Pheromone synthesis. Part 240: Cross-metathesis with Grubbs I (but not Grubbs II) catalyst for the synthesis of (R)-trogodermal (14-methyl-8-hexadecenal) to study the optical rotatory powers of compounds with a terminal sec-butyl group

Article abstract of DOI:10.1016/j.tet.2009.02.064

(R)-Trogodermal (14-methyl-8-hexadecenal), the sex pheromone of Trogoderma species of pest insects against stored products, and its (S)-isomer were synthesized by using olefin cross-metathesis between (R)- or (S)-7-methyl-1-nonene and 8-nonenyl acetate as the key step. This step was successful with Grubbs I but not with Grubbs II catalyst. The latter caused randomization of the carbon skeleton to give a mixture of abnormal products with both longer or shorter carbon chains than the desired product. The specific rotations of 18 newly and 6 previously synthesized compounds with a terminal sec-butyl group were measured to conclude them to be [α]_D +3.5 to +6.5 or -3.6 to -6.4.

Full text of DOI:10.1016/j.tet.2009.02.064

Tetrahedron 65 (2009) 3900–3909
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pheromone synthesis. Part 240: Cross-metathesis with Grubbs I (but not Grubbs
II) catalyst for the synthesis of (R)-trogodermal (14-methyl-8-hexadecenal) to
study the optical rotatory powers of compounds with a terminal sec-butyl groupq
*
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:
(R)-Trogodermal (14-methyl-8-hexadecenal), the sex pheromone of Trogoderma species of pest insects
against stored products, and its (S)-isomer were synthesized by using olefin cross-metathesis between
(R)- or (S)-7-methyl-1-nonene and 8-nonenyl acetate as the key step. This step was successful with
Grubbs I but not with Grubbs II catalyst. The latter caused randomization of the carbon skeleton to give
a mixture of abnormal products with both longer or shorter carbon chains than the desired product. The
specific rotations of 18 newly and 6 previously synthesized compounds with a terminal sec-butyl group
Received 23 February 2009
Accepted 25 February 2009
Available online 3 March 2009
Keywords:
Cross-metathesis
Optical rotation
Pheromone
were measured to conclude them to be [
a
]
D
þ3.5 to þ6.5 or ꢀ3.6 to ꢀ6.4.
Ó 2009 Elsevier Ltd. All rights reserved.
Trogodermal
1. Introduction
Trogoderma species of insects are notorious pests of stored
products. They use (E)-trogodermal and/or its (Z)-isomer [(R)-1 and
(R)-2, Scheme 1] as their female-produced sex pheromone.2 At the
early stage of the pheromone isolation in 1969, the alcohol 3 and
the methyl ester 4, both derived from 2, were erroneously identi-
fied as the pheromone candidates.3 The absolute configuration of
the levorotatory 3 and 4 of insect origin was determined as R by
synthesizing dextrorotatory (S)-3 from the known (S)-2-methyl-1-
butanol (5).4,5
Although these two pheromone aldehydes (R)-1 and (R)-2 as well
as their enantiomers have been synthesized repeatedly by us6–8 and
also by others,9–11 it is worthwhile to achieve a simple synthesis of
(R)-trogodermal (1) by olefin cross-metathesis reaction (AþB/C)
as shown in Scheme 1. Olefin cross-metathesis12–14 has been
employed advantageously in the synthesis of olefinic pheromones,15
including aliphatic pheromones with methyl-branchings.1,16 This
paper describes the successful execution of the above-mentioned
step (AþB/C) as assisted by Grubbs I (not by Grubbs II) catalyst,
leading to a new synthesis of (R)-trogodermal.
CHO
CHO
(E)-trogodermal (R)-1
(Z)-trogodermal (R)-2
OH
(R)-3
(R)-4
CO2Me
OH
OH
(S)-5
(S)-3
[α]D25 +5.31 (CHCl3)
OAc
+
A
B
cross metathesis
OAc
q
Pheromone synthesis, Part 240. For part 239, see Ref. 1.
C
* Tel.: þ81 3 3816 6889; fax: þ81 3 3813 1516.
E-mail address: kjk-mori@arion.ocn.ne.jp
Scheme 1. Structures of trogodermal and related compounds.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.064

K. Mori / Tetrahedron 65 (2009) 3900–3909
3901
Another important issue discussed in the present paper con-
cerns with the magnitude of specific rotations of compounds with
a terminal sec-butyl group like trogodermal. As shown in Scheme 1,
the specific rotation of (S)-3 was reported as þ5.31 in chloroform by
myself.4,5 Others also reported similar values.6–11 Recently in 2008,
however, there was a criticism against this value by an eminent
chemist insisting that the value þ5.31 was too large and could not
happen to be so, because no strongly absorbing chromophore was
present in (S)-3. I therefore decided to synthesize a number of
derivatives related to 3 so as to measure their specific rotations.
For many years I have been interested in the relationship be-
tween structure and optical rotatory power. The prevailing thought
in 1950s was expressed by Shriner, Adams, and Marvel as ‘No de-
ductions concerning the molecular rotation of a molecule can be
drawn from a knowledge of its structure.’17 This situation remained
unchanged until recent days, despite much efforts to solve the
problem.18,19 The situation has changed, however, due to very re-
cent progress in calculation of optical rotatory power by means of
time-dependent density functional theory.20 It is now possible to
calculate the sign of rotation of a certain molecule, although exact
prediction is still difficult as to the magnitude of rotation at a given
wavelength.21,22 Accordingly, it is worthwhile to prepare a number
of derivatives related to 3 and measure their optical rotations.
Treatment of (R)-8 with magnesium in THF furnished the corre-
sponding Grignard reagent, which was added to a cooled solution of
4-pentenyl tosylate in THF. Subsequent addition of dilithium tetra-
chlorocuprate according to Schlosser and Fouquet24 afforded (R)-9
contaminated with 11% of (3R,6R)-10 generated by the self-coupling
of(R)-8inthecourseofthepreparationoftheGrignardreagent.Since
complete removal of (3R,6R)-10 from (R)-9 was difficult, theobtained
mixture was used directly for the metathesis reaction. Synthesis of
(S)-9 was executed in the same manner, starting from commercially
available (S)-2-methyl-1-butanol (5). 8-Nonenyl acetate (12), an-
other partner of the cross-metathesis, was prepared by conventional
acetylation of commercially available 8-nonen-1-ol (11).
2.2. Synthesis of trogodermal (1) by cross-metathesis
Cross-metathesis between each of the enantiomers of 7-methyl-
1-nonene (9) and 8-nonenyl acetate (12) was achieved by using
Grubbs’ first generation catalyst [Grubbs I, (Cy3P)2Ru (]CHPh)Cl2,
Scheme 3].13,14 A mixture of (R)-9, 12 and Grubbs I catalyst (molar
ratio¼121:86:1) in dichloromethane was stirred and heated under
reflux for 5 h under argon, and the product was purified by silica gel
chromatography to give (3R,14R)-13 first, and then the desired (R)-
14 in 56% yield based on (R)-9 or 80% yield based on 12. Finally,
a small amount of 15, the homocoupling product of 12, was also
2. Results and discussion
a
2.1. Synthesis of the enantiomers of 7-methyl-1-nonene (9)
and 8-nonenyl acetate (12), the metathesis partners
+
OAc
(R)-9 (= A)
12 (= B)
Scheme 2 summarizes the synthesis of (R)- and (S)-7-methyl-1-
nonene (9) and 8-nonenyl acetate (12), the partners for cross-me-
tathesis reaction. Synthesis of (R)-9 started from (R)-2-methylbutanoic
acid (6, T. Hasegawa Co., >99.0% ee), which was prepared by treating
(ꢁ)-6 with Pseudomonas sp. TH-252-1.23 Reduction of (R)-6 with lith-
ium aluminum hydride afforded (R)-5, whose tosylate (R)-7 was
treated with lithium bromide in DMF to give (R)-2-methylbutyl
bromide (8) in 63% overall yield (three steps).
(3R,14R)-13
OR
+
(R)-14 R = Ac (= C), E/Z = 4:1
(R)-16 R = H
b
RO
+
OR
15 R = Ac
17 R = H
b
a
c
OR
Br
CO2H
(R)-6
c
OH
(R)-5 R = H
(R)-7 R = Ts
(R)-8
b
(R)-16
d
CHO
+
(R)-1, E/Z = 4:1
(R)-9 (= A)
(3R,6R)-10
Similarly
b
c
a
OH
OTs
Br
+
OAc
(S)-9
12
(S)-5
(S)-7
(S)-8
OR
d
+
(S)-14 R = Ac, E/Z = 4:1
(S)-16 R = H
b
(S)-9
(3S,6S)-10
c
OH
e
OH
OAc
(S)-16
11
12 (= B)
CHO
Scheme 2. Synthesis of the enantiomers of 7-methyl-1-nonene (9) and 8-nonenyl
acetate (12), the metathesis partners. Reagents: (a) LiAlH4, Et2O (quant.); (b) TsCl,
C5H5N [86% for (R)-7: quant. for (S)-7]; (c) LiBr, DMF [63% for (R)-8 based on (R)-6,
three steps; 78% for (S)-8 based on (S)-5, two steps]; (d) (i) Mg, THF; (ii)
H2C]CH(CH2)3OTs, THF, Li2CuCl4 [56% of (R)-9 based on (R)-8; 58% of (S)-9 based on
(S)-8]; (e) Ac2O, C5H5N (quant.).
(S)-1, E/Z = 4:1
Scheme 3. Synthesis of the enantiomers of trogodermal (1). Reagents: (a) 9 (17 mmol),
12 (12 mmol), Grubbs I [(Cy3P)2Ru(]CHPh)Cl2, 0.14 mmol], CH2Cl2, reflux, 6 h [56% of
(R)-14 based on (R)-9; 47% of (S)-14 based on (S)-9]; (b) NaOH, aq MeOH [62% for (R)-16;
67% for (S)-16]; (c) PCC (CrO3$C5H5N$HCl), SiO2, CH2Cl2 [88% for (R)-1: 91% for (S)-1].

3902
K. Mori / Tetrahedron 65 (2009) 3900–3909
obtained. Its basic hydrolysis gave crystalline diol (E)-17, mp 57.5–
58.0 ꢂC.
The obtained crude (R)-14 was a mixture of (R,E)-14 (71.7%),
(R,Z)-14 (14.7%) and 15 (13.6%) as estimated by GC–MS. Alkaline
GC–MS analysis of the acetate part obtained by silica gel chro-
matography revealed the product to be a complex mixture of ace-
tates, containing only 22% of the desired (S)-14, with molecular
weights different from that of (S)-14 by ꢁ14ꢃn (¼ꢁCH2ꢃn)
(Fig. 2a). The GC peaks were observed as doublets due to the
presence of (E)- and (Z)-isomers (E/Z¼ca. 4:1). It must be added that
the IR, 1H, and 13C NMR spectra of the mixture was almost in-
distinguishable from those of (S)-14 except some subtle changes in
the olefinic region. Complexity of the product could be noticed only
through GC–MS analysis. Then the hydrocarbon part of the me-
tathesis product was also analyzed by GC–MS, and it also turned
out to be a complex mixture as shown in Figure 2b. The GC peak at
retention time¼6.35 min could be identified as 8-methyl-2-decene
by comparison of its mass spectrum (MS) with that of the reference
MS of (Z)-8-methyl-2-decene.25
In order to clarify what happened in the course of the metath-
esis, the acetate mixture was converted to a mixture of alkanes by
successive treatments with (1) sodium hydroxide, (2) methane-
sulfonyl chloride, (3) lithium aluminum hydride, and (4) hydrogen
and 10% palladium–charcoal. For the purpose of comparison, (R)-14
as prepared in the presence of Grubbs I catalyst was also subjected
to the same sequence of treatments. Figure 3 shows the gas chro-
matograms of (a) the reference hydrocarbon originating from
(R)-14 prepared by Grubbs I-catalyzed metathesis, and (b) the
hydrocarbons originating from Grubbs II-catalyzed metathesis. The
structure of each of the alkanes was identified by comparison of its
MS with the reference MS of the known alkanes.25 The alkane
originated from (R)-14 prepared in the presence of Grubbs I catalyst
was (R)-3-methylhexadecane (21) as expected (Fig. 3a), while the
alkane mixture obtained by employing Grubbs II catalyst was
a beautiful blend of 3-methylalkanes ranging from 3-methyl-
dodecane to 3-methyldocosane (Fig. 3b).
hydrolysis of the crude (R)-14 followed by chromatographic puri-
24
fication gave (R)-16 as an E/Z mixture. Its specific rotation was [a]
D
ꢀ5.98 (c 4.24, CHCl3). Similarly, (S)-16 was synthesized from (S)-9
21
and 12 via (S)-14, and its specific rotation was [
a]
þ5.89 (c 4.83,
D
CHCl3). These values were in good accord with the previous value,
25
[
a]
þ5.31 (c 4.575, CHCl3), reported in 1973,4 and confirmed its
D
correctness.
Oxidation of (R)-16 with pyridinium chlorochromate (PCC) in
the presence of sodium acetate and silica gel in dichloromethane
25
gave (R)-trogodermal (1), [
a
]
ꢀ6.39 (c 4.02, Et3O), in 88% yield.
D
Addition of silica gel (180 wt % based on PCC) to the reaction mix-
ture facilitated the isolation of (R)-1 by removing the solid material
through Celite and concentrating the filtrate. (R)-Trogodermal (1)
was obtained as an E/Z mixture (E/Z¼81.9:18.1). Similarly, (S)-1,
25
[
a]
þ6.52 (c 3.07, CHCl3), was also synthesized from (S)-16 as an
D
E/Z mixture (E/Z¼78.1:21.9). The overall yield of (R)-1 was 19%
based on (R)-6 (seven steps).
2.3. Grubbs II catalyst causes randomization of the original
product of cross-metathesis by double bond migration
followed by further cross-metathesis
In one occasion Grubbs’ second generation catalyst (Grubbs II)
was employed for the cross-metathesis between (S)-9 and 12 under
the conditions (7 h in refluxing dichloromethane) successful with
Grubbs I catalyst (Fig. 1).
OAc
As shown in Figure 1, the genesis of the mixture must have taken
place by double bond migration of the desired product (S)-14 fol-
lowed by further cross-metathesis leading to randomization of the
carbon chain-length. 8-Methyl-2-decene shown in Figure 2b could
be generated from 7-methyl-1-nonene (9), the starting material, by
double bond migration to C-2 followed by the cross-metathesis of
the generated 7-methyl-2-nonene with 9. Double bond migration
of 8-nonenyl acetate (12), another starting material, to give 7-
nonenyl acetate would also give rise to 8-methyl-2-decene after
cross-metathesis with 9.
It might be possible, however, to employ Grubbs II catalyst
successfully for cross-metathesis by lowering the reaction tem-
perature and shortening the reaction time.15 Indeed, when the
metathesis of (S)-9 and 12 with Grubbs II catalyst in dichloro-
methane was stopped after 30 min at reflux temperature, less
randomization took place. Unfortunately, even in this case the
generated (S)-14 (Mþ¼296) was contaminated with about 20% of its
lower homologue (Mþ¼282) and also by some other higher and
lower homologues.
It is therefore recommended that the result of cross-metathesis
between type I olefins14 must always be checked by GC–MS or
HPLC-MS to secure the desired product only. In the case when the
desired product is crystalline and can readily be purified by re-
crystallization, some extent of randomization may be ignored. If the
product is an oil, its purity must be checked carefully. In laboratory
scale experiments, Grubbs I catalyst seems to be better than Grubbs
II for cross-metathesis between terminal olefins (type I olefin14),
avoiding extreme randomization.
+
(S)-9 (9.3 mmol)
12 (6.5 mmol)
Mes
N
N
Mes
Ph
Cl
Ru
Cl
PCy3
Grubbs II catalyst
(0.05 mmol)
CH2Cl2 (3 mL), reflux, 7 h
(CH2)4
(CH2)7OAc
(CH2)4
AcO(CH2)7
(3S,14S)-13
15
OAc
(S)-14 (E/Z = 4:1)
the desired initial product
Randomization by double bond migration and
further cross metathesis
A mixture of products with different molecular
weights as revealed by GC-MS [see Figure 2(a)]
1) NaOH 2) MsCl, C5H5N
3) LiAlH4 4) H2, Pd-C
2.4. Preparation and optical rotatory powers of compounds
with a terminal sec-butyl group
Identification by GC-MS [see Figure 3(b)]
Although the correctness of the magnitude of the optical rota-
Figure 1. Olefin cross-metathesis between (S)-9 and 12 with Grubbs II catalyst leading
to a complex mixture of products.
tion of (S)-16 reported in 19734 was reconfirmed, it seemed better

K. Mori / Tetrahedron 65 (2009) 3900–3909
3903
Figure 2. Olefin cross-metathesis between (S)-9 and 12 with Grubbs II catalyst. GC–MS analysis of the resulting mixture after 7 h-reflux in dichloromethane: (a) gas chromatogram
of the acetate part, and (b) gas chromatogram of the hydrocarbon part after separation by silica gel chromatography. All the olefinic compounds are E/Z (ca. 4:1) mixtures.
to further scrutinize the influence of functional groups on the op-
tical rotatory powers of a series of compounds with a terminal sec-
butyl group. Some people believe that a compound without any
chromophore should show only very small specific rotation. My
own experience indicates that even 3-methylalkanes with no
alkane 21 and alkene 23 were achieved via methanesulfonates 20
and 22, respectively. Accordingly, 19 was methanesulfonylated to
20, which was reduced with lithium aluminum hydride to give 3-
methylhexadecane (21). 3-Methyl-8-hexadecene (23) was obtained
from 16 via methanesulfonate 22. Hydrogenation of 23 gave 21,
which was identical with the sample prepared from 19. Methyla-
tion of 16 with potassium tert-butoxide and methyl iodide in DMF
gave 24, whose hydrogenation afforded 25.
functional group show measurable specific rotations of
[a]
D
ꢁ3–4.26
Scheme 4 summarizes the route by which (R)- and (S)-16
were converted to the enantiomers of unsaturated and saturated
acetates 14 and 18, saturated alcohol 19, alkane 21, alkene 23,
alkenyl ether 24, and alkyl ether 25. Measurements of specific
rotations of these compounds will tell us the influence of a
double bond, a hydroxy group, an acetoxy group, and a methoxy
group on the magnitude of specific rotation, and will reveal us
also the optical rotatory power of the asymmetric carbon
framework itself.
Table 1 shows the specific rotations [
]D¼[ ]DꢃMW/100 of compounds with a terminal (R)- or (S)-sec-
butyl group. All the observed specific rotations of 24 compounds
prepared by us fell in the range of [
a] and molar rotations
D
[f
a
a
]
D þ3.5 to þ6.5 and [ D ꢀ3.6 to
a
]
ꢀ6.4, while the molar rotations were in the range of þ12 to þ16
ꢀand ꢀ12 to ꢀ16. Accordingly, presence or absence of functional-
ities did not alter the magnitude of specific rotation remarkably. In
the case of the unsaturated alcohol (S)-16, its specific rotation was
Acetylation of 16 (E/Z¼ca. 4:1) gave 14 without contamination of
15. Catalytic hydrogenation of 14 over palladium–charcoal fur-
nished 18, while 16 was hydrogenated to give 19. Preparations of
[
a
]
þ6.1 in hexane, þ5.9 in chloroform, and þ6.3 in ethanol. This
D
may mean that no strong interaction exists between the hydroxy
group and the double bond of 16.

3904
K. Mori / Tetrahedron 65 (2009) 3900–3909
Figure 3. Identification of the hydrocarbon-framework of each of the products generated by olefin cross-metathesis between 9 and 12 by GC–MS of the deoxygenation products, (a)
gas chromatogram of the products obtained with Grubbs I catalyst followed by subsequent deoxygenation treatments 1–4 in Figure 1. [(R)-9 was employed]; (b) gas chromatogram
of the products obtained with Grubbs II catalyst followed by subsequent deoxygenation treatments. [(S)-9 was employed, and about the same amount of authentic (S)-14 was added
to the metathesis product so as to make the deoxygenation experiment successful with a sufficient amount of the starting material].
It is now clear that the compounds with terminal (R)- or (S)-sec-
butyl group show specific rotations around ꢀ3.6 to ꢀ6.4 or þ3.5 to
þ6.5, and the criticism against our experimental data turned out to
be without experimental support. It should be added that (S)-axi-
rotations of compounds with (R)- or (S)-3-methylhexadecane
skeleton were shown to be ꢀ3.6 to ꢀ6.4 or þ3.5 to þ6.5. The parent
alkane 3-methylhexadecane was with [
a]
D values of ꢀ5.7 [(R)-iso-
mer] and þ5.7 [(S)-isomer].
nellamine A (Table 1), a marine alkaloid, shows a large specific
23
rotation of [
a
]
þ40.1 (c 0.38, CHCl3).27 The conjugated double
D
4. Experimental
4.1. General
bond of axinellamine A is located vicinal to the chiral center. This
fact must have increased the magnitude of its specific rotation due
to the somewhat skewed stereochemistry of the conjugated diene
system.
Boiling points and a melting point are uncorrected values. Re-
fractive indices (nD) were measured on 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
3. Conclusion
Cross-metathesis with Grubbs I catalyst was shown to be a quick
way to synthesize an aliphatic pheromone with a stereogenic
center such as (R)-trogodermal (1). Grubbs II catalyst was found to
cause extensive side reactions in this particular case.29 Specific
spectra (400 MHz, TMS at
NMR spectra (100 MHz, CDCl3 at
recorded on a Jeol JNM-AL 400 spectrometer. GC–MS were mea-
sured on Agilent Technologies 5975 inert XL. HRMS were recorded
d
¼0.00 as internal standard) and 13C
d
¼77.0 as internal standard) were

K. Mori / Tetrahedron 65 (2009) 3900–3909
3905
added dropwise to an ice-cooled and stirred suspension of
LiAlH4 (5.0 g, 120 mmol) in dry Et2O (100 mL). The mixture was
stirred for 1 h at 0–5 ꢂC. The excess LiAlH4 was destroyed by
slowlyadding water. The mixture was then acidified with ice and
dil. HCl, and extracted with Et2O. The extract was washed with
satd NaHCO3 solution and brine, dried (MgSO4), and concen-
trated under atmospheric pressure to give crude (R)-5 (10.6 g,
quant.) as an oil. nmax (film): 3348 (s, OH),1047 (s, C–O),1016 (m);
dH (CDCl3): 0.912 (3H, t, J 7.2, CH2CH3), 0.915 (3H, d, J 6.4, CHCH3),
1.19–1.25 (1H, m), 1.40–1.60 (2H, m), 3.40–3.55 (2H, m, CH2OH).
(ii) Powdered TsCl (27.0 g,142 mmol) was added portionwise to an
ice-cooled and stirred solution of (R)-5 (10.6 g, 118 mmol) in
dry pyridine (40 mL) at 0–5 ꢂC. The mixture was stirred for 2 h
at 0–5 ꢂC. It was then poured into ice-water and extracted with
Et2O. The extract was washed with dil. HCl, satd NaHCO3 so-
lution and brine, dried (MgSO4), and concentrated in vacuo to
give (R)-7 (25.2 g, 86%) as an oil. nmax (film): 1599 (w, arom.
C]C), 1360 (m), 1176 (s), 964 (m); dH (CDCl3): 0.83 (3H, t, J 7.6,
CH2CH3), 0.87 (3H, d, J 6.8, CHCH3), 1.10–1.22 (1H, m), 1.32–1.45
(1H, m), 1.65–1.75 (1H, m), 2.45 (3H, s, arom. CH3), 7.34 (2H, d, J
8.8, arom. H), 7.78 (2H, d, J 8.8, arom. H).
(iii) Powdered LiBr (15 g, 172 mmol) was added to a solution of (R)-
7 (25.2 g, 104 mmol) in dry DMF (70 mL) with shaking. The
mixture became homogeneous after exothermic reaction. It
was then stirred and heated at 60 ꢂC for 1.5 h. After cooling, the
mixture was diluted with ice and water, and the separated
heavy oil was collected. The aqueous layer was extracted with
a small amount of pentane. The combined organic solution was
washed with water and brine, dried (MgSO4), and concen-
trated under atmospheric pressure. The residue was distilled to
b
(CH2)13OR
(CH2)7OR
(R)- or (S)-16 R = H
(R)- or (S)-18 R = Ac
(R)- or (S)-19 R = H
a
(R)- or (S)-14 R = Ac
c
d
(CH2)13OH
(CH2)13OMs
(S)-20
(R)- or (S)-19
b
(CH2)7R
(CH2)12Me
(R)- or (S)-21
(R)- or (S)-16 R = OH
(R)- or (S)-22 R = OMs
(R)- or (S)-23 R = H
c
d
b
(CH2)7OR
(CH2)13OMe
(R)- or (S)-25
(R)- or (S)-16 R = H
(R)- or (S)-24 R = Me
e
Scheme 4. Synthesis of the enantiomers of 3-methylhexadecane (21) and their de-
rivatives from the enantiomers of 14-methyl-8-hexadecen-1-ol (16). Reagents: (a)
Ac2O, C5H5N [77% for (R)-14; 70% for (S)-14]; (b) H2, Pd–C, EtOAc [99% for (R)-18; 72%
for (S)-18; 89% for (R)-19; 90% for (S)-19; 80% for (R)-21; 90% for (S)-21; 93% for (R)-25;
98% for (S)-25]; (c) MsCl, C5H5N (quant.); (d) LiAlH4, THF, reflux [70% for (S)-21; 87% for
(R)-23; 78% for (S)-23]; (e) t-BuOK, DMF, MeI [88% for (R)-24; 80% for (S)-24].
on Jeol JMS-SX 102A. Column chromatography was carried out on
Merck Kieselgel 60 Art 1.07734.
give (R)-8 [11.2 g 63% based on (R)-6; three steps] as an oil. Bp
4.2. 2-Methylbutyl bromide (8)
25
117–119 ꢂC (atm press); n2D2¼1.4434; [
a
]
ꢀ3.59 (c 3.03, pen-
D
tane); nmax (film): 2964 (s), 2931 (m), 2875 (m), 1460 (m), 1381
(m), 1230 (m), 650 (m); dH (CDCl3): 0.91 (3H, t, J 7.2, CH2CH3),
1.01 (3H, d, J 7.2, CHCH3), 1.20–1.35 (1H, m), 1.40–1.55 (1H, m),
1.65–1.76 (1H, m), 3.30–3.45 (2H, m).
4.2.1. (R)-Isomer
(i) A solution of (R)-6 (T. Hasegawa Co., >99.0% ee as analyzed by GC
on ChiramixÒ,28 12.0 g, 118 mmol) in dry Et2O (20 mL) was
Table 1
Specific rotation [
a
]
D and molar rotations [f]D¼[a
]DꢃMW/100 of compounds with a terminal (R)- or (S)-sec-butyl groupa
X
[
a
]
D
[
f]
D
X
[
a
]
D
[f]
D
X
X
(R)-23b
(R)-16
(R)-1
(R)-14
(R)-24
Me
CH2OH
CHO
CH2OAc
CH2OMe
ꢀ6.4
ꢀ6.0
ꢀ6.4
ꢀ5.1
ꢀ5.8
ꢀ15
ꢀ15
ꢀ16
ꢀ15
ꢀ15
(S)-23b
(S)-16c
(S)-1
(S)-14
(S)-24
Me
CH2OH
CHO
CH2OAc
CH2OMe
þ6.3
þ5.9
þ6.5
þ5.1
þ5.7
þ15
þ15
þ16
þ15
þ15
(CH2)12
X
(CH2)12X
(R)-21
(R)-19
(R)-18
(R)-25
Me
ꢀ5.7
ꢀ5.0
ꢀ4.0
ꢀ4.8
ꢀ14
ꢀ13
ꢀ12
ꢀ13
(S)-21
(S)-19
(S)-18
(S)-25
Me
þ5.7
þ5.3
þ4.2
þ4.6
þ14
þ14
þ13
þ12
CH2OH
CH2OAc
CH2OMe
CH2OH
CH2OAc
CH2OMe
(CH2)8Me
(CH2)10Me
(CH2)12Me
Ref. 26
Ref. 26
ꢀ4.1
ꢀ3.6
ꢀ3.6
ꢀ15
ꢀ14
ꢀ15
þ4.2
þ3.7
þ3.5
þ15
þ15
þ15
(CH2)8Me
(CH2)10Me
(CH2)12Me
[ ]D
+40
[
D
+76
N
H
(S)-axinellamine A (ref. 27)
a
All the rotations except for trogodermal (1, X¼CHO) were measured as CHCl3 solutions.4–10,26,27 The rotations of (R)- and (S)-trogodermals (1) were measured as Et2O
solutions as reported previously.7–9
b
All of these olefinic compounds are ca. 4:1 mixtures of (E)- and (Z)-isomers.
c
21
19
This compound (S)-16 showed [
a
]
þ6.1 in hexane and [
a
]
þ6.3 in EtOH.
D
D

3906
K. Mori / Tetrahedron 65 (2009) 3900–3909
4.2.2. (S)-Isomer
4.5. 14-Methyl-8-hexadecenyl acetate 14
In the same manner as described above, (S)-5 [Tokyo Kasei (TCI),
28.4 g, 322 mmol] yielded, via (S)-7, 38.0 g (78%, two steps) of (S)-8.
4.5.1. (R)-Isomer
25
Bp 117–119 ꢂC (atm press): n2D2¼1.4440; [
a
]
þ3.74 (c 4.76, pen-
Grubbs’ first generation catalyst (Grubbs I, Aldrich, Lot number
01928CJ, 80 mg, 0.1 mmol) was added to a solution of (R)-9 (2.4 g,
17 mmol) and 12 (2.2 g,12 mmol) in dry CH2Cl2 (5 mL). The wine red
solution was stirred and heated under reflux for 3 h under Ar. Then
an additional amount of Grubbs I catalyst (30 mg, 0.04 mmol) was
added, and the stirring was continued for another 3 h, when the
evolution of ethylene ceased. The mixture was left to stand for 3 days
at room temperature, and concentrated in vacuo. The residue was
chromatographed over SiO2 (25 g). Elution with hexane gave
(3R,14R)-13 [1.32 g, nmax (film): 2960 (s), 2925 (s), 2856 (s),1462 (m),
1377 (m), 966 (m)]. Further elution with hexane/EtOAc (15:1) gave
crude (R)-14 [2.84 g, 56% based on (R)-9 or 80% based on 12] con-
taminated with 13.6% of 15. Properties of crude (R)-14: nmax (film):
1743 (s, C]O), 1238 (s, C–O), 1038 (m), 968 (m); dH (CDCl3): 0.80–
0.90 (6H, m, CH3ꢃ2),1.02–1.18 (2H, m),1.20–1.40 (17H, m),1.56–1.65
(2H, m),1.92–2.06 (2H, m), 2.04 (3H, s, CH3CO), 4.05 (2H, t-like, J 6.8,
CH2O), 5.32–5.41 (2H, m, CH]CH); GC–MS [column: HP-5MS, 5%
phenylmethylsiloxane, 30 mꢃ0.25 mm i.d.; press: 60.7 kPa; 70–
230 ꢂC (þ10 ꢂC/min)]: tR 18.3 [14.7%; (R,Z)-14],18.4 [71.7%; (R,E)-14],
23.2 min (13.6%, 15); MS of (R,Z)-14 (70 eV, EI): m/z 296 (1) [Mþ,
C19H36O2], 236 (36, MþꢀAcOH),137 (19),123 (38),110 (40),109 (63),
97 (48), 96 (100), 95 (85), 82 (90), 81 (90), 67 (75), 55 (69), 43 (73);
MS of (R,E)-14 is identical with that of (R,Z)-14; MS of 15 (70 eV, EI):
m/z 340 (1) [Mþ, C20H36O4], 280 (2), 251 (1), 237 (2), 220 (2,
Mþꢀ2AcOH),149 (10),135 (28),121 (34), 95 (58), 81 (70), 67 (72), 55
(48), 43 (100). Pure (R)-14 could be prepared by acetylation of (R)-16
(see 4.8.1). The crude (R)-14 was used directly in the next step. Fur-
ther elution with hexane/EtOAc (15:1) gave 15 (0.3 g); nmax (film):
1741 (s, CO), 1240 (s, C–O), 1039 (m), 968 (w); dH (CDCl3): 1.25–1.40
(16H, br s), 1.58–1.68 (4H, m), 1.94–2.02 (4H, m), 2.04 (6H, s,
CH3COꢃ2), 4.05 (4H, t-like, J 6.8, CH2O), 5.33–5.40 (2H, m, CH]CH).
D
tane). Its spectral data were identical with those of (R)-8.
4.3. 7-Methyl-1-nonene 9
4.3.1. (R)-Isomer
A Grignard reagent was prepared from (R)-8 (9.1 g, 60 mmol),
Mg (1.7 g, 71 mmol) and a catalytic amount of I2 in dry THF
(40 mL) under Ar. This was added through a syringe to a stirred
and cooled solution of 4-pentenyl tosylate [nmax (film): 1641 (m,
C]C), 1599 (m, arom. C]C), 1362 (s), 1188 (s), 1176 (s), 970 (m),
920 (m); dH (CDCl3): 1.71–1.80 (2H, m), 2.05–2.12 (2H, m), 2.45
(3H, s, CH3), 4.04 (2H, t-like, J 10.8), 4.92–5.00 (2H, m), 5.63–5.75
(1H, m), 7.35 (2H, d, J 8.0), 7.80 (2H, d, J 8.0); 10.0 g, 41 mmol] in
dry THF (30 mL) at ꢀ70 to ꢀ55 ꢂC under Ar. Subsequently, a so-
lution of Li2CuCl4 in THF (0.1 M, 1.5 mL, 0.15 mmol) was added
through a syringe, and the stirred mixture was left to stand
overnight under Ar with gradual warming to room temperature.
The mixture was quenched with ice and NH4Cl solution, and
extracted with a small amount of pentane. The pentane solution
was washed with water and brine, dried (MgSO4), and concen-
trated at atmospheric pressure. The residue was distilled to give
(R)-9 contaminated with 6% of (3R, 6R)-10 [4.7 g, 82% based on
the tosylate or 56% based on (R)-8]. Bp 80–86 ꢂC/57 Torr;
26
n2D2¼1.4230; [
a
]
ꢀ11.1 (c 3.28, pentane); nmax (film): 3078 (w),
D
1641 (m, C]C), 1462 (m), 1379 (m), 991 (s); dH 0.845 (3H, d, J 7.6,
CHCH3), 0.849 (3H, t, J 7.6, CH2CH3), 1.05–1.20 (2H, m), 1.20–1.41
(8H, m), 2.00–2.10 (2H, q-like, C]CCH2), 4.90–5.03 (2H, m,
C]CH2), 5.75–5.88 (1H, m, CH]C); GC–MS [column: HP-5MS, 5%
phenylmethylsiloxane, 30 mꢃ0.25 mm i.d.; press: 52.8 kPa;
temp: 50–160 ꢂC (þ10 ꢂC/min)–220 ꢂC (þ4 ꢂC/min)]: tR 6.08 [6%,
(3R,6R)-10], 6.47 min [94%, (R)-9]. MS of (3R,6R)-10 (70 eV, EI):
m/z 142 (3) [Mþ, C10H22], 113 (24), 112 (10), 85 (8), 71 (77), 57
(100), 56 (25), 43 (38), 41 (26), 29 (17); MS of (R)-9 (70 eV, EI):
m/z 140 (2) [Mþ,C10H20], 111 (65), 83 (55), 70 (95), 69 (100), 57
(80), 56 (59), 55 (88), 41 (80). HRMS calcd for C10H20: 140.1565,
found: 140.1555.
4.5.2. (S)-Isomer
In the same manner as described for (R)-14, (S)-9 (5.02 g,
35.7 mmol), 12 (4.23 g, 22.8 mmol) and Grubbs I catalyst (200 mg,
0.24 mmol) in dry CH2Cl2 (10 mL) gave 2.9 g of (3S,14S)-13 and 5.0 g
[47% based on (S)-9 and 74% based on 12] of crude (S)-14. Pure (S)-
14 could be prepared by acetylation of (S)-16 (see 4.8.2). The crude
(S)-14 was used directly in the next step.
4.3.2. (S)-Isomer
In the same manner as described for (R)-9, (S)-8 (18.9 g,
125 mmol), Mg (3.4 g, 140 mmol), 4-pentenyl tosylate (20.0 g,
83 mmol), and Li2CuCl4 in THF (0.1 M, 3 mL, 0.3 mmol) yielded (S)-9
contaminated with 9% of (3S,6S)-10 [10.1 g, 87% based on 4-pen-
4.5.3. Metathesis with Grubbs II catalyst
In the same manner as described for (R)-14, a solution of (S)-9
(1.30 g, 9.3 mmol), 12 (1.20 g, 6.5 mmol) and Grubbs II catalyst
(Aldrich, Lot number 08410TC, 43 mg, 0.05 mmol) in dry CH2Cl2
(3 mL) was stirred and heated under reflux for 7 h. The mixture was
concentrated, and the residue was chromatographed over SiO2
(20 g). Elution with hexane gave hydrocarbon fraction (719 mg, for
its GC–MS see Fig. 2b). Elution with hexane/EtOAc (15:1) gave ac-
etate fraction (1.440 g, for its GC–MS see Fig. 2a). Further elution
with hexane/EtOAc (15:1) gave the second acetate fraction
(194 mg).
tenyl tosylate on 58% based on (S)-8]. Bp 77–80 ꢂC/50 Torr;
27
n2D1]1.4226; [
a
]
þ11.3 (c 3.44, pentane). Its spectral properties
D
were identical with those of (R)-9. GC [under the same conditions
for (R)-9]: tR 6.08 [9%, (3S,6S)-10], 6.48 [91%, (S)-9]. HRMS calcd for
C10H20: 140.1565, found: 140.1547.
4.4. 8-Nonenyl acetate (12)
Acetic anhydride (10 mL, 10.8 g, 105 mmol) was added to a so-
lution of 11 (10.0 g, 70 mmol) in dry pyridine (30 mL) with shaking.
The mixture was left to stand for 3 days at room temperature. It was
then poured into ice-water and extracted with Et2O. The extract
was washed with water, dil. HCl, satd NaHCO3 solution and brine,
dried (MgSO4), and concentrated in vacuo. The residue was distilled
to give 12 (12.9 g, quant.). Bp 138–140 ꢂC/50 Torr; nD21¼1.4332; nmax
(film): 1743 (s), 1641 (w), 1240 (s), 1041 (m), 910 (m); dH (CDCl3):
1.27–1.42 (8H,m), 1.58–1.66 (2H, m), 2.05 (3H, s, CH3CO), 2.00–2.08
(2H, m), 4.05 (2H, t-like, J 6.4, CH2OAc), 4.90–5.03 (2H, m, C]CH2),
5.75–5.87 (1H, m, CH]C). HRMS (doped with LiI) calcd for
C11H20O2Li: 191.1623, found: 191.1611.
4.6. 14-Methyl-8-hexadecen-1-ol 16
4.6.1. (R)-Isomer
A solution of crude (R)-14 (2.8 g, 9.5 mmol) in THF (30 mL) was
added to a solution of NaOH (3.0 g, 75 mmol) in H2O (15 mL) and
MeOH (30 mL). The mixture was stirred and heated under reflux for
40 min, and then concentrated in vacuo. The residue was diluted
with water and extracted with Et2O. The extract was washed with
water and brine, dried (MgSO4), and concentrated in vacuo. The
residue was chromatographed over SiO2 (20 g). Elution with hex-
ane/EtOAc (5:1) gave 1.5 g (62%) of (R)-16 as an oil. n2D1¼1.4598;

K. Mori / Tetrahedron 65 (2009) 3900–3909
3907
21
25
[
a]
ꢀ5.98 (c 4.34, CHCl3); nmax (film): 3334 (s, OH), 1057 (m, C–O),
n2D3¼1.4506; [
a
]
ꢀ5.12 (c 2.36, CHCl3); nmax (film): 1743 (s, C]O),
D
D
966 (m); dH (CDCl3): 0.844 (3H, d, J 7.6, CHCH3), 0.846 (3H, t, J 6.4,
CH2CH3), 1.04–1.19 (2H, m), 1.20–1.92 (18H, m), 1.52–1.62 (2H, m),
1.92–2.06 (4H, m), 3.64 (2H, m, CH2O), 5.34–5.42 (2H, m, CH]CH);
dC (CDCl3): 11.5, 12.3, 25.8, 26.6, 27.0, 27.02, 27.2, 27.3, 30.0, 31.6,
32.8, 63.1, 130.1, 130.3. HRMS calcd for C17H34O: 254.2610, found:
254.2606. Further elution with EtOAc gave (E)-17 as rhombs from
EtOAc/hexane. Mp 57.5–58.0 ꢂC; nmax (Nujol): 3351 (s, OH),1065 (m,
C–O), 966 (s); dH (CDCl3): 1.23–1.50 (18H, m), 1.50–1.60 (4H, m),
1.92–2.05 (4H, m), 3.64 (4H, t-like, J 6.4, CH2Oꢃ2), 5.32–5.42 (2H,
m); dC (CDCl3): 25.8, 29.1, 29.3, 29.6, 32.6, 32.8, 63.1, 130.3. HRMS
calcd for C16H32O2: 256.2402, found: 256.2404.
1238 (s, C–O), 1039 (m), 966 (m), 758 (m); dH (CDCl3): 0.84 (3H, d, J
8, CHCH3), 0.85 (3H, t, J 7.6, CH2CH3), 1.05–1.20 (2H, m), 1.20–1.40
(15H, m),1.62 (2H, m),1.98 (4H, m), 2.04 (3H, s, COCH3), 4.05 (2H, t, J
6.8, CH2OAc), 5.32–5.46 (2H, m); dC (CDCl3): 25.8, 25.9, 26.6, 26.7,
27.1, 27.2, 28.6, 29.0, 29.1, 29.46, 29.52, 29.6, 29.9, 30.1, 32.5, 32.6,
34.4, 36.4, 64.6, 129.6 and 130.0 [(Z)-isomer], 129.9 and 130.4 [(E)-
isomer] (E/Z¼4:1),171.0 (C]O); GC–MS [same conditions as for (R)-
1]: tR 18.30 [19.4%, (Z)-isomer], 18.40 min [80.6% (E)-isomer]; MS of
(R,E)-14 (70 eV, EI): m/z 296 (2) [Mþ, C19H36O2], 236 (29), 207 (7),
166 (6), 151 (10), 137 (21), 123 (39), 109 (63), 96 (100), 82 (85), 67
(70), 55 (62), 43 (64). (R,Z)-14 showed the same MS. HRMS (doped
with LiI) calcd for C19H36O2Li: 303.2875, found: 303.2874.
4.6.2. (S)-Isomer
In the same manner as described for (R)-16, crude (S)-14 (5.6 g,
18.9 mmol) and NaOH (4.0 g,100 mmol) gave 3.2 g (67%) of (S)-16 as
4.8.2. (S)-Isomer
In the same manner as described for (R)-14, (S)-16 (500 mg)
24
a colorless oil after chromatography over SiO2 (40 g). Crystalline (E)-
yielded 410 mg (70%) of (S)-14. n2D4¼1.4492; [
a]
þ5.07 (c 3.30,
D
21
17 (1.1 g) was also obtained. Properties of (S)-16: n2D1¼1.4590; [
a
]
D
CHCl3). Its spectral data were identical with those of (R)-14. GC
[same conditions as for (R)-14]: tR 18.30 [21.0%, (Z)-isomer],
18.40 min [79.0%, (E)-isomer]. HRMS (doped with LiI) calcd for
C19H36OLi: 303.2875, found: 303.2884.
þ5.89 (c 4.83, CHCl3). Its spectral properties were identical with
those of (R)-16. HRMS calcd for C17H34O: 254.2610, found: 254.2610.
4.7. 14-Methyl-8-hexadecenal 1
4.9. 14-Methylhexadecyl acetate 18
4.7.1. (R)-Isomer
A solution of (R)-16 (604 mg, 2.3 mmol) in dry CH2Cl2 (10 mL)
was added to a stirred and ice-cooled suspension of pyridinium
chlorochromate (PCC, 3.6 g, 16.7 mmol), SiO2 (6.5 g), and sodium
acetate (0.5 g) at 0–5 ꢂC under Ar. Addition of SiO2 facilitates the
isolation of the product. After stirring for 2 h at 0–5 ꢂC, the brown-
colored mixture was filtered through Celite. The Celite layer was
washed with Et2O, and the combined filtrates were concentrated in
vacuo. The residue was chromatographed over SiO2 (12 g). Elution
4.9.1. (R)-Isomer
Palladium–charcoal (10%, 0.1 g) was added to a solution of (R)-
14 (330 mg, 1.1 mmol) in EtOAc (10 mL). The suspension was stirred
under H2 (balloon) for 2 h at room temperature. The suspension
was filtered through SiO2 (5.0 g). The SiO2 column was washed with
EtOAc, and the combined EtOAc solution was concentrated in vacuo
to give (R)-18 (330 mg, 99%). n2D3¼1.4422; [
a]
ꢀ4.02 (c 2.59,
25
D
CHCl3); nmax (film): 1743 (s, C]O), 1238 (s, C–O), 1041 (m); dH
(CDCl3): 0.84 (3H, d, J 6.0, CHCH3), 0.85 (3H, t J 6.8, CH2CH3), 1.04–
1.18 (2H, m), 1.20–1.40 (23H, m), 1.61 (2H, m), 2.04 (3H, s, COCH3),
4.05 (2H, t, J 6.8, CH2OAc); dC (CDCl3): 27.1, 28.6, 29.2, 29.47, 29.48,
29.5, 29.6, 29.62, 29.65, 29.67, 29.7, 29.9, 30.0, 34.4, 36.6, 64.6, 171.0
(C]O); GC–MS [same conditions as for (R)-1]: tR 18.58 min (92.8%);
MS (70 eV, EI): m/z 299 (0.5) [Mþþ1, C19H38O2þ1], 238 (3)
[MþꢀAcOH], 209 (18), 139 (15),125 (31), 111 (54), 97 (92), 83 (88),
70 (100), 57 (64), 43 (78). HRMS (doped with LiI) calcd for
C19H38O2Li: 305.3032, found: 305.3024.
with hexane/EtOAc (15:1) gave (R)-1 as a colorless oil (531 mg, 88%).
25
n2D1¼1.4573; [
a
]
ꢀ6.39(c 4.02, Et2O);nmax (film): 1728 (s, C]O), 966
D
(m); dH (CDCl3): 0.841 (3H, d, J 7.6, CHCH3), 0.845 (3H, t, J 7.6,
CH2CH3), 1.05–1.18 (2H, m), 1.20–1.41 (15H, m), 1.58–1.70 (2H, m),
1.92–2.08 (4H, m), 2.40–2.48 (2H, m), 5.32–5.42 (2H, m, CH]CH),
9.76 (1H, s-like, CHO); dC (CDCl3): 11.4, 19.2, 22.0, 26.7, 28.9, 29.0,
30.1, 32.4, 32.6, 34.4, 36.5, 43.8, 64.3, 129.4 and 130.0 [(Z)-isomer],
129.9 and 130.4 [(E)-isomer] (E/Z¼4:1), 202.6; GC–MS [column: HP-
5MS, 5% phenylmethylsiloxane, 30 mꢃ0.25 mm i.d.; carrier gas: He;
press: 60.7 kPa; temp: 70–230 ꢂC (þ10 ꢂC/min)]: tR 16.46 min
[18.1%, (Z)-isomer], 16.53 min [81.9%, (E)-isomer]; MS of (R,E)-1
(70 eV, EI): m/z 252 (10) [Mþ, C17H32O], 234 (11), 223 (6), 205 (4),149
(10),135 (18),123 (20),121 (27),109 (35), 98 (42), 97 (45), 96 (35), 95
(47), 83 (67), 81 (52), 70 (100), 55 (81), 41 (55). (R,Z)-1 showed the
same MS. HRMS calcd for C17H32O: 252.2453, found: 252.2447.
4.9.2. (S)-Isomer
In the same manner as described for (R)-18, (S)-14 (500 mg,
1.7 mmol) yielded 424 mg (72%) of (S)-18. n2D4¼1.4426; [
a]
þ4.23
22
D
(c 4.24, CHCl3). Its spectral data were identical with those of (R)-18.
GC [same conditions as for (R)-1]: tR 18.58 min (94.9%). HRMS
(doped with LiI) calcd for C19H38O2Li: 305.3032, found: 305.3032.
4.7.2. (S)-Isomer
In the same manner as described for (R)-1, (S)-15 (602 mg,
2.4 mmol)wasoxidizedwithPCC(3.6 g,16.7 mmol)inthepresenceof
4.10. 14-Methyl-1-hexadecanol 19
NaOAc (0.5 g) and SiO2 (6.5 g) in CH2Cl2 (40 mL) to give 550 mg (91%)
24
of (S)-1. n2D4¼1.4578; [
a]
D
þ6.52 (c 3.07, Et2O). The spectral properties
4.10.1. (R)-Isomer
of (S)-1 were identical with those of (R)-1. GC [same conditions as for
(R)-1]: tR 16.46 min [21.9%, (Z)-isomer],16.54 min [78.1%, (E)-isomer].
HRMS calcd for C17H32O: 252.2453, found: 252.2448.
Palladium–charcoal (10%, 0.1 g) was added to a solution of (R)-
16 (200 mg, 0.8 mmol) in EtOAc (5 mL). The suspension was stirred
under H2 (balloon) for 1.5 h at room temperature. The suspension
was filtered through SiO2 (2 g). The SiO2 column was washed with
EtOAc, and the combined EtOAc solution was concentrated in vacuo
4.8. Pure 14-methyl-8-hexadecenyl acetate 14
to give (R)-19 (180 mg, 89%), which was a solid in a refrigerator but
23
4.8.1. (R)-Isomer
remained as an oil at room temperature. n2D4¼1.4516; [
a]
ꢀ4.98 (c
D
Acetic anhydride (3 mL) was added to a solution of (R)-16
(500 mg, 2 mmol) in dry pyridine (5 mL), and the mixture was left
to stand at room temperature for 3 days. The mixture was poured
into ice-water and extracted with Et2O. The ether solution was
washed with dil. HCl, satd NaHCO3 solution and brine, dried
(MgSO4), and concentrated in vacuo to give 450 mg (77%) of (R)-14.
2.55, CHCl3); nmax (film): 3330 (m, OH), 1057 (m, C–O); dH (CDCl3):
0.84 (3H, d, J 6.0, CHCH3), 0.85 (3H, t, J 6.8, CH2CH3), 1.05–1.17 (2H,
m), 1.26 (24H, m), 1.55 (2H, m), 3.64 (2H, t, J 6.4, CH2OH); dC (CDCl3):
29.4, 29.5, 29.59, 29.61, 29.65, 29.67, 29.68, 29.72, 30.0, 32.8, 34.4,
36.6, 63.0. HRMS (doped with LiI) calcd for C17H36OLi: 263.2926,
found: 263.2928.

3908
K. Mori / Tetrahedron 65 (2009) 3900–3909
4.10.2. (S)-Isomer
to give crude (R)-22 (830 mg, quant.), nmax (film): 1356 (s), 1176 (s),
In the same manner as described for (R)-19, (S)-16 (1.87 g,
970 (s). This was used for the next step without further purification.
22
7.4 mmol) yielded 1.70 g (90%) of (S)-19. n2D4¼1.4516; [
a]
D
þ5.27 (c
2.51, CHCl3). Its spectral datawere identical with those of (R)-19. HRMS
4.13.2. (S)-Isomer
(doped with LiI) calcd for C17H36OLi: 263.2926, found: 263.2922.
In the same manner as described above, (S)-16 (2.0 g, 7.9 mmol)
yielded crude (S)-22 (3.3 g, quant.). This was used for the next step
without further purification.
4.11. (S)-14-Methylhexadecyl methanesulfonate 20
Methanesulfonyl chloride (1.0 mL, 1.48 g, 12.9 mmol) was added
dropwise to a stirred and ice-cooled solution of (S)-19 (1.22 g,
4.8 mmol) in dichloromethane (3 mL) and dry pyridine (3 mL) at 0–
5 ꢂC. The stirring was continued for 1 h at 0–5 ꢂC. The mixture was
then poured into ice-water and extracted with Et2O. The ether so-
lution was washed with dil. HCl, satd NaHCO3 solution and brine,
dried (MgSO4), and concentrated in vacuo to give 1.60 g (quant.) of
crude (S)-20, nmax (film): 1344 (s), 1169 (s), 983 (s), 947 (s). This was
employed in the next step without further purification.
4.14. 3-Methyl-8-hexadecene 23
4.14.1. (R)-Isomer
A solution of crude (R)-22 (830 mg, 2.4 mmol) in dry THF (5 mL)
was added dropwise to a stirred suspension of LiAlH4 (200 mg,
5.3 mmol) in dry THF (7 mL). The mixture was stirred and heated
under reflux for 1.5 h. It was then poured into ice–dil. HCl and
extracted with Et2O. The ether solution was washed with water,
satd NaHCO3 solution, dried (MgSO4), and concentrated in vacuo.
The residue was chromatographed over SiO2 (3.5 g). Elution with
pentane gave (R)-23 [500 mg, 87% based on (R)-16]. n2D4¼1.4444;
4.12. 3-Methylhexadecane 21
24
[a
]
ꢀ6.35 (c 2.15, CHCl3); nmax (film): 2958 (s), 2925 (s), 2854 (s),
D
1462 (m), 1377 (w), 966 (m); dH (CDCl3): 0.84 (3H, t, J 6.0, CH2CH3),
0.84 (3H, d, J 7.2, CHCH3), 0.88 (3H, t, J 6.4, CH2CH3), 1.04–1.20 (2H,
m), 1.20–1.40 (17H, m), 1.92–2.08 (4H, m), 5.33–5.36 [0.4H, m, (Z)-
isomer], 5.37–5.43 [1.6H, m, (E)-isomer]; dC (CDCl3): 11.4, 14.1, 19.2,
22.6, 26.6, 26.8, 27.22, 27.24, 29.1, 29.20, 29.23, 29.48, 29.49, 29.67,
29.78, 29.97, 30.1, 31.9, 32.60, 32.87, 34.3, 34.4, 36.5, 129.73 and
129.76 [(Z)-isomer], 130.20 and 130.23 [(E)-isomer], (E/Z¼ca. 4:1);
GC–MS [same conditions as for (R)-1]: tR 14.09 [20.0%, (R,Z)-23],
14.18 min [74.9%, (R,E)-23]; MS of (R,E)-23 [same as that of (R,Z)-23;
70 eV, EI]: m/z 238 (19) [Mþ, C17H34], 209 (8), 181 (1), 168 (3), 153
(5), 139 (8), 125 (18), 111 (30), 97 (54), 83 (69), 70 (100), 55 (52), 41
(43). HRMS calcd for C17H34: 238.2661, found: 238.2652.
4.12.1. (R)-Isomer
Palladium–charcoal (10%, 0.1 g) was added to a solution of (R)-23
(350 mg, 1.5 mmol) in EtOAc (10 mL). The suspension was stirred
underH2 (balloon)for 1.5 hatroomtemperature. Thesuspensionwas
filtered through SiO2 (6.0 g). The SiO2 column was washed with
hexane, and the combined organic solution was concentrated in
23
vacuo to give (R)-21 (282 mg, 80%). n2D2¼1.4372; [
a]
ꢀ5.73 (c 1.97,
D
CHCl3);nmax (film):2958(m), 2924(s), 2854(s),1464(m),1377(w);dH
(CDCl3): 0.84 (3H, d, J 6.0, CHCH3), 0.85 (3H, t, J 6.8, CH2CH3), 0.88 (3H,
t, J 6.8, CH2CH3), 1.05–1.20 (2H, m), 1.20–1.35 (25H, m); dC (CDCl3):
11.4,14.1,15.5,19.2, 22.7, 27.1, 29.3, 29.4, 29.5, 29.65, 29.70, 29.73, 30.0,
31.9, 34.4; GC–MS [same condition as for (R)-1]: tR 14.37 min (94.0%).
MS (70 eV, EI): m/z 240 (1) [Mþ, C17H36], 211 (54),182 (9),169 (5),155
(9), 141 (13), 127 (15), 113 (19), 99 (26), 85 (61), 71 (72), 57 (100), 43
(40). HRMS calcd for C17H36: 240.2817, found: 240.2823.
4.14.2. (S)-Isomer
In the same manner as described for (R)-23, crude (S)-22, (3.3 g,
7.9 mmol) yielded (S)-23 [1.48 g, 78% based on (S)-16], n2D4¼1.4440;
23
[a
]
þ6.28 (c 3.88, CHCl3). Its spectral data were identical with
D
4.12.2. (S)-Isomer from (S)-20
those reported for (R)-23. GC [same conditions as for (R)-1]: tR 14.09
A solution of (S)-20 (1.60 g, 0.5 mmol) in THF (10 mL) was added
to a stirred suspension of LiAlH4 (0.8 g, 21 mmol) in THF (20 mL)
under Ar. The mixture was stirred and heated under reflux for 1 h,
then poured into ice–dil. HCl, and extracted with Et2O. The ether
solution was washed with water, satd NaHCO3 solution, brine, dried
(MgSO4), and concentrated in vacuo. The residue was chromato-
[23.2%, (S,Z)-23], 14.20 min [70.0% (S,E)-23]. HRMS calcd for C17H34
238.2661, found: 238.2667.
:
4.15. 1-Methoxy-14-methyl-8-hexadecene 24
graphed over SiO2 (10 g). Elution with pentane gave (S)-21 (840 mg,
4.15.1. (R)-Isomer
23
70%). n2D4¼1.4372; [
a
]
þ5.66 (c 6.38, CHCl3). Its spectral data were
D
Potassium tert-butoxide (500 mg, 4.5 mmol) was added to
a stirred solution of (R)-16 (505 mg, 2 mmol) in dry DMF (5 mL) at
50 ꢂC under Ar. After stirring for 30 min, methyl iodide (2 mL, 3.1 g,
21 mmol) was added in one portion to the stirred and homoge-
neous solution. After the exotheromic reaction, KI separated. The
mixture was stirred and heated at 80 ꢂC for 1 h, then poured into
ice-water, and extracted with hexane. The hexane solution was
washed with water and brine, dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed over SiO2 (5 g). Elution
identical with those of (R)-21. GC [same conditions as for (R)-1]: tR
14.37 min (90.0%). HRMS calcd for C17H36
240.2815.
: 240.2817, found:
4.12.3. (S)-Isomer from (S)-23
In the same manner as described for (R)-21, (S)-23 (996 mg,
4.2 mmol) was hydrogenated over 10% palladium–charcoal to give
23
(S)-21 (900 mg, 90%). n2D4¼1.4372; [
a]
þ4.92 (c 4.63, CHCl3). Its
D
with hexane/EtOAc (15:1) gave (R)-24 (470 mg, 88%). n2D4¼1.4492;
spectral data were identical with those of (R)-21. GC [same condi-
tions as for (R)-1]: tR 14.37 min (93.4%). HRMS calcd for C17H30
240.2817, found: 240.2818.
:
24
[a
]
ꢀ5.77 (c 2.63, CHCl3); nmax (film): 1377 (m, C–O), 966 (m); dH
D
(CDCl3): 0.83 (3H, d, J 6.4, CHCH3), 0.85 (3H, t, J 7.2, CH2CH3), 1.02–
1.18 (2H, m), 1.20–1.40 (15H, m), 1.52–1.61 (2H, m), 1.92–2.07 (4H,
m), 3.33 (3H, s, OCH3), 3.36 (2H, t, J 6.8, CH2O), 5.32–5.34 [0.4H, m,
(R,Z)-24], 5.34–5.42 [1.6H, m, (R,E)-24]; dC (CDCl3): 11.4, 19.2, 26.1,
26.6, 29.1, 29.3, 29.5, 29.56, 29.63, 30.0, 32.55, 32.60, 34.4, 36.44,
36.48, 58.5, 129.6 and 129.8 [(Z)-isomer], 130.13 and 130.25
[(E)-isomer]. HRMS [same conditions as for (R)-1]: tR 16.52 [17.3%,
(R,Z)-24], 16.61 min [71.8% (R,E)-24]. MS of (R,E)-24 [same as that of
(R,Z)-24; 70 eV, EI]: m/z 268 (3) [Mþ, C18H36O], 236 (21), 208 (5),
194 (2), 179 (2), 166 (3), 151 (6), 137 (15), 123 (28), 109 (51), 96 (82),
4.13. 14-Methyl-8-hexadecenyl methanesulfonate 22
4.13.1. (R)-Isomer
Methanesulfonyl chloride (0.5 mL, 0.74 g, 6.5 mmol) was added
dropwise to a stirred and ice-cooled solution of (R)-16 (602 mg,
2.4 mmol) in dichloromethane (2 mL) and dry pyridine (2 mL) at 0–
5 ꢂC. The stirring was continued for 2 h at 0–5 ꢂC. The mixture was
then poured into ice-water, and worked up as described for (S)-20

K. Mori / Tetrahedron 65 (2009) 3900–3909
3909
82 (100), 67 (72), 55 (62), 45 (46). HRMS calcd for C18H36O:
268.2766, found: 268.2757.
and schemes. (R)-2-Methylbutanoic acid was kindly supplied by
T. Hasegawa Co.
4.15.2. (S)-Isomer
References and notes
In the same manner as described for (R)-24, (S)-16 (2.03 g,
8 mmol) yielded (S)-24 (1.71 g, 80%). n2D4¼1.4490; [
a
]
þ5.68 (c
22
1. Mori, K. Tetrahedron 2009, 65, 2798–2805.
D
2. Silverstein, R. M.; Cassidy, R. F.; Burkholder, W. E.; Shapas, T. J.; Levinson, H. Z.;
Levinson, A. R.; Mori, K. J. Chem. Ecol. 1980, 6, 911–917.
3. Rodin, J. O.; Silverstein, R. M.; Burkholder, W. E.; Gorman, J. E. Science 1969, 165,
904–906.
4. Mori, K. Tetrahedron Lett. 1973, 3869–3872.
5. Mori, K. Tetrahedron 1974, 30, 3817–3820.
4.94, CHCl3). Its spectral data were identical with those of (R)-24.
GC [same conditions as for (R)-1]: tR 16.53 [22.2%, (R,Z)-24],
16.63 min [67.6%, (R,E)-24]. HRMS calcd for C18H36O: 268.2766,
found: 268.2762.
6. Mori, K.; Suguro, T.; Uchida, M. Tetrahedron 1978, 34, 3119–3123.
7. Suguro, T.; Mori, K. Agric. Biol. Chem. 1979, 43, 409–410.
8. Mori, K.; Kuwahara, S.; Levinson, H. Z.; Levinson, A. R. Tetrahedron 1982, 38,
2291–2297.
4.16. 1-Methoxy-14-methylhexadecane 25
9. Rossi, R.; Carpita, A. Tetrahedron 1977, 33, 2447–2450.
10. Rossi, R.; Salvadori, P. A.; Carpita, A.; Niccoli, A. Tetrahedron 1979, 35, 2039–
2042.
11. Mori, K. In The Total Synthesis of Natural Products; ApSimon, J., Ed.; Wiley: New
York, NY, 1992; Vol. 9, pp 152–157.
12. Pederson, R. The Efficient Application of Olefin Metathesis in Pharmaceuticals and
Fine Chemicals, Sigma–Aldrich CheminarÒ 4.1 (2008). (Sigma–Aldrich com./
cheminars).
13. 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.
14. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
4.16.1. (R)-Isomer
Palladium–charcoal (0.1 g) was added to a solution of (R)-24
(335 mg, 1.25 mmol) in EtOAc (10 mL). The suspension was stirred
under H2 (balloon) for 1.5 h at room temperature. The suspension
was filtered through SiO2 (6.0 g). The SiO2 column was washed with
EtOAc, and the combined organic solution was concentrated in
vacuo to give (R)-25 (311 mg, 93%). n2D2¼1.4425; [
a
]
ꢀ4.83 (c 2.18,
24
D
CHCl3); nmax (film): 1464 (m), 1377 (w), 1120 (m); dH (CDCl3): 0.838
(3H, d, J 6.4, CHCH3), 0.853 (3H, t, J 7.2, CH2CH3), 1.02–1.19 (2H, m),
1.20–1.40 (23H, m),1.51–1.60 (2H, m), 3.33 (3H, s, OCH3), 3.36 (2H, t,
J 6.4, CH2O); dC (CDCl3): 11.4, 19.2, 26.1, 27.1, 29.48, 29.50, 29.6,
29.65, 29.68, 30.0, 32.8, 34.4, 36.6, 58.5, 63.0, 72.9; GC–MS [same
conditions as for (R)-1]: tR 16.81 min (90%). MS (70 eV, EI): m/z 269
(0.5) [Mþ, (C18H36O)ꢀ1], 238 (8), 209 (26), 181 (11), 168 (5), 153
(10), 139 (18), 125 (38), 111 (59), 97 (96), 83 (96), 70 (100), 57 (62),
45 (65). HRMS calcd for C18H38O: 270.2923, found: 270.2912.
15. Pederson, R. L.; Fellows, J. M.; Ung, T. A.; Ishihara, H.; Hajela, S. A. Adv. Synth.
Catal. 2002, 344, 728–735.
16. Mori, K.; Tashiro, T. Tetrahedron Lett., in press. doi:10.1016/j.tetlet.2009.02.046
17. Shriner, R. L.; Adams, R.; Marvel, C. S. In Organic Chemistry, an Advanced Treatise;
Gilman, H., Ed.; Wiley: New York, NY, 1943; Vol. 1, p 298.
18. Brewster, J. H. In Technique of Chemistry; Weissberger, A., Ed.; Wiley-Inter-
science: New York, NY, 1972; Vol. 4; Part III, Chapter XVII, pp 111–129.
19. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York,
NY, 1994; pp 1071–1093.
20. Polavarapu, P. L. Chem. Rec. 2007, 7, 125–136.
21. Taniguchi, T.; Monde, K.; Schlingmann, G.; Nakanishi, K.; Berova, N. Symposium
Papers, 50th Symposium on the Chemistry of Natural Products, Fukuoka, Sep
30–Oct 2, 2008; pp 281–284.
22. Taniguchi, T.; Monde, K.; Nakanishi, K.; Berova, N. Org. Biomol. Chem. 2008, 6,
4399–4405.
23. Hashimoto, H.; Tatehara, T. Jpn. Tokkyo Kokai 2005, 348727.
24. Fouquet, C.; Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13, 82–83.
25. McLafferty, F. W. Wiley Registry of Mass Spectral Data, 7th Ed. with NIST 2005
Spectral Data (Upgrade); Wiley: New York, NY, 2005; (CD-ROM).
26. Marukawa, K.; Takikawa, H.; Mori, K. Biosci. Biotechnol. Biochem. 2001, 65,
305–314.
27. Seki, M.; Mori, K. Eur. J. Org. Chem. 2001, 503–506.
28. Tamogami, S.; Awano, K.; Amaike, M.; Takagi, Y.; Kitahara, T. Flavour Fragrance J.
2001, 16, 349–352.
4.16.2. (S)-Isomer
In the same manner as described for (R)-25, (S)-24 (958 mg,
3.6 mmol) yielded (S)-25 (950 mg, 98%), n2D4¼1.4410; [
a]
þ4.55 (c
23
D
4.44, CHCl3). Its spectral data were identical with those of (R)-25.
GC [same conditions as for (R)-1]: tR 16.79 min (91%). HRMS calcd
for C18H38O: 270.2923, found: 270.2935.
Acknowledgements
My thanks are due to Mr. M. Kimura (president, Toyo Gosei Co.,
Ltd) for his support. I thank Mr. Y. Shikichi (Toyo Gosei Co.) for NMR
and GC–MS measurements, Dr. S. Tamogami (T. Hasegawa Co.) for
chiral GC analysis, and Dr. T. Tashiro (RIKEN) for preparing figures
29. Grubbs II (not Grubbs I) catalyst was found by GC–MS to cause extensive olefin
isomerizations at 60 ꢂC and less in the case of acyclic diene metathesis
(ADMET) polymerization, too: Fokou, P.-A.; Meier, M.-A.-R. J. Am. Chem. Soc.
2009, 131, 1664–1665.