Efficient synthesis of (R)- and (S)-3-octanol, (R)-2-dodecanol, (R)-2-methyl-4-heptanol and (R)-2-methyl-4-octanol: The pheromones of Myrmica scabrinodis, Crematogaster castanea, C. liengmei, C. auberti and Metamasius hemipterus

Article abstract of DOI:10.1016/S0040-4020(03)00254-0

A simple and efficient synthesis of optically active insect pheromones, such as (R)- and (S)-3-octanol, (R)-2-dodecanol, (R)-2-methyl-4-heptanol and (R)-2-methyl-4-octanol starting from non-racemic β-hydroxy sulfides has been established.

Full text of DOI:10.1016/S0040-4020(03)00254-0

Tetrahedron 59 (2003) 2457–2462
Efficient synthesis of (R)- and (S)-3-octanol, (R)-2-dodecanol,
(R)-2-methyl-4-heptanol and (R)-2-methyl-4-octanol:
the pheromones of Myrmica scabrinodis, Crematogaster castanea,
C. liengmei, C. auberti and Metamasius hemipterus
*
Byung Tae Cho and Dong Jun Kim
Department of Chemistry, Hallym University, Chunchon 200702, South Korea
Received 14 January 2003; revised 16 February 2003; accepted 17 February 2003
Abstract—A simple and efficient synthesis of optically active insect pheromones, such as (R)- and (S)-3-octanol, (R)-2-dodecanol, (R)-2-
methyl-4-heptanol and (R)-2-methyl-4-octanol starting from non-racemic b-hydroxy sulfides has been established. q 2003 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Recently much interests on optically active insect phero-
mones are rapidly growing since their enantiomers have
commonly different biological activities.1 For example, (R)-
3-octanol (1) is the sex attractant pheromone of Myrmica
scabrinodis,2 whereas its S-enantiomer is an alarm phero-
mone found in the ants Crematogaster castanea and C.
liengmei.3 On the other hand, (R)-2-dodecanol (2) is a
component of the hind leg tibial gland secretion of worker
ants of C. auberti.4 (R)-2-Methyl-4-heptanol (3) and (R)-2-
methyl-4-octanol (4) are identified as the male-produced
Figure 1.
aggregation pheromones of the West Indian sugarcane
weevils Metamasius hemipterus5 (Fig. 1). It has been
of aliphatic b-hydroxy sulfides could be simply upgraded by
reported that biological activities of these pheromones
a recrystallization of their 3,5-dinitrobenzoates. Since these
exhibit that their (R)-isomers are far more potent than (S)-
b-hydroxy sulfides could be converted to optically active
isomers.4,5 Methods for the synthesis of these chiral insect
secondary alcohols by in turn oxidation to b-hydroxy
pheromones include enzymatic resolution of racemic
sulfoxides, alkylation to dianions of the sulfoxides, and
secondary alkyl acetates for 1 and 2,6,7 alkylation of
desulfurization of the a-alkylated sulfoxides,13 this finding
optically active intermediates starting from chiral sub-
led us promptly to developing a new convenient route for
stances such as methyl (R) or (S)-3-hydroxypentanoate,8,9
the synthesis of optically active pheromones 1–4 using the
and (S)-leucine for 3 and 4.10 These pheromones are simple
b-hydroxy sulfides as starting materials.
secondary aliphatic alcohols. One of the most efficient
methods for obtaining optically active secondary alcohols is
the asymmetric reduction of prochiral ketones. Although a
number of stoichiometric and catalytic asymmetric reducing
2. Results and discussion
agents have been published,11 successful reductions for
Prior to performing this study, we first examined the
unhindered aliphatic ketones to give high enantioselectvity
synthesis of chiral pheromones (R)-1 and (R)-3 by
are quite rare.12 Recently we discovered that optical purities
asymmetric reduction of 3-octanone and 2-methyl-4-
heptanone with (S)-MeCBS-oxazaborolidine (12)-catalyzed
borane, which is one of the promising chiral reducing agents
Keywords: chiral insect pheromone; asymmetric reduction; chiral b-
hydroxy sulfides; dianion alkylation.
for prochiral ketone reduction. Unfortunately, the reduction
provided corresponding alcohols with moderate to low
*
Corresponding author. Tel.: þ82-33-240-8491; fax: þ82-33-251-8491;
e-mail: btcho@hallym.ac.kr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00254-0

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B. T. Cho, D. J. Kim / Tetrahedron 59 (2003) 2457–2462
Scheme 1. (i) (R) or (S)-MeCBS oxazaborolidine (12, 0.1 equiv.), N-ethyl-N-isopropylaniline–borane complex (13, 1.0 equiv.), THF, 258C 98–99%.
(ii) m-CPBA (1.1 equiv.), CH2Cl2, room temperature, 92–95%. (iii) 3,5-(NO2)2C6H3COCl (1.5 equiv.), TMEDA (1.0 equiv.), CH2Cl2, 97–99%. (iv) 2N
NaOH, MeOH, room temperature, 98–99%. (v) n-BuLi (2.8 equiv.), R0I (1.1 equiv.), THF, 278–208C, 72–93%. (vi) Raney Ni, MeOH, room temperature,
89–92%.
enantioselectivity, such as (R)-1 with 61% ee and (R)-3 with
18% ee. The synthetic routes for preparation of chiral
pheromones 1–4 using chiral b-hydroxy sulfides 6 as
staring materials are outlined in Scheme 1. The starting
material 6 was prepared by (R) or (S)-12-catalyzed
reduction of b-keto sulfides 5 according to our previous
procedure.14 The reduction provided 6 with 74–81% ee in
nearly quantitative yields. Enantiomeric purities of 6
obtained were determined by HPLC analysis using a
25 cm Whelk-O1 or Chiralcel OD-H chiral column.
Acylation of 6 with 1.5 equiv. of 3,5-dinitrobenzoyl
chloride in the presence of 1.0 equiv. of TMEDA in
dichloromethane15 at room temperature provided 3,5-
dinitrobenzoates 60 of the corresponding alcohols in 96–
98% yield as light yellow solids. To improve optical purities
of 60, these were recrystallized in appropriate solvents. Thus
optical purity of 60a was increased from 74% ee to 96% ee
by twice recrystallization in ethyl ether and that of 60b was
increased from 81% ee to 98% ee by a single recrystalliza-
tion in ethyl acetate. However, the improvement for 60c was
unsuccessful. Instead, this was successfully achieved by a
single recrystallization of a diastereomeric mixture of
sulfoxide ester 70c from dichloromethane–hexane. The
sulfoxide ester 70c was prepared in 93% yield by oxidation
of 6c with m-chloroperbenzoic acid (m-CPBA) in dichloro-
methane at 08C. Optical purity of 70c after recrystallization
was increased from 79% ee to 99% ee.16 The results are
summarized in Table 1. These esters were hydrolyzed with
2N NaOH in methanol at room temperature to give 6a,b and
7c without racemization. Alkylation to the dianions of
b-hydroxy sulfoxides with alkyl iodides17 was carried out as
follows. Oxidation of (S)-6a with 96% ee and (S)-6b with
98% ee with m-CPBA in dichloromethane at room
temperature afforded b-hydroxy sulfoxides (S)-7a and (S)-
7b in 92 and 95% yield, respectively.18 After (S)-7a was
treated with 2.8 equiv. of n-butyl lithium in THF at 2788C,
Table 1. Preparation of optically active 6
Before recrystallizationa
Compound Yield (%)b
After recrystallizationa
% ee
Yield (%)b % ee Configuration
6a
98
98
97
99
74c,14
76c
81e,14
79c
62d
64d
80f
51g
96c
96c
98e
99c
S
R
S
S
ent-6a
6b
6c
Compound 6 was prepared by the reduction of b-keto sulfides 5 using
1.0 equiv. of N-ethyl-N-isopropylaniline–borane complex 13 in the
presence of 0.1 equiv. of CBS-oxazaborolidine 12 in THF at 258C; Ref. 14.
a
Achieved by recrystallization of 3,5-dinitrobenzoates of 6 or its sulfoxide
7c.
Isolated yield.
Determined by HPLC analysis using a Whelk-O1 chiral column.
Isolated yield obtained from twice recrystallization of 3,5-dinitrobenzo-
ate of 6a or ent-6a from ethyl ether, followed by hydrolysis of the ester.
Determined by HPLC analysis using a Chiralcel OD-H chiral column.
Isolated yield obtained from a single recrystallization of 3,5-dinitro-
b
c
d
e
f
benzoate of 6b from ethyl acetate, followed by hydrolysis of the ester.
Isolated yield obtained from a single recrystallization of 3,5-dinitro-
g
benzoate of 7c from dichloromethane–hexane, followed by hydrolysis of
the ester and subsequent deoxygenation.

B. T. Cho, D. J. Kim / Tetrahedron 59 (2003) 2457–2462
2459
followed by addition of 1.1 equiv. of methyl iodide, the
reaction mixture was allowed to warm to 208C to give
a-methylated sulfoxide 8 in 93% yield. Treatment of 8 with
Raney-nickel19 in methanol at room temperature provided
(R)-3-octanol with 96% ee in 90% yield. The result
indicates that no racemization occurs during sulfoxidation,
alkylation and desulfurization. Using the same method-
ology, (S)-1 with 96% ee from ent-8 was obtained.
Similarly, desulfurization of 7c, of which optical purity
was improved by recrystallization of 70c afforded (R)-2 with
99% ee. The same method for 9 and 10 obtained by
a-alkylation of (S)-7b with ethyl iodide and n-propyl iodide,
respectively, provided (R)-3 and (R)-4 with 98% ee.
5 using 13 as the hydride source. Using the same
methodology, ent-6a and (S)-6c were prepared.
4.3.1. (2R)-(2)-1-(p-Toluenesulfanyl)-2-heptanol ent-6a.
Rf 0.4 (EtOAc/hexane 1:4); oil; 98% yield; IR (neat, cm21):
3404, 2911, 1490, 799; 1H NMR (200 MHz, CDCl3) d 0.87
(t, 3H, J¼6.4 Hz), 1.27–1.49 (m, 8H), 2.32 (s, 3H), 2.45 (d,
1H, J¼3.1 Hz), 2.78 (dd, 1H, J¼9.0, 13.6 Hz), 3.11 (dd, 1H,
J¼3.2, 13.6 Hz), 3.63 (m, 1H), 7.11 (d, 2H, J¼7.9 Hz), 7.31
(d, 2H, J¼8.2 Hz); 13C NMR (50 MHz, CDCl3) d 14.67,
21.73, 23.22, 26.02, 32.46, 36.68, 43.68, 69.88, 130.57,
131.61, 132.05, 137.61. Calcd for C14H22OS: C, 70.54; H,
9.30; S, 13.45. Found: C, 70.46; H, 9.36; S, 13.51;
[a]2D2¼235.6 (c 1.12, CHCl3), R; HPLC analysis using a
Whelk-O1 chiral column [iso-PrOH/hexane: 1:9; flow rate:
0.3 mL/min; detector: 254 nm] showed it to be 76% ee [tR
(S) 26.83 min and tR (R) 28.72 min].
3. Conclusion
We have established a new and simple synthesis of optically
active insect pheromones, such as (R)- and (S)-3-octanol,
(R)-2-dodecanol, (R)-2-methyl-4-heptanol, and (R)-2-
methyl-4-octanol starting from non-racemic b-hydroxy
sulfides. This method provided a general route for preparing
both R and S enantiomers of such pheromones with high
enantiomeric purities.
4.3.2. (2S)-(1)-1-(p-Toluenesulfanyl)-2-dodecanol 6c. Rf
0.47 (EtOAc/hexane 1:4); white solid; mp 38–408C; 99%
yield; IR (neat, cm21): 3382, 2915, 801; 1H NMR
(200 MHz, CDCl3) d 0.87 (t, 3H, J¼6.41 Hz), 1.25–1.58
(m, 18H), 2.32 (S, 3H), 2.45 (d, 1H, J¼3.36 Hz), 2.78 (dd,
1H, J¼8.85, 13.74 Hz), 3.10 (dd, 1H, J¼3.36, 13.74 Hz),
3.62 (m. 1H), 7.11 (d, 2H, J¼8.55 Hz), 7.31 (d, 2H,
J¼7.94 Hz); 13C NMR (50 MHz, CDCl3) d 14.76, 21.67,
23.34, 26.34, 29.99, 30.21, 30.26, 32.57, 36.75, 43.70,
69.96, 131.61, 130.57, 132.17, 137.60. Calcd for C19H32OS:
C, 73.97; H, 10.45; S, 10.39. Found: C, 73.99; H, 10.63; S,
10.29; [a]2D0¼þ24.96 (c 1.21, CHCl3), S; HPLC analysis
using a Whelk-O1 column [iso-PrOH/hexane: 1:99; flow
rate: 0.3 mL/min; detector: 254 nm] showed it to be 79% ee
[tR (S) 22.85 min and tR (R) 24.55 min].
4. Experimental
4.1. General
All operations with air-sensitive materials were carried out
under a nitrogen atmosphere in oven-dried glassware.
Liquid materials were transferred with a double-ended
needle. The reactions were monitored by TLC using silica
gel plates and the products were purified by flash column
chromatography on silica gel (Merck; 230–400 mesh).
NMR spectra were recorded at 200, 300 or 400 MHz for 1H
and 50, 75 or 100 MHz for 13C using Me4Si as the internal
standard in CDCl3. Optical rotations were measured with a
high-resolution digital polarimeter. Melting points were
uncorrected. Enantiomeric excesses (ees) of the products
were determined by HPLC analyses using a 4.6£25 mm
Whelk-O1 (Regis), Chiralpak OT or Chiralcel OD-H
(Daicel) chiral column and GC analysis using a
0.25 mm£30 m b-DEX 120 (Supelco) or G-TA (Astec)
chiral capillary column.
4.4. General procedure for preparation of 3,5-
dinitrobenzoates of 6 and improvement of their optical
purities
To a mixture of 6a, ent-6a, 6b or 6c (5 mmol) and TMEDA
(5 mmol) in dichloromethane (20 mL) was added a solution
of 3,5-dinitrobenzoyl chloride (7.5 mmol) in dichloro-
methane (20 mL) containing 2 drops of THF and the
mixture was stirred at room temperature for 12 h. To this
was added a saturated NaHCO3 solution (20 mL) with
vigorous stirring. Organic layer was separated and then
aqueous layer was extracted with dichloromethane
(3£20 mL). Combined extract was dried over anhydrous
Na2SO4, filtered and concentrated to give 60a–c in nearly
quantitative yields. The esters 60 obtained were recrystal-
lized with appropriate solvents.
4.2. Materials
Most of organic compounds utilized in this study were
commercial products of the highest purity. They were
further purified by distillation when necessary. THF was
distilled over sodium benzophenone ketyl and stored in
ampules under nitrogen atmosphere. The CBS reagent 12
and N-ethyl-N-isopropylaniline–borane complex 13 were
purchased from the Aldrich Chemical Company, Inc.
4.4.1. Compound 60a and ent-60a. 98% Yield; light yellow
solid; IR (KBr, cm21): 2980, 1728, 1545, 1344, 1273, 1167,
1076; 1H NMR (200 MHz, CDCl3) d 0.87 (t, 3H,
J¼6.10 Hz), 1.31–1.83 (m, 8H), 2.16 (s, 3H), 3.23 (d, 2H,
J¼5.49 Hz), 5.37 (m, 1H), 6.97 (d, 2H, J¼7.94 Hz), 7.28 (d,
2H, J¼7.94 Hz), 8.95 (d, 2H, J¼2.14 Hz), 9.19 (t, 1H,
J¼2.14 Hz); 13C NMR (50 MHz, CDCl3) d 14.61, 21.51,
23.09, 25.59, 32.10, 33.96, 39.04, 77.41, 122.83, 130.08,
130.47, 131.60, 132.36, 134.47, 137.55, 149.12, 162.70.
Calcd for C21H24N2O6S: C, 58.32; H, 5.59; N, 6.48; S, 7.41.
Found: C, 58.37; H, 5.79; N, 6.49; S, 7.62; Twice
recrystallizaton of this ester with 74% ee from ethyl ether
4.3. Preparation of optically active b-hydroxy sulfides 6
According to our previous procedure,14 (S)-6a with 74% ee
and (S)-6b with 81% ee were prepared by (S)-CBS
oxazaborolidine (12)-catalyzed reduction of b-keto sulfides

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B. T. Cho, D. J. Kim / Tetrahedron 59 (2003) 2457–2462
provided 60a with 96% ee in 62% yield; mp 82–848C;
[a]2D0¼þ127 (c 1.1, CHCl3), S; HPLC analysis using a Whelk-
O1 column [iso-PrOH/hexane: 1:99; flow rate: 0.6 mL/min;
detector: 254 nm] showed it to be 96% ee [tR (R) 25.48 min
and tR (S) 27.44 min]. Using the same methodology, optical
purity of ent-60a was increased from 74% ee to 96% ee in 64%
yield. [a]2D0¼2126.9 (c 0.9, CHCl3), R.
4.4.2. Compound 60b. 96% Yield; light yellow solid; IR
(KBr, cm21): 2960, 1734, 1541, 1343, 1270, 1163, 1073; 1H
NMR (200 MHz, CDCl3) d 0.94 (d, 6H, J¼5.80 Hz), 1.61–
1.89 (m, 3H), 2.15 (s, 3H), 3.22 (d, 2H, J¼5.49 Hz), 5.48
(m, 1H), 6.95 (d, 2H, J¼7.94 Hz), 7.27 (d, 2H, J¼7.94 Hz),
8.94 (d, 2H, J¼2.14 Hz), 9.21 (t, 1H, J¼2.14 Hz); 13C NMR
(50 MHz, CDCl3) d 22.79, 23.64, 25.49, 30.36, 39.55,
43.07, 75.94, 122.78, 130.04, 130.46, 131.54, 132.44,
134.50, 137.52, 149.17, 162.70. Calcd for C20H22N2O6S:
C, 57.40; H, 5.30; N, 6.69; S, 7.66. Found: C, 57.46; H, 5.25;
N, 6.72; S, 7.54. A single recrystallizaton of this ester with
81% ee from ethyl acetate provided 60b with 98% ee in 80%
yield; mp 81–828C; [a]2D0¼þ135.97 (c 0.93, CHCl3), S;
HPLC analysis of 6a obtained from hydrolysis of this ester
(vide infra) using a Chiralcel OD-H column [iso-PrOH/
hexane: 1:99; flow rate: 0.6 mL/min; detector: 254 nm]
showed it to be 98% ee [tR (R) 21.28 min and tR (S)
22.58 min].
(75 MHz, CDCl3) d 14.53, 21.88, 23.05, 25.13, 29.45,
29.64, 29.68, 29.82, 29.88, 32.22, 34.57, 59.31, 71.28,
122.61, 124.26, 129.63, 130.20, 133.50, 136.55, 145.20,
148.59, 161.60. Calcd for C26H34N2O7S: C, 60.21; H, 6.61;
N, 5.40; S, 6.18. Found: C, 60.39; H, 6.51; N, 5.45; S, 6.08;
HPLC analysis using a Whelk-O1 column [EtOH/hexane:
1:9; flow rate: 1.0 mL/min; detector: 254 nm] showed it to
be 79% ee with the (Sc)-configuration [tR (Rc, Ss or Rs)
19.65 min, tR (Sc, Ss or Rs) 21.09 min, tR (Rc, Ss or Rs)
26.15 min and tR (Sc, Ss or Rs) 33.33 min]. 70c was recovered
from a single recrystallization in dichloromethane–hexane
in 53% yield; mp 108–1098C; 1H NMR (300 MHz, CDCl3)
d 0.87 (t, 3H, J¼6.3 Hz), 1.18–1.42 (m, 16H), 1.75–2.00
(m, 2H), 2.23 (s, 0.45), 2.39 (s, 2.55H), 3.10–3.17 (m, 2H),
5.67 (m, 1H), 7.23 (d, 0.30H, J¼7.7 Hz), 7.33 (d, 1.70H,
J¼7.7 Hz), 7.50–7.56 (m, 2H), 8.97 (d, 0.30H, J¼2.2 Hz),
9.17 (d, 1.70H, J¼2.2 Hz), 9.22 (t, 0.15H, J¼2.2 Hz), 9.26
(t, 0.85H, J¼2.2 Hz); 13C NMR (75 MHz, CDCl3) d 14.55,
21.84, 23.07, 25.37, 29.58, 29.67, 29.75, 29.86, 32.25,
34.60, 61.92, 71.97, 122.73, 124.19, 129.81, 130.20, 133.40,
133.82, 142.23, 148.75, 161.89. HPLC analysis using the
same conditions as described above was found to be .99%
ee having the (Sc)-configuration.
4.5. General procedure for hydrolysis of 60a,b and 70c
and sulfoxidation of 6
4.4.3. Compound 60c. Rf 0.43 (EtOAc/hexane 1:4); light
yellow solid; mp 90–918C; 97% yield; IR (KBr, cm21):
2974, 1729, 1554, 1352, 1281, 1172, 1071; 1H NMR
(300 MHz, CDCl3) d 0.87 (t, 3H, J¼4.4 Hz), 1.17–1.30 (m,
16H), 1.81–1.93 (m, 2H), 2.39 (s, 3H), 3.22 (d, 2H,
J¼5.4 Hz), 5.66 (m, 1H), 7.32 (d, 2H, J¼5.6 Hz), 7.53 (d,
2H, J¼5.4 Hz), 9.15 (d, 2H, J¼1.4 Hz), 9.24 (t, 1H,
J¼1.5 Hz); 13C NMR (75 MHz, CDCl3) d 14.55, 21.84,
23.07, 25.37, 29.58, 29.67, 29.75, 29.86, 29.91, 32.24,
34.60, 61.92, 71.97, 122.73, 124.19, 129.81, 130.40, 133.82,
140.43, 142.23, 148.75, 161.88. Calcd for C26H34N2O6S: C,
62.13; H, 6.82; N, 5.57; S, 6.38. Found: C, 62.21; H, 6.63; N,
5.55; S, 6.27. HPLC analysis using a Chiralcel OD-H column
[iso-PrOH/hexane: 1:9; flow rate: 0.5 mL/min; detector:
254 nm] showed it to be 79% ee [tR (R) 25.29 min, tR (S)
28.62 min]. Attempts to improve optical purity of this ester by
recrystallization from various solvents failed.
Hydrolysis. Compounds 60a,b and 70c (5 mmol) obtained
after improvement of their optical purities by recrystalliza-
tion was dissolved in methanol (50 mL), treated with 2N
NaOH (50 mL) and stirred for 20 min at room temperature.
After evaporation of methanol under reduced pressure,
residue was extracted with ethyl ether (3£10 mL). The
combined extract was dried over anhydrous MgSO4, filtered
and concentrated to give 6a,b and 7c in quantitative yields,
respectively. The sulfanyl or sulfinyl alcohols obtained
could be used for sulfoxidation or alkylation (vide infra)
without further purification.
Sulfoxidation. To a solution of 6 (4 mmol) in dichloro-
methane (20 mL) was added dropwise a solution of
m-chloroperbenzoic acid (4.4 mmol) in dichloromethane
(30 mL) for 10 min at 08C. After the mixture was stirred for
30 min at room temperature, organic layer was separated,
washed with 2N NaOH (2£10 mL) and brine (2£10 mL),
dried over anhydrous MgSO4, filtered and concentrated to
give 7, which could be used for alkylation without further
purification.
4.4.4. Preparation and recrystallization of 3,5-dinitro-
benzoate of (2S)-1-[(RS)-p-toluenesulfinyl]-2-dodecanol
70c. To a stirred solution of 60c with 79% ee (3 mmol) in
dichloromethane (15 mL), kept at 08C was added dropwise a
solution of m-chloroperbenzoic acid (3.3 mmol) in dichloro-
methane (25 mL). The solution was stirred at 08C, until the
TLC showed no staring material, and washed with 2N
NaOH (2£10 mL) and brine (2£10 mL). Organic layer was
dried over anhydrous MgSO4, filtered and concentrated to
give 70c; Rf 0.73 (EtOAc/hexane 1:1); light yellow solid; mp
98–1028C; 93% yield; IR (KBr, cm21): 2922, 1724, 1546,
1343, 1288, 1174, 1033; 1H NMR (300 MHz, CDCl3) d 0.87
(t, 3H, J¼6.3 Hz), 1.18–1.47 (m, 16H), 1.76–1.99 (m, 2H),
2.23 (s, 1.41H), 2.39 (s, 1.59H), 3.10–3.35 (m, 2H), 5.65
(m, 1H), 7.23 (d, 0.94H, J¼7.7 Hz), 7.33 (d, 1.06H,
J¼7.7 Hz), 7.50–7.56 (m, 2H), 8.98 (d, 0.94H, J¼
2.2 Hz), 9.17 (d, 1.06H, J¼2.2 Hz), 9.22 (t, 0.47H,
J¼2.2 Hz), 9.26 (t, 0.53H, J¼2.2 Hz); 13C NMR
4.5.1. (2S)-1-[(RS)-p-Toluenesulfinyl]-2-heptanol 7a. Rf
0.28 (EtOAc/hexane 1:1); oil; 92% yield; IR (neat, cm21):
3423, 2911, 1032; 1H NMR (300 MHz, CDCl3) d 0.81–0.88
(m, 3H), 1.29–1.67 (m, 8H), 2.43 (s, 3H), 2.63 (dd, 0.45H,
J¼1.8, 13.4 Hz), 2.77 (dd, 0.55H, J¼2.4, 13.1 Hz), 2.94 (dd,
0.55H, J¼9.2, 13.1 Hz), 3.04 (dd, 0.45H, J¼9.6, 13.6 Hz),
3.68 (d, 0.55H, J¼2.75 Hz), 3.77 (s, 0.45H), 4.15 (m,
0.45H), 4.30 (m, 0.55H), 7.35 (d, 2H, J¼7.94 Hz), 7.50–
7.58 (m, 2H); 13C NMR (50 MHz, CDCl3) d 14.64, 22.15,
23.20, 25.34, 25.43, 32.21, 32.30, 37.65, 37.92, 61.63,
63.05, 67.54, 69.63, 124.69, 130.89, 142.27, 142.74. Calcd
for C14H22O2S: C, 66.10; H, 8.72; S, 12.61. Found: C,
60.13; H, 8.60; S, 12.43. In the same manner as above, (R)-
7a was obtained from (R)-6a in 93% yield.

B. T. Cho, D. J. Kim / Tetrahedron 59 (2003) 2457–2462
2461
4.5.2. (2S)-4-Methyl-1-[(RS)-p-toluenesulfinyl]-2-penta-
nol 7b. Rf 0.31 (EtOAc/hexane 1:1); oil; 95% yield; IR
(neat, cm21): 3394, 2955, 1018; 1H NMR (300 MHz,
CDCl3) d 0.79–0.96 (m, 6H), 1.13–1.86 (m, 3H), 2.43 (s,
3H), 2.63 (dd, 0.48H, J¼1.8, 13.7 Hz), 2.75 (dd, 0.52H,
J¼2.4, 13.1 Hz), 2.93 (dd, 0.52H, J¼9.0, 13.3 Hz), 3.02 (dd,
0.48H, J¼9.5, 13.4 Hz), 3.02 (dd, 0.48H, J¼9.5, 13.4 Hz),
3.58–3.74 (m, 1H), 4.25 (m, 0.52H), 4.41 (m, 0.48H), 7.35
(d, 2H, J¼7.94 Hz), 7.54–7.57 (m, 2H); 13C NMR
(50 MHz, CDCl3) d 22.14, 22.63, 22.71, 23.59, 23.86,
24.80, 24.97, 46.58, 47.00, 62.26, 63.43, 65.74, 67.81,
124.68, 130.78, 142.27, 142.73. Calcd for C13H20O2S: C,
64.96; H, 8.39; S, 13.34. Found: C, 64.99; H, 8.39; S, 13.01.
(50 MHz, CDCl3) d 11.53, 12.94, 16.44, 20.00, 21.83,
24.21, 24.52, 24.57, 25.20, 44.17, 45.53, 70.14, 70.54,
71.92, 126.08, 130.75, 141.16, 142.82. Calcd for
C15H24O2S: C, 67.12; H, 9.01; S, 11.95. Found: C, 67.19;
H, 9.19; S, 11.78.
4.6.3. (4S,5RS)-2-Methyl-[(RS)-p-toluenesulfinyl]-4-octa-
nol 10. Rf 0.53 (EtOAc/hexane 1:1); oil; 72% yield; IR
(neat, cm21): 3230, 2963, 1022; 1H NMR (300 MHz,
CDCl3) d 0.58–1.90 (m, 16H), 2.48 (s, 3H), 2.73 (m, 1H),
3.68 (m, 0.46H), 4.29 (m, 1H), 4.46 (m, 0.54H), 7.31–7.62
(m, 4H); 13C NMR (50 MHz, CDCl3) d 14.74, 20.66, 21.84,
22.91, 24.57, 25.18, 29.04, 30.37, 44.25, 67.62, 70.61,
71.05, 126.14, 130.74, 141.08, 142.81. Calcd for
C16H26O2S: C, 68.04; H, 9.28; S, 11.35. Found: C, 68.08;
H, 9.25; S, 11.38.
4.5.3. (2S)-1-[(RS)-p-Toluenesulfinyl]-2-dodecanol 7c. Rf
0.35 (EtOAc/hexane 1:1); 42–438C; 96% yield; IR (KBr,
1
cm21): 3384, 2965, 1015; H NMR (300 MHz, CDCl3) d
0.87 (t, 3H, J¼6.6 Hz), 1.22–1.59 (m, 18H), 2.44 (s, 3H),
2.64 (dd, 0.85H, J¼1.9, 13.6 Hz), 2.77 (dd, 0.15H, J¼1.8,
13.1 Hz), 2.94 (dd, 0.15H, J¼9.6, 13.1 Hz), 3.06 (dd, 0.85H,
J¼9.6, 13.6 Hz), 3.79 (d, 0.85H, J¼3.0 Hz), 3.89 (br s,
0.15H), 4.15 (m, 0.85H), 4.31 (m, 0.15H), 7.36 (d, 2H,
J¼7.8 Hz), 7.53 (m, 2H); 13C NMR (75 MHz, CDCl3) d
14.58, 21.85, 23.10, 25.55, 29.72, 29.78, 29.89, 29.97,
32.28, 37.37, 61.91, 66.80, 124.19, 130.27, 130.37, 139.49,
141.73. Calcd for C19H32O2S: C, 70.32; H, 9.94; S, 9.88.
Found: C, 70.41; H, 9.76; S, 9.69.
4.7. General procedure for preparation of optically
active pheromones 1–4 by desulfurization of 70c and
8–10
According to the literature procedure,19 a solution of each of
70c and 8–10 (2 mmol) in anhydrous methanol (10 mL) was
added to a suspension of Raney-Ni (ca. 0.3 g) in anhydrous
methanol. After the mixture was stirred for 6 h at room
temperature, the Ni was removed by filtration on a celite
short column. The filtrate was concentrated to give the
product pheromones 1–4, which were further purified by a
flash chromatography on silica gel (230–400 mesh).
4.6. General procedure for alkylation
Under a nitrogen atmosphere, n-BuLi (5.6 mmol, 2.5 M in
hexane) was added dropwise to 7a or 7b (2 mmol) in
anhydrous THF (10 mL) at 2788C and the mixture was
stirred for 30 min at the same temperature. To this, alkyl
iodides (2.2 mmol) was added dropwise and the resulting
mixture was stirred for 30 min at 2788C, allowed to warm
to 208C over 2 h, and then quenched by addition of saturated
ammonium chloride (10 mL). The organic layer was
separated and the aqueous layer was extracted with ethyl
acetate (2£10 mL). The combined extract was dried over
anhydrous Na2SO4, filtered and concentrated to give 8–10.
The crude alkylated products obtained were further purified
by a flash column chromatography on silica gel (230–400
mesh).
4.7.1. (R)-(2)-3-Octanol (R)-1. Rf 0.28 (EtOAc/hexane
1:4); oil; 89% yield; IR (neat, cm21): 3360, 2931; 1H NMR
(200 MHz, CDCl3) d 0.89 (t, 3H, J¼6.26 Hz), 1.06–1.41
(m, 14H), 3.80 (m, 1H); 13C NMR (50 MHz, CDCl3) d
14.66, 23.28, 24.11, 26.09, 32.50, 40.00; HRMS calcd for
(C8H18Oþ–H2O): 112.1252. Found: 112.1258; [a]2D0¼
211.51 (c 1.02, CHCl3) R; {lit.9 [a]D20¼29.7 (CHCl3), R,
.99% ee}; GC analysis (column temperature: 408C,
isothermal; carrier gas: He; head pressure: 13 psi, flow
rate: 1 mL/min; detector: FID) using a G-TA column
(Astec) showed it to be 96% ee [tR (R) 7.21 min and tR (S)
7.64 min]. In the same manner as above, (S)-(þ)-1 with 96%
ee was obtained; [a]D20¼þ10.21 (c 1.02, CHCl3) S; {lit.9
[a]2D2¼þ10.1 (CHCl3), S, .99% ee}.
4.6.1. (2RS,3S)-2-[(RS)-p-Toluenesulfinyl]-3-octanol 8. Rf
0.31 (EtOAc/hexane 1:1); oil; 93% yield; IR (neat, cm21):
3394, 2955, 1018; 1H NMR (300 MHz, CDCl3) d 0.73–1.66
(m, 14H), 2.37 (s, 3H), 2.45 (m, 1H), 3.68 (m, 1H), 4.04 (m,
1H), 7.29 (d, 2H, J¼7.94 Hz), 7.39–7.49 (m, 2H); 13C
NMR (50 MHz, CDCl3) d 9.44, 14.61, 22.08, 23.15, 25.97,
32.15, 34.70, 62.52, 62.84, 70.06, 73.04, 125.54, 130.69,
139.35, 142.56. Calcd for C15H24O2S: C, 67.12; H, 9.01; S,
11.95. Found: C, 67.29; H, 9.12; S, 12.02. Using the same
methodology, ent-8 was obtained in 90% yield.
4.7.2. (R)-(2)-2-Dodecanol (R)-2. Rf 0.37 (EtOAc/hexane
1:4); oil; 92% yield; IR (neat, cm21): 3381, 2959; 1H NMR
(200 MHz, CDCl3) 0.88 (t, 3H, J¼6.41 Hz), 1.18 (d, 3H,
J¼6.10 Hz), 1.27–1.41 (m, 19H), 3.79 (m, 1H); 13C NMR
(50 MHz, CDCl3) d 14.75, 23.33, 24.11, 26.43, 29.99,
30.27, 32.56, 40.04, 68.87. Calcd for C12H26O: C, 77.35; H,
14.06. Found: C, 77.31; H, 14.08; [a]2D0¼26.53 (c 1.21,
CHCl3) R; {lit.4 [a]D20¼26.5 (c 1.11, CHCl3), R, 100%ee};
GC analysis of its acetate (column temperature: 1508C,
isothermal; He; head pressure: 13 psi, flow rate: 1 mL/min;
detector: FID) using a b-DEX 120 chiral column (Supelco)
showed it to be 99% ee [tR (R) 39.09 min and tR (S)
40.64 min].
4.6.2. (4S,5RS)-2-Methyl-[(RS)-p-toluenesulfinyl]-4-hep-
tanol 9. Rf 0.41(EtOAc/hexane 1:1); oil; 76% yield; IR
(neat, cm21): 3313, 2962, 1022; 1H NMR (300 MHz,
CDCl3) d 0.84–2.01 (m, 11H), 2.42 (s, 3H), 2.72 (m, 1H),
3.60 (d, 0.28H, J¼6.41 Hz), 4.13 (m, 0.28H), 4.28 (m,
0.72H), 4.53 (s, 0.72H), 7.33 (d, 2H, J¼7.94 Hz), 7.46 (d,
0.56H, J¼8.4 Hz), 7.61 (d, 1.44H, J¼8.4 Hz); 13C NMR
4.7.3. (R)-(2)-2-Methyl-4-heptanol (R)-3. Rf 0.40 (EtOA-
c/hexane 1:4); oil; 89% yield; IR (neat, cm21): 3422, 2910;
1H NMR (200 MHz, CDCl3) d 0.90 (d, 3H, J¼2.4 Hz), 0.93
(d, 3H, J¼2.4 Hz), 1.16–1.53 (m, 10H), 1.74 (m, 1H), 3.67

2462
B. T. Cho, D. J. Kim / Tetrahedron 59 (2003) 2457–2462
(m, 1H); 13C NMR (50 MHz, CDCl3) d 14.75, 19.43, 22.71,
24.15, 25.27, 40.94, 47.50, 70.36; HRMS calcd for
(C8H18Oþ–H2O): 112.1252. Found: 112.1230; [a]2D0¼
212.24 (c 0.4, MeOH) R; {lit.10 [a]D22¼211.9 (c 1.04,
MeOH), R, 99.1%ee; [a]2D2¼þ13.3 (c 1.11, MeOH), S,
97.6%ee}; HPLC analysis of its benzoate using a Chiralpak
OT column [MeOH; flow rate: 0.3 mL/min; detector:
254 nm] showed it to be 98% ee [tR (R) 25.94 min and tR
(S) 32.43 min].
10. Takenaka, M.; Takikawa, H.; Mori, K. Liebigs Ann. 1996,
1963–1964.
11. For reviews, see: (a) Seyden-Penne, J. Reductions by the
Alumino- and Borohydrides in Organic Synthesis; Wiley-
VCH: New York, 1997. (b) Ramachandran, P. V.; Brown,
H. C. In Reductions in Organic Synthesis. ACS Symposium
Series 641; Abdel-Magid, A. F., Ed.; American Chemical
Society: Washington, DC, 1996; pp 84–97. (c) Cho, B. T.;
Chun, Y. S. In Organoboranes for Syntheses. ACS Symposium
Series 783; Ramachandran, P. V., Brown, H. C., Eds.;
American Chemical Society: Washington, DC, 2001;
pp 122–135. (d) Itsuno, S. Org. React. 1998, 52, 395–576.
(e) Itsuno, S. Comprehensive Asymmetric Catalysts; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Vol. 3, pp 289–315. (f) Corey, E. J.; Helal, C. J. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1986–2012. (g) Daverio, P.;
Zanda, M. Tetrahedron: Asymmetry 2001, 12, 2225–2259.
12. NB-Enantride: (a) Midland, M. M.; Kazubski, A.; Woodling,
R. E. J. Org. Chem. 1991, 56, 1068–1074. NB-Enantride¼
lithium B-iso-2-(2-benzyloxy)-ethylapopinocampheyl-9-bora-
bicyo[3.3.1]nonyl hydride; Eapine-Hydride: (b) Ramachandran,
P. V.; Brown, H. C.; Swaminathan, S. Tereahedron: Asymmetry
1990, 1, 433–436. Eapine-Hydride¼lithium B-iso-2-ethyl-
apopinocampheyl-9-borabicyclo[3.3.1]nonyl hydride; (2R,5R)-
dimethylborolane/(2R,5R)-dimethyl-borolanyl methanesulfo-
nate: (c) Imai, T.; Tamura, T.; Yamamuro, A.; Sato, T.;
Wollmann, T. A.; Kennedy, R. M.; Masamune, S. J. Am.
Chem. Soc. 1986, 108, 7402–7404. Enzyme: (d) Keinan, E.;
Hafeli, E. K.; Steh, K. K.; Lamed, R. J. Am. Chem. Soc. 1986,
108, 162–169.
4.7.4. (R)-(2)-2-Methyl-4-octanol (R)-4. Rf 0.45 (EtOA-
c/hexane 1:4); oil; 90% yield; IR (neat, cm21): 3360, 2900;
1H NMR (200 MHz, CDCl3) d 0.89–0.94 (m, 9H), 1.16–
1.42 (m, 9H), 1.76 (m, 1H), 3.65 (m, 1H); 13C NMR
(50 MHz, CDCl3) d 14.70, 22.68, 23.40, 24.13, 25.23,
28.45, 38.42, 47.45, 70.58; HRMS calcd for (C9H20Oþ–
H2O): 126.1408. Found: 126.1389; [a]2D0¼211.95 (c 0.45,
MeOH) R, .98% ee; {lit.10 [a]2D2¼210.5 (c 1.17, MeOH),
R, 99.1%ee; [a]2D2¼þ11.6 (c 1.04, MeOH), S, 97.6%ee}.
Acknowledgements
This study was supported by the Hallym Academy of
Sciences at Hallym University (2002-21-03), Korea.
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