Combined Lewis acid catalysts in shotgun process: A convenient synthesis of the female sex pheromone of the red-bollworm moth

Article abstract of DOI:10.1016/S0040-4020(02)00970-5

The combined use of Lewis acid and distannoxane catalysts gives rise to a new variant of the shotgun process. The unwanted acetylation of a secondary homoallyl alcohol by the former catalyst is suppressed through hybridization with the latter resulting in one-pot aldehyde allylation and primary alcohol acetylation of ω-hydroxy alkanal without protection/deprotection procedures.

Full text of DOI:10.1016/S0040-4020(02)00970-5

Tetrahedron 58 (2002) 8211–8217
Combined Lewis acid catalysts in shotgun process: a convenient
synthesis of the female sex pheromone of the red-bollworm moth
*
Yoshifumi Nagano, Akihiro Orita and Junzo Otera
Department of Applied Chemistry, Okayama University of Science, Ridai-cho, Okayama 700-0005, Japan
Received 2 May 2002; accepted 15 May 2002
Abstract—The combined use of Lewis acid and distannoxane catalysts gives rise to a new variant of the shotgun process. The unwanted
acetylation of a secondary homoallyl alcohol by the former catalyst is suppressed through hybridization with the latter resulting in one-pot
aldehyde allylation and primary alcohol acetylation of v-hydroxy alkanal without protection/deprotection procedures. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
starting material seems to be extremely practical because
of facile availability of this compound through ozonolysis of
9-decen-1-ol. In a preceding report,3i the hydroxyl of 2 was
protected as a THP ether and the three carbon elongation
was achieved by treating the aldehyde function with vinyl
lithium followed by Wittig methylenation of the resulting
enal to give a terminal 1,3-diene moiety in a stepwise
manner. Finally, the tetrahydopyranyloxy group was con-
verted to the acetate. Our much simpler synthetic plan is
shown in Scheme 2. The key step is one-pot conversions of
both aldehyde and primary alcohol functions into the
homoallyl alcohol and the primary acetate, respectively,
leaving the resulting homoallylic alcohol function intact to
afford an intermediate 3. Then, dehydration completes a
compact synthetic route to 1.
Previously, we advanced a new concept for one-pot
reaction, ‘shotgun process’.1 This treatment allows multiple
reaction sites in a substrate to undergo separate transform-
ations in one pot and thus the tedious protection/deprotec-
tion procedure is no longer necessary resulting in
straightforward access to a target molecule. Another
advantage is the unique chemoselectivities that are not
feasible in simple elementary reactions. Scheme 1 presents
the simplest case where treatment of the substrate bearing
two reaction sites, A and B, with X alone leads to an
unsatisfactory outcome because the desired reaction
between A and X is interfered by the coexisting function
B. However, the situation is changed if another reagent Y
coexists that does not react with A but reacts with B much
faster than the reaction between A and X. Rapid consump-
tion of B enables the latter reaction to occur without
interference from B.2 It is further important to note in such
process that the respective reactions are strongly influenced
by the functionalities of the coexisting other substrates and
reagents. In this paper, we disclose that the combination of
Lewis acid catalysts also leads to alteration in catalytic
activity, thus giving rise to a useful variant of shotgun
process.
2. Results and discussion
First, an intermolecular process was screened by use of
nonanal and octanol substrates (Table 1). Since both
allylation of aldehyde4 and acetylation of hydroxyl5 are
catalyzed by Sc(OTf)3, the equimolar substrates were
exposed to a mixture of tetrallyltin (4) and Ac2O (5) in
the presence of 2 mol% of Sc(OTf)3 (entry 1). The allylation
of aldehyde and acetylation of the primary alcohol
The effectiveness of this new protocol will be exemplified
by a convenient synthesis of 9,11-dodecadien-1-yl acetate
(1), a female sex pheromone of the red-bollworm moth
Oiparopsis castanea, for which a number of synthetic
achievements were reported so far.3 Among them, a
synthetic route employing 9-hydroxynonanal (2) as a
Keywords: shotgun process; Lewis acid catalyst; allylation; acetylation.
*
Corresponding author. Tel.: þ81-86-256-9525; fax: þ81-86-256-4292;
e-mail: otera@high.ous.ac.jp
Scheme 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00970-5

8212
Y. Nagano et al. / Tetrahedron 58 (2002) 8211–8217
Table 3. Shotgun process by catalysts combined with 1,3-dicholoro-
tetrabutyldistannoxane
Scheme 2.
Table 1. Intermolecular shotgun process by various Lewis acid
Entry
L.A.
Yield (%)a
C8H17OH 8þC8H17OH
6
7
6þ7
8
1
2
3
4
5
Sc(OTf)3
Bi(OTf)3
Cu(OTf)2
TMSOTf
BF3·OEt2
92
94
96
92
92
5
4
3
3
3
97
98
99
95
95
99
99
97
93
96
0
0
0
0
0
99
99
97
93
96
Entry
L.A.
Yield (%)a
6
7
6þ7
8
C8H17OH 8þC8H17OH
a
Determined by GLC.
1
2
3
4
5
Sc(OTf)3
Bi(OTf)3
Cu(OTf)2 92
TMSOTf 93
BF3·OEt2 96
78 20
98
97
93
95
97
98
86
62
57
81
0
98
98
84
78
89
95
2
1
2
1
12
22
21
8
allyl acetate (Table 2, entries 2–5) under similar conditions.
Despite such advantage, the less active catalyst process
suffered from insufficient yields of the primary acetate.
a
Determined by GLC.
As such, we were confronted with the problems to decrease
the amount of homoallyl acetate without decreasing the
yield of the primary acetate in the Sc(OTf)3 system or to
increase the yield of the primary acetate without increasing
the amount of the homoallyl acetate with less active
catalysts. Mindful of our earlier success in effective
discrimination of primary alcohol from secondary or tertiary
alcohol with 1,3-dichlorotetraalkyldistannoxane catalyst,8
we were intrigued by making use of this catalyst to
overcome the above problems. Gratifyingly, the hybridiz-
ation of a Lewis acid (2 mol%) and the distannoxane
(10 mol%) led to an almost perfect shotgun process (Table
3). In the Sc(OTf)3-based reaction, the yield of 7 was
decreased to 5% concomitant with increase in the yield of 6,
whereas the primary alcohol acetylation was not deterio-
rated at all (entry 1). On the other hand, octanol was
completely acetylated with the other catalysts although the
proceeded quantitatively. Unfortunately, however, the
homoallyl alcohol also underwent acetylation beyond the
limit allowed for synthetic purpose. This is reasonable
because Sc(OTf)3 is a highly powerful catalyst for
acetylation of even secondary and tertiary alcohols.
Notwithstanding, it should be pointed out that the
acetylation of the homoallyl alcohol was greatly retarded
in the shotgun process. As shown in entry 1, Table 2,
exposure of nonanal in the absence of octanol to 4 and 5
resulted in acetylation of most of the in situ produced
homoallyl alcohol. Apparently, the coexisting octanol
works for suppressing the homoallyl alcohol acetylation.
Then, we employed less active Lewis acids (Table 1, entries
2–5). Although these catalysts had not been known to effect
the reaction between aldehyde and 4 except Cu(OTf)2,6 the
allylation took place quantitatively. Remarkably, the
acetylation of the homoallyl alcohol was almost sup-
pressed.7 This also exemplifies the unique feature of the
shotgun process because the reaction in the absence of
octanol predominantly or exclusively furnished the homo-
Table 4. Allylation/acetylation of v-hydroxynonanal by combined
catalysts
Table 2. Allylation in the presence of Ac2O by various Lewis acid
Entry
1
L.A.
Productsa
Sc(OTf)3
Entry
L.A.
Yield (%)a
6
7
2
Bi(OTf)3
3 (87%); 9 (5%); 10 (2%);
1b
2
3
4
Sc(OTf)3
Bi(OTf)3
Cu(OTf)2
TMSOTf
BF3·OEt2
9
85
63
68
95
60
31
21
0
3b
4
Cu(OTf)2
TMSOTf
BF3·OEt2
3 (84%); 9 (8%); 10 (5%); 11 (trace)
3 (90%); 9 (4%); 10 (2%); 11 (1%)
3 (89%); 9 (6%); 10 (trace)
5
5
28
a
a
Isolated yield based on 2 after column chromatography.
Reaction time: 15 h.
Determined by GLC.
Reaction time: 1 h.
b
b

Y. Nagano et al. / Tetrahedron 58 (2002) 8211–8217
Table 5. Allylation/acetylation of v-hydroxynonanal by single or combined catalysts
8213
Entry
1
Nucleophiles
Catalyst(s)
Productsa
4 (0.3 equiv.)
5 (6 equiv.)
Sc(OTf)3 (2 mol%)
3 (40%); 9 (21%)
10 (19%); 11 (12%)
2b
4 (0.3 equiv.)
Sc(OTf)3 (2 mol%)
3b
4c
4 (0.3 equiv.)
5 (6 equiv.)
Sc(OTf)3 (2 mol%),
9 (77%); 12 (7%)
(ClBu2SnOSnBu2Cl)2 (10 mol%)
Sc(OTf)3 (2 mol%),
(ClBu2SnOSnBu2Cl)2 (10 mol%)
a
Isolated yield based on 2 after column chromatography.
The crude products mixture was acetylated.
Reaction time: 8 h.
b
c
amount of 7 was increased slightly but within the limit for
synthetic use.
shotgun process. The merits of this process are further
apparent from comparison with reactions given in the last
two entries in Table 5. Reaction with 4 alone provided 9 in
77% yield together with 12 (7% yield after acetylation)
(entry 3). Obviously, a part of the initial allylation product
was consumed by the remaining aldehyde function. Thus,
rapid disappearance of this function in the shotgun process
(Table 4, entry 1) avoided the acetal formation. When Ac2O
was exposed to 2 in the absence of 4, the products were
constituted by acylal triacetate 13 and unidentifiable
byproducts (Table 5, entry 4). Again, it is evident that
exclusive acetylation of the primary hydroxyl in the shotgun
process was achieved by rapid consumption of the aldehyde
which otherwise would furnish the acylal. Notably, the
combined catalyst system holds the same characteristic
features as previously observed for the single Sc(OTf)3
catalyst: acceleration of allylation by Ac2O and retardation
of acetylation by aldehyde.1 The former feature is apparent
from the comparison between entry 1 in Table 4 and entry 3
in Table 5: the allylation yield was lowered from 97 to 83%
(¼77%þ7£2/3%) when Ac2O was absent. The acceleration
of allylation rate by Ac2O was further substantiated by
comparison between entries 1 and 2 in Table 6: reaction of 2
with 4 alone resulted in only 37% conversion (i.e. 63%
recovery of the hydrazone of 2) with a 22% yield of 8 after
5 min.
Armed with the above results, we addressed ourselves to
explore the shotgun process with the substrate 2. As shown
in Table 4, all the combined catalysts furnished the desired
product 3 in high yields through allylation of aldehyde and
acetylation of primary alcohol although small amounts of
diacetate 9 and diol 10 were formed. Achievement of such
high preference for 3 is specific to the shotgun process with
combined catalysts, the characteristic features of which
were scrutinized with Sc(OTf)3 catalyst (Table 5). When the
shotgun process was conducted with Sc(OTf)3 alone, no
selectivity was attained with acetylation resulting in all
three possible modes of acetylation products, 3, 9, and 11,
together with naked diol 10 (entry 1). A simple allylation in
the absence of 5 (entry 2) enabled the allylation to proceed
only moderately (60%¼51%þ13£2/3%), and what is
worse, a portion of the allylation product 10 was caught
by unreacted aldehyde to give acetal 12 (after acetylation).
When the reaction with the combined catalysts was
quenched with Me2NNH2 in 5 min,9 it turned out that the
allylation was complete while the acetylation proceeded
only in 5% yield (Table 6, entry 1), a typical feature of the
Table 6. Hydrazine quench after 5 min
Most importantly, the success of shotgun process with the
combined catalysts lies in the modification of Sc(OTf)3.
Normally, this catalyst effects acetylation with a 1 mol%
concentration or less even for secondary and tertiary
Entry
1
Nucleophiles
Products
4 (0.3 equiv.)
5 (6 equiv.)
2
4 (0.3 equiv.)
aDetermined as diacetate 8.
Scheme 3.

8214
Y. Nagano et al. / Tetrahedron 58 (2002) 8211–8217
Table 7. Interaction between (ClBu2SnOSnBu2Cl)2 and Sc(OTf)3 studied
by 119Sn NMR spectra
Ratio of
(ClBu2SnOSnBu2Cl)2 and Sc(OTf)3
d
(ppm)
Scheme 4. Reaction conditions: (i) Et3N (1.2 equiv.), MsCl (1.1 equiv.),
CH2Cl2, 08C, 2 h: 95%; (ii) DBU (3.0 equiv.), toluene, reflux, 12 h: 75%
(E/Z¼80:20); (iii) I2, benzene, room temperature, 12 h: 91% (E/Z¼89:11).
100:0
1:2
5:1
290.0, 2140.2
262.4, 2108.7
265.3, 290.9, 2141.2, 2151.6
completed the synthesis of 1 (Scheme 4). Mesylation of 3
followed by elimination afforded the target molecule. The
E,Z ratio of 1 thus obtained was found to be 80:20, the same
value produced by red-bollworm moth. It is known that the
attractiveness of 3 is highest for the E content of 88–93%.3b
The diene with an 89%-E content was obtained by treating
the above reaction product with I2 in benzene.
In 1.0 mmol containing C8H17OH.
alcohols. Thus, it is rather surprising that the high selectivity
for primary alcohol was attained in the present shotgun
protocol. This is probably ascribed to generation of a new
scandium species upon mixing with the distannoxane so that
the activity for acetylation has been killed while the efficacy
for allylation is retained. It should be noted, however, that
retardation of the acetylation activity of Sc(OTf)3 is not
solely responsible for the high selectivity. The effect of
addition of the distannoxane to Sc(OTf)3 for suppressing
acetylation of a secondary homoallyl alcohol after the
aldehyde allylation is shown in Scheme 3. Actually, with
Sc(OTf)3 alone, most of the homoallyl alcohol was
acetylated, yet even in the presence of the distannoxane
catalyst, the acetylation occurred on a major portion of the
alcohol. In striking contrast, upon addition of a primary
alcohol to this reaction system, the acetylation of the
secondary homoallyl alcohol was almost suppressed con-
comitant with quantitative formation of the primary acetate
(Eq. (1)). It follows that the coexistence of both ditannoxane
and primary alcohol is crucial for killing the acetylation
activity of Sc(OTf)3. Although no information about the
newly generated active species is available at the moment,
the interaction between Sc(OTf)3 and the distannoxane was
apparent from 119Sn NMR spectra (Table 7): addition of an
equimolar amount of Sc(OTf)3 to the distannoxane resulted
in complete diappearance of signals at 290.0 and
140.2 ppm diagnostic of the free distannoxane with
alternative emergence of a new set of signals at 262.4
and 2108.7 ppm. For the same composition as the standard
shotgun conditions (5:1 distannoxane/Sc(OTf)3), a new set
of signals at 265.3 and 151.6 ppm was observed in addition
to the original one (at 290.9 and 2141.2 ppm). Apparently,
Sc(OTf)3 was modified to a new species while a major part
of the distannoxane remained as its innate form under these
conditions. Probably, the former is active only for the
aldehyde allylation and the latter plays a crucial role in the
selective acetylation. This was supported by the fact that the
selectivity as well as the yield of 3 was slightly decreased
when the concentration of the distannoxane was reduced to
5 mol% in the standard shotgun reaction as entry 1 in Table
4. Conceivably, the shotgun process with other Lewis acids
possesses similar features although the interaction of these
species with the distannoxane is somewhat different.
In summary, hybridization of the distannoxane with Lewis
acids enables aldehyde allylation and selective acetylation
of primary alcohol in one pot, giving rise to a new variant of
shotgun process. In this protocol, no protection–deprotec-
tion procedure is needed and multi-step synthetic processes
can enjoy compaction. Since similar preferable modification
may be available with other combination of catalysts, the
new version disclosed herein will find a broad range of
applications. Finally, it is worthy to note that combination of
different reactions does not lead to the simple super-
imposition of elementary reactions. The interactions
between functional groups in substrates and reagents as
well as catalysts alter the reaction modes. Of course, both
positive and negative effects may arise from these
interactions. If such effects are taken in positively, the
shotgun process will be able to develop a new horizon in
synthetic chemistry.
3. Experimental
3.1. General
All reactions were carried out under an atmosphere of
nitrogen with freshly distilled solvents, unless otherwise
noted. CH2Cl2 was distilled from CaH2. Silica gel (Daiso
gel IR-60) was used for Column chromatography. NMR
spectra were recorded at 208C on JEOL Lambda 300 and
500 instruments and calibrated with tetramethylsilane
(TMS) as an internal reference. The following abbreviations
are used to indicate multiplicities: s singlet; d doublet; t
triplet; q quartet; m multiplet. Mass spectra were recorded
on a Jeol MStation JMS-700 spectrometer.
3.1.1. The preparation of 9-hydroxynonanal 2. A stream
of ozone was bubbled through a solution of 9-decen-1-ol
(1.56 g, 10.0 mmol) in CH2Cl2 (40 mL) at 2788C until the
solution turned to pale blue, and then a stream of N2 was
bubbled through the solution until the solution turned to
colorless. Triethylamine (2.79 mL, 20.0 mmol) was added
and the mixture was stirred at room temperature for 5 h.
After addition of NaHCO3 aq. (20 mL) and usual workup
(AcOEt/water), the combined organic layer was washed
with brine. After drying over Na2SO4 and filtration, the
organic layer was concentrated under reduced pressure. The
crude mixture was subjected to column chromatography on
Frorisilw (3:2 hexane/AcOEt) and subsequent Kugelrohr
ð1Þ
With 3 in high yield as mentioned above in hand, we

Y. Nagano et al. / Tetrahedron 58 (2002) 8211–8217
8215
distillation (1508C/1.0 mm Hg) to afford 2 (853 mg, 54%).
2: 1H NMR (300 MHz, CDCl3) d 1.33–1.66 (m, 12H), 2.43
(dt, J¼1.8, 7.3 Hz, 2H), 3.64 (t, J¼6.6 Hz, 2H), 9.77 (t,
J¼1.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 22.0, 25.6,
29.0, 29.1, 29.2, 32.7, 43.8, 62.9, 203.0. HRMS (EI) calcd
for C9H18O2: 158.1307. Found: 158.1320.
filtration, the organic layer was concentrated under reduced
pressure. GC analysis of the crude mixture showed the
formation of 6 (92% yield), 7 (5% yield) and 8 (99% yield).
3.1.5. Table 4 (entry 1 as representative procedure). To a
suspension of Sc(OTf)3 (10.0 mg, 0.02 mmol), (ClBu2-
SnOSnBu2Cl)2 (110 mg, 0.10 mmol) and 2 (158 mg,
1.00 mmol) in CH2Cl2 (9 mL) were added a mixture of
tetraallyltin (0.07 mL, 0.30 mmol) and Ac2O (0.57 mL,
6.00 mmol) in CH2Cl2 (1 mL) at 258C. After the mixture
had been stirred for 12 h, NaHCO3 aq. (10 mL) and NH4F
(800 mg) were added, and insoluble solids were removed by
filtration. After usual workup (AcOEt/water), the organic
layer was washed with NaHCO3 aq. and brine. After drying
over Na2SO4 and filtration, the organic layer was concen-
trated under reduced pressure. The crude mixture was
subjected to column chromatography on silica gel to afford
9 (19:1 hexane/AcOEt, 23 mg, 8% yield), 3 (17:3
hexane/AcOEt, 213 mg, 88% yield) and 10 (3:2 hexane/A-
3.1.2. Table 1 (entry 1 as representative procedure). To a
suspension of Sc(OTf)3 (10.0 mg, 0.02 mmol) in CH2Cl2
(8 mL) were added a mixture of nonanal (142 mg,
1.00 mmol) and octanol (130 mg, 1.00 mmol) in CH2Cl2
(1 mL) and then a mixture of tetraallyltin 4 (0.07 mL,
0.30 mmol) and Ac2O 5 (0.57 mL, 6.00 mmol) in CH2Cl2
(1 mL) at 258C. After the mixture had been stirred for 8 h,
NaHCO3 aq. (10 mL) and NH4F (800 mg) were added, and
insoluble solids were removed by filtration. After usual
workup (AcOEt/water), the organic layer was washed with
NaHCO3 aq. and brine. After drying over Na2SO4 and
filtration, the organic layer was concentrated under reduced
pressure. GC analysis of the crude mixture showed the
formation of 6 (78% yield), 7 (20% yield) and 8 (98%
yield). 6: 1H NMR (300 MHz, CDCl3) d 0.88 (t, J¼6.6 Hz,
3H), 1.28–1.46 (m, 14H), 2.09–2.35 (m, 2H), 3.60–3.68
(m, 1H), 5.11–5.17 (m, 2H), 5.77–5.09 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 14.1, 22.6, 25.6, 29.2, 29.55, 29.64,
31.9, 36.8, 41.9, 70.7, 117.0, 134.9. HRMS (EI) calcd for
C12H24O: 184.1827. Found: 184.1827. 7: 1H NMR
(500 MHz, CDCl3) d 0.88 (t, J¼6.7 Hz, 3H), 1.26–1.55
(m, 14H), 2.03 (s, 3H), 2.25–2.35 (m, 2H), 4.91 (qui,
J¼6.3 Hz, 1H), 5.04–5.09 (m, 2H), 5.71–5.79 (m, 1H). 13C
NMR (125 MHz, CDCl3) d 14.1, 21.2, 22.6, 25.2, 29.2,
29.41, 29.43, 31.8, 33.5, 38.6, 73.3, 117.5, 133.8, 170.7.
HRMS (EI) calcd for C14H26O2: 226.1933. Found:
226.1934.
1
cOEt, 2 mg, 1% yield). 10: H NMR (300 MHz, CDCl3) d
1.32–1.61 (m, 14H), 2.05–2.35 (m, 2H), 3.64 (t, J¼6.6 Hz,
3H), 5.10–5.18 (m, 2H), 5.76–5.90 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 25.6, 25.7, 29.3, 29.49, 29.51, 32.7,
36.7, 41.9, 63.0, 70.6, 118.1, 134.9. HRMS (EI) calcd for
C12H24O2: 200.1776. Found: 200.1778. 9: 1H NMR
(300 MHz, CDCl3) d 1.29–1.66 (m, 14H), 2.04 (s, 3H),
2.05 (s, 3H), 2.22–2.37 (m, 2H), 4.05 (t, J¼6.8 Hz, 2H),
4.91 (qui, J¼6.2 Hz, 1H), 5.04–5.11 (m, 2H), 5.68–5.82
(m, 1H). 13C NMR (75 MHz, CDCl3) d 21.0, 21.2, 25.2,
25.8, 28.5, 29.1, 29.31, 29.33, 33.5, 38.6, 64.6, 73.3, 117.5,
133.8, 170.8, 171.2. HRMS (EI) calcd for C16H28O4:
284.1988. Found: 284.1986. 3: 1H NMR (300 MHz,
CDCl3) d 1.31–1.66 (m, 14H), 1.75 (br, 1H), 2.05 (s, 3H),
2.09–2.35 (m, 2H), 3.60–3.68 (m, 1H), 4.05 (t, J¼6.7 Hz,
2H), 5.11–5.17 (m, 2H), 5.77–5.90 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 21.0, 25.6, 25.8, 28.5, 29.1, 29.4, 29.5,
36.7, 41.9, 64.6, 70.6, 118.0, 134.9, 171.2. HRMS (EI) calcd
for C14H26O3: 242.1882. Found: 242.1855.
3.1.3. Table 2 (entry 1 as representative procedure) and
Scheme 3 (Sc(OTf)3-catalyzed allylation in the presence
of Ac2O). To a suspension of Sc(OTf)3 (10.0 mg,
0.02 mmol) in CH2Cl2 (8 mL) were added nonanal
(142 mg, 1.00 mmol) in CH2Cl2 (1 mL), and then a mixture
of tetraallyltin (0.07 mL, 0.30 mmol) and Ac2O (0.57 mL,
6.00 mmol) in CH2Cl2 (1 mL) at 258C. After the mixture
had been stirred for 1 h, NaHCO3 aq. (10 mL) and NH4F
(800 mg) were added, and insoluble solids were removed by
filtration. After usual workup (AcOEt/water), the organic
layer was washed with NaHCO3 aq. and brine. After drying
over Na2SO4 and filtration, the organic layer was concen-
trated under reduced pressure. GC analysis of the crude
mixture showed the formation of 6 (9% yield) and 7 (85%
yield).
3.1.6. Table 5 (entry 1). To a suspension of Sc(OTf)3
(10.0 mg, 0.02 mmol) and 2 (158 mg, 1.00 mmol) in
CH2Cl2 (9 mL) were added a mixture of tetraallyltin
(0.07 mL, 0.30 mmol) and Ac2O (0.57 mL, 6.00 mmol) in
CH2Cl2 (1 mL) at 258C. After the mixture had been stirred
for 12 h, NaHCO3 aq. (10 mL) and NH4F (800 mg) were
added, and insoluble solids were removed by filtration.
After usual workup (AcOEt/water), the organic layer was
washed with NaHCO3 aq. and brine. After drying over
Na2SO4 and filtration, the organic layer was concentrated
under reduced pressure. The crude mixture was subjected to
column chromatography on silica gel to afford 9 (19:1
hexane/AcOEt, 60 mg, 21% yield), 3 (17:3 hexane/AcOEt,
97 mg, 40% yield), 11 (17:3 hexane/AcOEt, 29 mg, 12%
yield) and 10 (3:2 hexane/AcOEt, 38 mg, 19% yield). 11: 1H
NMR (300 MHz, CDCl3) d 1.29–1.60 (m, 14H), 2.03 (s,
3H), 2.22–2.37 (m, 2H), 3.63 (t, J¼6.6 Hz, 2H), 4.91 (qui,
J¼6.2 Hz, 1H), 5.04–5.10 (m, 2H), 5.68–5.82 (m, 1H). 13C
NMR (75 MHz, CDCl3) d 21.2, 25.2, 25.6, 29.2, 29.3, 29.4,
32.7, 33.5, 38.6, 62.9, 73.3, 117.5, 133.8, 170.8. HRMS (EI)
calcd for C14H26O3: 242.1882. Found: 242.1875.
3.1.4. Table 3 (entry 1 as representative procedure) and
Eq. (1). To a suspension of Sc(OTf)3 (10.0 mg, 0.02 mmol)
and (ClBu2SnOSnBu2Cl)2 (110 mg, 0.10 mmol) in CH2Cl2
(8 mL) were added a mixture of nonanal (142 mg,
1.00 mmol) and octanol (130 mg, 1.00 mmol) in CH2Cl2
(1 mL), and then a mixture of tetraallyltin (0.07 mL,
0.30 mmol) and Ac2O (0.57 mL, 6.00 mmol) in CH2Cl2
(1 mL) at 258C. After the mixture had been stirred for 8 h,
NaHCO3 aq. (10 mL) and NH4F (800 mg) were added, and
insoluble solids were removed by filtration. After usual
workup (AcOEt/water), the organic layer was washed with
NaHCO3 aq. and brine. After drying over Na2SO4 and
3.1.7. Table 5 (entry 2). To a suspension of Sc(OTf)3
(10.0 mg, 0.02 mmol) and 2 (158 mg, 1.00 mmol) in

8216
Y. Nagano et al. / Tetrahedron 58 (2002) 8211–8217
CH2Cl2 (10 mL) were added tetraallyltin (0.07 mL,
0.30 mmol) at 258C. After the mixture had been stirred for
12 h, NaHCO3 aq. (10 mL) and NH4F (800 mg) were added,
and insoluble solids were removed by filtration. After usual
workup (AcOEt/water), the organic layer was washed with
NaHCO3 aq. and brine. After drying over Na2SO4 and
filtration, the organic layer was concentrated under reduced
pressure. The crude mixture was subjected to column
chromatography on silica gel (3:2 hexane/AcOEt) to afford
a mixture of 10 and triol form of 12. To these crude products
were added pyridine (2 mL) and Ac2O (0.75 mL,
8.00 mmol) at 08C, and the mixture was stirred at room
temperature for 12 h. After addition of 1N HCl at 08C and
usual workup (AcOEt/water), the combined organic layer
was washed with H2O, NaHCO3 aq. and brine. After drying
over Na2SO4 and filtration, the organic layer was concen-
trated under reduced pressure. The crude mixture was
subjected to column chromatography on silica gel to afford
9 (19:1 hexane/AcOEt, 145 mg, 51% yield) and 12 (19:1
hexane/AcOEt, 29 mg, 13% yield). 12: 1H NMR (500 MHz,
CDCl3) d 1.25–1.64 (m, 42H), 2.03 (s, 6H), 2.05 (s, 3H),
2.25–2.35 (m, 4H), 3.39 (dt, J¼6.7, 9.2 Hz, 2H), 3.55 (dt,
J¼6.7, 9.2 Hz, 2H), 4.05 (t, J¼6.9 Hz, 2H), 4.45 (t,
J¼5.6 Hz, 1H), 4.91 (qui, J¼6.3 Hz, 2H), 5.04–5.09 (m,
4H), 5.71–5.79 (m, 2H). 13C NMR (125 MHz, CDCl3) d
21.0, 21.2, 24.8, 25.3, 25.9, 26.2, 28.6, 29.2, 29.39, 29.40,
29.42, 29.5, 29.9, 33.4, 33.5, 38.6, 64.6, 65.5, 73.3, 103.1,
117.5, 133.8, 170.8, 171.3. HRMS (EI) calcd for C39H70O8:
666.5071. Found: 666.5062.
organic layer was concentrated under reduced pressure. The
crude mixture was subjected to column chromatography on
silica gel to afford 13 (17:3 hexane/AcOEt, 248 mg, 82%
1
yield). 13: H NMR (500 MHz, CDCl3) d 1.31 (m, 10H),
1.59–1.77 (m, 4H), 2.05 (s, 3H), 2.08 (s, 6H), 4.05 (t,
J¼6.7 Hz, 2H), 6.77 (t, J¼5.6 Hz, 1H). 13C NMR
(125 MHz, CDCl3) d 20.7, 20.9, 23.2, 25.7, 28.4, 28.91,
28.93, 29.1, 33.0, 64.4, 90.4, 168.9, 171.1. HRMS (EI) calcd
for C15H26O6: 302.1729. Found: 302.1749.
3.1.10. Table 6 (entry 1). To a suspension of Sc(OTf)3
(10.0 mg, 0.02 mmol), (ClBu2SnOSnBu2Cl)2 (110 mg,
0.10 mmol) and 2 (158 mg, 1.00 mmol) in CH2Cl2 (9 mL)
was added a mixture of tetraallyltin (0.07 mL, 0.30 mmol)
and Ac2O (0.57 mL, 6.00 mmol) in CH2Cl2 (1 mL) at 258C,
and the mixture was stirred for 5 min. After addition of
Me2NNH2 (1 mL), the mixture was stirred for 10 min, and
NaHCO3 aq. (10 mL) and NH4F (800 mg) were added. The
insoluble solids were removed by filtration. After usual
workup (AcOEt/water), the organic layer was washed with
NaHCO3 aq. and brine. After drying over Na2SO4 and
filtration, the organic layer was concentrated under reduced
pressure. The crude mixture was subjected to column
chromatography on silica gel to afford 3 (17:3 hexane/A-
cOEt, 12 mg, 5% yield) and 10 (3:2 hexane/AcOEt, 180 mg,
90% yield).
3.1.11. Table 6 (entry 2). To a suspension of Sc(OTf)3
(10.0 mg, 0.02 mmol), (ClBu2SnOSnBu2Cl)2 (110 mg,
0.10 mmol) and 2 (158 mg, 1.00 mmol) in CH2Cl2
(10 mL) was added tetraallyltin (0.07 mL, 0.30 mmol) at
258C, and the mixture was stirred for 5 min. After addition
of Me2NNH2 (1 mL), the mixture was stirred for 10 min,
and NaHCO3 aq. (10 mL) and NH4F (800 mg) were added.
The insoluble solids were removed by filtration. After usual
workup (AcOEt/water), the organic layer was washed with
NaHCO3 aq. and brine. After drying over Na2SO4 and
filtration, the organic layer was concentrated under reduced
pressure. The crude mixture was subjected to column
chromatography on silica gel to afford hydrazone of 2 (1:1
hexane/AcOEt, 126 mg, 63% yield) and a mixture of 10 and
triol form of 12 (3:2 hexane/AcOEt). To the mixture of 10
and triol form of 12 were added pyridine (2 mL) and Ac2O
(0.75 mL, 8.00 mmol) at 08C, and the mixture was stirred at
room temperature for 12 h. After addition of 1N HCl at 08C
and usual workup (AcOEt/water), the combined organic
layer was washed with H2O, NaHCO3 aq. and brine. After
drying over Na2SO4 and filtration, the organic layer was
concentrated under reduced pressure. The crude mixture
was subjected to column chromatography on silica gel to
afford 9 (19:1 hexane/AcOEt, 63 mg, 22% yield) and 12
(19:1 hexane/AcOEt, trace). hydrazone of 2: 1H NMR
(300 MHz, CDCl3) d 1.32–1.57 (m, 12H), 2.19–2.26 (m,
3H), 2.72 (s, 3H), 3.61 (t, J¼6.6 Hz, 2H), 6.67 (t, J¼5.6 Hz,
1H). 13C NMR (125 MHz, CDCl3) d 25.6, 27.6, 29.0, 29.2,
29.3, 32.6, 32.9, 43.4, 62.7, 140.2. HRMS (EI) calcd for
C11H24N2O: 200.1889. Found: 200.1879.
3.1.8. Table 5 (entry 3). To a suspension of Sc(OTf)3
(10.0 mg, 0.02 mmol), (ClBu2SnOSnBu2Cl)2 (110 mg,
0.10 mmol) and 2 (158 mg, 1.00 mmol) in CH2Cl2
(10 mL) was added tetraallyltin (0.07 mL, 0.30 mmol) at
258C. After the mixture had been stirred for 12 h, NaHCO3
aq. (10 mL) and NH4F (800 mg) were added, and insoluble
solids were removed by filtration. After usual workup
(AcOEt/water), the organic layer was washed with NaHCO3
aq. and brine. After drying over Na2SO4 and filtration, the
organic layer was concentrated under reduced pressure. The
crude mixture was subjected to column chromatography on
silica gel (3:2 hexane/AcOEt) to afford a mixture of 10 and
triol form of 12. To these crude products were added
pyridine (2 mL) and Ac2O (0.75 mL, 8.00 mmol) at 08C,
and the mixture was stirred at room temperature for 12 h.
After addition of 1N HCl at 08C and usual workup
(AcOEt/water), the combined organic layer was washed
with H2O, NaHCO3 aq. and brine. After drying over Na2SO4
and filtration, the organic layer was concentrated under
reduced pressure. The crude mixture was subjected to
column chromatography on silica gel to afford 9 (19:1
hexane/AcOEt, 219 mg, 77% yield) and 12 (19:1 hexa-
ne/AcOEt, 15 mg, 7% yield).
3.1.9. Table 5 (entry 4). To a suspension of Sc(OTf)3
(10.0 mg, 0.02 mmol), (ClBu2SnOSnBu2Cl)2 (110 mg,
0.10 mmol) and 2 (158 mg, 1.00 mmol) in CH2Cl2
(10 mL) was added Ac2O (0.57 mL, 6.00 mmol) at 258C.
After the mixture had been stirred for 8 h, NaHCO3 aq.
(10 mL) and NH4F (800 mg) were added, and insoluble
solids were removed by filtration. After usual workup
(AcOEt/water), the organic layer was washed with NaHCO3
aq. and brine. After drying over Na2SO4 and filtration, the
3.1.12. Table 7 ((ClBu2SnOSnBu2Cl)2/Sc(OTf)351:2 as
representative procedure). To a suspension of Sc(OTf)3
(246 mg, 0.50 mmol) and (ClBu2SnOSnBu2Cl)2 (276 mg,
0.25 mmol) in CH2Cl2 (0.7 mL) was added octanol
(157 mL, 1.00 mmol) at room temperature and the mixture

Y. Nagano et al. / Tetrahedron 58 (2002) 8211–8217
8217
was stirred for 1 h. The mixture was transferred to an NMR
sample tube, and 119Sn NMR was measured with reference
to Me4Sn as an external standard and by use of d8-toluene as
an external lock. Signals at 262.4 and 2108.7 ppm were
observed.
the organic layer was concentrated under reduced pressure.
The crude mixture was subjected to column chromatog-
raphy on silica gel to afford 1 (19:1 hexane/Et2O, 146 mg,
91% yield, E/Z¼89:11).
3.1.13. Scheme 3 (allylation by use of Sc(OTf)3 and
(ClBu2SnOSnBu2Cl)2 in the presence of Ac2O). To a
suspension of Sc(OTf)3 (10.0 mg, 0.02 mmol) and (ClBu2-
SnOSnBu2Cl)2 (110 mg, 0.10 mmol) in CH2Cl2 (8 mL) was
added nonanal (142 mg, 1.00 mmol) in CH2Cl2 (1 mL) and
then a mixture of tetraallyltin (0.07 mL, 0.30 mmol) and
Ac2O (0.57 mL, 6.00 mmol) in CH2Cl2 (1 mL) at 258C.
After the mixture had been stirred for 1 h, NaHCO3 aq.
(10 mL) and NH4F (800 mg) were added, and insoluble
solids were removed by filtration. After usual workup
(AcOEt/water), the organic layer was washed with NaHCO3
aq. and brine. After drying over Na2SO4 and filtration, the
organic layer was concentrated under reduced pressure. GC
analysis of the crude mixture showed the formation of 6
(28% yield) and 7 (69% yield).
References
1. Orita, A.; Nagano, Y.; Nakazawa, K.; Otera, J. Synlett 2000,
599.
2. In this sense, the shotgun process is different from another
protocol, parallel recognition, where the multiple reactions
proceed simultaneously: (a) Chen, J.; Otera, J. Angew. Chem.
Int. Ed. Engl. 1998, 37, 91. (b) Chen, J.; Otera, J. Tetrahedron
Lett. 1998, 39, 1767. (c) Chen, J.; Sakamoto, K.; Orita, A.;
Otera, J. Tetrahedron 1998, 54, 8411.
3. Isolation: (a) Nesbitt, B. F.; Beevor, P. S.; Cole, R. A.; Lester,
R.; Poppi, R. G. J. Insect. Physiol. 1975, 21, 1091. (b) Henrick,
C. A. Tetrahedron 1977, 33, 1845. Synthesis: (c) Nesbitt, B. F.;
Beevor, P. S.; Cole, R. A.; Lester, R.; Poppi, R. G. Tetrahedron
Lett. 1973, 4669. (d) Mori, K. Tetrahedron 1974, 30, 3807. (e)
Babler, J. H.; Martin, M. J. J. Org. Chem. 1977, 42, 1799. (f)
Babler, J. H.; Invergo, B. J. J. Org. Chem. 1979, 44, 3723. (g)
Mandai, T.; Yasuda, H.; Kaito, M.; Tsuji, J.; Yamaoka, R.;
Fukami, H. Tetrahedron 1979, 35, 309. (h) Yasuda, A.; Tanaka,
S.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn 1979, 52,
1752. (i) Wollenberg, R. H.; Peries, R. Tetrahedron Lett. 1979,
297. (j) Knox, G. R.; Thom, I. G. J. Chem. Soc., Chem.
Commun. 1981, 373. (k) Rossi, R.; Carpita, A.; Quirici, M. G.
Tetrahedron 1981, 37, 2617. (l) Ranganathan, S.; Kumar, R.;
Maniktala, V. Synth. Commun. 1982, 12, 921. (m) Yamamoto,
Y.; Saito, Y.; Maruyama, K. Tetrahedron Lett. 1982, 23, 4597.
(n) Snider, B. B.; Phillips, G. B. J. Org. Chem. 1983, 48, 464.
(o) Hayashi, T.; Yanagida, M.; Matsuda, Y.; Oishi, T.
Tetrahedron Lett. 1983, 24, 2665. (p) Bloch, R.; Abecassis,
J.; Hassan, D. Can. J. Chem. 1984, 62, 2019. (q) Hsio, C.-N.;
Shechter, H. Tetrahedron Lett. 1984, 25, 1219. (r) Sato, T.;
Okura, S.; Otera, J.; Nozaki, H. Tetrahedron Lett. 1987, 28,
6299.
3.1.14. Scheme 4 (step i: mesylation). To a solution of 3
(242 mg, 1.00 mmol) in CH2Cl2 (5 mL) was added
triethylamine (0.17 mL, 1.20 mmol) and methanesulfonyl
chloride (0.09 mL, 1.10 mmol) at 08C. After the mixture had
been stirred for 2 h, NaHCO3 aq. (10 mL) was added. After
usual workup (AcOEt/water), the combined organic layer
was washed with brine. After drying over Na2SO4 and
filtration, the organic layer was concentrated under reduced
pressure. The crude mixture was subjected to column
chromatography on silica gel to afford mesylate of 3 (17:3
hexane/AcOEt, 305 mg, 95% yield). Mesylate of 3: 1H
NMR (300 MHz, CDCl3) d 1.31–1.73 (m, 14H), 2.05 (s,
3H), 2.45–2.50 (m, 2H), 3.00 (s, 3H), 4.05 (t, J¼6.7 Hz,
2H), 4.73 (qui, J¼6.1 Hz, 1H), 5.14–5.19 (m, 2H), 5.73–
5.87 (m, 1H). 13C NMR (75 MHz, CDCl3) d 21.0, 24.9,
25.8, 28.5, 29.05, 29.13, 29.2, 34.1, 38.7, 39.0, 64.5, 82.8,
118.9, 132.5, 171.2. HRMS (EI) calcd for C15H28O5S:
320.1657. Found: 320.1683.
4. Hachiya, I.; Kobayashi, S. J. Org. Chem. 1993, 58, 6958.
5. Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560.
3.1.15. Scheme 4 (step ii: preparation of 9,11-dodeca-
dien-1-yl acetate 1). To a solution of mesylate of 3
(305 mg, 0.95 mmol) in toluene (10 mL) was added DBU
(0.43 mL, 2.85 mmol) at room temperature, and then the
mixture was heated to reflux for 12 h. After addition of
water (10 mL) at room temperature and usual workup
(AcOEt/water), the combined organic layer was washed
with 1N HCl, NaHCO3 aq. and brine. After drying over
Na2SO4 and filtration, the organic layer was concentrated
under reduced pressure. The crude mixture was subjected to
column chromatography on silica gel to afford 1 (19:1
hexane/Et2O, 160 mg, 75% yield, E/Z¼80:20).
6. Kobayashi, S.; Nagayama, S.; Busujima, T. Chem. Lett. 1997,
959.
7. Acetylation with these Lewis acids. (a) Bi(OTf)3: Orita, A.;
Tanahashi, C.; Kakuda, A.; Otera, J. Angew. Chem. Int. Ed.
2000, 39, 2877. (b) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera,
J. J. Org. Chem. 2001, 66, 8926. (c) Cu(OTf)2: Saravanan, P.;
Singh, V. K. Tetrahedron Lett. 1999, 40, 2611. (d) TMSOTf:
Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A.
J. Org. Chem. 1998, 63, 2342. (e) BF3·OEt2: Masaki, Y.; Imada,
T.; Kawai, M. Chem. Pharm. Bull. 1994, 42, 179.
8. Orita, A.; Sakamoto, K.; Hamada, Y.; Mitsutome, A.; Otera, J.
Tetrahedron 1999, 55 2899.
3.1.16. Scheme 4 (iodine-catalyzed isomerization of 1). A
solution of 1 (160 mg, 0.71 mmol), I2 (1 mg) in benzene
(10 mL) was stirred for 12 h at room temperature under
atmosphere of Ar. After addition of Na2S2O3 aq. and usual
workup (AcOEt/water), the combined organic layer was
washed with brine. After drying over Na2SO4 and filtration,
9. Aqueous quenching is not employable because the reaction of 4
with aldehydes proceeds in the presence of water.4 We have
found that addition of Me2NNH2 can quench the reaction
instantaneously to allow the quantitative analysis.