Synthesis of (1S,2R,12S)-2-hydroxy-11-dihydroneocembrene

Article abstract of DOI:10.1016/S0957-4166(99)00376-6

Aiming at the asymmetric total synthesis of trinervitane-type diterpenes, an efficient synthetic route to the title compound was explored starting from the THP ether of pivaloyloxy geraniol 11e. The coupling reaction with Grignard reagent 14 bearing the s

Full text of DOI:10.1016/S0957-4166(99)00376-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3691–3700
Synthesis of (1S,2R,12S)-2-hydroxy-11-dihydroneocembrene1
Tadahiro Kato,∗ Shin-ichi Ebihara, Tohru Furukawa, Hirota Tanahashi and
Masahiro Hoshikawa
Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka 1-3, Shinjuku ku, Tokyo 162-8601,
Japan
Received 1 July 1999; accepted 4 August 1999
Abstract
Aiming at the asymmetric total synthesis of trinervitane-type diterpenes, an efficient synthetic route to the
title compound was explored starting from the THP ether of pivaloyloxy geraniol 11e. The coupling reaction
with Grignard reagent 14 bearing the stereogenic carbon proceeded smoothly to give the THP ether of (11S)-10-
dihydrogeranylgeraniol 10. Conversion to the corresponding acid chloride through the intermediate 9, followed by
cyclization, afforded the dihydrocembrene derivative 8, from which the title compound 7 was prepared. © 1999
Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Two decades ago, Prestwich and his co-workers characterized2 defense substances from termite
soldiers as exemplified by compounds 1a and 1b, the carbon skeleton of which was named trinervitane
(Fig. 1). We have been very interested in the synthesis of the trinervitane-type diterpenes and have
explored a synthetic route3 in which the formation of cembrene skeleton 3 from acyclic acid chloride 2,
followed by subsequent ring closure to the secotrinervitane skeleton 5 through the hydroxyneocembrene
4, constitute the crucial steps to the tricyclic trinervitane skeleton 6 in racemic form, as summarized in
Scheme 1.
In order to carry out the asymmetric synthesis of 1 based on our protocol as shown in Scheme 1,
we chose the title compound 7 for the key intermediate corresponding to 4. This paper deals with the
preparation of the key intermediate 7 possessing the correct absolute configuration for the synthesis of
trinervitanes 1 based on Scheme 1.
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00376-6

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Figure 1. Typical trinervitanes from termites
Scheme 1. Synthetic route to trinervitane skeleton 6
2. Results and discussion
Scheme 2 illustrates the retrosynthetic route to compound 7, in which the acyclic (11S)-10-
dihydrogeranylgeranioic acid 9 is derived from the allyl alcohol 10 (R=H). The coupling reaction of
geraniol derivative 11 bearing a leaving group (X) with the Grignard reagent 14 should provide the
dihydrogeranylgeraniol 10. The leaving group (X) of 11 can be derived from the terminal hydroxyl
group of 12, which in turn was introduced by the oxidation of the terminal methyl group of geranyl
acetate 13.4 The commercially available (R)-(+)-citronellol 154 was selected as the chiral source of the
Grignard reagent 14.
Scheme 2. The synthetic route to the title compound 7
The Grignard reagent was easily prepared by the sequential reactions of conversion of 15 to the
tosylate, followed by replacement of the tosyl group with bromine by reaction with LiBr in acetone
and finally by addition of Mg in the presence of catalytic amounts of iodine. The hydroxy geranyl
acetate 12 (R=Ac) was prepared by the established method5 of SeO2 oxidation of geranyl acetate 13.
The terminal hydroxyl group of 12 (R=Ac) was first protected with a bulky pivaloyl group (11, X=OPiv,
R=Ac) in order to differentiate the two allylic primary hydroxyl groups. The acetate group was selectively
hydrolyzed with K2CO3 in MeOH to give the pivaloyloxy alcohol (11, X=OPiv, R=H) and then the OH

T. Kato et al. / Tetrahedron: Asymmetry 10 (1999) 3691–3700
3693
group was protected with a TBDMS group. Treatment of the pivaloyloxy TBDMS ether with KOH in
MeOH provided the hydroxy TBDMS ether (11, X=OH, R=TBDMS), from which 11 (a–d) in Table 1
were prepared by the usual reactions as described in the Experimental. The pivaloyloxy THP ether 11e
was obtained from the pivaloyloxy alcohol (11, X=OPiv, R=H) by the usual procedure in high yield.
Table 1
Li2CuCl4-Catalyzed reaction of 11 with Grignard reagent 14a
In the C–C bond formation with the Grignard reagent, the coupling reaction of the allyl chloride 11a
gave an inseparable 1:1 mixture of the desired product 10 and its isomer 16, the latter being formed
by SN20 displacement (run 1). The existence of 16 was shown from the observation of an isopropenyl
group in the NMR spectra of the reaction products. After some trials, we found that formation of the
undesired product 16 could be averted when the acetate group was selected as the leaving group. By
employment of Li2CuCl4, as reported by Bäckvall and co-workers,6 the α displacement predominated
to give 10 in moderate yield (runs 2 and 3).7 Changing the leaving group to benzoate and pivalate
effected no improvement in the yield in the presence of Me2S8 (runs 4 and 5). Since the low yield of
the coupling reaction might be attributed to the existence of the TBDMS as a protecting group (runs
2–5), THP was selected as the protecting group to provide 11e, which afforded the coupling product 10
(R=THP) exclusively in 91% yield (run 7). It was also found that the addition of Me2S is not essential
for the coupling reaction (run 8).
The conversion of 10 (R=THP) to the corresponding carboxylic acid 9 was straightforward; depro-
tection of the THP group with p-TsOH in MeOH (98% yield), followed by oxidation with Dess–Martin
periodinane9 to the aldehyde (90% yield) and then NaClO2 oxidation (98% yield), furnished the carbo-
xylic acid 9. By treatment with SOCl2 and pyridine, 9 was converted to the corresponding acid chloride,
which was allowed to react with SnCl4 in CH2Cl2 at −78°C, providing the chloroketone 8 in 56%
yield as a crystalline product, mp 104°C. It is evident that the 12S asymmetric center controlled the
stereochemistry of the ring-closure reaction. The dehydrochlorination of 8 was first attempted by use of
LiBr and Li2CO3 in DMF at 105°C, resulting in the formation of a 2:1 mixture of isopropenyl 17 (61%)
and isopropylidene 18 (33%) ketones, respectively. When the LiBr–Li2CO3 conditions were applied to
the cembrene derivative 3, the dehydrochlorination proceeded selectively to lead to the predominant for-
mation of the isopropenyl ketone in 77% yield.10 After several trials, the dehydrochlorination proceeded
effectively by the reaction of SiO2 and K2CO3 in hexane at room temperature, providing the isopropenyl
ketone 17 in 78% yield, accompanying the formation of the isomeric ketone 18 in 9% yield.

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When the isopropenyl ketone 17 was submitted to reduction with DIBAH at −78°C, no stereoselectiv-
ity was observed, giving a 1:1 mixture of cis- and trans-alcohols 7 and 19, respectively. By employment
of these reduction conditions, we expected the predominant formation of the cis-alcohol 7, since we
had found that the reduction of the cembrene derivative 3 (isopropenyl instead of chloroisopropyl)
proceeded stereoselectively under the same conditions, affording the corresponding cis-alcohol 4 as a
major product.11 After several attempts, we found that the reduction of 17 with DIBAH in the presence
of n-BuLi, the conditions of which were reported by Kim and Ahn,12 furnished a 9:1 mixture of 7 and 19
in 90% yield. The conformation of the 14-membered ring in the dihydro analog 17 seems more mobile
than that of the cembrene derivative 3 due to the lack of one double bond in the 14-membered ring. The
stereochemistry of the reduction products 7 and 19 was deduced from the coupling mode of the C2-
protons and NOESY experiments in the NMR spectra as summarized in Table 2. The large coupling
constant of 2-H with 1-H in 19 (J1,2=9.8 Hz) indicates the trans relationship while the small value
(J1,2=0.9 Hz) in 7 supports the cis configuration, respectively. In addition to the J values, the existence
of NOESY correlation between 2-H and 4-Me in both compounds suggests the partial conformations of
7 and 19, as depicted in Fig. 2.13
Table 2
1H NMR data of cis-7 and trans-19 alcohols (270 MHz, CDCl3)
Figure 2. Partial conformations of allyl alcohols 7 and 19
The cis-alcohol 7 was converted to the benzoate, the CD spectrum of which clearly showed the positive
Cotton effect with λext (∆ε)=250.9 nm (+0.49) in MeOH, indicating (2R) configuration.14 Since the cis
relationship between the 1 and 2 positions of 7 is supported by NMR evidence, (1S) configuration is
assignable to 7. The title compound 7 possesses the correct configuration in relation to C-1, C-2 and
C-12 stereochemistries; hence, the further cyclization to the secotrinervitane skeleton can be reasonably
expected, and the result will be reported in due course.

T. Kato et al. / Tetrahedron: Asymmetry 10 (1999) 3691–3700
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3. Experimental
3.1. General
1
Unless otherwise noted, H NMR and 13C NMR spectra were recorded on solutions in CDCl3 with
SiMe4 as an internal standard with JEOL FX-90Q (90 MHz), JNM-EX 270L (270 MHz) and GSX-500
(500 MHz) spectrometers. Chemical shifts are reported in δH and δC, and J-values are in Hertz. The
following abbreviations were used to explain multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. Infrared spectra were recorded on a Hitachi 270-30 spectrophotometer. The mass
spectra were measured with a Hitachi M80B spectrometer. Optical rotations were measured on a JASCO
DIP-370 polarimeter with a path length of 1 dm. Concentrations are given in g/100 ml. CD spectra were
measured with a JASCO J-725 circular dichroism polarimeter. Column chromatographic purification was
carried out using Kieselgel 60, Art 7734 (70–230 mesh). Thin-layer chromatography was carried out on
aluminum sheets coated with 60F254 silica. Plates were developed using a spray of 0.5% anisaldehyde
in 2 M sulfuric acid. Solvents and commercially available reagents were dried and purified if necessary
before use according to standard procedures. The purities of all the derivatives described in this paper
were confirmed by 13C NMR spectra. The usual work-up involved dilution of the reaction mixture with
water, extraction with ether and evaporation after washing the organic extracts with water and brine,
followed by drying over Na2SO4.
3.2. 8-Hydroxy-geranyl acetate 12 (R=Ac)
After a mixture of geranyl acetate 13 (115 g, 0.95 mol), 80% tert-butyl hydroperoxide (180 ml, 1.47
mol), SeO2 (1.3 g, 11.7 mmol) and salicylic acid (8.92 g, 64.5 mmol) in CH2Cl2 (230 ml) was stirred at
room temperature for 24 h, water was added and then extracted with ether. The ether solution was worked
up as usual and the residue was purified by SiO2 column chromatography eluted with hexane:AcOEt
40:1 to obtain the allyl alcohol 12 (R=Ac) (61 g, 49%) and recovered acetate 13 (38 g, 33%). 12 (R=Ac):
colorless oil. EI-MS m/e (relative intensity) 212 (M+, 1.6%), 194 (4.7), 152 (74), 134 (100) and 84 (70).
IR (CCl4) 3700–3200, 1740, 1232 and 1020 cm−1. δH (270 MHz, CDCl3) 1.49 (s, 3H), 1.67 (s, 3H), 2.06
(s, 3H), 4.00 (s, 2H), 4.59 (d, 2H, J=6.9 Hz), 5.33 (d, 1H, J=6.9 Hz) and 5.37 (t, 1H, J=7.1 Hz). δC (67.8
MHz, CDCl3) 13.7 (q), 16.4 (q), 21.0 (q), 25.7 (t), 39.1 (t), 61.4 (t), 68.7 (t), 118.6 (d), 125.1 (d), 135.3
(s), 141.8 (s) and 171.3 (s).
3.3. 8-Pivaloyloxy-geranyl acetate 11 (X=OPiv, R=Ac)
After a mixture of allyl alcohol 12 (R=Ac) (18.5 g, 87.2 mmol), pivaloyl chloride (21.4 ml, 174 mmol),
pyridine (212 ml, 261 mmol) and DMAP in CH2Cl2 (550 ml) was stirred at room temperature for 1 h,
MeOH was added and the mixture was poured into water. The residue obtained by usual work-up was
purified by SiO2 column chromatography eluted with hexane:AcOEt (25:1) to give the pivaloyl ester
(23.3 g, 89%). 11 (X=OPiv, R=Ac): colorless oil. EI-MS m/e (relative intensity) 296 (M+, 4.7%), 237
(11), 194 (1.9), 134 (9) and 57 (15). IR (CCl4) 1740, 1240 and 1162 cm−1. δH (270 MHz, CDCl3), 1.21
(s, 9H), 1.64 (s, 3H), 1.71 (s, 3H), 2.06 (s, 3H), 4.44 (s, 2H), 4.59 (d, 2H, J=7.3 Hz) and 5.38 (m, 2 H).
δC (67.8 MHz CDCl3) 13.8 (q), 16.4 (q), 21.0 (q), 25.8 (t), 27.2 (q, 3C), 38.8 (s), 38.9 (t), 61.3 (t), 69.7
(t), 118.7 (d), 127.8 (d), 130.8 (s), 141.6 (s), 171.0 (s) and 178.3 (s).

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3.4. 8-Pivaloyloxy-geraniol 11 (X=OPiv, R=H)
After a mixture of acetoxy pivaloyl ester 11 (X=OPiv, R=Ac) (20 g, 67.6 mmol) and K2CO3 (11.2
g, 81.1 mmol) in MeOH (600 ml) was stirred at room temperature for 1 h, water (500 ml) was added
to the mixture and extracted with ether. The residue provided by usual work-up was purified by SiO2
column chromatography eluted with hexane:AcOEt (20:1) to afford the pivaloyloxy alcohol (15 g, 87%).
11 (X=OPiv, R=H): colorless oil. EI-MS m/e (relative intensity) 254 (M+, 7%), 236 (3), 169 (2), 152
(35), 134 (61) and 57 (21). δH (270 MHz, CDCl3) 1.21 (s, 9H), 1.64 (s, 3H), 1.67 (s, 3H), 4.15 (d, 2H,
J=6.9 Hz), 4.44 (s, 2H) and 5.41 (m, 2H). δC (125.7 MHz, CDCl3) 13.8 (q), 16.1 (q), 25.8 (t), 27.2 (q,
3C), 38.9 (s), 38.9 (t), 59.1 (t), 69.9 (t), 124.2 (d), 128.2 (d), 130.4 (s), 138.3 (s) and 178.4 (s).
3.5. 8-Pivaloyloxy-geranyl THP 11e (X=OPiv, R=THP)
A mixture of pivaloyloxy alcohol 11 (R=H) (20.1 g, 79.3 mmol), 3,4-dihydro-2-H-pyrane (8.69 ml,
95.2 mmol) and p-TsOH (0.75 g, 4.00 mmol) in CH2Cl2 (600 ml) was stirred at room temperature
for 1 h and then water was poured into the mixture. After usual work-up, the residue was purified by
SiO2 column chromatography eluted with hexane:AcOEt (40:1) to give the pivaloyloxy THP ether 11e
(X=OPiv, R=THP) (24.7 g, 92%): colorless oil. EI-MS m/e (relative intensity) 338 (M+, 10%), 254 (15),
236 (11), 152 (72), 134 (100) and 57 (34). δH (270 MHz, CDCl3) 1.21 (s, 9H), 1.64 (s, 3H), 1.68 (s, 3H),
3.51 (m, 1H), 3.97 (m, 2H), 4.24 (m, 1H), 4.44 (s, 2H), 4.63 (t, 1H, J=3.5 Hz) and 5.40 (m, 2H). δC (67.8
MHz, CDCl3) 13.8 (q), 16.4 (q), 19.6 (t), 25.5 (t), 25.9 (t), 27.2 (q, 3C), 30.7 (t), 38.8 (s), 39.0 (t), 62.2
(t), 63.6 (t), 69.8 (t), 97.8 (d), 121.1 (d), 128.2 (d), 130.5 (s), 139.5 (s) and 178.2 (s).
3.6. TBDMS ethers 11 (a–d)
A mixture of pivaloyloxy alcohol 11 (X=OPiv, R=H) (10.6 g, 41.7 mmol), tert-butyldimethylsilyl
chloride (12.6 g, 83.4 mmol), imidazole (8.51 g, 125 mmol) and DMAP in DMF (320 ml) was stirred at
room temperature for 1 h under nitrogen atmosphere. After dilution with water, the mixture was worked
up as usual and the residue was purified by SiO2 column chromatography eluted with hexane:AcOEt
(15:1) to give TBDMS ether 11d (X=OPiv, R=TBDMS) (14.1 g, 92%). After the pivaloyloxy TBDMS
ether (15.3 g, 41.7 mmol) in 2N KOH–MeOH (208 ml, 0.42 mol) was stirred at room temperature for
7 h, the mixture was poured into water and treated as usual. The residue was purified by SiO2 column
chromatography eluted with hexane:AcOEt (18:1) to give TBDMS alcohol 11 (X=OH, R=TBDMS)
(8.9 g, 75%). A mixture of the TBDMS alcohol (1.0 g, 3.52 mmol) and triphenylphosphine (1.66 g,
6.34 mmol) in CCl4 (6 ml) was refluxed at 80°C for 20 h. After cooling, aq NaHCO3 solution was
added to the mixture and treated as usual to get the residue. The residue was purified by Florisil column
chromatography eluted with hexane:AcOEt (40:1) to get allyl chloride 11a (X=Cl, R=TBDMS) (852 mg,
80%). δH (90 MHz, CDCl3) 0.04 (s, 6H), 0.88 (s, 9H), 1.60 (s, 3H), 1.72 (s, 3H), 2.08 (bs, 4H), 3.99
(s, 2H), 4.16 (d, J=7.7 Hz, 2H) and 5.38 (m, 2H). TBDMS ethers 11b (X=OAc) were prepared from
TBDMS alcohol 11 (X=OH, R=TBDMS) (1.0 g) by the action of Ac2O (0.66 ml), pyridine (0.85 ml) and
DMAP in CH2Cl2 (30 ml) to obtain 11b (1.08 g, 94%) after SiO2 column chromatography. Similarly,
11c (X=OBz) was prepared from 11 (X=OH) (500 mg) by the action of BzCl (0.41 ml), pyridine (0.43
ml) and DMAP in CH2Cl2 (15 ml) in 81% yield (553 mg).

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3697
3.7. Grignard reagent 14 from (R)-citronellol 15
After a mixture of (R)-(+)-citronellol (50 g, 0.32 mmol) and tosyl chloride (73 g, 0.39 mmol) in
pyridine (300 ml) was stirred at 0°C for 15 h under nitrogen atmosphere, aq NaHCO3 solution was
added and the mixture was treated by usual work-up to obtain the tosylate (97 g, 93%) after passing
through a short SiO2 column eluted with hexane:AcOEt (80:1). Tosylate: colorless oil. EI-MS m/e
(relative intensity) 310 (M+, 7%), 173 (10), 138 (81), 123 (77), 81 (100) and 69 (60). [α]30=+3.0 (c
D
1.00, MeOH). δH (270 MHz, CDCl3) 0.82 (d, 3H, J=6.6 Hz), 1.57 (s, 3H), 1.67 (s, 3H), 2.45 (s, 3H),
4.06 (t, 2H, J=6.6 Hz), 5.02 (t, 1H, J=7.1 Hz), 7.34 (d, 2H, J=8.6 Hz) and 7.79 (d, 2H, J=8.3 Hz). δC
(67.8 MHz, CDCl3) 17.6 (q), 19.0 (q), 21.6 (q), 25.2 (t), 25.7 (q), 28.8 (d), 35.6 (t), 36.7 (t), 69.1 (t),
124.3 (d), 127.9 (d, 2C), 129.8 (d, 2C), 131.4 (s), 133.2 (s) and 144.7 (s). A mixture of the tosylate
(97 g, 0.30 mol) and LiBr (38.7 g, 0.45 mol) in anhydrous acetone (580 ml) was stirred at 56°C for 15
h, diluted with water and then extracted with hexane. The combined organic layers were successively
washed with aq Na2S2O3 solution and then brine. The organic layer was dried over Na2SO4 and the
solvent was removed. The residue was passed through a short SiO2 column eluted with hexane to obtain
the citronellyl bromide (58 g, 89%) as a colorless oil. EI-MS m/e (relative intensity) 220 (M++2, 9%),
218 (M+, 9%) and 69 (100). δH (270 MHz, CDCl3) 0.90 (d, 3H, J=6.3 Hz), 1.61 (s, 3H), 1.69 (s, 3H),
3.43 (m, 2H) and 5.09 (m, 1H). δC (67.8 MHz, CDCl3) 17.7 (q), 18.9 (q), 25.3 (t), 25.7 (q), 31.4 (d), 32.0
(t), 36.6 (t), 40.0 (t), 124.4 (d) and 131.4 (s).
3.8. 10-Dihydrogeranylgeranyl THP ether 10 (R=THP)
Into the stirred anhydrous THF solution (25 ml) of pivaloyloxy THP ether 11 (X=OPiv, R=THP) (5.0
g, 14.8 mmol) and 0.1 M THF solution of Li2CuCl4 (7.4 ml, 0.74 mmol) was added dropwise the cooled
Grignard reagent 14 in THF solution at −78°C under nitrogen atmosphere. The Grignard reagent 14 was
freshly prepared from citronellyl bromide (13.0 g, 59.1 mmol) and Mg (1.7 g, 70.9 mmol) in THF (65 ml)
by stirring at room temperature for 1 h under nitrogen atmosphere after addition of a catalytic amount of
iodine. The reaction mixture was continuously stirred overnight after removal of the cooling bath. After
careful addition of aq NH4Cl solution, the mixture was worked up as usual. The residue was purified by
SiO2 column chromatography with hexane:AcOEt (80:1) to obtain the coupled product (5.1 g, 92%). 10
(R=THP): colorless oil. HRMS calcd for C25H44O2: 376.3341. Found: 376.3340. [α]29=−2.2 (c 1.00,
D
MeOH). δH (270 MHz, CDCl3) 0.86 (d, 3H, J=6.3 Hz), 1.58 (s, 3H), 1.60 (s, 3H), 1.68 (s, 6H), 3.51 (m,
1H), 3.94 (m, 2H), 4.24 (m, 1H), 4.63 (t, 1H, J=3.5 Hz), 5.10 (m, 2H) and 5.36 (t, 1H, J=6.7 Hz). δC
(125.7 MHz, CDCl3) 15.9 (q), 16.4 (q), 17.6 (q), 19.6 (q), 19.7 (t), 25.4 (t), 25.6 (t, 2C), 25.7 (q), 26.3
(t), 30.8 (t), 32.3 (d), 36.6 (t), 37.1 (t), 39.7 (t), 40.0 (t), 62.2 (t), 63.6 (t), 97.7 (d), 120.7 (d), 123.7 (d),
125.1 (d), 130.9 (s), 135.6 (s) and 140.2 (s).
3.9. 10-Dihydrogeranylgeranioic acid 9
The MeOH (670 ml) solution of the coupled product 10 (R=THP) (22.2 g, 58.9 mmol) and p-TsOH
(1.12 g, 5.89 mmol) was kept at room temperature for 1 h and the reaction mixture was worked up as
usual. The residue was purified by SiO2 column chromatography with hexane:AcOEt (10:1) to get allyl
alcohol 10 (R=H) (16.8 g, 98%): colorless oil. HRMS calcd for C20H36O: 292.2765. Found: 292.2764.
[α]28=-3.2 (c 1.00, MeOH). δH (270 MHz, CDCl3) 0.86 (d, 3H, J=6.6 Hz), 1.59 (s, 3H), 1.60 (s, 3H),
D
1.69 (s, 6H), 4.15 (d, 2H, J=6.9 Hz), 5.11 (m, 2H) and 5.43 (m, 1H). δC (67.8 MHz, CDCl3) 15.9 (q),
16.3 (q), 17.6 (q), 19.6 (q), 25.4 (t), 25.6 (t), 25.7 (q), 26.3 (t), 32.3 (d), 36.6 (t), 37.1 (t), 39.6 (t), 40.0

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(t), 59.3 (t), 123.4 (d), 123.6 (d), 125.1 (d), 130.9 (s), 135.7 (s) and 139.6 (s). The CH2Cl2 solution
of Dess–Martin periodinane (28.7 g, 0.28 mol) was added to the vigorously stirred CH2Cl2 (500 ml)
solution of the allyl alcohol (16.5 g, 56.5 mmol) and pyridine (22.9 ml, 0.28 mol) at room temperature
and the stirring was continued for 30 min. After dilution with ether, aq Na2S2O3 and then aq NaHCO3
solutions were successively added and the reaction mixture was stirred for an additional 10 min. The
mixture was worked up as usual and the resulting residue was purified by SiO2 column chromatography
with hexane:AcOEt (20:1) to afford the α,β-unsaturated aldehyde (14.8 g, 90%) as colorless oil. δH (270
MHz, CDCl3) 0.86 (d, 3H, J=6.3 Hz), 1.60 (s, 6H), 1.68 (s, 3H), 2.17 (s, 3H), 5.11 (m, 2H), 5.88 (d,
1H, J=7.9 Hz) and 9.99 (d, 1H, J=7.9 Hz). δC (67.8 MHz, CDCl3) 16.0 (q), 17.6 (q), 19.6 (q), 25.3 (t),
25.4 (t), 25.6 (t), 25.7 (q, 2C), 32.3 (d), 36.6 (t), 37.1 (t), 39.9 (t), 40.7 (t), 122.3 (d), 125.1 (d), 127.4
(d), 131.0 (s), 137.0 (s), 163.8 (s) and 191.2 (s). To the aldehyde (4.6 g, 15.9 mmol) in a stirred mixed
solvent of CH3CN (26 ml) and DMSO (52 ml) was dropped aqueous solution (62 ml) of NaH2PO4 (5.7
g, 47.7 mmol) and NaClO2 (2.4 g, 27.0 mmol) at 0°C and the stirring was continued for 2 h at the same
temperature. After stirring the mixture for 2 days at room temperature, the reaction mixture was acidified
by adding 4N aq HCl, extracted with ether and the ether solution was worked up as usual to obtain the
carboxylic acid 9 (7.0 g, 98%) as a colorless oil. HRMS calcd for C20H34O2: 306.2559. Found: 306.2549.
IR (CCl4) 1694, 1642, 1452, 1378, 1250 and 892 cm−1. δH (270 MHz, CDCl3) 0.86 (d, 3H, J=6.6 Hz),
1.60 (s, 6H), 1.68 (s, 3H), 2.17 (s, 3H), 5.11 (m, 2H) and 5.69 (s, 1H). δC (67.8 MHz, CDCl3) 15.9 (q),
17.6 (q), 19.1 (q), 19.6 (q), 25.3 (t), 25.6 (t), 25.7 (q), 25.9 (t), 32.3 (d), 36.5 (t), 37.1 (t), 39.9 (t), 41.3
(t), 115.3 (d), 122.5 (d), 125.1 (d), 130.9 (s), 136.6 (s), 162.9 (s) and 172.3 (s).
3.10. Preparation of chloroketone 8
Into a stirred benzene solution (60 ml) of the carboxylic acid 9 (2.0 g, 6.53 mmol) and pyridine (0.6
ml, 7.84 mmol) was added dropwise SOCl2 (1.4 ml, 19.6 mmol) at 0°C and the stirring was continued
for 1 h. After complete removal of the white precipitate by filtration through a glass filter, the volatile
materials were removed in vacuo below 30°C to obtain crude acid chloride. The CH2Cl2 solution of the
crude acid chloride was added dropwise to the stirred CH2Cl2 (212 ml) solution of SnCl4 (0.23 ml, 19.6
mmol) at −78°C over 2 h and the stirring was continued for a further 20 min at the same temperature.
After addition of pyridine (0.16 ml, 1.96 mmol), the CH2Cl2 solution was successively washed with
3N H2SO4 twice and then aq NaHCO3 solution, and brine. The residue, obtained by evaporation of the
CH2Cl2 solution after drying with Na2SO4, was purified by SiO2 column chromatography eluted with
hexane:AcOEt (50:1) to obtain chloroketone 8 (1.17 g, 56%) as white crystals. Mp 102–104°C (n-Hex.).
HRMS calcd for C20H33ClO: 324.2220. Found: 324.2222. Anal. calcd for C20H33ClO: C, 73.93; H,
10.24. Found: C, 74.00; H, 10.40. [α]24=+142.1 (c 1.00, MeOH). IR (CCl4) 2928, 2856, 1684, 1618,
D
1456, 1378 and 1116 cm−1. δH (270 MHz, CDCl3) 0.78 (d, 3H, J=6.4 Hz), 1.57 (s, 3H), 1.64 (s, 6H),
2.00 (s, 3H), 3.11 (dd, 1H, J=3.6 and 11.5 Hz), 4.96 (m, 1H) and 6.21 (s, 1H). δC (67.8 MHz, CDCl3)
15.0 (q), 16.2 (q), 17.6 (q), 21.5 (t), 24.0 (t), 25,3 (t), 26.8 (d), 30.2 (q), 30.3 (q), 34.5 (t, 2C), 36.8 (t),
40.4 (t), 60.2 (d), 72.1 (s), 124.5 (d), 128.8 (d), 134.6 (s), 156.1 (s) and 202.7 (s).
3.11. Dehydrochlorination of chloroketone 8
After a mixture of the chloroketone 8 (2.54 g, 7.9 mmol), Merck silica gel (12.7 g) and K2CO3 (10.9
g, 79 mmol) in hexane (1270 ml) was stirred for 2 days at room temperature, the insoluble solids were
removed through a SiO2 pad and the pad was washed with benzene. The combined organic layers were
removed and the residue was separated by SiO2 column chromatography eluted with CHCl3 to obtain

T. Kato et al. / Tetrahedron: Asymmetry 10 (1999) 3691–3700
3699
isopropenyl ketone (1.73 g, 78%) and isopropylidene ketone (200 mg, 9%), respectively. Isopropenyl
ketone 17: colorless oil. HRMS calcd for C20H32O: 288.2453. Found: 288.2456. [α]29=+86.1 (c 1.00,
D
MeOH). δH (270 MHz, CDCl3) 0.83 (d, 3H, J=6.6 Hz), 1.55 (s, 3H), 1.74 (s, 3H), 2.20 (s, 3H), 3.16 (dd,
1H, J=5.0 and 10.2 Hz), 4.89 (s, 2H), 4.95 (m, 1H) and 6.09 (s, 1H). δC (67.8 MHz, CDCl3) 15.5 (q),
18.0 (q), 18.3 (q), 21.5 (q), 22.9 (t), 24.5 (t), 26.1 (t), 28.8 (d), 33.9 (t, 2C), 38.1 (t), 40.4 (t), 58.6 (d),
112.3 (t), 124.4 (d), 124.7 (d), 135.2 (s), 143.8 (s), 157.0 (s) and 202.2 (s). Isopropylidene ketone 18:
colorless oil. HRMS calcd for C20H32O: 288.2453. Found: 288.2448. [α]26=+60.6 (c 1.00, MeOH). δH
D
(270 MHz, CDCl3) 0.82 (d, 3H, J=6.3 Hz), 1.56 (s, 3H), 1.75 (s, 3H), 1.80 (s, 3H), 2.05 (s, 3H), 4.96
(t, 1H, J=6.2 Hz) and 6.08 (s, 1H). δC (67.8 MHz, CDCl3) 15.9 (q), 18.0 (q), 19.2 (q), 20.8 (q), 22.3
(q), 23.0 (t), 24.5 (t), 27.2 (t), 30.9 (d), 34.1 (t), 36.0 (t), 38.2 (t), 40.8 (t), 124.1 (d), 126.4 (d), 134.3 (s),
135.4 (s), 139.0 (s), 155.8 (s) and 199.7 (s).
3.12. Reduction of isopropenyl ketone 17
The reducing reagent was prepared by addition of 1.0 M solution of n-BuLi in hexane (0.65 ml, 1.04
mmol) to 1.0 M solution of DIBAH in hexane (1.1 ml, 1.04 mmol) and the mixture was diluted with
anhydrous toluene (15 ml). This solution of reducing reagent was added dropwise to the isopropenyl
ketone 17 (100 mg, 0.35 mmol) in a stirred 1:1 mixed solvent (3 ml) of hexane and toluene at −78°C
under nitrogen atmosphere. After further stirring for 1 h at the same temperature, 2N HCl was added to
make the mixture acidic and then the mixture was worked up as usual. The residue was purified by SiO2
column chromatography eluted with hexane:AcOEt (25:1) to isolate cis-alcohol 7 (775 mg, 78%) and
trans isomer 19 (11.7 mg, 12%) as colorless oil. 7: colorless oil. HRMS calcd for C20H34O: 290.2610.
Found: 290.2611. [α]24=−54.0 (c 1.00, MeOH). δH (270 MHz,CDCl3) 0.81 (d, 3H, J=6.6 Hz), 1.58 (s,
D
3H), 1.63 (s, 3H), 1.83 (s, 3H), 4.44 (dd, 1H, J=0.9 and 7.9 Hz), 4.82 (s, 1H), 4.95 (m, 1H), 4.99 (s, 1H)
and 5.35 (d, 1H, J=7.9 Hz). δC (67.8 MHz, CDCl3) 15.6 (q), 16.3 (q), 19.6 (t), 20.5 (q), 22.8 (t), 23.0
(t), 25.1 (q), 29.4 (d), 30.9 (t), 32.9 (t), 38.6 (t), 39.3 (t), 49.7 (d), 70.0 (d), 111.4 (t), 124.4 (d), 127.4
(d), 134.2 (s), 135.4 (s) and 145.9 (s). 19: colorless oil. EIMS m/e (relative intensity) 290 (M+, 100%),
272 (33), 239 (47), 150 (60), 97 (62), 69 (77) and 55 (58). δH (270 MHz, CDCl3) 0.83 (d, 3H, J=6.9
Hz), 1.59 (s, 3H), 1.65 (s, 3H), 1.70 (s, 3H), 4.10 (dd, 1H, J=9.2 and 9.9 Hz), 4.89 (s, 1H), 4.90 (bs, 1H),
5.02 (s, 1H) and 5.07 (m, 1H). δC (67.8 MHz, CDCl3) 16.5 (q), 16.9 (q), 17.5 (q), 20.5 (q), 21.1 (t), 23.0
(t), 24.7 (t), 28.8 (d), 30.5(t), 30.9 (t), 38.1 (t), 39.5 (t), 53.4 (d), 68.6 (d), 116.3 (t), 124.4 (d), 127.6 (d),
134.4 (s), 138.3 (s) and 144.7 (s).
3.13. Benzoate of 7
A mixture of allyl alcohol 7 (204 mg, 0.74 mmol), pyridine (0.17 ml, 1.40 mmol), benzoyl chloride
(0.16 ml, 2.10 mmol) and DMAP (trace) in CH2Cl2 (10 ml) was stirred at room temperature for 18 h
under nitrogen atmosphere. The mixture was diluted with MeOH and worked up as usual to obtain the
residue. The residue was purified by SiO2 column chromatography eluted with hexane:AcOEt (20:1)
to afford the benzoate of 7 as colorless oil. HRMS calcd for C27H38O2: 394.2872. Found: 394.2885.
[α]27=−65.6 (c 1.00, MeOH). δH (270 MHz, CDCl3) 0.84 (d, 3H, J=6.3 Hz), 1.59 (s, 3H), 1.76 (s, 3H),
D
1.79 (s, 3H), 4.78 (s, 1H), 4.84 (s, 1H), 4.97 (t, 1H, J=6.5 Hz), 5.37 (d, 1H, J=8.6 Hz), 5.81 (d, 1H, J=8.6
Hz), 7.49 (m, 3H) and 8.03 (m, 2H). δC (67.8 MHz, CDCl3) 15.9 (q), 16.2 (q), 20.5 (q), 20.9 (t), 21.6
(q), 22.5 (t), 25.1 (t), 29.0 (d), 30.8 (t), 33.1 (t), 38.4 (t), 39.4 (t), 48.8 (d), 74.9 (d), 112.6 (t), 124.1 (d),
124.4 (d), 128.2 (d, 2C), 129.5 (d, 2C), 130.9 (s), 132.6 (d), 134.3 (s), 137.4 (s), 145.0 (s) and 165.8 (s).

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T. Kato et al. / Tetrahedron: Asymmetry 10 (1999) 3691–3700
References
1. This constitutes part 59 of the series of cyclization of polyenes. Part 58, see: Kato, T.; Nagae, K.; Hoshikawa, M.
Tetrahedron Lett. 1999, 40, 1941–1944.
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3. Kato, T.; Tanaka, M.; Hoshikawa, M.; Yagi, M. Tetrahedron Lett. 1998, 39, 7553–7556 and references cited therein.
4. Geranyl acetate 13 and R-(+)-citronellol 15 were, respectively, kindly supplied by Kurarey Co. Ltd and Takasago
Perfumery Co. Ltd, to whom we are grateful.
5. For an example, Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526–5528.
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1
7. When Li2CuCl4 was employed (runs 2–8 in Table 1), the isomeric product 16 was not detected in the H and 13C NMR
spectra of the crude reaction products.
8. See Ref. 6 and Klaveren, M. V.; Persson, E. S. M.; Grove, D. M.; Bäckvall, J. E.; Koten, G. V. Tetrahedron Lett. 1994, 32,
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NMR spectrum [Kato, T.; Kabuto, C.; Kim, K. H.; Takayanagi, H.; Uyehara, T.; Kitahara, Y. Chem. Lett. 1977, 827–830].
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