.9, 29.3,
29.5 (!2), 29.6 (!2), 29.8, 31.7, 31.9, 72.4, 83.4, 171.7.
1
3
Anal. Calcd for C H O : C, 71.07; H, 11.18. Found: C,
16 30
3
71.37; H, 11.26.
C H O S $1/5 H O: C, 63.00; H, 9.57. Found: C, 62.93;
1
9
34
2
2
2
H, 9.38.
4.2.13. (5R,6S)-(K)-6-Acetoxy-5-hexadecanolide (1). The
mixture of 15 (310 mg, 1.15 mmol), Ac O (0.33 mL,
2
3
0
.5 mmol) and 4-(dimethylamino)pyridine (42 mg,
.34 mmol) in dry pyridine (16 mL) was stirred at room
4.2.10. (2R)-2-[(1R)-1-Hydroxy-2-(2-octyl-1,3-dithian-2-
yl)ethyl]cyclopentanone (13). R 0.38 (hexane/AcOEt 2:1);
f
2
0
temperature. After 4 h, the mixture was quenched with 10 M
aq K CO and extracted with CHCl . The combined extracts
were dried (MgSO ), concentrated, and purified by silica gel
column chromatography (hexane/AcOEt 2:1) to give 1
(352 mg, 100%) as a colorless oil; R 0.23 (hexane/AcOEt
[
a] K70.3 (c 0.83, CHCl ); FTIR (neat): 3483, 1722,
3
456, 1418; H NMR: 0.88 (3H, t, JZ7.1 Hz), 1.30 (10H,
D
1
1
m), 1.43 (1H, m), 1.55 (1H, m), 1.75–2.10 (8H, m), 2.14–
2
3
3
4
2
2
2
.26 (3H, m), 2.35 (1H, m), 2.47 (1H, dd, JZ15.2, 9.3 Hz),
.75–2.80 (2H, m), 2.89 (1H, ddd, JZ14.0, 9.5, 3.2 Hz),
.95 (1H, ddd, JZ14.0, 9.5, 3.0 Hz), 4.07 (1H, s), 4.14 (1H,
f
2
1
10
24
2
:1); [a] K36.8 (c 1.55, CHCl ) (lit. [a] K36.8 (c 1.0,
D 3 D
1
1
3
CHCl )); FTIR (neat): 1744, 1466, 1371, 1230; H NMR:
0
1
6
1
1
2
1
dd, JZ9.3, 5.6 Hz); C NMR: 14.1, 20.6, 22.7, 24.0, 25.1,
3
.88 (3H, t, JZ6.9 Hz), 1.25 (16H, s), 1.55–1.70 (4H, m),
.77–2.01 (2H, m), 2.08 (3H, s), 2.46 (1H, ddd, JZ17.8, 9.2,
.8 Hz), 2.60 (1H, dt, JZ17.8, 6.4 Hz), 4.35 (1H, ddd, JZ
2
5
6
6.1, 26.4, 26.7, 29.3, 29.4, 29.8, 31.8, 39.1, 39.3, 42.3,
2.4, 54.0, 69.2, 221.4. Anal. Calcd for C H O S : C,
3.64; H, 9.56. Found: C, 63.56; H, 9.31.
1
9 34 2 2
1
3
1.0, 4.9, 3.4 Hz), 4.98 (1H, dt, JZ7.8, 5.1 Hz); C NMR:
4.1, 18.3, 21.0, 22.7, 23.5, 25.3, 29.3(0), 29.3(9), 29.4(4),
9.4(8), 29.5(3), 29.5(5), 29.6(1), 31.9, 74.3, 80.5, 170.5,
70.9. Anal. Calcd for C H O : C, 69.19; H, 10.32.
4
(
.2.11. (2R)-2-[(1S)-1-Hydroxyundecyl]cyclopentanone
14). To a solution of 12 (882 mg, 2.46 mmol) in AcOEt
1
8 32 4
(
100 mL) was added Raney-Ni (40 g; Aldrich Raney-Ni
Found: C, 69.41; H, 10.51.
2
800 was washed successively with H O (!3), MeOH
2
20
(
!3), and AcOEt (!3)), and the mixture was stirred at
room temperature for 1 h. The insoluble material was
removed by filtration and washed thoroughly with AcOEt
and MeOH. After evaporation of the solvent, the crude
product was purified quickly by silica gel column
chromatography (CHCl /Et O 4:1) to give 14 (388 mg,
Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Culture, and Sports, Japan, as well as a Special
Research Grant for Green Science from Kochi University.
We also thank Prof. Y. Fukuyama of Tokushima Bunri
University for MS/HRMS measurements.
3
2
6
2%) as a colorless oil; R 0.39 (CHCl /Et O 4:1); FTIR
f 3 2
1
(
neat): 3419, 1730, 1468, 1454; H NMR: 0.88 (3H, t, JZ
6
2
.8 Hz), 1.26 (16H, s), 1.4–1.6 (2H, m), 1.6–2.0 (3H, m),
.03–2.15 (3H, m), 2.15–2.24 (1H, m), 2.28–2.36 (1H, m),

316
H. Ikishima et al. / Tetrahedron 62 (2006) 311–316
Tetrahedron: Asymmetry 1997, 8, 633–638. (c) Olagbemiro,
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1
1
6. The absolute configurations of all products shown in Table 1
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5
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1
7. Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
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5
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5% yield, 11 (81% ee)/12 (90% ee) 6:94. The important effect
9
of water in this type of asymmetric aldol reactions was also
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3
024–3025. (d) Darbre, T.; Machuqueiro, M. Chem. Commun.
2
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6
7
. Sun, B.; Peng, L.; Chen, X.; Li, Y.; Li, Y.; Yamasaki, K.
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1
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8
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8
9
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2
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4
1
9. The absolute configuration of 12 was confirmed after
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1
0. Kotsuki, H.; Kadota, I.; Ochi, M. J. Org. Chem. 1990, 55,
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4
20. After numerous trials with alternative procedures, we found
Raney-Ni (Aldrich Raney 2800) in AcOEt to be most
satisfactory. The use of MeOH or EtOH as a solvent gave
poorer results.
1
1. (a) Bonini, C.; Checconi, M.; Righi, G.; Rossi, L. Tetrahedron
1995, 51, 4111–4116. (b) Lohray, B. B.; Venkateswarlu, S.