Synthesis of the tricyclic dihydrofuran moiety of azadirachtin: Efficient transformation of the Claisen rearrangement intermediate into a functionalized tricyclic dihydrofuran core

Article abstract of DOI:10.1016/j.tet.2003.10.062

Azadirachtin is a C-seco limonoid, derived from the neem tree. Previously, we reported the synthesis of the right and left segments of azadirachtin, in addition to the coupling reaction of the modeled ester utilizing Claisen rearrangement. Herein we report the transformation of the modeled rearrangement product into a tricyclic dihydrofuran, which would be expected to have bioactivity against insects.

Full text of DOI:10.1016/j.tet.2003.10.062

Tetrahedron 59 (2003) 10287–10294
Synthesis of the tricyclic dihydrofuran moiety of azadirachtin:
efficient transformation of the Claisen rearrangement
intermediate into a functionalized tricyclic dihydrofuran core
b
a
b
b
Jun Ishihara,a Yohei Ikuma, Susumi Hatakeyama, Takanori Suzuki and Akio Murai
,
*
aGraduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
bDivision of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 28 August 2003; accepted 14 October 2003
Abstract—Azadirachtin is a C-seco limonoid, derived from the neem tree. Previously, we reported the synthesis of the right and left
segments of azadirachtin, in addition to the coupling reaction of the modeled ester utilizing Claisen rearrangement. Herein we report the
transformation of the modeled rearrangement product into a tricyclic dihydrofuran, which would be expected to have bioactivity against
insects.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
biological activity.10 In the course of our synthetic studies
on 1, we found that the coupling between the left and right
moieties could be cleanly achieved by means of Claisen
rearrangement of the corresponding ester.11 We were
therefore interested in the transformation of the modeled
rearrangement product into the functionalized tricyclic
The higher plants have acquired chemical defence
mechanisms against the attack of pathogens and insects.
Tropical trees, especially, are known to have the highly
elaborated chemical defence mechanisms, which have
gradually been elucidated by recent progress of bio-
chemistry.1 Azadirachtin (1) is a C-seco limonoid, isolated
in 1968 from the seeds of Indian neem tree, Azadirachta
indica A. Juss (Fig. 1).2 This natural product has shown
strong bioactivity against insects, including repellent and
antifeedant activities. Despite its high insect antifeedant
activity, azadirachtin shows no apparent phytotoxicity and
is remarkably non-toxic to higher animals. The structure
and relative stereochemistry were clarified in 1985 by Kraus
and Ley,3 and the absolute configuration was determined in
1992.4 Although several groups have reported synthetic
studies on azadirachtin,5 total synthesis has not yet been
achieved. The biological studies6 and structure–activity
relationships7 of 1 have been investigated utilizing various
derivatives. Ley and co-workers demonstrated that the
stereochemistry at C-7 and the bridging oxygen substituent
at C-6 are responsible for insect antifeedant activity using
various derivatives and degradative compounds.8 Interest-
ingly, they also showed that the tricyclic dihydrofuran
moiety, the right wing moiety, had still rather potent
antifeedant activity.9 Recently, conformational calculations
have been carried out by Baldoni and co-workers in order to
determine the structural characteristics responsible for the
Keywords: azadirachtin; Claisen rearrangement; deoxygenation.
*
Corresponding author. Tel./fax: þ81-95-819-2427;
e-mail: jishi@net.nagasaki-u.ac.jp
Figure 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.062

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J. Ishihara et al. / Tetrahedron 59 (2003) 10287–10294
dihydrofuran core of 1, which would be expected to have
bioactivity against insects.
liquid ammonia, which is known to be amenable to the
deoxygenation in complex molecules.16 Hence, introduction
of a PON group into 4a readily afforded compound 5a. We
then subjected 5a to Benkeser and Birch reductions,
respectively. However, both reductions resulted in pre-
dominant hydrogenation of the exo-olefin rather than the
deoxygenation. The desired deoxygenation was eventually
achieved when 5a was treated with lithium naphthalenide in
THF,17 resulting in 6a in 44% yield. Meanwhile, exposure
of 4 to MeP(OPh)3I and NaBH3CN in HMPA at 1008C18
afforded 6 in 29% yield at single step. This result showed
that hydride reduction of the iodide could proceed smoothly
in this substrate. Consequently, we were pleased to find that
iodination of 4 to 5 and subsequent NaBH4 reduction in
DMSO at 1008C generated 6 in 81% yield.19
2. Deoxygenation of hydroxyl group at neopentyl
position
The Ireland–Claisen rearrangement of the modeled ester 2
readily proceeded to afford the carboxylic acid 3 in good
yield as we previously reported (Scheme 1).12 Methyl
esterification of 3 and subsequent DIBAL-H reduction gave
the alcohol 4. Since lactone functionality must be installed
into the genuine substrate, sequential conversion of 3 to 4
(ClCO2Et, Et3N, THF, 08C and then NaBH4, MeOH,
2608C)13 would therefore be practically feasible. Com-
pound 4a could be also prepared by similar method to 4.
3. Transformation of exo-olefin into endo-olefin
Next we envisaged isomerization of the exo-olefin in 6 to
the endo-olefin 7 (Scheme 2). Although application of allyl
isomerization using transition metals is well documented,
compound 6 resisted those reactions.20 All attempts of
isomerization of 6 in the presence of transition metals
[RhCl(PPh3)3/iPr2NEt, PdCl2(PhCN)2, and RhCl3·3H2O]
were unsuccessful, most of which resulted in quantitative
recovery of 6. From these results it was postulated that the
bulky DEIPS group inhibited the transition metal from
approaching the allylic hydrogen to be reacted. These
disappointing results led us to examine the allyl isomeriza-
tion after removal of the DEIPS group. Crabtree catalyst
{Ir(cod)[PCH3(C6H5)2]2}PF6,21 a cationic catalyst, was
considered an alternative because it would be accessible
from the a-side in 8 via its coordination to the hydroxyl
group. Unfortunately, treatment of 8 with Crabtree catalyst
furnished the saturated compound 9 in 40% yield, along
with recovery of 8 in 60% yield. According to the
stereochemistry at hydrogenated position in 9, the catalyst
apparently was able to coordinate to the hydroxyl group at
a-side however was unable to cause the isomerization.
Scheme 1. Synthesis of methyl compound 6. Reagents and conditions:
(i) KHMDS, TMSCI/Et3N, PhMe, 278!708C, 12 h (87%); (ii) CH2N2,
Et2O, 08C, 30 min; (iii) DIBAL-H, CH2Cl2, 2788C, 1 h (,100% for 2
steps); (iv) Et3N, ClCO2Et, THF, 08C, 40 min; (v) NaBH4, MeOH,
278!2608C, 19 h (4: 60% for 2 steps, recovered 3: 40%); (vi) LiHMDS,
(Me2N)2P(O)Cl, THF, TMEDA, 238C, 13 h (87%); (vii) Li naphthalenide,
THF, 0!238C (44%); (viii) imidazole, PPh3, I2, PhH, 238C, 4 h (93%);
(ix) NaBH4, DMSO, 1008C, 2 h (87%).
Deoxygenation of the hydroxyl group in 4 and 4a seemed to
be difficult due to its hindered neopentyl position. We
initially attempted a Barton–McCombie type process via
xanthates under various conditions.14 Disappointingly,
treatment of the corresponding methyl dithiocarbonate,
derived from 4a, with AIBN/Ph2SiH2 or (PhCOO)2/
Scheme 2. Attempted reactions for allyl isomerization. Reagents and
conditions: (i) Bu4NF, THF, 08C, 40 min (100%); (ii) {lr(cod)[PCH3(C6-
H5)2]2}PF6, THF, 408C (40%, 8: 60%).
15
Ph2SiH2 furnished none of the desired products. In
addition, Ph2SiH2-mediated radical reduction of the
imidazoyl thiocarbonate also gave a complex mixture,
presumably because the proximal exo-olefin reacted with
the resulting primary radical. Alternatively, we tried
alkaline metal reduction of phosphodiamidate (PON) in
Recently, Ley demonstrated that the primary radical 10a
was predominantly captured by hydrogen radical over the
tertiary radical 10b owing to the steric hindrance (Fig. 2).5k
This result prompted us to attempt the isomerization by
radical reaction. Breslow and Baldwin have developed the

J. Ishihara et al. / Tetrahedron 59 (2003) 10287–10294
10289
Scheme 3. Synthesis of endo-olefin compound. Reagents and conditions:
(i) mCPBA, NaHCO3, CH2Cl2, 238C, 18 h (90%); (ii) BF3·Et2O, CH2Cl2,
2558C, 7 h (78%) (a:b¼3;1); (iii) KHMDS, HMPA, THF, 2558C, 20 min
then NBS, 2 h (71%); (iv) LiBr, Li2CO3, DMF, 1258C, 13 h (97%);
(v) NaBH4, CeCl3·7H2O, MeOH, 08C, 1 h (78%); (vi) VO(acac)2, TBHP,
CH2Cl2, 238C, 3.5 h (100%); (vii) 12, PPh3, Imidazole, THF 238C, 8 h
(82%); (viii) NaBH4, MeCN, reflux, 18 h (88%); (ix) PhSeH, Amberlyst-
15, MS-4A, CH3CN, 258C, 30 min; (x) H2O2, Py, CH2Cl2, 08C, 30 min
(recovered 22: 22%); (xi) Bu4NF, THF, 08C, 10 min (19% for 3 steps).
Figure 2.
ingenious remote oxidations, which were controlled by
remote functionalities excited by photo-irradiation.22 It was
therefore hoped that the a-bromobenzoate group in 11 or the
a-bromobenzyl group in 12 could serve as a remote
functionality to induce the allyl radical preferentially.
Unfortunately, these methodologies concluded unsatis-
factorily to give compounds 13 and 14, respectively.
with VO(acac)2, TBHP afforded the epoxide 20 exclusively
in a good yield. The stereochemistry of the epoxide could be
confirmed by NOESY spectra of 20. It was postulated that
the reagent was accessible to the less hindered b-side of the
tricyclic molecule, thus generating the desired selectivity.
The second deoxygenation was performed under the similar
conditions to those described for 5. Treatment of 20 with I2,
Ph3P and imidazole furnished iodide 21 which after
subsequent NaBH4 reduction in CH3CN successfully
afforded 22 in 88% yield. It should be noted that the
epoxide was intact under the reduction conditions. The
transformation of 22 into dihydrofuran was accomplished
by Ley’s procedure.27 Selenylation of 22 and oxidation
formed the dihydrofuran, which was followed by removal of
DEIPS with Bu4NF to give the desired tricyclic dihydro-
furan 23 in 19% yield for 3 steps, accompanied by recovery
of 22 in 22% yield.
All other attempts of allylic isomerization (PhSO2NSO,23
NBS/hn NIS/iPr2NEt or SeO2) for 6 were unsuccessful.
In this event, we found an alternative route for the
transformation of the exo-olefin to the endo-olefin
(Scheme 3). This route commenced with the epoxidation
of 6 with mCPBA affording 15 exclusively in 90% yield,24
followed by treatment with BF3·OEt2 at 2558C to give a
mixture of aldehydes 16 (3.1:1) in 78% yield. When we
performed the bromination at a-position of the aldehyde
with KHMDS, HMPA and NBS in THF at 2608C, the
bromide 17 was obtained in 71% yield. Fortunately, the
elimination of the bromide with LiBr and Li2CO3 in DMF
proceeded smoothly to generate the a,b-unsaturated
aldehyde 18 in 97% yield.25
4. Conclusion
The Claisen rearrangement product 3 was converted into the
deoxygenated compound 6 via sequential iodination and
NaBH4 reduction in good yield. Although direct isomeriza-
tion of the exo-olefin of 6 to the endo-olefin was fruitless, an
alternative route involving transformation of 6 into the a,b-
aldehyde 18 could be established. The aldehyde 18 was
Having established a procedure for the transformation of
exo-olefin into endo-olefin, we turned our attention towards
the final part of the synthesis. Luche reduction26 of 19 with
NaBH4, CeCl3·7H2O in MeOH, followed by epoxidation

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J. Ishihara et al. / Tetrahedron 59 (2003) 10287–10294
converted into the desired tricyclic dihydrofuran 23 via
selective epoxidation and deoxygenation. Consequently, we
have developed an efficient method for the transformation of
the rearranged product into the tricyclic dihydrofuran. The
biological activity of 23 thus prepared is under
investigation.
(c 2.27, CHCl3); nmax (cm21) (neat) 2935, 2863, 1737, 1452,
1365, 1315, 1274, 1247, 1195, 1166, 1132, 1101, 1074,
1029, 962, 937, 881, 844, 761, 727, 665; dH (300 MHz,
CDCl3) 5.95 (1H, brd, J¼2.4 Hz), 5.31 (1H, dd, J¼3.9,
5.9 Hz), 4.92 (1H, s), 4.86 (1H, d, J¼1.7 Hz), 4.80 (1H, d,
J¼1.9 Hz), 4.63 (1H, br s), 3.44 (3H, s), 2.90 (1H, brd,
J¼5.0 Hz), 2.39–2.29 (1H, m), 2.35 (1H, dd, J¼5.9,
15.2 Hz), 2.29 (1H, dd, J¼3.9, 15.2 Hz), 2.12 (1H, brd,
J¼11.6 Hz), 1.92–1.85 (1H, m), 2.05–1.24 (10H, m),
1.00–0.89 (13H, m), 0.70–0.61 (4H, m); EI-MS-LR m/z
(Int.%), 466 (Mþ, 7), 437 (Mþ2Et, 3), 423 (Mþ2iPr, 12),
389 (64), 338 (68), 293 (49); EI-MS-HR, calcd for
C22H35O6Si (Mþ2iPr): 423.2203, found 423.2200.
5. Experimental
5.1. General information
Solvents and reagents were dried and distilled before use.
Tetrahydrofuran (THF) and toluene (PhMe) were distilled
from sodium benzophenone ketyl. CH2Cl2, pyridine, and
Et3N were distilled from CaH2. DMSO was distilled under
reduced pressure from CaH2. EtOH and MeOH were
distilled from their magnesium alkoxides. Normal reagent-
grade solvents were used for flash chromatography and
extraction. All reactions were monitored by TLC with
precoated Silica gel plates (Merck, silica gel 60 F254
1.05715.25). Visualization was achieved via UV light, a
5.6% ethanolic p-anisaldehyde solution containing 5.6% of
concentrated H2SO4-heat, and 10% ethanolic phospho-
molybdic acid solution-heat. For flash chromatography was
utilized Silica gel (YMG, silica gel SIL-60-400/230W or
Kanto Kagaku, silica gel 60N, spherical neutral, 37563-84).
Melting points were measured in open capillary tubes and
are uncorrected. IR spectra were obtained on a Hitachi
model 270-30 and JASCO model FT/IR-230 infrared
spectrophotometer in neat state. The 1H NMR spectra
were recorded on a JEOL model AL-300 (300 MHz), a-400
(400 MHz) and a VARIAN model Gemini 300 (300 MHz)
spectrometers in CDCl3. The 13C NMR spectra were
measured on a VARIAN Gemini 300 (75 MHz), Unity
plus 500 (125 MHz) and spectrometer in CDCl3. Chemical
shifts (d) were reported with tetramethylsilane
(d¼0.00 ppm) or CHCl3 (d¼7.26 ppm) as internal stan-
dards. Splitting patterns were designated as ‘s, d, t, q, m, and
br’; indicating ‘singlet, doublet, triplet, quartet, multiplet,
and broad,’ respectively. Optical rotations were recorded on
JASCO model DIP-370 and P-1020 digital polarimeters
using CHCl3 as a solvent. High-resolution mass spectra
were obtained on a JEOL model JMS-HX-110 and JMS-
DX303 mass spectrometer under EI condition. All reactions
were carried out under anhydrous conditions and argon
atmosphere, unless otherwise noted.
5.1.2. (1R,2S,4S,6R,8S)-1-{2-(Diethylisopropylsilyloxy)-
4-methoxy-10-methylene-5,7-dioxatricyclo[6.2.1.02,6]-
undec-9-yl}-cyclohexanecarboxylic acid (3). To a solution
of 2 (367 mg, 0.79 mmol) in PhMe (7 mL) was added a
solution of KHMDS (0.5 M in PhMe, 6.3 mL, 3.15 mmol) at
2788C and the mixture was stirred at 2788C for 1 h. A
mixture of TMSCl (2.5 mL, 19.7 mmol) and Et3N (2.5 mL,
17.9 mmol) in PhMe (2.5 mL) was centrifuged at 2000 rpm
for 5 min and the supernatant (3.0 mL) was added to the
reaction mixture at 2788C. The stirring mixture was
warmed gradually to 708C over 3 h and stirring was
continued at the same temperature for an additional 11 h.
The solution was cooled to the ambient temperature, and the
reaction was diluted with sat. NH4Cl (10 mL) at 08C. The
mixture was adjusted to pH 3 by 2 M HCl, and the aqueous
layer was extracted with Et2O (2£15 mL). Drying over
MgSO4, concentration, and flash chromatography (silica gel
13 g, hexane:EtOAc, 6:1) afforded 3 (264 mg, 0.57 mmol,
72%) as a white amorphous; [a]2D6¼þ22.5 (c 1.01, CHCl3);
nmax (cm21) (neat) 3095, 2937, 2875, 1727, 1699, 1461,
1454, 1413, 1380, 1322, 1284, 1270, 1240, 1191, 1170,
1132, 1081, 1037, 1012, 966, 937, 898, 881, 761, 725, 665;
dH (300 MHz, CDCl3) 5.30 (1H, dd, J¼4.0, 6.2 Hz), 5.26
(1H, br s), 5.18 (1H, br s), 4.91 (1H, s), 4.48 (1H, br s), 3.43
(3H, s), 2.87 (1H, br s), 2.77 (1H, brd, J¼5.0 Hz), 2.33 (1H,
dd, J¼4.0, 15.0 Hz), 2.25 (1H, dd, J¼6.2, 15.0 Hz), 2.14
(1H, brd, J¼10.6 Hz), 2.05–2.02 (2H, m), 1.62 (4H, m),
1.48–1.15 (5H, m), 1.00–0.89 (13H, m), 0.68–0.60 (4H,
m); EI-MS-LR m/z (Int.%), 437 (Mþ2Et, 9), 423 (Mþ2iPr,
100), 391 (36), 293 (76); EI-MS-HR, calcd for C22H35O6Si
(Mþ2iPr): 423.2203, found: 423.2205.
5.1.3. {1-[(1R,2S,4S,6R,8S)-2-Diethylisopropylsilyloxy-4-
methoxy-10-methylene-5,7-dioxatricyclo[6.2.1.02,6]-
undec-9-yl]-cyclohexyl}-methanol (4). To a solution of 3
(13.8 mg, 29.6 mmol) in THF (0.5 mL) were added Et3N
(8.3 mL, 59.6 mmol) and ethyl chloroformate (5.7 mL,
59.6 mmol) at 08C, and the mixture was stirred at 08C for
40 min. The mixture was diluted with MeOH (0.2 mL), and
NaBH4 (7.8 mg, 206 mmol) was then added to the reaction
mixture at 2788C. The solution was stirred at 2788C for
20 h, at 2708C for 46.5 h, and then at 2608C for 19 h. To
the mixture was added 0.5 M HCl (2 mL), and the aqueous
layer was extracted with Et2O (3£3 mL). The combined
organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was subjected to flash
chromatography (silica gel, 3 g, hexane:EtOAc, 5:1) to
afford 4 (8.1 mg, 17.8 mmol, 60%) as a pale yellow oil,
along with carboxylic acid 3 (5.5 mg, 11.8 mmol, 40%). 4;
5.1.1. Cyclohexanecarboxylic acid (1R,2S,4S,6R,8S)-2-
(diethylisopropylsilyloxy)-4-methoxy-5,7-dioxatri-
cyclo[6.2.1.02,6]undec-9-en-10-ylmethyl ester (2). To a
mixture of EDCI·HCl (1.66 g, 8.66 mmol) and DMAP
(1.02 g, 7.31 mmol) in CH2Cl2 (10 mL) was added
cyclohexanecarboxylic acid (937 mg, 7.31 mmol) at 08C.
After stirring for 15 min, a solution of allyl alcohol (1.19 g,
3.34 mmol) in CH2Cl2 (10 mL) was added dropwise and
stirring was continued at 238C for 2 h. The mixture was
diluted with sat. NH4Cl (30 mL), and the aqueous layer was
extracted with Et2O (3£30 mL). The combined organic
extracts were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was subjected to flash chromato-
graphy (silica gel 50 g, hexane:EtOAc, 10:1 to 6:1) to afford
2 (1.43 g, 3.06 mmol, 92%) as a colorless oil; [a]2D6¼þ70.2

J. Ishihara et al. / Tetrahedron 59 (2003) 10287–10294
10291
[a]2D6¼þ37.5 (c 0.91, CHCl3); dH (300 MHz, CDCl3) 5.30
(1H, dd, J¼4.0, 6.2 Hz), 5.29 (1H, br s), 5.25 (1H, br s), 4.91
(1H, s), 4.50 (1H, br s), 3.56–3.48 (2H, m), 3.44 (3H, s),
2.79 (2H, m), 2.36 (1H, dd, J¼4.0, 15.0 Hz), 2.25 (1H, dd,
J¼6.2, 15.0 Hz), 2.05 (1H, brd, J¼12.8 Hz), 1.78 (1H, ddd,
J¼2.8, 5.9, 12.8 Hz), 1.70–1.45 (10H, m), 1.01–0.88 (13H,
m), 0.69–0.60 (4H, m); nmax (cm21) (neat) 3477, 2931,
2865, 1461, 1415, 1380, 1348, 1322, 1299, 1270, 1238,
1189, 1133, 1072, 1037, 966, 941, 900, 881, 858, 757, 725,
665, 559 cm21; EI-MS-LR m/z (Int.%), 437 (65), 409
(Mþ2iPr, 34), 377 (30), 293 (100); EI-MS-HR, calcd for
C22H37O5Si (Mþ2iPr): 409.2410, found: 409.2400.
m); EI-MS-LR m/z (Int.%) 436 (Mþ, 0.7), 393 (Mþ2iPr,
88), 361 (38), 293 (100), 265 (47); EI-MS-HR, calcd for
C25H44O4Si (Mþ): 436.3009, found: 436.3008.
5.1.6. 1-{(1R,2S,4S,6R,8S,10R)-2-Diethylisopropylsilyl-
oxy-4-methoxy-10-methylene-5,7-dioxa-10-oxirane-
spiro-tricyclo[6.2.1.02,6]undec-9-yl}-1-methylcyclo-
hexane (15). To a stirred mixture of 6 (8.9 mg, 20.4 mmol)
in CH2Cl2 (1 mL) were added mCPBA (10.5 mg,
0.0608 mmol) and NaHCO3 (12.0 mg, 0.143 mmol) at
08C, and the mixture was stirred at 238C for 18 h. The
reaction mixture was diluted with sat. Na2S2O3 (2 mL) and
sat. NaHCO3 (2 mL) and the aqueous layer was extracted
with ether (3£5 mL). Drying over MgSO4, concentration,
and flash chromatography (silica gel, 1.5 g, hexane:EtOAc,
8:1) afforded 15 (8.3 mg, 18.4 mmol, 90%) as a colorless oil;
[a]2D3¼þ103 (c 0.06, CHCl3); nmax (cm21) (neat) 2929,
1776, 1731, 1457, 1376, 1317, 1191, 1128, 1079, 1039, 968,
935, 852, 727; dH (300 MHz, CDCl3) 5.28 (1H, dd, J¼4.1,
5.8 Hz), 5.14 (1H, s), 4.46 (1H, br s), 3.43 (3H, s), 3.08
(1H, d, J¼4.7 Hz), 2.88 (1H, d, J¼4.7 Hz), 2.36 (1H, br s),
2.34 (1H, dd, J¼4.1, 14.7 Hz), 2.25 (1H, dd, J¼5.8,
14.7 Hz), 2.04 (1H, brd, J¼12.6 Hz), 1.94 (1H, brd,
J¼5.2 Hz), 1.89 (1H, m), 1.57–1.21 (10H, m), 1.07–0.88
(16H, m), 0.70–0.64 (4H, m); EI-MS-LR m/z (Int. %) 421
(7), 409 (Mþ 2iPr, 17), 377 (43), 355 (66), 281 (42);
EI-MS-HR, calcd for C22H37O5Si (Mþ2iPr): 409.2410,
found: 409.2406.
5.1.4. 1-{(1R,2S,4S,6R,8S)-2-Diethylisopropylsilyloxy-4-
methoxy-10-methylene-5,7-dioxatricyclo[6.2.1.02,6]-
undec-9-yl}-1-iodomethyl-cyclohexane (5). To a solution
of alcohol 4 (989 mg, 2.06 mmol) in PhH (10 mL) were
added imidazole (750 mg, 11.0 mmol), PPh3 (2.74 g,
10.4 mmol), and a solution of I2 (2.60 g, 10.2 mmol) in
PhH (8 mL). After stirring at 238C for 11 h, the reaction was
diluted with ether and sat. NaHCO3 (5 mL). To the mixture
was added a solution of I2 in PhH until the solution persisted
in yellow–brown color. After addition of sat. Na2S2O3
(20 mL), the mixture was extracted with ether (3£25 mL),
dried over MgSO4, and concentrated. The residue was
subjected to flash chromatography (silica gel, 30 g,
hexane:EtOAc, 8:1) to furnish iodide
5
(1.08 g,
1.92 mmol, 93%) as pale yellow amorphous;
a
[a]2D6¼þ64.4 (c 0.67, CHCl3); nmax (cm21) (neat) 2931,
2865, 1460, 1376, 1237, 1190, 1167, 1132, 1105, 1080,
1069, 1037, 966, 937, 881, 758, 722, 665, 603; dH
(300 MHz, CDCl3), 5.30 (1H, dd, J¼4.2, 6.1 Hz), 5.29
(1H, br s), 5.25 (1H, br s), 4.94 (1H, s), 4.44 (1H, br s), 3.52
(1H, d, J¼10.5 Hz), 3.44 (3H, s), 3.42 (1H, d, J¼10.5 Hz),
2.85 (1H, br s), 2.76 (1H, brd, J¼5.5 Hz), 2.34 (1H, dd,
J¼4.2, 14.9 Hz), 2.24 (1H, dd, J¼6.1, 14.9 Hz), 2.04 (1H,
brd, J¼12.8 Hz), 1.68–1.17 (11H, m), 1.01–0.85 (13H, m),
0.69–0.61 (4H, m); EI-MS-LR m/z (Int.%) 533 (Mþ2Et, 3),
519 (Mþ2iPr, 70), 487 (27), 437 (31), 293 (100); EI-MS-
HR, calcd for C22H36O4ISi (Mþ2iPr): 519.1428; found:
519.1425.
5.1.7. (1R,2S,4S,6R,8S,10R)-10-Bromo-2-(diethyliso-
propylsilyloxy)-4-methoxy-9-(1-methylcyclohexyl)-5,7-
dioxatricyclo[6.2.1.02,6]undecane-10-carbaldehyde (17).
To a solution of 15 (43.5 mg, 96.1 mmol) in CH2Cl2
(1.5 mL) was added dropwise BF3·OEt2 (61 mL,
0.481 mmol) at 2558C. After stirring for 7 h, the mixture
was diluted with sat. NaHCO3 (2 mL), and the aqueous
layer was extracted with Et2O (4£2 mL). The combined
organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was subjected to flash
chromatography (silica gel, 5.0 g, hexane:EtOAc, 10:1 to
6:1) to afford a diastereomixture (a:b¼3.1:1) of 16
(34.1 mg, 75.0 mmol, 78%) as a colorless oil.
5.1.5. 1-{(1R,2S,4S,6R,8S)-2-Diethylisopropylsilyloxy-4-
methoxy-10-methylene-5,7-dioxatricyclo[6.2.1.02,6]-
undec-9-yl}-1-methylcyclohexane (6). To a solution of 5
(4.8 mg, 8.5 mmol) in DMSO (0.5 mL) was added NaBH4
(ca. 10 mg, excess) at 238C, and the mixture was stirred at
1008C for 2 h. The mixture was diluted with 0.5 M HCl
(2.0 mL), and the aqueous layer was extracted with Et2O
(3£3 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo. The residue
was subjected to flash chromatography (silica gel, 0.8 g,
hexane:EtOAc, 15:1) to afford 6 (3.2 mg, 7.4 mmol, 87%) as
To a mixture of 16 (19.1 mg, 42.2 mmol) and HMPA
(51.4 ml, 0.295 mmol) in THF (0.5 mL) was added dropwise
a solution of KHMDS (0.5 M in PhMe, 0.26 mL,
0.128 mmol) at 2608C. After stirring for 20 min, a solution
of NBS (51.2 mg, 0.288 mmol) in THF (0.8 mL) was added
and stirring was continued at the same temperature for 2 h.
The reaction was diluted with sat. NH4Cl (2 mL) and sat.
Na2S2O3 (2 mL), and the aqueous layer was extracted with
Et2O (4£5 mL). Drying over MgSO4, concentration, and
flash chromatography (silica gel, 3.0 g, hexane:EtOAc, 8:1)
afforded 17 (15.8 mg, 30.0 mmol, 71%) as a colorless oil;
[a]2D3¼28.05 (c 0.174, CHCl3); nmax (cm21) (neat) 2935,
2875, 1722, 1455, 1376, 1189, 1126, 1037, 725; dH
(300 MHz, CDCl3) 9.55 (1H, s), 5.24 (1H, t, J¼4.8 Hz),
4.96 (1H, s), 4.45 (1H, br s), 3.41 (3H, s), 3.25 (1H, br s),
2.96 (1H, br s), 2.33 (1H, brd, J¼4.7 Hz), 2.23 (2H, br s),
1.56–1.19 (11H, m), 1.05–0.94 (16H, m), 0.73–0.66 (4H,
m); EI-MS-LR m/z (Int. %) 501 (Mþ2Et, 7), 487 (Mþ2iPr,
8), 457 (100), 409 (64), 393 (63); EI-MS-HR, calcd for
C22H36O5SiBr (Mþ2iPr): 487.1515, found: 487.1514.
a colorless oil; [a]2D5¼þ38.6 (c 0.35, CHCl3); nmax (cm21
)
(neat) 2929, 2864, 1462, 1414, 1376, 1322, 1299, 1284,
1270, 1239, 1189, 1168, 1132, 1105, 1077, 1037, 1015, 966,
940, 912, 882, 858, 761, 731, 665, 647, 576; dH (300 MHz,
CDCl3) 5.30 (1H, dd, J¼4.0, 6.2 Hz), 5.23 (1H, br s), 5.18
(1H, br s), 4.91 (1H, s), 4.43 (1H, br s), 3.44 (3H, s), 2.74
(1H, d, J¼5.7 Hz), 2.62 (1H, br s), 2.35 (1H, dd, J¼4.0,
14.9 Hz), 2.24 (1H, dd, J¼6.2, 14.9 Hz), 2.00 (1H, brd,
J¼12.7 Hz), 1.64 (1H, ddd, J¼2.7, 5.7, 12.7 Hz), 1.55–1.25
(10H, m), 1.00–0.92 (13H, m), 0.81 (3H, s), 0.69–0.60 (4H,

10292
J. Ishihara et al. / Tetrahedron 59 (2003) 10287–10294
5.1.8. (1R,2S,4S,6R,8S,10R)-2-(Diethylisopropylsilyl-
oxy)-4-methoxy-9-(1-methylcyclohexyl)-5,7-dioxatri-
cyclo[6.2.1.02,6]undec-9-ene-10-carbaldehyde (18). To a
solution of 17 (24.6 mg, 46.3 mmol) in DMF (1.0 mL) were
added LiBr (42.7 mg, 0.492 mmol) and Li2CO3 (35.2 mg,
0.476 mmol) at 238C, and the mixture was stirred at 1258C
for 13 h. The mixture was diluted with brine (2.0 mL), and
the aqueous layer was extracted with Et2O (4£2 mL). The
combined organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was subjected to
flash chromatography (silica gel, 1.2 g, hexane:EtOAc, 8:1)
to afford 18 (20.2 mg, 44.9 mmol, 97%) as a pale yellow oil;
[a]2D3¼þ97.1 (c 0.63, CHCl3); nmax (cm21) (neat) 2931,
2865, 1670, 1454, 1187, 1130, 1076, 1029, 723;dH
(300 MHz, CDCl3) 10.36 (1H, s), 5.31 (1H, dd, J¼3.3,
6.3 Hz), 4.94 (1H, s), 4.87 (1H, br s), 3.59 (1H, d,
J¼5.2 Hz), 3.45 (3H, s), 2.40 (1H, dd, J¼6.3, 15.1 Hz),
2.30 (1H, dd, J¼3.3, 15.1 Hz), 2.09 (1H, d, J¼11.8 Hz),
1.94–1.87 (2H, m), 1.77 (1H, ddd, J¼3.0, 5.2, 11.8 Hz),
1.66–1.23 (8H, m), 1.30 (3H, s), 1.03–0.84 (13H, m),
0.67–0.57 (4H, m); EI-MS-LR m/z (Int.%) 450 (Mþ, 1.0),
421 (Mþ2Et, 80), 407 (Mþ2iPr, 17), 375 (55); EI-MS-HR,
calcd for C25H42O5Si (Mþ): 450.2801, found: 450.2813.
J¼3.0, 6.3 Hz), 4.56 (1H, br s), 4.31 (1H, dd, J¼7.4,
12.4 Hz), 4.02 (1H, dd, J¼6.0, 12.4 Hz), 3.41 (3H, s), 2.90
(1H, d, J¼5.2 Hz), 2.58 (1H, m), 2.44 (1H, dd, J¼6.3,
15.4 Hz), 2.36 (1H, dd, J¼3.0, 15.4 Hz), 1.73–1.43 (12H,
m),1.23 (3H, s), 1.06–0.88 (13H, m), 0.79–0.69 (4H, m); dC
(75 MHz, CDCl3) 129.0, 108.0, 106.7, 68.0, 62.3, 62.1,
46.4, 45.3, 29.7, 26.4, 25.9, 22.0, 17.6, 17.5, 17.3, 14.1, 7.3,
7.1, 4.8, 4.7; EI-MS-LR m/z (Int.%) 468 (Mþ, 1.9), 425
(Mþ2iPr, 10), 393 (39), 244 (78); EI-MS-HR, calcd for
C25H44O6Si (Mþ): 468.2907, found: 468.2916.
5.1.11. (1S,3R,5S,7S,8R,9R,11R)-7-(Diethylisopropylsilyl-
oxy)-9-iodomethyl-5-methoxy-11-(1-methylcyclohexyl)-
2,4,10-trioxatetracyclo[6.3.1.03,709,11]dodecane (21). To a
solution of alcohol 20 (6.2 mg, 13.2 mmol) in THF (0.5 mL)
were added imidazole (28.0 mg, 0.411 mmol), PPh3
(53.0 mg, 0.202 mmol) and a solution of I2 (51.0 mg,
201 mmol) in THF (0.5 mL). After stirring at 238C for 8 h,
the reaction was diluted with sat. NaHCO3 (1 mL) at 08C.
To the mixture was added a solution of I2 in THF until the
solution persisted in yellow–brown color. After addition of
sat. Na2S2O3 (20 mL) at 08C, the aqueous layer was
extracted with ether (4£2 mL), dried over MgSO4, and
concentrated. The residue was subjected to flash chroma-
tography (silica gel, 1.5 g, hexane:EtOAc, 10:1) to furnish
iodide 21 (6.2 mg, 10.8 mmol, 82%) as white solids;
[a]2D3¼þ12.5 (c 0.30, CHCl3); nmax (cm21) (neat) 2929,
2863, 1457, 1373, 1315, 1247, 1195, 1124, 1085, 883, 767,
723; dH (300 MHz, CDCl3) 5.28 (1H, s), 5.25 (1H, dd,
J¼2.7, 6.3 Hz), 4.63 (1H, br s), 4.43 (1H, d, J¼9.6 Hz), 3.77
(1H, d, J¼9.6 Hz), 3.40 (3H, s), 2.90 (1H, brd, J¼5.2 Hz),
2.42 (1H, dd, J¼6.3, 15.7 Hz), 2.32 (1H, dd, J¼2.7,
15.7 Hz), 1.77–1.34 (12H, m), 1.25 (3H, s), 1.06–0.83
(13H, m), 0.80–0.64 (4H, m); EI-MS-LR m/z (Int. %) 547
(Mþ2OMe, 8.7), 534 (21), 451 (100); EI-MS-HR, calcd for
C24H40O4SiI (Mþ2OMe): 547.1741, found: 547.1729.
5.1.9. {(1R,2S,4S,6R,8S,10R)-2-(Diethylisopropylsilyl-
oxy)-4-methoxy-9-(1-methylcyclohexyl)-5,7-dioxa-tri-
cyclo[6.2.1.02,6]undec-9-en-10-yl}-methanol (19). To a
solution of 18 (11.6 mg, 25.7 mmol) in MeOH (1 mL)
were added CeCl3·7H2O (55 mg, 0.148 mmol) and NaBH4
(5.6 mg, 0.148 mmol) at 08C. After stirring at 08C for 1 h,
the mixture was diluted with sat. NaHCO3 (1 mL) and brine
(1 mL). The aqueous layer was extracted with ether
(3£2 mL), dried over MgSO4, and concentrated. The
residue was subjected to flash chromatography (silica gel,
1.5 g, hexane:EtOAc, 8:1) to furnish 19 (9.0 mg, 20.0 mmol,
78%) as a pale yellow oil; [a]2D5¼þ55.1 (c 0.45, CHCl3);
nmax (cm21) (neat) 3486, 2929, 2865, 1457, 1191, 1126,
1072, 1024, 979, 723; dH (C6D6, 300 MHz) 5.27 (1H, s),
5.23 (1H, dd, J¼2.5, 6.3 Hz), 4.64 (1H, br s), 4.59 (1H, d,
J¼14.3 Hz), 4.37 (1H, d, J¼14.3 Hz), 3.36 (3H, s), 3.19
(1H, d, J¼4.9 Hz), 2.30 (1H, dd, J¼2.2, 15.4 Hz), 2.18 (1H,
dd, J¼6.3, 15.4 Hz), 2.17 (1H, d, J¼11.5 Hz), 1.84–1.64
(2H, m), 1.60 (1H, ddd, J¼3.3, 4.9, 11.5 Hz), 1.37–1.13
(8H, m), 1.10 (3H, s), 1.05–0.83 (13H, m), 0.79–0.57 (4H,
m); EI-MS-LR m/z (Int.%) 452 (Mþ, 6.9), 421 (Mþ2OMe,
25), 377 (100), 359 (50), 346 (64); EI-MS-HR, calcd for
C25H44O5Si (Mþ): 452.2958, found: 452.2936.
5.1.12. (1S,3R,5S,7S,8R,9R,11R)-7-(Diethylisopropylsilyl-
oxy)-9-methyl-5-methoxy-11-(1-methylcyclohexyl)-
2,4,10-trioxatetracyclo[6.3.1.03,709,11]dodecane (22). To a
solution of 21 (3.2 mg, 5.5 mmol) in CH3CN (1.0 mL) was
added NaBH4 (6.1 mg, 0.161 mmol) at 08C, and the mixture
was refluxed for 18 h. The reaction was diluted with brine
(2 mL), and the aqueous layer was extracted with Et2O
(3£2 mL). Drying over MgSO4, concentration, and flash
chromatography (silica gel, 1.5 g, hexane:EtOAc, 10:1)
furnished 22 (2.2 mg, 4.9 mmol, 88%) as a colorless oil;
[a]2D6¼þ17.3 (c 0.11, CHCl3); nmax (cm21) (neat) 2927,
2865, 1457, 1371, 1267, 1193, 1126, 1079, 1033, 964, 723;
dH (300 MHz, CDCl3) 5.29 (1H, s), 5.26 (1H, dd, J¼3.6,
5.8 Hz), 4.52 (1H, br s), 3.41 (3H, s), 2.43 (1H, brd,
J¼4.7 Hz), 2.34 (1H, brd, J¼5.8 Hz), 2.33 (1H, brd,
J¼3.6 Hz), 1.77 (3H, s), 1.70–1.43 (12H, m), 1.23 (3H,
s), 1.03–0.95 (13H, m), 0.74–0.68 (4H, m); EI-MS-LR m/z
(Int.%) 452 (Mþ, 2.5), 421 (Mþ2OMe, 2.0), 409 (Mþ2iPr,
3.4), 377 (4.6), 263 (100); EI-MS-HR, calcd for C25H44O5Si
(Mþ): 452.2958, found: 452.2966.
5.1.10. {(1S,3R,5S,7S,8R,9R,11R)-7-(Diethylisopropyl-
silyloxy)-5-methoxy-11-(1-methylcyclohexyl)-2,4,10-
trioxa-tetracyclo[6.3.1.03,709,11]dodec-9-yl}-methanol
(20). To a solution of 19 (5.7 mg, 12.6 mmol) in CH2Cl2
(1.0 mL) were added VO(acac)2 (1.0 mg, 3.77 mmol) and a
solution of TBHP (3.05 M in CH2Cl2, 43 ml, 131 mmol) at
08C, and the mixture was stirred at 238C for 3.5 h. The
mixture was diluted with sat. Na2S2O3 (2 mL), and the
aqueous layer was extracted with Et2O (3£2 mL). Drying
over MgSO4, concentration, and flash chromatography
(silica gel, 1.2 g, hexane:EtOAc, 8:1) afforded 20
(12.6 mmol, 100%) as a colorless oil; [a]2D4¼þ22.4 (c
0.25, CHCl3); nmax (cm21) (neat) 3494, 2935, 2867, 1457,
1373, 1317, 1241, 1195, 1126, 1083, 1033, 958, 887, 765,
723; dH (300 MHz, CDCl3) 5.33 (1H, s), 5.27 (1H, dd,
5.1.13. (1S,3S,7S,8S,9S,11S)-7-Hydroxy-9-methyl-11-(1-
methylcyclohexyl)-2,4,10-trioxatetracyclo[6.3.1.03,7
09,11]dodec-5-ene (23). To a mixture of 22 (6.5 mg,
14.4 mmol) and MS4A (ca. 20 mg) in CH3CN (1 mL) was
added dropwise PhSeH (30.5 ml, 287 mmol) at 238C.

J. Ishihara et al. / Tetrahedron 59 (2003) 10287–10294
10293
1971, 17, 969. (c) Butterworth, J. H.; Morgan, E. D.; Percy,
G. R. J. Chem. Soc., Perkin Trans. 1 1972, 2445. (d) Morgan,
E. D.; Butterworth, J. H. Phytochemistry 1973, 12, 391.
Amberlyst 15 was added and the mixture was stirred at 238C
for 30 min. After filtration through Celite and NaHCO3, the
filtrate and washings were concentrated in vacuo to afford a
crude selenide. The crude selenide was used for next
reaction without further purification.
¨
3. (a) Kraus, W.; Bokel, M.; Klenk, A.; Pohnl, H. Tetrahedron
Lett. 1985, 26, 6435. (b) Broughton, H. B.; Ley, S. V.; Slawin,
A. M. Z.; Williams, D. J.; Morgan, E. D. J. Chem. Soc., Chem.
Commun. 1986, 46. (c) Turner, C. J.; Tempesta, M. S.; Taylor,
R. B.; Zagorski, M. G.; Termini, J. S.; Schroeder, D. R.;
Nakanishi, K. Tetrahedron 1987, 43, 2789.
To a solution of crude selenyl compound in CH2Cl2
(1.0 mL) were added dropwise 35% H2O2 (5 drops) and
pyridine (5 drops) at 08C, and the mixture was stirred for
30 min. To the solution was added dropwise sat. Na2S2O3
(2 mL), and the aqueous layer was extracted with Et2O
(2£3 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo. The residue
was subjected to flash chromatography (silica gel, 1.2 g,
hexane:EtOAc, 10:1 to 5:1) to afford a crude dihydrofuran
(1.6 mg), along with recovered 22 (1.4 mg, 3.1 mmol) in
22% yield.
4. Ley, S. V.; Lovell, H.; Williams, D. J. J. Chem. Soc., Chem.
Commun. 1992, 1304.
5. (a) Ley, S. V.; Denholm, A. A.; Wood, A. Nat. Prod. Rep.
1993, 109. and references cited therein. (b) Nishikimi, Y.;
Iimori, T.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989,
54, 3354. (c) Henry, K. J., Jr.; Fraser-Reid, B. J. Org. Chem.
1994, 59, 5128. (d) Watanabe, H.; Watanabe, T.; Mori, K.
Tetrahedron 1996, 52, 13939. (e) Watanabe, H.; Watanabe, T.;
Mori, K.; Kitahara, K. Tetrahedron Lett. 1997, 38, 4429.
(f) Scheliger, H.; Winterfeldt, E. Chirality 1997, 9, 454.
(g) Haag, D.; Chen, X.-T.; Fraser-Reid, B. Chem. Commun.
1998, 2577. (h) Ley, S. V.; Gutteridge, C. E.; Pape, A. R.;
Spilling, C. D.; Zumbrunn, C. Synlett 1999, 1295. (i) Nicolaou,
K. C.; Follmann, M.; Roecker, A. J.; Hunt, K. W. Angew.
Chem. Int. Ed. 2002, 41, 2103. (j) Nicolaou, K. C.; Roecker,
A. J.; Follmann, M.; Baati, R. Angew. Chem. Int. Ed. 2002, 41,
2107. (k) Durand-Reville, T.; Gobbi, L. B.; Gray, B. L.; Ley,
S. V.; Scott, J. S. Org. Lett. 2002, 4, 3847. (l) Nicolaou, K. C.;
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To a solution of the dihydrofuran (1.6 mg) in THF (1 mL)
was added dropwise a solution of TBAF (1.0 M in THF,
11.4 ml, 11.4 mmol) at 08C. After stirring for 10 min, the
mixture was diluted with sat. NH4Cl (2.0 mL), and
the aqueous layer was extracted with Et2O (2£3 mL). The
residue was subjected to flash chromatography (silica gel,
1.5 g, hexane:EtOAc, 10:1 to 4:1) to furnish 23 (0.8 mg,
2.7 mmol, 19% for 3 steps) as white solids; [a]2D5¼2112 (c
0.04, CHCl3); nmax (cm21) (neat) 3442, 2925, 2856, 1698,
1617, 1523, 1459, 1018, 773; dH (300 MHz, CDCl3) 6.49
(1H, d, J¼2.7 Hz), 5.51 (1H, s), 5.15 (1H, d, J¼2.7 Hz),
4.48 (1H, d, J¼3.6 Hz), 2.39 (1H, d, J¼5.8 Hz), 1.82 (3H,
s), 1.76–1.15 (12H, m), 1.27 (3H, s); dC (125 MHz, CDCl3)
147.9, 108.3, 107.5, 83.4, 76.4, 75.9, 65.7, 46.5, 35.3, 27.3,
26.0, 22.4, 22.0, 17.4, 14.1; EI-MS-LR m/z (Int. %) 292
(Mþ, 0.9), 192 (100); EI-MS-HR, calcd for C17H24O4 (Mþ):
292.1675, found: 292.1674.
6. (a) Simmonds, M. S.; Blaney, W. M.; Grossman, R. B.; Ley,
S. V. J. Insect Physiol. 1995, 41, 555. (b) Nisbet, A. J.; Mordue
(Luntz), A. J.; Grossman, R. G.; Jennens, L.; Ley, S. V.;
Mordue, W. Arch. Insect Biochem. Physiol. 2001, 46, 78.
7. Yamasaki, B.; Kloche, J. A. J. Agric. Food Chem. 1987, 35,
467.
8. Ley, S. V.; Anderson, J. C.; Blaney, W. M.; Jones, P. S.;
Lidert, Z.; Morgan, E. D.; Robinson, N. G.; Santafianos, D.;
Simmonds, M. S. J.; Toogood, P. L. Tetrahedron 1989, 45,
5175.
Acknowledgements
This work was financially supported by Grants-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (13680665 and
14044001) and The Akiyama Foundation.
9. Ley, V. S.; Santafianos, D.; Blaney, W. M.; Simmonds, M. S.
J. Tetrahedron Lett. 1987, 28, 221.
´
10. (a) Baldoni, H. A.; Enriz, R. D.; Jauregui, E. A.; Csizmadia,
I. G. J. Mol. Struct. (Theochem) 1996, 363, 167. (b) Baldoni,
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´
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