Synthesis of all the stereoisomers of 6-methyl-2-octadecanone, 6,14-dimethyl-2-octadecanone, and 14-methyl-2-octadecanone, the components of the female-produced sex pheromone of a moth, Lyclene dharma dharma

Article abstract of DOI:10.1016/j.tet.2009.01.092

All of the stereoisomers of the components of the female-produced sex pheromone of a moth, Lyclene dharma dharma, were synthesized. They are (R)- and (S)-6-methyl-2-octadecanone, (6R,14R)-, (6R,14S)-, (6S,14R)-, and (6S,14S)-6,14-dimethyl-2-octadecanone, and (R)- and (S)-14-methyl-2-octadecanone. Enantiomers of citronellal and methyl (S)-3-hydroxy-2-methylpropanoate were the starting materials, and olefin cross metathesis was employed as the key reaction.

Full text of DOI:10.1016/j.tet.2009.01.092

Tetrahedron 65 (2009) 2798–2805
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of all the stereoisomers of 6-methyl-2-octadecanone, 6,14-dimethyl-2-
octadecanone, and 14-methyl-2-octadecanone, the components of the
female-produced sex pheromone of a moth, Lyclene dharma dharmaq
*
Kenji Mori
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, Wakahagi 4-2-1, Inba-mura, Inba-gun, Chiba 270-1609, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 January 2009
Received in revised form 26 January 2009
Accepted 26 January 2009
Available online 31 January 2009
All of the stereoisomers of the components of the female-produced sex pheromone of a moth, Lyclene
dharma dharma, were synthesized. They are (R)- and (S)-6-methyl-2-octadecanone, (6R,14R)-, (6R,14S)-,
(6S,14R)-, and (6S,14S)-6,14-dimethyl-2-octadecanone, and (R)- and (S)-14-methyl-2-octadecanone. En-
antiomers of citronellal and methyl (S)-3-hydroxy-2-methylpropanoate were the starting materials, and
olefin cross metathesis was employed as the key reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Citronellal, (R) and (S)
Methyl-branched ketones
Methyl (S)-3-hydroxy-2-methylpropanoate
Olefin cross metathesis
Pheromone
1. Introduction
metathesis can be used advantageously to prepare them in a simple
manner.
In 2007 Ando and his co-workers investigated the female-pro-
duced sex pheromone of a Lithosiinae moth, Lyclene dharma
dharma, in the Iriomote Islands, Okinawa.2 They identified three
electroantennographically active components of the sex phero-
mone as 6-methyl-2-octadecanone (1, Fig. 1), 6,14-dimethyl-2-
octadecanone (2), and 14-methyl-2-octadecanone (3) in a ratio of
about 2:1:1. In continuation of our long-standing project to clarify
the absolute configuration of pheromones,3 I decided to synthesize
all the possible stereoisomers of 1, 2, and 3. Their bioassay will
hopefully clarify the bioactive stereoisomers.
Scheme 1 shows the retrosynthetic analysis of (R)-1, (6R,14R)-2,
and (R)-3. These ketones can be prepared by hydrogenation of
olefinic ketones A, B, and C, respectively, which can be prepared by
cross metathesis by employing the Grubbs’ first generation catalyst
O
n-C12H25
6-methyl-2-octadecanone (1)
(50 ng/female)
There are several methyl-branched 2-alkanones among chiral
insect pheromones, and they have been prepared by employing
traditional carbon–carbon single bond formation reactions such as
Grignard reaction and alkylation of alkynes.4 Advent of olefin cross
metathesis reaction5–7 opened a new possibility to employ it as the
key-step in pheromone synthesis.8,9 Although ring-closing me-
tathesis has frequently been used,10–14 there are not so many ap-
plications of cross metathesis in pheromone synthesis.15,16 In the
present case of the synthesis of all the stereoisomers of 1–3, cross
O
n-C4H9
(CH2)7
6,14-dimethyl-2-octadecanone (2)
O
n-C4H9
(CH2)11
14-methyl-2-octadecanone (3)
1 : 2 : 3 = 2 : 1 : 1
q
Pheromone synthesis, Part 239. For Part 238, see Ref. 1.
* Tel.: þ81 3 3816 6889; fax: þ81 3 3813 1516.
E-mail address: kjk-mori@arion.ocn.ne.jp
Figure 1. Structures of the components of the female-produced sex pheromone of
a moth, L. dharma dharma. A female moth produces about 50 ng of 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.092

K. Mori / Tetrahedron 65 (2009) 2798–2805
2799
O
O
O
n-C12H25
n-C4H9
(CH2)7
n-C4H9
(CH2)11
(R)-1
(6R,14R)-2
(R)-3
O
O
O
n-C8H17
n-C4H9
n-C4H9
A
B
C
Grubbs I
Grubbs I
Grubbs I
O
O
n-C8H17
n-C4H9
D
E
F
G
PCy3
Ru
Cl
Cl
Ph
OH
PCy3
CHO
MeO2C
(S)-I
OH
Grubbs I
(R)-H
J
Scheme 1. Retrosynthetic analysis of (R)-1, (6R,14R)-2, and (R)-3. The starting materials D, H, I, and J are commercially available.
(Grubbs I). Accordingly, cross metathesis of 1-decene (D) with (S)-
c
a
6-methyl-9-decen-2-one (E) generates A, while (R)-6-methyl-1-
decene (F) and E gives B. The ketone C can be prepared from F and
9-decen-2-one (G). As to the supply of the two metathesis partners,
D is commercially available, while G is readily synthesized from
commercially available 6-hepten-1-ol (J). The commercially
available enantiomers of citronellal (H), which are widely used as
chiral building blocks,9,17 are to be converted to the enantiomers of
E. Another chiral building block F can be synthesized from com-
mercially available methyl (S)-3-hydroxy-2-methylpropanoate (I).
This paper reports a successful synthesis of all the stereoisomers of
1–3 along the line described above. The present method serves as
a general protocol for the synthesis of methyl-branched ketones.
CHO
OR
(R)-5 R = H
(R)-4 (= H)
b
(R)-6 R = Ac
d
e
h
OAc
OHC
OAc
O
(R)-7
(R)-8
g
OR
I
(R)-9 R = H
(R)-10 R = Ts
(R)-11
f
O
2. Results and discussion
O
i
2.1. Synthesis of ketones (R)- and (S)-13 and 18, the
metathesis partners
CO2Et
(6R,3RS)-12
(S)-13 (= E)
Similarly
Scheme 2 summarizes the synthesis of the key building blocks
(R)- and (S)-13 (¼E) and 18 (¼G). (R)-Citronellal (4) was converted
to the known aldehyde (R)-8 in 93% overall yield by the steps
depicted.18 Treatment of (R)-8 with methylenetriphenylphosphor-
ane was followed by the hydrolysis of the acetate group with so-
dium hydroxide to give (R)-9. Tosylation of (R)-9 afforded (R)-10,
which was treated with sodium iodide in N,N-dimethylformamide
(DMF) to give (R)-11. Alkylation of ethyl acetoacetate with (R)-11
O
CHO
(S)-4
(R)-13
g
h
OR
I
14 R = H (= J)
15 R = Ts
16
f
yielded (6R,3RS)-12, whose hydrolysis and decarboxylation fur-
26
nished the desired building block (S)-13, [
a
]
ꢀ2.81 (c 4.29, hex-
D
O
O
i
ane), in 27% overall yield based on (R)-4 (eight steps). Similarly, (R)-
25
13, [
a
]
þ2.90 (c 3.64, hexane), was prepared from (S)-citronellal
D
(4). Enantioselective GC analysis of (R)- and (S)-13 revealed them to
be of 97.2% ee and 97.6% ee, respectively (see Experimental). It
should be added that 9 is a useful metathesis partner for the syn-
thesis of 3-methyl-branched 1-alkanols.19
CO2Et
17
18 (= G)
Scheme 2. Synthesis of unsaturated ketones (R)- and (S)-13 and 18. Reagents: (a)
LiAlH4, Et2O; (b) Ac2O, C5H5N (93% for two steps); (c) MCPBA, CH2Cl2 (quant.); (d)
HIO4$2H2O, THF, Et2O (quant.); (e) (1) Ph3P(Me)Br, n-BuLi, THF; (2) NaOH, MeOH, H2O
(48–50%, two steps); (f) TsCl, C5H5N (93–96% for 10, 69% for 15); (g) NaI, DMF (82–
84%); (h) MeCOCH2CO2Et, K2CO3, DMF, Me2CO; (i) KOH, MeOH, H2O (68–72%, two
steps).
Preparation of the achiral ketone 18 was straightforward start-
ing from 6-hepten-1-ol (14). The corresponding tosylate 15 was
converted to iodide 16. Alkylation of ethyl acetoacetate with 16

2800
K. Mori / Tetrahedron 65 (2009) 2798–2805
gave 17, which was treated with potassium hydroxide in aqueous
methanol to give 18 in 42% overall yield based on 14 (four steps).
G. It was therefore planned that 6 equiv of D or F were to be used
for 1 equiv of E or G so as to increase the yield of the desired cross
metathesis product based on E or G. Thus, 5–7 mol % (to E or G) of
Grubbs I catalyst was added to a solution of the two metathesis
partners in dichloromethane, and the mixture was stirred and
heated under reflux for 4–6 h under argon. The progress of the
reaction could be monitored by evolution of ethylene, which en-
larged the argon balloon. After the reaction mixture was left to
stand overnight or longer to allow the decomposition of the cat-
alyst, which facilitated the removal of the trace of the ruthenium
residue, it was concentrated, and the residue was purified by silica
gel chromatography. After elution of alkene i, the cross metathesis
product (S)-31 resulting from 30 and (S)-13 was obtained as an oil
in 83% yield based on (S)-13. The olefinic ketone (S)-31 was im-
2.2. Synthesis of alkenes (R)- and (S)-26, the other metathesis
partners
Scheme 3 shows the synthesis of the other key building blocks
(R)- and (S)-26 (¼F). Methyl (S)-3-hydroxy-2-methylpropanoate
(19) was chosen as the starting material, and converted to both the
enantiomers of 26 by employing Schlosser’s copper-catalyzed
Grignard coupling reaction as the key chain-elongation method-
ology.20 The hydroxy ester (S)-19 was converted to (R)-25 by the
known method as depicted.21 Treatment of (R)-25 with 3-bute-
nylmagnesium bromide in the presence of dilithium tetra-
25
mediately hydrogenated over 10% palladium–charcoal in ethyl
chlorocuprate afforded (R)-26, [
a]
ꢀ1.40 (c 3.76, Et2O), in 43%
D
26
acetate to give (R)-1, [
a
]
þ0.35 (c 4.08, hexane), as an oil in 89%
overall yield based on (S)-19 (seven steps).
D
yield. Since the double bond of (S)-31 was immediately hydro-
genated and disappeared in the final product (R)-1, its E/Z ratio
was not determined. The overall yield of (R)-1 was 17% based on
b
d
RO
OTHP
OR
MeO2C
citronellal [(R)-4, ten steps] and 74% based on the utilized alkene
(R)-21 R = H
(S)-22 R = Ts
(S)-19 (= I) R = H
(S)-20 R = THP
a
c
28
30 (two steps). Similarly, 30 and (R)-13 yielded (S)-1, [
a
]
ꢀ0.38
D
(c 3.63, hexane), as an oil. The mass spectrum of (R)- or (S)-1 was
identical with that of the naturally occurring pheromone com-
ponent 1.2
f
OR
n-C4H9
(R)-26 (= F)
n-C4H9
(R)-23 R = THP
(R)-24 R = H
(R)-25 R = Ts
By starting from (R)-26 and (S)-13, (6S,14R)-32 was obtained in
e
c
86% yield based on (S)-13, which was hydrogenated to give
27
(6R,14R)-2, [
a]
ꢀ0.50 (c 2.65, hexane), as an oil. Similarly, (S)-26
D
Similarly
24
and (S)-13 afforded (6R,14S)-2, [
(R)-26 and (R)-13 furnished (6S,14R)-2, [
as an oil; (S)-26 and (R)-13 gave (6S,14S)-2, [
a
]
þ1.54 (c 3.07, hexane), as an oil;
D
27
g
d
a
]
ꢀ1.16 (c 3.07, hexane),
26
D
THPO
OTs
RO
a
]
D
þ0.65 (c 3.81,
hexane), as an oil. The overall yield of (6R,14R)-2 was 21% based on
citronellal [(R)-4, ten steps], or 34% based on methyl (S)-3-hydroxy-
2-methylpropanoate [19, nine steps, based on the utilized (R)-26],
and that of (6R,14S)-2 was 24% based on (S)-4 (ten steps) and 32%
based on (S)-19 (nine steps). The mass spectrum of each of the
synthetic stereoisomers of 2 was identical with that of the naturally
occurring pheromone component 2.
(S)-22
(R)-27 R = THP
(R)-28 R = H
(R)-29 R = Ts
h
c
n-C4H9
(S)-26
Scheme 3. Synthesis of olefins (R)- and (S)-26. Reagents: (a) 3,4-dihydro-2H-pyran,
TsOH, Et2O (quant.); (b) LiAlH4, Et2O (90%); (c) TsCl, C5H5N (quant.); (d) n-C3H7MgBr,
Li2CuCl4, THF [71% for (S)-26]; (e) TsOH, MeOH (70%, two steps); (f)
CH2]CH(CH2)2MgBr, Li2CuCl4, THF (69%, two steps); (g) CH2]CH(CH2)2MgBr, Li2CuCl4,
THF; (h) AcOH, THF, H2O (55%, two steps).
Cross metathesis of (R)-26 with achiral 18 gave (R)-33 in 78%
25
yield based on 18, which was hydrogenated to give (R)-3, [a]
D
ꢀ0.60 (c 3.07, hexane), as an oil. Similarly, (S)-26 and 18 yielded
24
(S)-3, [
a
]
þ1.05 (c 3.13, hexane), as an oil. The overall yield of
D
(R)-3 was 27% based on 14 (six steps) or 28% based on (S)-19 [nine
steps, based on the utilized (R)-26], and that of (S)-3 was 23%
based on (S)-19 [nine steps, based on the utilized (S)-26]. The
mass spectrum of each of the synthetic stereoisomers of 3 was
identical with that of the naturally occurring pheromone com-
ponent 3.
For the synthesis of (S)-26, the tosylate (S)-22, whose (R)-
isomer was known,22 was subjected to the Schlosser coupling20
with 3-butenylmagnesium bromide to give (R)-27. Tosylate (R)-
29 of the corresponding alcohol (R)-28 was then treated with
propylmagnesium bromide in the presence of dilithium tetra-
25
chlorocuprate to give (S)-26, [
a
]
þ1.71 (c 4.20, Et2O), in 35%
The enantiomeric purities of the final products 1, 2, and 3 were
considered to be ca. 97% ee, reflecting the enantiomeric purities of
the starting materials. Their direct evaluation by GC was
unsuccessful.
D
overall yield based on (S)-19 (seven steps). The enantiomers
of 26 were analyzed by GC on two different chiral station-
ary phases [octakis-(2,3-di-O-methoxymethyl-6-O-t-butyldi-
methylsilyl)-g
-cyclodextrin23 and ChiramixÒ24]. Unfortunately
they were inseparable on these two stationary phases. Ac-
cordingly, direct evaluation of their enantiomeric purities was
impossible. It can be assumed that they are of 99.9% ee,
reflecting the high enantiomeric purity (99.9% ee) of the
starting (S)-19.
3. Conclusion
All of the eight possible stereoisomers of 1, 2, and 3, the
components of the female-produced sex pheromone of a moth
L. dharma dharma, were synthesized by employing cross
metathesis as the key-step. The cross metathesis was achieved
in the average yield of 82% (79–92%), and shown to be an
2.3. Synthesis of all the stereoisomers of 1, 2, and 3 by cross
metathesis and subsequent hydrogenation
excellent method to quickly prepare
compounds.
a number of similar
In comparison to ring-closing metathesis, cross metathesis is
rather underdeveloped, because it lacks the entropic driving force,
and is complicated by self-metathesis of each of the two partners.
In the present case, the olefin partners D and F (see Scheme 4) are
more readily available than the unsaturated ketone partners E and
Bioassay of these isomers of 1, 2, and 3 is now in progress by
Professor T. Ando and his co-workers, and the results will be pub-
lished in due course. Preliminary results showed that (S)-1 and (S)-
3 were more attractive than (R)-1 and (R)-3 against L. dharma
dharma males.

K. Mori / Tetrahedron 65 (2009) 2798–2805
2801
O
O
a
n-C8H17
+
+
n-C8H17
30 (= D)
n-C8H17
n-C8H17
i
(S)-31
(S)-13 (= E)
O
b
n-C12H25
(R)-1
O
O
+
n-C8H17
n-C12H25
30
(R)-13
(S)-1
O
a
n-C4H9
+
+
n-C4H9
n-C4H9
(R)-26 (= F)
(S)-13 (= E)
ii
O
O
b
n-C4H9
n-C4H9
(CH2)7
(6S,14R)-32
(6R,14R)-2
O
O
O
O
O
O
+
n-C4H9
(S)-26
n-C4H9
(CH2)7
(S)-13
(R)-13
(R)-13
(6R,14S)-2
+
+
+
n-C4H9
(R)-26
n-C4H9
(CH2)7
(6S,14R)-2
n-C4H9
(S)-26
n-C4H9
(CH2)7
(6S,14S)-2
O
b
a
n-C4H9
+
n-C4H9
n-C4H9
(R)-26
18 (= G)
ii
O
O
n-C4H9
n-C4H9
(CH2)11
(R)-33
(R)-3
O
O
+
n-C4H9
(S)-26
n-C4H9
(CH2)11
18
(S)-3
Scheme 4. Synthesis of all the stereoisomers of 1, 2, and 3. Reagents: (a) Grubbs I catalyst, CH2Cl2 (79–92%, average 82%); (b) H2, 10% Pd–C, EtOAc (77–93%; average 88%).
4. Experimental
4.1. General
d
¼77.0 as internal standard) were recorded on a Jeol JNM-AL 400
spectrometer. GC–MS were measured on Agilent Technologies 5975
inert XL. HRMS were recorded on a Jeol JMS-SX 102A. Column
chromatography was carried out on Merck Kieselgel 60 Art 1.07734.
Boiling points are uncorrected values. Refractive indices (nD) were
measured on an Atago DMT-1 refractometer. Optical rotations were
measured on a Jasco P-1020 polarimeter. IR spectra were measured
on a Jasco FT/IR-410 spectrometer.1H NMR spectra (400 MHz, TMS at
4.2. 3-Methyl-6-hepten-1-ol 9
Enantiomers of citronellal (4, Takasago, ca. 97% ee) were the
starting materials.
d
¼0.00 as internal standard) and 13C NMR spectra (100 MHz, CDCl3 at

2802
K. Mori / Tetrahedron 65 (2009) 2798–2805
4.2.1. (R)-Isomer
C]C), 910 (s, CH]CH2); dH (CDCl3): 0.89 (3H, d, J 6.4, CHCH3), 1.18–
1.30 (1H, m), 1.37–1.47 (1H, m), 1.54–1.70 (2H, m), 1.84–1.92 (1H,
m), 1.95–2.15 (2H, m), 3.12–3.29 (2H, m), 4.92–5.04 (2H, m,
CH]CH2), 5.70–5.86 (1H, m, CH]CH2). HRMS calcd for C8H15I:
238.0218, found: 238.0218.
A solution of n-BuLi in hexane (1.6 M, 120 mL, 192 mmol) was
added dropwise to a cooled and stirred suspension of Ph3P(Me)Br
(61 g, 171 mmol) in dry THF (250 mL) at ꢀ30 ꢁC under Ar. The
mixture was stirred for 10 min at 0–5 ꢁC and cooled again at
ꢀ70 ꢁC. A solution of crude (R)-8 [33.1 g, prepared from 161 mmol
of (R)-6] in dry THF (50 mL) was added to the cooled and stirred
Wittig reagent at ꢀ60 to ꢀ50 ꢁC over 15 min. The stirring was
continued overnight, and the temperature was allowed to reach
room temperature. The mixture was then shaken with hexane and
MeOH/H2O (2:1, 150 mL). The hexane/THF layer was separated,
washed successively with MeOH/H2O (2:1, 50 mL), water and brine,
dried (MgSO4), and concentrated in vacuo. The residual oil (ca. 30 g)
was dissolved in MeOH (150 mL), and mixed with NaOH (12 g,
300 mmol) in H2O (75 mL). The mixture was stirred and heated
under reflux for 1 h. It was then diluted with water, and extracted
with hexane. The extract was washed with water and brine, dried
(MgSO4), and concentrated in vacuo. The residue was distilled to
4.4.2. (S)-Isomer
In the same manner, (S)-10 (20.0 g, 71 mmol) gave 14.0 g (83%)
of (S)-11 as a colorless and dense oil, bp 105–108 ꢁC/28 Torr; nD27
25
1.4968; [
a
]
D
þ12.7 (c 4.93, hexane). Its spectral data were identical
with those of (R)-11. HRMS calcd for C8H15I: 238.0218, found:
238.0218.
4.5. 3-Ethoxycarbonyl-6-methyl-9-decen-2-one 12
4.5.1. (3RS,6R)-Isomer
Powdered K2CO3 (32.0 g, 232 mmol) was added to a stirred so-
lution of (R)-11 (14.9 g, 63 mmol), ethyl acetoacetate (11.2 g,
86 mmol), and DMF (10 mL) in acetone (150 mL). The mixture was
stirred and heated under reflux for 7 h under Ar, and then con-
centrated in vacuo to remove acetone. The residue was diluted with
water, and extracted with diethyl ether. The ether extract was
washed with dil. NaHCO3 aq solution containing a small amount of
Na2S2O3 and brine, dried (MgSO4), and concentrated in vacuo to
give 17.6 g (quant.) of crude (3RS, 6R)-12, nmax (film): 3078 (w,
C]CH2), 1718 (s, C]O), 1641 (m, C]C), 1242 (s), 1149 (s), 1041 (m),
910 (m). This was used in the next step without further purification.
give 10.2 g (50%) of (R)-9 as a colorless oil, bp 110–112 ꢁC/40 Torr,
25
n2D1 1.4430; [
a
]
þ4.06 (c 3.58, hexane); nmax (film): 3334 (s, OH),
D
3078 (m, C]CH2), 1641 (m, C]¼C), 1059 (s, C–O), 908 (s,
CH]CH2); dH (CDCl3): 0.91 (3H, d, J 6.8, CHCH3), 1.25–1.29 (1H, m),
1.37–1.41 (2H, m), 1.57–1.63 (3H, m), 1.64–2.09 (2H, m), 3.60–3.75
(2H, m, CH2O), 4.92–5.03 (2H, m, CH]CH2), 5.75–5.86 (1H, m,
CH]CH2). HRMS calcd for C8H15O (MþꢀH): 127.1123, found:
127.1129.
4.2.2. (S)-Isomer
In the same manner, (S)-6 (33.4 g, 156 mmol) yielded 9.5 g (48%)
4.5.2. (3RS, 6S)-Isomer
26
of (S)-9 as a colorless oil, bp 128–134 ꢁC/98 Torr, nD26 1.4418; [
a]
D
In the same manner, (S)-11 (14.0 g, 59 mmol) gave 18.0 g
(quant.) of crude (3RS,6S)-12. Its IR spectrum was identical with
that of (3RS,6R)-12. This was used in the next step without further
purification.
ꢀ4.04 (c 4.54, hexane). Its spectral data were identical with those of
(R)-9. HRMS calcd for C8H15O(MþꢀH): 127.1123, found: 127.1129.
4.3. 3-Methyl-6-heptenyl tosylate 10
4.3.1. (R)-Isomer
4.6. 6-Methyl-9-decen-2-one 13
Tosyl chloride (17.2 g, 91 mmol) was added to a stirred and ice-
cooled solution of (R)-9 (10.2 g, 80 mmol) in dry pyridine (30 mL) at
5–10 ꢁC. The mixture was left to stand overnight in a refrigerator. It
was then diluted with ice-water, and extracted with diethyl ether.
The ether solution was washed with water, dil. HCl, water, NaHCO3
aq solution and brine, dried (MgSO4), and concentrated in vacuo to
give 20.9 g (93%) of (R)-10 as an oil, nmax (film): 3074 (w, C]CH2),
1641 (m, C]C), 1599 (m, arom. C]C), 1360 (s), 1178 (s), 945 (s), 663
(s); dH (CDCl3): 0.84 (3H, d, J 6.8, CHCH3), 2.45 (3H, s, C6H4CH3),
4.02–4.12 (2H, m, CH2O), 4.91–4.99 (2H, m, CH]CH2), 5.68–5.80
(1H, m, CH]CH2), 7.35 (2H, J 8.0, arom. H), 7.79 (2H, d, J 8.0, arom.
H). This was employed in the next step without further purification.
4.6.1. (S)-Isomer
The crude (3RS,6R)-12 (17.6 g) was mixed with 10% aq solution
of KOH (80 mL,143 mmol) and MeOH (80 mL), and the mixture was
stirred and heated under reflux for 30 min, and left to stand over-
night at room temperature. It was then diluted with water, and
extracted with diethyl ether. The ether extract was washed with
water and brine, dried (MgSO4), and concentrated in vacuo. The
residue was distilled to give 7.6 g (72%, two steps) of (S)-13. This
was redistilled to give 6.8 g of pure (S)-13, bp 90–92 ꢁC/18 Torr or
bp 95–98 ꢁC/10 Torr, n2D7 1.4394; [
a
]
ꢀ2.81 (c 4.29, hexane); nmax
26
D
(film): 3076 (m, C]CH2), 1718 (s, C]O), 1641 (m, C]C), 1360 (m),
1165 (m), 995 (m), 910 (m); dH (CDCl3): 0.88 (3H, d, J 6.4, CHCH3),
1.08–1.15 (1H, m), 1.15–1.34 (2H, m), 1.36–1.48 (2H, m), 1.50–1.65
(2H, m), 1.95–2.10 (2H, m), 2.13 (3H, s, COCH3), 2.40 (2H, t, J 7.6,
CH2CO), 4.90–5.03 (2H, m, CH]CH2), 5.74–5.86 (1H, m, CH]CH2).
GC [Instrument: Agilent 7890 GC; Column: 50% octakis-(2,3-di-O-
4.3.2. (S)-Isomer
In the same manner, (S)-9 (9.5 g, 74 mmol) yielded 20.0 g (96%) of
(S)-10 as an oil. Its spectral data were identical with those of (R)-10.
4.4. 3-Methyl-6-heptenyl iodide 11
methoxymethyl-6-O-t-butyldimethylsilyl)-g-cyclodextrin (MOMT-
BDMSGCD),23 30 mꢂ0.25 mm i.d.; carrier gas: He; flow rate:
0.7 mL/min; temp: 40–180 ꢁC (þ0.7 ꢁC/min); injection temp:
230 ꢁC; detector (F1D) temp: 250 ꢁC]: tR¼96.4 min (1.2%); 96.9 min
(98.8%). Enantiomeric purity of (S)-13 was 97.6% ee. HRMS calcd for
C11H20O: 168.1515, found: 168.1516.
4.4.1. (R)-Isomer
Powdered sodium iodide (31 g, 207 mmol) was added to a so-
lution of (R)-10 (20.9 g, 75 mmol) in dry DMF (150 mL) with vig-
orous stirring. After exothermic reaction, the homogeneous and
colored solution was stirred and heated at 80 ꢁC for 40 min. After
cooling, the mixture was diluted with ice-water, and extracted with
pentane. The pentane solution was washed with water containing
a small amount of Na2S2O3 and brine, dried (MgSO4), and concen-
trated in vacuo. The residue was distilled to give 15.0 g (84%) of (R)-
4.6.2. (R)-Isomer
In the same manner, the crude (3RS,6S)-12 (18.0 g) gave 7.2 g
(76%, two steps) of (R)-13. This was redistilled to give 6.2 g of pure
25
(R)-13, bp 89–91 ꢁC/7 Torr or 90–92 ꢁC/7 Torr, n2D7 1.4392; [
a]
D
11 as a colorless and dense oil, bp 116–118 ꢁC/47 Torr, nD27 1.4968;
þ2.90 (c 3.64, hexane). Its spectral data were identical with those of
(S)-13. GC [same conditions as for (S)-13]: tR¼96.4 min (98.6%);
29
[
a]
ꢀ12.4 (c 4.12, hexane); nmax (film): 3076 (m, C]CH2), 1639 (m,
D

K. Mori / Tetrahedron 65 (2009) 2798–2805
2803
96.9 min (1.4%). Enantiomeric purity of (R)-13 was 97.2% ee. HRMS
calcd for C11H20O: 168.1514, found: 168.1513.
cooled solution of (R)-29 (15.7 g, 56 mmol) in dry THF (60 mL) at
ꢀ60 to ꢀ50 ꢁC under Ar. Subsequently, a solution of Li2CuCl4 in THF
(0.1 M, 3 mL, 0.3 mmol) was added dropwise to the stirred mixture,
which was left to stand overnight with gradual rise of the tem-
perature to room temperature. The mixture was worked up as
described for the preparation of (R)-26. The residual oil was dis-
4.7. 6-Heptenyl tosylate 15
In the same manner as described for the preparation of 10, 14
(5.0 g, 44 mmol) gave 8.1 g (69%) of 15 as a slightly yellowish oil,
nmax (film): 1641 (w, C]C), 1599 (w, arom. C]C), 1362 (s), 1176 (s);
dH (CDCl3): 1.25–1.40 (4H, m), 1.60–1.70 (2H, m), 1.94–2.02 (2H, m),
2.45 (3H, s, C6H4CH3), 4.02 (2H, t, J 6.4, OCH2), 4.90–5.05 (2H, m,
CH]CH2), 5.68–5.85 (1H, m, CH]CH2), 7.34 (2H, d, J 8.0, arom. H),
7.78 (2H, d, J 8.0, arom. H). This was employed for the next step
without further purification.
tilled to give 6.1 g (71%, two steps) of (S)-26 as a colorless oil, bp 93–
25
98 ꢁC/48 Torr, n2D7 1.4240; [
a
]
þ1.71 (c 4.20, Et2O). Its spectral data
D
were identical with those of (R)-26. HRMS calcd for C11H22
:
154.1721, found: 154.1713.
4.11. (R)-2-Methyl-6-hepten-1-ol THP ether 27
A solution of the Grignard reagent was prepared from 3-butenyl
bromide (28.0 g, 207 mmol) and Mg (5.4 g, 235 mmol) in dry THF
(100 mL) under Ar. This was added dropwise to a stirred and cooled
solution of (S)-22 (33.0 g, 100 mmol) in dry THF (120 mL) at ꢀ60 to
ꢀ50 ꢁC under Ar. Subsequently, a solution of Li2CuCl4 in THF (0.1 M,
4 mL, 0.4 mmol) was added dropwise to the stirred mixture, which
was left to stand overnight with gradual rise of the temperature to
room temperature. The mixture was worked up as described for the
preparation of (R)-26 to give crude (R)-27 (23.5 g) as a colorless oil,
nmax (film): 3076 (w, C]CH2), 1641 (w, C]C), 1120 (m), 1034 (s),
908 (m). This was employed for the next step without further
purification.
4.8. 6-Heptenyl iodide 16
In the same manner as described for the preparation of 11, 15
(8.1 g, 30 mmol) gave 5.5 g (82%) of 16 as an oil, bp 90–100 ꢁC/
40 Torr, n2D7 1.4902; nmax (film): 3076 (w, C]CH2), 1641 (m, C]C),
1207 (m), 1173 (m), 993 (m), 912 (s); dH (CDCl3): 1.38–1.50 (4H, m),
1.75–1.90 (2H, m), 2.02–2.12 (2H, m), 3.19 (2H, t, J 6.8, OCH2), 4.92–
5.05 (2H, m, CH]CH2), 5.74–5.87 (1H, m, CH]CH2). HRMS calcd for
C7H13I: 224.0062, found: 224.0062.
4.9. 9-Decen-2-one 18
In the same manner as described for the preparation of 12 and
13, 16 (5.5 g, 24 mmol) was converted to 6.3 g of crude 17, which
gave 2.5 g (68%, two steps) of 18, bp 83–85 ꢁC/7 Torr, nD27 1.4360;
nmax (film): 3076 (w, C]CH2), 1718 (s, C]O), 1641 (m, C]C), 1360
(m), 1165 (m), 993 (m), 910 (m); dH (CDCl3): 1.24–1.32 (2H, m), 1.32–
1.45 (2H, m), 1.54–1.61 (2H, m), 2.00–2.08 (2H, m), 2.13 (3H, s,
COCH3), 2.42 (2H, t, J 3.2, COCH2), 4.90–5.04 (2H, m, CH]CH2),
5.74–5.86 (1H, m, CH]CH2). HRMS calcd for C10H18O: 154.1358,
found: 154.1359.
4.12. (R)-2-Methyl-6-hepten-1-ol 28
The above described crude (R)-27 (23.5 g) was dissolved in
a mixture of THF (100 mL), AcOH (50 mL) and H2O (50 mL). The
mixture was stirred and heated under reflux for 6 h. After cooling, it
was diluted with water, and extracted with diethyl ether. The ether
extract was washed with water, 10% NaOH aq solution and brine,
dried (MgSO4), and concentrated in vacuo to give a crude oil
(17.6 g). This was chromatographed over SiO2 (80 g). Elution with
hexane gave 4.7 g of non-polar impurities, and further elution with
pentane/Et2O (2:1) gave 12.8 g of crude (R)-28. This was distilled to
4.10. 6-Methyl-1-decene 26
give 7.1 g (55%, three steps) of pure (R)-28, bp 106–109 ꢁC/43 Torr,
25
4.10.1. (R)-Isomer
n2D7 1.4412; [
a]
þ12.8 (c 3.22, hexane); nmax (film): 3348 (s, OH),
D
Hydroxy ester (S)-19 (Mitsubishi Rayon Co., 99.9% ee as esti-
mated and guaranteed by Dr. K. Sakashita of Mitsubishi Rayon Co.
The enantiomeric purity of 19 can be determined by HPLC analysis
of the corresponding MTPA ester.22) was converted to (R)-25 by the
known method.21 A solution of the Grignard reagent was prepared
from 3-butenyl bromide (22 g,163 mmol) and Mg (4.3 g,179 mmol)
in dry THF (90 mL) in a usual manner under Ar. This was added
dropwise to a stirred and cooled solution of (R)-25 (23.4 g,
86.5 mmol) in dry THF (80 mL) at ꢀ60 to ꢀ50 ꢁC under Ar. Sub-
sequently, a solution of Li2CuCl4 in THF (0.1 M, 3 mL, 0.3 mmol) was
added dropwise to the stirred mixture, which was left to stand
overnight with gradual rise of the temperature to room tempera-
ture. The mixture was poured into ice–dil. NH4Cl aq solution, and
extracted with diethyl ether. The ether extract was washed with
ether and brine, dried (MgSO4), and concentrated in vacuo. The
3078 (m, C]CH2), 1641 (m, C]C), 1034 (s, C–O), 995 (m), 910 (s); dH
(CDCl3): 0.92 (3H, d, J 6.8, CHCH3), 1.07–1.18 (1H, m), 1.20–1.50 (3H,
m), 1.58–1.68 (2H, m), 2.00–2.10 (2H, m), 3.41 (1H, dd J 7.2, 6.0,
CHOH), 3.50 (1H, dd, J 7.2, 6.0, CHOH), 4.92–5.04 (2H, m, CH]CH2),
5.75–5.88 (1H, m, CH]CH2). HRMS calcd for C8H16O: 128.1201,
found: 128.1198.
4.13. (R)-2-Methyl-6-heptenyl tosylate 29
Tosyl chloride (13.3 g, 70 mmol) was added to a stirred and ice-
cooled solution of (R)-28 (7.1 g, 55 mmol) in pyridine (30 mL) at 5–
10 ꢁC. The mixture was left to stand overnight in a refrigerator.
Usual work-up as described for the preparation of (R)-10 afforded
(R)-29 (15.7 g, quant.) as a colorless oil, nmax (film): 2932 (w,
C]CH2), 1641 (w, C]C), 1598 (m, arom. C]C), 1362 (s), 1178 (s),
1097 (m), 964 (s), 814 (s), 667 (s); dH (CDCl3): 0.88 (3H, d, J 6.8,
CHCH3), 1.06–1.16 (1H, m), 1.20–1.40 (3H, m), 1.72–1.81 (1H, m),
1.92–2.02 (2H, m), 3.80 (1H, dd J 6.4, 5.2, CHO), 3.88 (1H, dd, J 6.4,
5.2, CHO), 4.90–5.00 (2H, m, CH]CH2), 5.70–5.80 (1H, m,
CH]CH2), 7.34 (2H,d, J 8.4, arom. H), 7.78 (2H,d, J 8.4, arom. H). This
was employed for the next step without further purification.
residue was distilled to give 9.3 g (69%, two steps) of (R)-26 as
25
a colorless oil, bp 90–95 ꢁC/43 Torr, nD27 1.4260, [
a]
ꢀ1.40 (c 3.76,
D
Et2O); nmax (film): 3078 (m, C]CH2), 1641 (m, C]C), 993 (m), 910
(s); dH (CDCl3): 0.85 (3H, d, J 6.4, CHCH3), 0.89 (3H, t, J 6.8, CH2CH3),
1.05–1.15 (2H, m), 1.20–1.50 (9H, m), 2.00–2.09 (2H, m), 4.90–5.03
(2H, m, CH]CH2), 5.75–5.90 (1H, m CH]CH2). HRMS calcd for
C11H22: 154.1721, found: 154.1723.
4.14. 6-Methyl-9-octadecen-2-one 31
4.10.2. (S)-Isomer
A solution of n-propylmagnesium bromide was prepared from
n-propyl bromide (14.8 g, 120 mmol) and Mg (3.0 g, 125 mmol) in
dry THF (50 mL) under Ar. This was added dropwise to a stirred and
4.14.1. (S)-Isomer
A wine-red solution of (Cy3P)2Ru(]CHPh)Cl2 (Grubbs I catalyst,
Aldrich, 82 mg, 0.1 mmol), 30 (2.82 g, 20 mmol), and (S)-13

2804
K. Mori / Tetrahedron 65 (2009) 2798–2805
(535 mg, 3.2 mmol) in dry CH2Cl2 (5 mL) was stirred and heated
under reflux for 4 h under Ar. The mixture was left to stand over-
night at room temperature. Then the solvent was removed in vacuo,
and the dark residue in hexane was chromatographed over SiO2
(23 g). Elution with hexane gave n-C8H17CH]CHn-C8H17 (i, 2.5 g).
Further elution with hexane/EtOAc (15:1) afforded (S)-31 [737 mg,
83% based on (S)-13] as a slightly yellowish oil, nmax (film): 1720 (s,
C]O), 1163 (m), 968 (m); dH (CDCl3): 0.86 (3H, d, J 6.4, CHCH3), 0.87
(3H, t, J 6.4, CH2CH3), 1.05–1.20 (2H, m), 1.20–1.50 (14H, m), 1.50–
1.65 (3H, m), 1.90–2.05 (4H, m), 2.13 (3H, s, COCH3), 2.40 (2H, t, J 7.2,
COCH2), 5.30–5.42 (2H, CH]CH). This was employed in the next
step without further purification.
1720 (s, C]O), 1163 (m), 968 (m); dH (CDCl3): 0.80–0.92 (9H, m,
CH3), 1.05–1.18 (2H, m), 1.18–1.47 (14H, m), 1.48–1.68 (2H, m), 1.90–
2.08 (4H, m), 2.13 (3H, s, COCH3), 2.40 (2H, t, J 7.2, COCH2), 5.30–
5.43 (2H, m, CH]CH); MS (70 eV, EI): m/z: 294 (11) [Mþ, C20H38O],
276 (6), 236 (17), 139 (20), 123 (16), 111 (35), 109 (36), 95 (39), 81
(35), 69 (41), 55 (45), 43 (100). This was employed in the next step
without further purification. Further elution with hexane/EtOAc
(3:1) gave 82 mg of polar and colored by-product, presumably
enedione generated from (S)-13.
4.16.2. (6S,14S)-Isomer
In the same manner, a solution of (S)-26 (2.025 g, 13.2 mmol),
(S)-13 (336 mg, 2.0 mmol), and Grubbs I catalyst (85 mg initially
and 30 mg after 2 h) in CH2Cl2(5 mL) was stirred and heated under
reflux for 5 h under Ar. Subsequent work-up gave 470 mg (92%) of
(6S,14S)-32 as an oil. Its IR and 1H NMR spectra were identical with
those of (6S,14R)-32.
4.14.2. (R)-Isomer
In the same manner, 30 (2.8 g) and (R)-13 (533 mg) with Grubbs
I catalyst (82 mg) in CH2Cl2 (5 mL) furnished 710 mg [80% based on
(R)-13] of (R)-31. Its spectral data were identical with those of (S)-
31. This was employed in the next step without further purification.
4.16.3. (6R,14R)-Isomer
4.15. 6-Methyl-2-octadecanone 1
In the same manner, a solution of (R)-26 (2.0195 g, 13.1 mmol),
(R)-13 (362 mg, 2.2 mmol), and Grubbs I catalyst (85 mgþ35 mg) in
CH2Cl2 (5 mL) was stirred and heated under reflux for 6.5 h under
Ar. Subsequent work-up gave 480 mg (76%) of (6R,14R)-32 as an oil.
Its IR and 1H NMR spectra were identical with those of (6S,14R)-32.
4.15.1. (R)-Isomer
10% Palladium on charcoal (300 mg) was added to a solution of
(S)-31 (730 mg, 2.6 mmol) in EtOAc (15 mL). The suspension was
stirred under H2 (balloon) for 3 h at room temperature. The mixture
was then filtered through Celite and the catalyst and Celite were
washed with EtOAc. The filtrate was concentrated in vacuo, and the
residue was chromatographed over SiO2 (15 g). The column was
washed with hexane. Elution with hexane/EtOAc (50:1) gave (R)-1
4.16.4. (6R,14S)-Isomer
In the same manner, a solution of (S)-26 (2.023 g, 13.1 mmol),
(R)-13 (364 mg, 2.2 mmol), and Grubbs I catalyst (82 mgþ 50 mg)
was stirred and heated under reflux for 5 h under Ar. Subsequent
work-up gave 465 mg (73%) of (6R,14S)-32 as an oil. Its IR and 1H
NMR spectra were identical with those of (6S,14R)-32.
(652 mg, 89%) as a colorless oil, which solidified in a deep freezer,
26
n2D7 1.4434; [
a
]
þ0.35 (c 4.08, hexane); nmax (film): 1720 (s, C]O),
D
1464 (m), 1360 (m), 1165 (m), 721 (w); dH (CDCl3): 0.85 (3H, d, J 6.4,
CHCH3), 0.88 (3H, t, J 6.4, CH2CH3), 1.05–1.15 (2H, m), 1.20–1.35
[22H, m, (1.26, s)], 1.85–1.95 (1H, m), 1.50–1.65 (2H, m), 2.13 (3H, s,
COCH3), 2.07 (2H, t, J 7.6, COCH2); dC (CDCl3): 14.2, 19.6, 21.5, 22.7,
23.0, 27.1, 29.4, 29.7, 29.9, 30.0, 32.0, 32.7, 36.6, 36.9, 44.2, 209.1
(C]O); GC–MS [Column: HP-5MS 5% phenylmethylsiloxane,
30 mꢂ0.25 mm i.d.; press: 60.7 kPa; temp: 70–230 ꢁC (þ10 ꢁC/
min)]: tR 8.97 min (1.7%), 17.24 (4.1%), 18.25 (92.0%, 1). MS of (R)-1
(70 eV, EI): m/z: 282 (4) [Mþ, C19H38O], 264 (68), 239 (18), 123 (16),
110 (30),109 (35), 95 (30), 85 (43), 71 (57), 58 (100), 43 (87). The MS
was identical with that of the naturally occurring 1. HRMS calcd for
C19H38O: 282.2923, found: 282.2921.
4.17. 6,14-Dimethyl-2-octadecanone 2
4.17.1. (6R,14R)-Isomer
10% Palladium–charcoal (200 mg) was added to a solution of
(6R,14R)-32 (530 mg, 1.8 mmol) in EtOAc (15 mL). The suspension
was stirred under H2 (balloon) for 3 h at room temperature. Sub-
sequent work-up and chromatographic purification over SiO2
(6.5 g) gave 484 mg (91%) of (6R,14R)-2 as a colorless oil, n2D7 1.4460;
27
[a
]
ꢀ0.50 (c 2.65, hexane); nmax (film): 1720 (s, C]O), 1462 (s),
D
1377 (m), 725 (m); dH (CDCl3): 0.80–0.92 (9H, m, CH3), 1.05–1.15
(4H, m), 1.15–1.40 (20H, m), 1.50–1.65 (2H, m), 2.13 (3H, s, COCH3),
2.40 (2H, t, J 7.2, COCH2); dC (CDCl3): 14.1, 19.5, 19.7, 21.4, 22.6, 23.0,
27.0, 27.1, 29.2, 29.3, 29.7, 29.8, 32.59, 32.63, 36.5, 36.8, 36.9, 37.1,
44.1, 209.1 (C]O); GC–MS [same conditions as for (R)-1]: tR
8.98 min (6%), 18.77 (92%, 2), 19.30 (2%). MS of (6R,14R)-2 (70 eV,
EI): m/z: 296 (6%) [Mþ, C20H40O], 278 (63), 253 (15), 236 (13), 123
(20), 110 (42), 109 (41), 95 (32), 85 (45), 71 (55), 58 (92), 43 (100).
The MS was identical with that of the naturally occurring 2. HRMS
calcd for C20H40O: 296.3079, found: 296.3082.
4.15.2. (S)-Isomer
In the same manner, (R)-31 (700 mg) afforded 657 mg (93%) of
(S)-1 as a colorless oil. This solidifies in a deep freezer, n2D7 1.4438;
28
[
a]
ꢀ0.38 (c 3.63, hexane). GC [same conditions as reported for
D
(R)-1]: tR 8.97 min (3.4%), 17.2 (3.0%), 18.2 (91.5%, 1). Its spectral data
(IR, 1H, and 13C NMR, MS) were identical with those of (R)-1. HRMS
calcd for C19H38O: 282.2923, found: 282.2928.
4.16. 6,14-Dimethyl-9-octadecen-2-one-32
4.17.2. (6R,14S)-Isomer
4.16.1. (6S,14R)-Isomer
In the same manner, (6S,14S)-32 (470 mg, 1.9 mmol) gave
24
A wine-red solution of Grubbs I catalyst (85 mg, 0.1 mmol), (R)-
26 (2.018 g,13.1 mmol) and (S)-13 (358 mg, 2.1 mmol) in dry CH2Cl2
(5 mL) was stirred and heated under reflux for 4 h under Ar, when
evolution of ethylene almost ceased. An additional amount of
Grubbs I (36 mg, 0.04 mmol) was added to the mixture, and the
stirring and refluxing were continued for additional 1.75 h. The
mixture was left to stand overnight at room temperature. Then the
mixture was concentrated in vacuo, and the residue was chroma-
tographed over SiO2 (20 g). Elution with hexane gave alkene ii
(1.52 g). Further elution with hexane/EtOAc (15:1) gave 543 mg
[86% based on (S)-13] of (6S,14R)-32 as a yellowish oil, nmax (film):
459 mg (96%) of (6R,14S)-2, n2D7 1.4462; [
a
]
þ1.54 (c 3.07, hexane).
D
GC [same conditions as for (R)-1]: tR 17.73 min (2%), 18.77 (95%),
19.30 (3%). Its spectral data (IR, 1H, and 13C NMR and MS) were
identical with those described for (6R,14R)-2. HRMS calcd for
C20H40O: 296.3079, found: 296.3079.
4.17.3. (6S,14R)-Isomer
In the same manner, (6R,14R)-32 (475 mg, 1.6 mmol) gave
27
440 mg (92%) of (6S,14R)-2, n2D7 1.4470; [
a
]
ꢀ1.16 (c 3.07, hexane).
D
GC [same conditions as for (R)-1]: tR 16.68 min (3%), 17.73 (2%),
18.77 [95%, (6R,14R)-2]. Its spectral data (IR, 1H, and 13C NMR and

K. Mori / Tetrahedron 65 (2009) 2798–2805
2805
MS) were identical with those described for (6R,14R)-2. HRMS calcd
for C20H40O: 296.3079, found: 296.3077.
is identical with that of the naturally occurring 3. HRMS calcd for
19H38O: 282.2923, found: 282.2923.
C
4.17.4. (6S,14S)-Isomer
4.19.2. (S)-Isomer
In the same manner, (6R,14S)-32 (400 mg, 1.6 mmol) gave
In the same manner, (S)-33 (495 mg, 1.8 mmol) gave 405 mg
26
24
352 mg (77%) of (6S,14S)-2, n2D7 1.4466; [
a
]
þ0.65 (c 3.81, hexane).
(82%) of (S)-3, n2D7 1.4468; [
a
]
D
þ1.05 (c 3.13, hexane). GC [same
D
GC [same conditions as for (R)-1]: tR 16.68 min (1%), 17.73 (2%),
18.77 [97%, (6S,14S)-2]. Its spectral data (IR, 1H, and 13C NMR and
MS) were identical with those described for (6R,14R)-2. HRMS calcd
for C20H40O: 296.3079, found: 296.3082.
conditions as for (R)-1] tR 17.27 min (2%), 17.66 (2%), 18.34 [96%, (S)-
3]. Its spectral data (IR, 1H, and 13C NMR and MS) were identical
with those of (R)-3. HRMS calcd for C19H38O: 282.2923, found:
282.2926.
4.18. 14-Methyl-9-octadecen-2-one 33
Acknowledgements
4.18.1. (R)-Isomer
My thanks are due to Mr. M. Kimura (President, Toyo Gosei Co.,
Ltd) for his support. I am indebted to Prof. T. Ando (Tokyo University
of Agriculture and Technology) for bioassay and discussion. I thank
Mr. Y. Shikichi (Toyo Gosei Co., Ltd) for NMR and GC–MS mea-
surements, Dr. S. Tamogami (T. Hasegawa Co.) for enantioselective
GC analysis, and Dr. T. Tashiro (RIKEN) for preparing Figure and
Schemes. Both (R)-citronellal and (S)-citronellal were supplied by
Takasago International Corporation, and methyl (S)-3-hydroxy-2-
methylpropanoate was provided by Mitsubishi Rayon Co.
A solution of Grubbs I catalyst (82 mg and then 30 mg, total
112 mg, 0.14 mmol), (R)-26 (2.00 g, 13 mmol), and 18 (325 mg,
2.1 mmol) in CH2Cl2 (5 mL) was stirred and heated under reflux for
5 h under Ar. The mixture was left to stand overnight at room
temperature. Subsequent work-up gave 460 mg (78% based on 18)
of (R)-33, nmax (film): 1720 (s, C]O), 1163 (m), 968 (m); dH (CDCl3):
0.84 (3H, d, J 6.8, CHCH3), 0.90 (3H, t, J 6.8, CH2CH3), 1.00–1.11 (2H,
m), 1.15–1.40 (14H, m), 1.45–1.60 (3H, m), 1.85–2.00 (4H, m), 2.13
(3H, s, COCH3), 2.41 (2H, t, J 7.6, COCH2), 5.30–5.40 (2H, m, HC]CH).
This was employed in the next step without further purification.
References and notes
4.18.2. (S)-Isomer
1. Tashiro, T.; Osada, K.; Mori, K. Biosci. Biotechnol. Biochem. 2008, 72, 2398–2402.
2. Yamamoto, M.; Kamata, T.; Nguyen, D. D.; Adachi, Y.; Kinjo, M.; Ando, T. Biosci.
Biotechnol. Biochem. 2007, 71, 2860–2863.
3. Mori, K. Bioorg. Med. Chem. 2007, 15, 7505–7523.
4. Mori, K. Tetrahedron 2008, 64, 4061–4071.
5. Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann,
D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58–71.
6. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
7. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923.
8. Mori, K. Curr. Org. Synth. 2004, 1, 11–29.
In the same manner, Grubbs I catalyst (85 mg and then 25 mg,
total 110 mg, 0.14 mmol), (S)-26 (1.50 g, 9.7 mmol), and 18 (334 mg,
2.2 mmol) in CH2Cl2 (5 mL) were stirred and heated under reflux
for 7 h under Ar. The mixture was left to stand overnight at room
temperature. Subsequent work-up gave 501 mg (81%) of (S)-33. Its
IR and 1H NMR spectra were identical with those of (R)-33. This was
employed in the next step without further purification.
4.19. 14-Methyl-2-octadecanone 3
9. Mori, K. Top. Curr. Chem. 2004, 239, 1–50.
10. Scholl, M.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 1425–1428.
11. Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942–3943.
12. Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. Tetrahedron Lett. 2000, 41,
583–586.
13. Kurosawa, S.; Mori, K. Eur. J. Org. Chem. 2001, 4395–4399.
14. Sabitha, G.; Fatima, N.; Reddy, E. V.; Yadav, J. S. Tetrahedron Lett. 2008, 49, 6087–
6089.
15. Pederson, R. L.; Fellows, I. M.; Ung, T. A.; Ishihara, H.; Hajela, S. A. Adv. Synth.
Catal. 2002, 344, 728–735.
16. van Zijl, A. W.; Azymanski, W.; Lo´pez, F.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2008, 73, 6994–7002.
4.19.1. (R)-Isomer
10% Palladium–charcoal (200 mg) was added to a solution of
(R)-33 (438 mg, 1.6 mmol) in EtOAc (15 mL). The suspension was
stirred under H2 (balloon) for 2 h at room temperature. Subsequent
work-up and chromatographic purification over SiO2 (5 g) gave
361 mg (82%) of (R)-3. This solidifies in a deep freezer, n2D7 1.4428;
25
[
a]
ꢀ0.60 (c 3.07, hexane); nmax (film): 1720 (s, C]O), 1466 (s),
D
1360 (m), 1163 (m), 721 (m); dH (CDCl3): 0.84 (3H, d, J 6.8, CHCH3),
0.89 (3H, t, J 6.4, CH2CH3), 1.03–1.12 (2H, m), 1.18–1.90 (23H, m),
1.55–1.60 (2H, m), 2.13 (3H, s, O]CCH3), 2.41 (2H, t, J 7.6, O]CCH2),
dC (CDCl3): 14.1,19.7, 22.6, 23.0, 23.9, 27.1, 28.9, 29.2, 29.3, 29.4, 29.5,
29.6, 30.0, 36.8, 37.1, 43.8, 209.1, (C]O); GC–MS [same conditions
as for (R)-1]: tR 18.34 min [90%, (R)-3], 18.82 (10%). MS of (R)-3
(70 eV, EI): m/z: 282 (21) [Mþ, C19H38O], 264 (16), 222 (11), 127 (8),
109 (13), 96 (21), 85 (28), 71 (62), 59 (71), 58 (100), 43 (94). The MS
17. Lenardao, E. J.; Botteselle, G. V.; de Azambuja, F.; Perin, G.; Jacob, R. G. Tetra-
˜
hedron 2007, 63, 6671–6712.
18. Mori, K.; Wu, J. Liebigs Ann. Chem. 1991, 439–443.
19. Mori, K.; Tashiro, T. Tetrahedron Lett., in press.
20. Fouquet, C.; Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13, 82–83.
21. Mori, K.; Horikiri, H. Liebigs Ann. 1996, 501–505.
22. Mori, K. Tetrahedron 1983, 39, 3107–3109.
23. Takahisa, E.; Engel, K.-H. J. Chromatogr., A 2005, 1063, 181–192.
24. Tamogami, S.; Awano, K.; Amaike, M.; Takagi, Y.; Kitahara, T. Flavour Fragr. J.
2001, 16, 349–352.