Novel oxepane formation by TiCl4-catalyzed nucleophilic cleavage of 1- alkoxymethyl-6,8-dioxabicyclo[3.2.1]octanes

Article abstract of DOI:10.1016/S0040-4020(00)00009-0

Introduction of an alkoxymethyl group at the C1 position in the 6,8- dioxabicyclo[3.2.1]octane system enabled novel formation of oxepane compounds in TiCl-4-catalyzed acetal cleavage reactions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00009-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1065–1080
Novel Oxepane Formation by TiCl4-Catalyzed Nucleophilic
Cleavage of 1-Alkoxymethyl-6,8-dioxabicyclo[3.2.1]octanes
*
*
Kenshu Fujiwara, Arika Amano, Tetsuo Tokiwano and Akio Murai
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 2 December 1999; accepted 20 December 1999
Abstract—Introduction of an alkoxymethyl group at the C1 position in the 6,8-dioxabicyclo[3.2.1]octane system enabled novel formation of
oxepane compounds in TiCl4-catalyzed acetal cleavage reactions. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
acid between O8 and the oxygen of the alkoxymethyl func-
tion at C1. Thus, bicyclic acetals having an alkoxy-methyl
group at C1 (4a–e) and a methyl group at C1 (4f) were
designed as substrates for the cleavage reaction.
Lewis acid-catalyzed nucleophilic cleavage of the C5–O8
bond in a 6,8-dioxabicyclo[3.2.1]octane system (1) (path B
in Scheme 1) which produces an oxepane (3) is an attractive
method for the preparation of the segments for natural fused
polycyclic ethers.1 In fact, however, the cleavage reaction of
1 has produced exclusively an oxane (2) through a break of
the C5–O6 bond (path A) in every case using DIBAH,2–4 a
combination of triethylsilane (Et3SiH) with a Lewis acid,2,3
or a combination of allyltrimethylsilane with BF3·OEt2.5
Recently, Rychnovsky has reported the first oxepane-
selective formation in the system only under cyanation
conditions.6,7 In this context, we have developed a general
procedure leading to production of oxepanes from 6,8-
dioxabicyclo[3.2.1]octanes. Here, the selective formation
of the oxepane derivatives by reductive and allylative
cleavage of bicyclic acetals using chelation of TiCl4 is
described.8
Preparation of bicyclic acetals
Acetals 4a–f were prepared via diols 16a–f (Scheme 3).
Diol 16a was synthesized from glycerol (8). Reaction of 8
with benzaldehyde gave an inseparable 4:3 mixture of
acetals 9 and 10. Methylation of the mixture followed by
separation afforded 11 (49%). Acetal 11 was treated with
TiCl4 and Et3SiH9 to produce 13 selectively, which was
oxidized and coupled with 4-(tert-butyldiphenylsilyloxy)-
1-butynyl lithium to give 15 (53%). Removal of the benzyl
group and reduction of the alkynyl part of 15 with Pd/C and
H2 yielded diol 16a (70%). Diols 16b–e were synthesized
from the common b-hydroxy ester 20, which was prepared
in 81% yield from e-caprolactone (17) by a 3-step process,
including diastereoselective aldol reaction, reported by
Abiko and Masamune.10 Mesylation of 20 followed by
DBU-mediated elimination and reduction with DIBAH
produced E-allyl alcohol 21 in 89% yield, which was
converted to 16b (98%) by methylation and dihydroxylation
and to 16d (70%) by benzylation and dihydroxylation. On
Results and Discussion
The general concept in an exclusive cleavage reaction of the
bicyclic system toward the oxepane formation is outlined in
Scheme 2. We planned the selective fixation of a Lewis acid
on O8 in order to enhance the cleaving ability of the C5–O8
bond rather than the C5–O6 bond by chelation of the Lewis
the other hand, reaction of 20 with DCC in the presence of
11
˚
CuCl and molecular sieves 4 A followed by reduction
Scheme 1.
Keywords: bicyclic heterocyclic compounds; cleavage reactions; ethers; oxepanes.
* Corresponding authors. E-mail: amurai@sci.hokudai.ac.jp
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00009-0

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K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
Scheme 2.
Scheme 3. Reagents and conditions: (a) benzaldehyde, PPTS, benzene, reflux, 5 h, 9:10ˆ4:3; (b) t-BuOK, MeI, THF, 20ЊC, 30 min, 11: 49% from 8; (c) TiCl4,
Et3SiH, CH2Cl2, Ϫ78ЊC, 30 min; (d) TPAP, NMO, MS4A, CH2Cl2–MeCN (10:1), 20ЊC, 1 h; (e) TBDPSOCH2CH2CxCLi, THF, Ϫ78ЊC, 20 min, 53% from
11; (f) H2, 10% Pd/C, 20ЊC, 70%; (g) NaOMe, MeOH, 20ЊC, 1.5 h; (h) TBDPSCl, imidazole, DMF, 20ЊC, 2 h, 92% from 17; (i) Bu2BOTf, i-Pr2Net, Ϫ78ЊC,
30 min, then MeCHO,Ϫ78ЊC, 1.5 h, 88% (syn:antiˆ96:4); (j) MsCl, Et3N, CH2Cl2, 0ЊC, 1.5 h; (k) DBU, CH2Cl2, 20ЊC, 1 day; (1) DIBAH, CH2Cl2, Ϫ78ЊC,
1.5 h, 21: 89% from 20; (m) DCC, CuCl, MS4A, benzene, reflux 1 day; (n) DIBAH, CH2Cl2, Ϫ78ЊC, 1.5 h, 22: 77% from 20; (o) t-BuOK, MeI, THF, 20ЊC; (p)
OsO4, NMO, 1,4-dioxane–H2O (3:1), 20ЊC, 16b: 98% from 21, 16c: 89% from 22; (q) BnBr, NaH, TBAI, THF, 20ЊC, 1 day; (r) OsO4, NMO, 1,4-dioxane–H2O
(3:1), 20ЊC, 16d: 70% from 21, 16e: 78% from 22; (s) TBDPSCl, imidazole, DMF, 0ЊC, 40 min, 94%; (t) m-CPBA, CH2Cl2, 20ЊC, 3 h, 94%; (u) LiEt3BH, THF,
0ЊC, 1 h, 98%; (v) DMSO, (COCl)2, Ϫ78ЊC, 30 min, then Et3N, Ϫ78!0ЊC, 1 h, 76%; (w) Tebbe reagent, toluene, 20ЊC, 10 min, 92%; (x) OsO4, NMO, 1,4-
dioxane–H2O (3:1), 20ЊC, 1.5 h, ϳ100%; (y) 2,2-dimethoxypropane, PPTS, CH2Cl2, 20ЊC, 27a: 98%, 27b: 89%, 27c: 81%, 27d: 96%, 27e: 96%, 27f: 96%; (z)
TBAF, THF, 20ЊC, 28a: 98%, 28b: 92%, 28c: ϳ100%, 28d: ϳ100%, 28e: ϳ92%, 28f: 100%; (aa) TPAP, NMO, MS4A, CH2Cl2–MeCN (10:1), 20ЊC, 29a:
85%, 29d: 80%, 29e: 81%, 29f: 81%; (bb) DMSO, (COCl)2, Ϫ78!Ϫ45ЊC, 30 min, then Et3N, Ϫ45!0ЊC, 20 min, 29b: 90%, 29c: 85%; (cc) TsOH·H2O,
CH2Cl2, 20ЊC, 4a: 80%, 4b: 79%, 4c: 78%, 4d: 78%, 4e: 78%, 4f: 66%.

K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
1067
Table 1.
Entry
Substrate
Reagent(s) (equiv.)
Temp. (ЊC)
Time
Yielda (%)
30:31
4 Recoverya (%)
1
2
4a
DIBAH (8)
Et3SiH (8)
TiCl4 (4)
20
Ϫ78
2 days
1 h
81
62
30a:31a
0:100b
54:46b
–
17
3
4
5
6
7
8
Et3SiH (8)
SnCl4 (2.4)
Et3SiH (8)
Sn(OTf)2 (2.4)
Et3SiH (8)
BF3·OEt2 (2.4)
Et3SiH (8)
AlMe3 (2.4)
Et3SiH (8)
Et2AlCl (2.4)
Et3SiH (8)
AlCl3 (2.4)
DIBAH (4)
Et3SiH (8)
TiCl4 (2.4)
Et3SiH (12)
SnCl4 (3.6)
DIBAH (4)
Et3SiH (8)
TiCl4 (2.4)
Et3SiH (8)
SnCl4 (2.4)
DIBAH (4)
Et3SiH (8)
TiCl4 (4)
Ϫ78
Ϫ78!0
20
4 h
5 h
24 h
94
82
99
43
41
75
0:100c
0:100b
0:100b
59:41b
0:100b
4:96b
–
–
20
20
20
20
3 h
–
2 days
2 days
2 days
50
31
–
9
10
4b
4c
20
Ϫ78
2 days
1 h
100
74
30b:31b
30c:31c
0:100b
74:26b
–
–
11
Ϫ78
5.5 h
43
0:100b
–
12
13
20
Ϫ78
3 days
1 h
77
98
0:100b
99:1b
–
–
14
Ϫ78
0
20
1.5 h
0.5 h
2 days
4 h
60
0:100b
–
15
16
4d
4e
4f
59
50
30d:31d
30e:31e
30f:32f
0:100b
49:51b
13
35
Ϫ78
17
18
DIBAH (4)
Et3SiH (8)
TiCl4 (4)
DIBAH (4)
Et3SiH (8)
TiCl4 (2.4)
20
Ϫ78
2 days
4 h
50
82
2:98b
93:7b
43
–
19
20
20
Ϫ78
3 days
0.5 h
46
65
0:100c
0:100c
52
–
a Isolated yield.
b Determined by GC.
1
c Determined by H NMR (300 MHz).
gave Z-allyl alcohol 22 (77%). Diols 16c and 16e were
derived from 22 similarly as described for 16b and 16d,
respectively. Preparation of 16f was commenced from
5-hexenol (23). Protection of 23 followed by epoxidation
and regioselective reduction afforded 25 (87%), which was
converted to 16f (70%) by Swern oxidation,12 followed by
olefination with Tebbe reagent13 and dihydroxylation. All
acetals 4a–f were constructed from the corresponding diols
16a–f through a common 4-step sequence: protection of the
diol part, desilylation, oxidation, and acidic cyclization.
reactions of 4a–d produced only the corresponding oxanes
31a–d: acetals 4a–4c gave the oxanes in high yield
(77–100%, entries 1, 9, and 12), while the cleavage
reactions of 4d–e proceeded very slowly and gave oxanes
in moderate yields (50–59%) with recovered substrates
(entries 15 and 17). A combination of Et3SiH with TiCl4
provided satisfactory results.14 The best selectivity of
oxepane was observed in 4c which had an a-methyl group
at C7 (98%, 30c:31cˆ99:1; entry 13). Interestingly, the
selectivity in b-methyl-substituted 4b (30b:31bˆ74:26;
entry 10) was worse than in 4c but better than in unsubsti-
tuted 4a (30a:31aˆ54:46; entry 2).15 The corresponding
benzyloxymethyl compounds 4d and 4e also afforded
oxepanes in comparable selectivities (30d:31dˆ49:51,
entry 16; 30e:31eˆ93:7, entry 18) with 4b and 4c. When
these reactions were attempted at temperatures higher than
Ϫ78ЊC in order to accelerate the reaction, removal of the
benzyl group predominated over the normal cleavage. The
Reductive cleavage of bicyclic acetals
At first, we explored the reagent system suitable for the
oxepane-selective reductive cleavage of alkoxymethyl-
substituted bicyclic acetals 4a–4e. All reactions were
carried out in CH2Cl2 under the conditions noted in Table
1. When DIBAH was used solely as a reductant, all the

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K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
Figure 1. Observed HMBC in 6- and 7-membered cyclic ethers (30 and 31).
cleavage reactions of 4a–c with Et3SiH–SnCl4 produced
only oxanes 31a–c although SnCl4 is a bis-coordinating
Lewis acid similar to TiCl4. In the cases of Et3SiH–
Sn(OTf)2 and Et3SiH–BF3·OEt2, only oxanes were given
(entries 4 and 5). Among the aluminum Lewis acids
investigated here such as AlMe3, Et2AlCl, and AlCl3 (entries
6, 7, and 8), only AlMe3 produced a significant amount of
the oxepane 30a as a mixture with 31a from 4a
(30a:31aˆ59:41; entry 6).16 However, reactions of the
other substrates with this reagent system occurred too
slowly to produce any cleavage products. Notably, SnCl4,
which is a bis-coordinate Lewis acid similar to TiCl4 and
more acidic than AlMe3, could not produce an oxepane. It is
deduced from the results that the strength of Lewis acidity is
not essential for oxepane formation. Thus, we found that the
combination of Et3SiH and TiCl4 is most effective for
oxepane-selective reductive cleavage of 1-alkoxymethyl-
6,8-dioxabicyclo[3.2.1]octanes.
peaks between C1 and H6 and between C6 and H1 observed
in all the HMBC spectra of 30a–e verified the oxepane
frameworks of 30a–e. The oxane skeletons of 31a–f were
confirmed by the cross-peaks between C5 and H1 observed
in all the HMBC spectra of 31a–f.
Allylative cleavage of bicyclic acetals
Next, allylative cleavage of 1-alkoxymethyl-6,8-dioxabicyclo-
[3.2.1]octanes was examined as an analogy of the reductive
cleavage. Treatment of 4d with allyltrimethylsilane in the
presence of TiCl4 in CH2Cl2 at Ϫ78ЊC gave a mixture of
oxepane 32 (ϳ48%), oxane 33 (ϳ12%), and a small amount
of 4d (ϳ8%) as well as a mixture of debenzylated oxepane
34 (ϳ15%) and oxane 35 (ϳ15%). It is to be noted that the
stereochemistry of C4 of 32 was opposite to that of 34. The
ratio of oxepanes (32ϩ34) to oxanes (33ϩ35) amounted to
7:3 by 1H NMR. On the other hand, the reaction of 4e under
the same conditions produced only debenzylated oxepane
38 as a single stereoisomer in ϳ90% yield. Interestingly,
allyltrimethylsilane showed higher oxepane selectivity in
the cleavage reaction of either 4d or 4e with TiCl4 than
Et3SiH.17 Thus, an alkoxymethyl substituent at C1 in the
bicyclic acetal system induced oxepane formation also in
allylative cleavage with allyltrimethylsilane catalyzed by
TiCl4 (Scheme 4).
Next, the bicyclic acetal 4f having no internal ligand was
examined. Use of a mixture of Et3SiH and TiCl4 as well as
of DIBAH provided only oxane 31f but not oxepane 30f
(entries 19 and 20). This result shows that the presence of
an alkoxymethyl group at C1 in the 6,8-dioxabicyclo[3.2.1]-
octane skeleton is necessary for the oxepane-selective
cleavage reaction.
The structures of oxepanes 30a–e and oxanes 31a–f were
determined by their NMR analyses (Fig. 1). Both the cross-
The structures of the products were determined by NMR
analyses. Benzyl ethers 32 and 33 were analyzed as such,
Scheme 4.

K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
1069
reactions were carried out in oven-dried (Ͼ130ЊC) glass-
ware sealed under a positive pressure of dry argon from a
manifold or balloon. Sensitive liquids and solutions were
transferred by syringe or cannula through rubber septa.
Reactions were run at noted temperature and stirred with a
Teflon-covered magnetic stirring bar. All commercially
available reagents were used without further purification
with the following exceptions. THF was distilled from
sodium-benzophenone ketyl under argon. Dichloromethane
(CH2Cl2) and diisopropylethylamine (i-Pr2NEt) were
distilled from CaH2 under argon prior to use. Analytical
TLC was performed with 0.25 mm Silica Gel 60 plates
with a 254 nm fluorescent indicator from Merck. Plates
were developed in a covered chamber and visualized by
ultraviolet light and by treatment with acidic anisaldehyde
stain followed by heating. Flash chromatography was
performed on YMC Silica Gel 60 (230–400 mesh) as a
stationary phase. Melting points were obtained using a
Yanagimoto micro melting point apparatus without calibra-
tion. NMR spectra were measured on a JEOL alpha-400 (1H
at 400 MHz, 13C at 100 MHz), a JEOL FT-270 (1H at
270 MHz), or a JEOL AL-300 (1H at 300 MHz) magnetic
Figure 2. Observed HMBC in 7-membered cyclic ethers (32, 36, 39).
while diols 34, 35, and 36 were analyzed after conversion to
the corresponding benzoates 36, 37, and 39. The oxepane
frameworks of 32, 36, and 39 were confirmed by the cross-
peaks between C4 and H9 and between C9 and H4 observed
in all the HMBC spectra of 32, 36, and 39 (Fig. 2). The
relative configurations at C4 of these oxepanes were verified
by the NOEs between H3 and H9 in 32 and between H4 and
H9 in 36 as well as the NOEs between H3 and H9 and
between H4 and H10 in 39 (Fig. 3). Although the cross-
peak between H4 and C8 was not detected in the HMBC
spectra of both 33 and 37, the NOEs between H4 and H9
were observed in both the compounds (Fig. 3), which
confirmed their oxane framework and the stereochemistry
at C4.
1
resonance spectrometer. H NMR spectra are reported as
chemical shifts in parts-per-million (ppm) based on tetra-
methylsilane (0 ppm) or one of the signals of the solvent
(noted in each case). 13C NMR spectra are reported as
chemical shifts in ppm based on one of the signals of the
solvent (noted in each case) and recorded with complete
heterodecoupling. Position numbering of cyclic ethers in
NMR data is specified in Figs. 1–3. Infrared spectra were
measured on a Hitachi model 270-30 or a JEOL Winspec-
100 infrared spectrometer in noted states. Low and high
resolution mass spectra were measured on a JEOL DX303
mass spectrometer under electron ionization (EI) condition,
a JEOL JMS-AX500 mass spectrometer under EI condition,
or a JEOL JMS-600 mass spectrometer under EI or
chemical ionization (CI, isobutane was used as reagent
gas) condition. Analytical gas–liquid phase chroma-
tography was performed on a Hitachi model 163 instru-
ment equipped with a FID-detector and a capillary
column of FFAP (GASUKURO KOGYO Inc. Japan,
25000×0.25 mm) with helium as carrier gas. Preparative
liquid chromatography was achieved on a JASCO 880-PU
instrument equipped with a JASCO 875-UV detector and a
packed column (YMC-Pack SIL-06, 250×10 mm or
250×20 mm) with hexane–EtOAc as a liquid phase.
Conclusion
In the reductive cleavage reaction catalyzed by TiCl4, 6,8-
dioxabicyclo[3.2.1]octanes having an alkoxymethyl group
at C1 as an internal ligand led to novel oxepane formation.
Benzyloxymethyl compounds 4d and 4e showed oxepane
selectivity comparable with that of methoxymethyl
compounds 4b and 4c in the reaction. Stereochemistry of
the methyl substituent at C7 in the bicyclic acetal strongly
affected the selectivity. Cleavage with allyltrimethylsilane
and TiCl4 in this bicyclic acetal system also disclosed the
oxepane formation. Application of these reactions to the
total syntheses of natural products and a detailed mechan-
istic study on the stereochemistry of these reactions are
currently under way in our laboratory.
Experimental
General
2-Phenyl-4-methoxymethyl-1,3-dioxolane (11). A mixture
of glycerol (2.77 g, 30.1 mmol), benzaldehyde (3.1 ml,
The following general procedures were used in all reactions
unless otherwise noted. Oxygen- and moisture-sensitive
Figure 3. Observed NOEs in allyl-substituted 6- and 7-membered cyclic ethers (32, 33, 36, 37, and 39).

1070
K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
30.1 mmol), and pyridinium p-toluenesulfonate (PPTS)
(0.38 g, 1.50 mmol) in benzene (150 ml) was refluxed for
5 h. During the reaction, water was removed by Dean–Stark
trap. Then, saturated aqueous NaHCO3 (50 ml) was added
and the mixture was extracted with ether (150 ml). The
organic layer was washed with brine (300 ml). The brine
was extracted with ether (2×150 ml). The combined organic
layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to provide a crude
mixture of acetals 9 and 10 (5.761 g, 9:10ˆ4:3). The
crude mixture and iodomethane (5.6 ml, 90.2 mmol) were
dissolved in THF (100 ml) and cooled to 0ЊC. To the
mixture, t-BuOK (6.75 g, 60.16 mmol) was added and the
reaction mixture was warmed to 20ЊC, and stirred for
30 min. Then, saturated aqueous NaHCO3 (50 ml) was
added and the mixture was extracted with EtOAc
(100 ml). The organic layer was washed with saturated
Na2S2O3 (50 ml) and brine (50 ml). The combined aqueous
layers were extracted with EtOAc (2×100 ml). The
combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography
(silica gel, hexane/EtOAcˆ20!5) provided acetal 11
(2.94 g, 49% from glycerol) as a pale yellow oil. 11: a 1:1
diastereomer mixture; 1H NMR (300 MHz, CDCl3) d 7.31–
7.52 (10H, m), 5.95 (1H, s), 5.81 (1H, s), 4.32–4.46 (2H, m),
4.24 (1H, dd, Jˆ6.6, 8.1 Hz), 4.11 (1H, dd, Jˆ7.0, 8.1 Hz),
3.95 (1H, dd, Jˆ5.5, 8.1 Hz), 3.83 (1H, dd, Jˆ6.8, 8.3 Hz),
3.45–3.63 (4H, m), 3.44 (3H, s), 3.42 (3H, s); IR (film) nmax
2984, 2932, 2884, 1458, 1396, 1220, 1200, 1108, 1072,
1028, 974, 758, 698 cmϪ1; LR-EIMS m/z 71 (33.3%), 91
(bp), 149 (59.9%), 194 (27.0%, M); HR-EIMS calcd for
C11H14O3 [M]: 194.0943, found: 194.0927.
7.19–7.74 (15H, m), 4.60 (2H, s), 3.76 (2H, t, Jˆ7.2 Hz),
3.45–3.59 (4H, m), 3.39 (3H, s), 2.50 (2H, t, Jˆ7.2 Hz),
1.04 (9H, s); IR (film) nmax 3464, 3072, 2932, 2860, 1474,
1456, 1430, 1110, 824, 738, 702, 614 cmϪ1; LR-EIMS m/z
91 (bp, [C7H7]), 199 (87.7%, [Ph2SiOH]), 337 (43.0%,
[TBDPSOC5H6O]), 459 (3.8%, [MϪC2H7O]); HR-EIMS
calcd for C29H35O3Si [MϪC2H7O]: 459.2355, found:
459.2361.
tert-Butyldiphenylsilyl 5,6-dihydroxy-5-methoxymethyl-
hexyl ether (16a). A mixture of 15 (844.2 mg, 1.686 mmol)
and 10% Pd/C (100 mg) in MeOH (15 ml) was stirred at
20ЊC for 8–47 h under a hydrogen atmosphere, and then
the catalyst was removed by filtration through Celite.
Since the benzyl group of 15 resisted hydrogenolysis and
the catalyst lost its activity gradually during the reaction, it
was necessary for completion of the reaction to repeat the
above operation for three times. The filtrate was con-
centrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, hexane/
EtOAcˆ10!0.5) provided diol 16a (491.1 mg, 70%) as a
1
colorless oil and recovered 15 (185.0 mg, 22%). 16a: H
NMR (300 MHz, CDCl3) d 7.30–7.74 (10H, m), 3.66
(2H, t, Jˆ6.2 Hz), 3.58 (2H, Jˆ4.8 Hz), 3.32–3.50 (2H,
m), 3.37 (3H, s), 2.67 (1H, s), 2.35 (1H, dd, Jˆ4.8,
7.7 Hz), 1.36–1.49 (6H, m), 1.04 (9H, s); IR (film) nmax
3420, 3072, 2936, 2896, 2860, 1474, 1464, 1430, 1112,
1062, 1008, 972, 822, 748, 702, 688, 612 cmϪ1; LR-EIMS
m/z 199 (bp, [Ph2SiOH]), 371 (6.6%, [MϪCH2OCH3]), 385
(6.6%, [MϪCH2OH]), 417 (0.2%, [MϩH]); HR-EIMS
calcd for C24H37O4Si [MϩH]: 417.2461, found: 417.2446.
Methyl 6-(tert-butyldiphenylsilyloxy)hexanoate (19). To
a solution of sodium methoxide in methanol, prepared from
sodium (1.037 g, 45.12 mmol) and methanol (90 ml), was
added e-caprolactone (17) (5 ml, 45.12 mmol) at 0ЊC. The
mixture was stirred at 20ЊC for 40 min and then cooled to
0ЊC. To the mixture was added 1 M aqueous HCl (90 ml)
and the mixture was stirred for 20 min and extracted with
ether (200 ml). The organic layer was washed with water
(50 ml) and brine (50 ml), dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to give
crude methyl 6-hydroxyhexanoate (18) (6.737 g). The
alcohol 18, imidazole (6.758 g, 99.27 mmol), and TBDPSCl
(12.9 ml, 49.6 mmol) were dissolved in DMF (7 ml) and the
mixture was stirred at 20ЊC for 2 h. Then, the mixture was
diluted with saturated aqueous NaHCO3 (35 ml) and
extracted with ether (3×150 ml). The combined organic
layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, hexane/
EtOAcˆ5) provided 19 (14.901 g, 86% from e-capro-
lactone) as a colorless oil. 19: 1H NMR (270 MHz,
CDCl3) d 7.30–7.71 (10H, m), 3.66 (3H, s), 3.61–3.69
(2H, m), 2.29 (2H, t, Jˆ7.5 Hz), 1.30–1.69 (6H, m), 1.04
(9H, s); IR (film) nmax 2936, 2860, 1740, 1430, 1196, 1168,
1112, 824, 740, 704, 688, 614 cmϪ1; LR-EIMS m/z 183
(21.2%), 213 (78.4%), 327 (bp), 328 (27.9%), 353
(MϪOMe, 8.3%), 383 (M, 0.09%); HR-EIMS calcd for
C22H29O2Si [MϪOMe]: 353.1937, found: 353.1922.
6-Benzyloxy-5-hydroxy-5-methoxymethyl-3-hexynyl tert-
butyldiphenylsilyl ether (15). To a solution of acetal 11
(1.944 g, 10.01 mmol) and Et3SiH (6.4 ml, 40 mmol) in
CH2Cl2 (50 ml) was added TiCl4 (1.65 ml, 15.0 mmol) at
Ϫ78ЊC. The reaction mixture was stirred for 30 min, diluted
with brine (30 ml) and water (30 ml), and extracted with
CH2Cl2 (5×50 ml). The combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure to provide crude alcohol 13
(2.862 g). To a mixture of the alcohol 13, 4-methylmorpho-
line N-oxide (NMO) (1.81 g, 15.02 mmol), and molecular
˚
sieves 4 A (2 g) in CH2Cl2–MeCN (10:1, 55 ml) was added
tetrapropylammonium perruthenate (TPAP) (0.07 g,
0.2 mmol) at 20ЊC. The reaction mixture was stirred for
2 h and then subjected directly to flash chromatography
(silica gel, ether) to give ketone 14 (2.095 g). To a solution
of 3-butynyl tert-butyldiphenylsilyl ether (6.18 g,
20.02 mmol) in THF (40 ml) was added BuLi (12.5 ml,
1.60 M in hexane, 20.0 mmol) dropwise at Ϫ78ЊC. The
mixture was stirred at Ϫ78ЊC for 1 h and at 0ЊC for
30 min, and then cooled to Ϫ78ЊC again. To the mixture
was added 14 in THF (10 ml) dropwise at Ϫ78ЊC. The
reaction mixture was stirred for 20 min, diluted with brine
(50 ml), and extracted with ether (3×100 ml). The combined
organic layers were dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. Purification of
the residue by flash chromatography (silica gel, hexane/
EtOAcˆ5!EtOAc) provided 15 (2.387 g, 48% from 11)
as a colorless oil. 15: 1H NMR (300 MHz, CDCl3) d
Methyl (2Sء,10Rء)-6-(tert-butyldiphenylsilyloxy)-2-(10-
hydroxyethyl)hexanoate (20). To a solution of 19

K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
1071
(1.94 g, 5.05 mmol) and i-Pr2NEt (1.94 ml, 11.1 mmol) in
CH2Cl2 (25 ml) was added Bu2BOTf (10.1 ml, 1.0 M in
CH2Cl2, 10.1 mmol) dropwise at Ϫ78ЊC, and the mixture
was stirred for 30 min. Then, a solution of acetaldehyde
(0.565 ml, 10.1 mmol) in CH2Cl2 (20 ml) was added drop-
wise, and the mixture was stirred for 1.5 h. Phosphate buffer
(pH 7, 60 ml) and MeOH (120 ml) were added to the stirred
mixture at Ϫ78ЊC and then 36% aqueous H2O2 (30 ml) and
MeOH (60 ml) were added. The mixture was stirred at 0ЊC
for 1 h and then concentrated to the residue, which was
diluted with water (100 ml) and extracted with ether
(3×200 ml). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, hexane/EtOAcˆ2) provided 20
(1.896 g, 88% from 19, syn/antiˆ96:4) as a colorless oil
and recovered 19 (453.0 mg, 23%). 20: 1H NMR
(270 MHz, CDCl3) d 7.31–7.22 (10H, m), 3.98 (1H, dq,
Jˆ4.6, 6.6 Hz), 3.69 (3H, s), 3.65 (2H, t, Jˆ6.5 Hz), 2.41
(1H, dt, Jˆ4.6, 9.9 Hz), 2.31 (1H, d, Jˆ4.6 Hz), 1.22–1.81
(6H, m), 1.18 (3H, d, Jˆ6.6 Hz), 1.04 (9H, s); IR (film) nmax
3460, 2936, 2860, 1738, 1430, 1200, 1166, 1112, 824, 740,
704, 688, 614 cmϪ1; LR-EIMS m/z 95 (48.5%), 199 (bp),
213 (47.4%), 293 (91.1%), 295 (36.3%), 339 (32.0%), 371
(27.7%), 397 (MϪOMe 4.7%), 429 (MϩH, 0.14%);
HR-EIMS calcd for C24H33O3Si [MϪOMe]: 397.2199,
found: 397.2207.
1258, 1192, 1134, 1112, 742, 704 cmϪ1; LR-EIMS m/z 181
(31.1%), 213 (63.9%), 353 (bp), 379 (MϪOMe, 2.95%);
HR-EIMS calcd for C24H31O2Si [MϪOMe]: 379.2093,
found: 379.2100. To
a solution of 20-2 (1.471 g,
3.582 mmol) in CH2Cl2 (20 ml) was added DIBAH
(9.63 ml, 0.93 M in hexane, 8.96 mmol) at Ϫ78ЊC, and
the mixture was stirred for 2.5 h. MeOH (6 ml) was added
dropwise at Ϫ78ЊC and then saturated aqueous potassium
sodium tartrate (10 ml) was added at 20ЊC. The mixture was
stirred for 1 h and extracted with EtOAc (3×100 ml). The
combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, hexane/EtOAcˆ2) provided 21 (1.274 g, 93%) as a
1
colorless oil. 21: H NMR (270 MHz, CDCl3) d 7.30–
7.74 (10H, m), 5.51 (1H, q, Jˆ6.6 Hz), 4.01 (2H, t,
Jˆ6.1 Hz), 2.10 (2H, t, Jˆ7.4 Hz), 1.61 (3H, d,
Jˆ6.6 Hz), 1.13–1.58 (4H, m), 1.04 (9H, s); IR (film)
nmax 3336, 3072, 3052, 2936, 2860, 1474, 1464, 1430,
1392, 1106, 1028, 998, 824, 740, 702, 686, 614 cmϪ1
;
LR-EIMS m/z 67 (53.0%), 81 (20.2%), 109 (bp), 199
(62.1%), 325 (MϪt-Bu, 1.61%); HR-EIMS calcd for
C20H25O2Si [MϪt-Bu]: 325.1624, found: 325.1640.
(Z)-2-[4-(tert-Butyldiphenylsilyloxy)butyl]-2-butenol (22).
A mixture of 20 (1.510 g, 3.526 mmol), DCC (873.0 g,
4.231 mmol), CuCl (453.8 mg, 4.584 mmol), and molecular
˚
sieves 4 A (1.0 g) in benzene (36 ml) was refluxed for 14 h.
(E)-2-[4-(tert-Butyldiphenylsilyloxy)butyl]-2-butenol (21).
A mixture of 20 (2.040 g, 4.764 mmol), Et3N (1.99 ml,
14.3 mmol), and MsCl (0.55 ml, 7.15 mmol) in CH2Cl2
(20 ml) was stirred at 0ЊC for 2 h. Then, the mixture was
diluted with saturated aqueous NaHCO3 (40 ml) and
extracted with CH2Cl2 (3×100 ml). The combined organic
layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, hexane/
EtOAcˆ3) provided methyl (2Sء,10Rء)-6-(tert-butyl-
diphenylsilyloxy)-2-(10-methanesulfonyloxyethyl)hexano-
The mixture was cooled to room temperature and filtered
through Celite. Brine (50 ml) was added to the filtrate, and
the mixture was extracted with EtOAc (3×100 ml). The
combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, hexane/EtOAcˆ5) provided methyl (Z)-2-[4-(tert-
butyldiphenylsilyloxy)butyl]-2-butenoate (20-3) (1.395 g,
1
96%) as a colorless oil. 20-3: H NMR (270 MHz, CDCl3)
d 7.32–7.73 (10H, m), 5.94 (1H, q, Jˆ6.9 Hz), 3.72 (3H, s),
3.65 (2H, t, Jˆ6.1 Hz), 2.23 (2H, t, Jˆ7.0 Hz), 1.94 (3H, d,
Jˆ6.9 Hz), 1.15–1.83 (4H, m), 1.04 (9H, s); IR (film) nmax
2936, 2860, 2120, 1722, 1430, 1256, 1234, 1192, 1148,
1112, 824, 740, 702, 614 cmϪ1; LR-EIMS m/z 183
(21.6%), 213 (65.2), 353 (MϪt-Bu, bp); HR-EIMS calcd
for C21H25O3Si [MϪt-Bu]: 353.1473, found: 353.1560. To
a solution of 20-3 (1.233 g, 3.003 mmol) in CH2Cl2 (20 ml)
was added DIBAH (8.07 ml, 0.93 M in hexane, 7.51 mmol)
at Ϫ78ЊC, and the mixture was stirred for 75 min. MeOH
(7 ml) was added dropwise at Ϫ78ЊC and then saturated
aqueous potassium sodium tartrate (80 ml) was added at
20ЊC. The mixture was stirred for 2 h and extracted with
EtOAc (3×150 ml). The combined organic layers were dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash chro-
matography (silica gel, hexane/EtOAcˆ5) provided 22
1
ate (20-1) (2.333 g, 97%) as a pale yellow oil. 20-1: H
NMR (270 MHz, CDCl3) d 7.31–7.76 (10H, m), 4.92
(1H, qn, Jˆ6.6 Hz), 3.70 (3H, s), 3.64 (2H, t, Jˆ6.1 Hz),
3.00 (3H, s), 2.65 (1H, ddd, Jˆ3.9, 6.6, 10.4 Hz), 1.44 (3H,
d, Jˆ6.6 Hz), 1.19–1.80 (6H, m), 1.04 (9H, s); IR (film)
nmax 2936, 2860, 1740, 1430, 1388, 1360, 1202, 1178,
1112, 974, 914, 822, 742, 704, 688, 614 cmϪ1; LR-EIMS
m/z 95 (47.0%), 213 (51.5%), 277 (33.0%), 353 (bp), 354
(27.8%), 475 (MϪOMe, 1.88%); HR-EIMS calcd for
C25H35O5SiS [MϪOMe]: 475.1974, found: 475.1977.
Next, a mixture of 20-1 (2.437 g, 4.810 mmol) and DBU
(2.45 ml, 16.36 mmol) in CH2Cl2 (12 ml) was stirred at
20ЊC for 15 h. Then, the mixture was diluted with 0.5 M
aqueous HCl (50 ml) and extracted with CH2Cl2
(3×100 ml). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, hexane/EtOAcˆ2) provided methyl
(E)-2-[4-(tert-butyldiphenylsilyloxy)butyl]-2-butenoate
1
(1.035 g, 90%) as a colorless oil. 22: H NMR (270 MHz,
CDCl3) d 7.33–7.74 (10H, m), 5.37 (1H, q, Jˆ6.9 Hz), 4.14
(2H, d, Jˆ4.6 Hz), 3.67 (2H, t, Jˆ6.3 Hz), 2.09 (2H, t,
Jˆ7.3 Hz), 1.68 (3H, d, Jˆ6.9 Hz), 0.85–1.62 (4H, m),
1.04 (9H, s); IR (film) nmax 3328, 3072, 3052, 2940, 2860,
1474, 1464, 1430, 1112, 740, 702, 688, 614 cmϪ1; LR-
EIMS m/z 67 (16.6%), 109 (bp), 139 (17.4%), 199
(98.0%), 325 (MϪt-Bu, 5.09%); HR-EIMS calcd for
C20H25O2Si [MϪt-Bu]: 325.1624, found: 325.1622.
1
(20-2) (1.847 g, 94%) as a colorless oil. 20-2: H NMR
(270 MHz, CDCl3) d 7.31–7.73 (10H, m), 6.85 (1H, q,
Jˆ7.3 Hz), 3.71 (3H, s), 3.66 (2H, t, Jˆ6.0 Hz), 2.30 (2H,
t, Jˆ7.5 Hz), 1.77 (3H, d, Jˆ7.3 Hz), 1.17–1.66 (4H, m),
1.04 (9H, s); IR (film) nmax 2948, 2860, 1716, 1430, 1280,

1072
K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
(2Rء,3Rء)-2-[4-(tert-Butyldiphenylsilyloxy)butyl]-1-
methoxybutane-2,3-diol (16b). A mixture of 21 (1.124 g,
2.938 mmol), MeI (0.55 ml, 8.8 mmol), and t-BuOK
(659.4 mg, 5.88 mmol) in THF (20 ml) was stirred at 20ЊC
for 30 min. The reaction was quenched with saturated
aqueous NaHCO3 (50 ml). After extractive work up
(AcOEt×3), the combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, hexane/EtOAcˆ5) provided (E)-2-[4-
(tert-butyldiphenylsilyloxy)butyl]-1-methoxy-2-butene
4.337 mmol), BnBr (0.77 ml, 6.5 mmol), TBAI (1.6 g,
4.6 mmol), and NaH (60% in mineral oil, 312.3 mg,
7.81 mmol) in THF (50 ml) was stirred at 20ЊC for 1 h.
The reaction was quenched with saturated aqueous
NaHCO3 (50 ml). After extractive work up (AcOEt×3),
the combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, hexane/EtOAcˆ5) provided an inseparable mixture of
(E)-1-benzyloxy-2-[4-(tert-butyldiphenylsilyloxy)butyl]-2-
butene (21-2) and BnBr (2.867 g) as well as recovered 21
(215.8 mg, 13%). 21-2: 1H NMR (270 MHz, CDCl3) d
7.22–7.70 (15H, m), 5.54 (1H, q, Jˆ6.8 Hz), 4.43 (2H, s),
3.90 (2H, s), 3.66 (2H, t, Jˆ6.2 Hz), 2.11 (2H, t, Jˆ7.6 Hz),
1.62 (3H, d, Jˆ6.8 Hz), 1.39–1.60 (4H, m), 1.04 (9H, s).
The above mixture of 21-2 and BnBr, NMO (1.21 g,
10.33 mmol), and OsO4 (5 mg/ml in t-BuOH, 11.7 ml,
0.23 mmol) was dissolved in 1,4-dioxane–water (3:1,
60 ml) and the mixture was stirred at 20ЊC for 3 h. Then,
the mixture was treated with saturated aqueous Na2S2O3
(50 ml) and stirred for 30 min. After extractive workup
(EtOAc×3), the combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, hexane/EtOAcˆ5!2) provided diol
1
(21-1) (1.142 g, 98%) as a pale yellow oil. 21-1: H NMR
(270 MHz, CDCl3) d 7.31–7.74 (10H, m), 5.50 (1H, q,
Jˆ6.5 Hz), 3.79 (2H, s), 3.67 (2H, t, Jˆ6.1 Hz), 3.26 (3H,
s), 2.07 (2H, t, Jˆ7.6 Hz), 1.62 (3H, d, Jˆ6.5 Hz), 1.19–
1.58 (4H, m), 1.04 (9H, s); IR (film) nmax 2936, 2860, 2820,
1430, 1112, 824, 740, 702, 614 cmϪ1; LR-EIMS m/z 109
(bp), 339 (23.6%, [MϪt-Bu]), 396 (0.3%, [M]); HR-EIMS
calcd for C25H36O2Si [M]: 396.2485, found: 396.2490.
Next, a mixture of 21-1 (1.199 g, 3.024 mmol), NMO
(0.80 g, 6.80 mmol), and OsO4 (5 mg/ml in t-BuOH,
7.57 ml, 0.151 mmol) in 1,4-dioxane–H2O (2.8:1, 47.5 ml)
was stirred at 20ЊC for 1 h. Then, the mixture was treated
with saturated aqueous Na2S2O3 (80 ml) and stirred for
20 min. After extractive workup (EtOAc×3), the combined
organic layers were dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, hexane/
EtOAcˆ2) provided diol 16b (1.332 g, ϳ100%) as a pale
1
16d (1.620 g, 70% from 21) as a colorless oil. 16d: H
NMR (300 MHz, CDCl3) d 7.60–7.69 (4H, m), 7.27–7.46
(11H, m), 4.56 (1H, d, Jˆ11.8 Hz), 4.49 (1H, d,
Jˆ11.8 Hz), 2.90 (1H, d, Jˆ3.5 Hz), 2.63 (1H, s), 1.29–
1.64 (6H, m), 1.10 (3H, d, Jˆ6.4 Hz), 1.04 (9H, s); IR
(film) nmax 3456, 2936, 2860, 1430, 1112, 738, 700,
614 cmϪ1; LR-EIMS m/z 91 (bp), 199 (29.5%), 461
(MϪCH3CHOH, 1.58%); HR-EIMS calcd for C29H37O3Si
[MϪCH3CHOH]: 461.2512, found: 461.2487.
1
yellow oil. 16b: H NMR (300 MHz, CDCl3) d 7.63–7.69
(4H, m), 7.33–7.46 (6H, m), 3.84 (1H, dq, Jˆ3.5, 6.4 Hz),
3.67 (2H, t, Jˆ6.3 Hz), 3.46 (1H, d, Jˆ9.4 Hz), 3.40 (1H, d,
Jˆ9.4 Hz), 3.37 (3H, s), 2.62 (1H, s), 1.25–1.65 (6H, m),
1.12 (3H, d, Jˆ6.4 Hz), 1.05 (9H, s); IR (film) nmax 3456,
2396, 2864, 1430, 1112, 740, 702 cmϪ1; LR-EIMS m/z 199
(bp, [Ph2SiOH]), 385 (22.1%, [MϪCH2OCH3]); HR-EIMS
calcd for C23H33O3Si [MϪCH2OCH3]: 385.2199, found:
385.2195.
(2Rء,3Sء)-2-[4-(tert-Butyldiphenylsilyloxy)butyl]-1-
benzyloxybutane-2,3-diol (16e) was prepared from 22 via
(Z)-1-benzyloxy-2-[4-(tert-butyldiphenylsilyloxy)butyl]-2-
butene (22-2) in 78% yield similarly as described for 16d.
(2Rء,3Sء)-2-[4-(tert-Butyldiphenylsilyloxy)butyl]-1-
methoxybutane-2,3-diol (16c) was prepared from 22 via
(Z)-2-[4-(tert-butyldiphenylsilyloxy)butyl]-1-methoxy-2-
butene (22-1) in 89% yield (22!22-1: 92%, 22-1!16c:
97%) similarly as described for 16b. 22-1: a colorless oil;
1H NMR (270 MHz, CDCl3) d 7.31–7.75 (10H, m), 5.44
(1H, q, Jˆ6.9 Hz), 3.91 (2H, s), 3.66 (2H, t, Jˆ6.3 Hz), 3.28
(3H, s), 2.05 (2H, brt, Jˆ7.1 Hz), 1.66 (3H, d, Jˆ6.9 Hz),
1.20–1.61 (4H, m), 1.04 (9H, s); IR (film) nmax 2932, 2896,
2860, 1430, 1112, 824, 740, 702, 614 cmϪ1; LR-EIMS m/z
109 (bp), 339 (21.6%, [MϪt-Bu]), 396 (0.4%, [M]); HR-
EIMS calcd for C25H36O2Si [M]: 396.2485, found:
396.2494. 16c: a colorless oil; 1H NMR (270 MHz,
CDCl3) d 7.32–7.72 (10H, m), 3.60–3.72 (1H, m), 3.66
(2H, t, Jˆ6.6 Hz), 3.56 (1H, d, Jˆ9.6 Hz), 3.37 (3H, s),
3.33 (1H, d, Jˆ9.6 Hz), 1.33–1.65 (6H, m), 1.18 (3H, d,
Jˆ6.6 Hz), 1.04 (9H, s); IR (film) nmax 3456, 2936, 2864,
1430, 1112, 740, 702 cmϪ1; LR-EIMS m/z 199 (bp,
[Ph2SiOH]), 385 (29.3%, [MϪCH2OCH3]); HR-EIMS
calcd for C23H33O3Si [MϪCH2OCH3]: 385.2199, found:
385.2196.
22-2: a colorless oil; H NMR (300 MHz, CDCl3) d 7.61–
1
7.70 (6H, m), 7.20–7.45 (9H, m), 5.44 (1H, q, Jˆ6.8 Hz),
4.58 (1H, d, Jˆ9.0 Hz), 4.45 (1H, d, Jˆ9.0 Hz), 4.00 (2H,
s), 3.65 (2H, t, Jˆ6.1 Hz), 2.09 (2H, t, Jˆ6.6 Hz), 1.62 (3H,
1
d, Jˆ6.8 Hz), 1.40–1.59 (4H, m), 1.04 (9H, s). 16e: H
NMR (300 MHz, CDCl3) d 7.60–7.71 (6H, m), 7.27–7.47
(9H, m), 4.14 (1H, d, Jˆ7.2 Hz), 4.09 (1H, d, Jˆ7.2 Hz),
3.68 (1H, q, Jˆ6.6 Hz), 3.65 (2H, t, Jˆ6.4 Hz), 3.63 (1H, d,
Jˆ9.4 Hz), 3.43 (1H, d, Jˆ9.4 Hz), 3.12 (1H, s), 1.30–1.60
(6H, m), 1.15 (3H, d, Jˆ6.6 Hz), 1.04 (9H, s); IR (film) nmax
3448, 2936, 2960, 1430, 1112, 740, 702, 612 cmϪ1; LR-
EIMS m/z 91 (bp), 199 (34.0%), 461 (MϪCH3CHOH,
2.69%); HR-EIMS calcd for C29H37O3Si [MϪCH3CHOH]:
461.2512, found: 461.2504.
tert-Butyldiphenylsilyl 5-hexen-1-yl ether (24). A mixture
of 5-hexenol (23) (1.1 ml, 9.16 mmol), imidazole (1.277 g,
18.76 mmol), and TBDPSCl (2.4 ml, 9.23 mmol) in DMF
(0.5 ml) was stirred at 20ЊC for 40 min. The reaction
mixture was purified directly by flash chromatography
(silica gel, hexane/EtOAcˆ10) to provide 24 as a colorless
oil (2.973 g, 94%). 24: 1H NMR (300 MHz, CDCl3) d 7.63–
7.70 (4H, m), 7.33–7.46 (6H, m), 5.79 (1H, tdd, Jˆ6.6,
10.1, 17.1 Hz), 4.90–5.03 (2H, m), 3.66 (2H, t,
(2Rء,3Rء)-2-[4-(tert-Butyldiphenylsilyloxy)butyl]-1-
benzyloxybutane-2,3-diol (16d). A mixture of 21 (1.660 g,

K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
1073
Jˆ6.2 Hz), 2.04 (2H, brq, Jˆ7.1 Hz), 1.40–1.63 (4H, m),
1.05 (9H, s); IR (film) nmax 3072, 3051, 2999, 2931, 2986,
2858, 1472, 1463, 1428, 1389, 1112, 1007, 998, 910, 823,
741, 724, 701, 688, 622, 614 cmϪ1; LR-EIMS m/z 199
(54.7%, C12H11OSi), 281 (bp, [MϪt-Bu]); HR-EIMS calcd
for C18H21OSi [MϪt-Bu]: 281.1362, found: 281.1313.
(3H, s), 1.49–1.73 (4H, m), 1.04 (9H, s); IR (film) nmax
3071, 3049, 3014, 2999, 2954, 2931, 2894, 2858, 1718,
1472, 1463, 1428, 1410, 1389, 1361, 1189, 1162, 1112,
1029, 1008, 998, 823, 741, 702, 688, 622, 614 cmϪ1; LR-
EIMS m/z 199 (bp, C12H11OSi), 297 (79.2%, [MϪt-Bu]);
HR-EIMS calcd for C18H21O2Si [MϪt-Bu]: 297.1311,
found: 297.1315. To Cp2TiCl2 (1.062 g, 4.265 mmol) was
added AlMe3 (2.0 M in toluene, 4.23 ml, 8.46 mmol)
dropwise at 20ЊC, and the mixture was stirred for 91 h.
Then, 25-1 (998.7 mg, 2.820 mmol) in THF (8 ml) was
added at 20ЊC. After 10 min, 2 M aqueous NaOH (ca.
1 ml) was added dropwise until the evolution of CH4 ceased.
Then, anhydrous MgSO4 was added. The mixture was
filtered through Celite and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, hexane/EtOAcˆ10) provided 26
(918.9 mg, 92%) as a pale yellow oil. 26: 1H NMR
(300 MHz, CDCl3) d 7.64–7.70 (4H, m), 7.33–7.46 (6H,
m), 4.69 (1H, brs), 4.64 (1H, brs), 3.67 (2H, t, Jˆ6.1 Hz),
1.99 (2H, brt, Jˆ6.9 Hz), 1.70 (3H, s), 1.44–1.62 (4H, m),
1.05 (9H, s); IR (film) nmax 3071, 3050, 3015, 2999, 2932,
2895, 2858, 1649, 1590, 1487, 1472, 1462, 1428, 1389,
1374, 1362, 1188, 1112, 1037, 1030, 1007, 998, 978, 887,
823, 766, 740, 723, 701, 688, 622, 614 cmϪ1; LR-EIMS m/z
199 (45.0%, C12H11OSi), 295 (bp, [MϪt-Bu]); HR-EIMS
calcd for C19H23OSi [MϪt-Bu]: 295.1518, found: 295.1524.
tert-Butyldiphenylsilyl 5-hydroxyhexyl ether (25). A
mixture of 24 (2.917 g, 8.616 mmol) and m-CPBA (75%
w/w, 2.447 g, 10.635 mmol) in CH2Cl2 (30 ml) was stirred
at 20ЊC for 3 h. The mixture was diluted with hexane
(50 ml), washed with 1 M aqueous NaOH (2×20 ml),
dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by
flash chromatography (silica gel, hexane/EtOAcˆ10)
provided tert-butyldiphenylsilyl 5,6-epoxyhexyl ether
1
(24-1) as a colorless oil (2.866 g, 94%). 24-1: H NMR
(300 MHz, CDCl3) d 7.63–7.70 (4H, m), 7.33–7.46 (6H,
m), 3.67 (2H, t, Jˆ6.1 Hz), 2.85–2.93 (1H, m), 2.73 (1H,
dd, Jˆ4.0, 5.1 Hz), 2.44 (1H, dd, Jˆ2.8, 5.1 Hz), 1.47–1.68
(6H, m), 1.05 (9H, s); IR (film) nmax 3071, 3048, 3014,
2998, 2931, 2858, 1472, 1462, 1428, 1389, 1112, 1008,
998, 823, 741, 702, 688, 622, 614 cmϪ1; LR-EIMS m/z
199 (bp, C12H11OSi), 297 (69.9%, [MϪt-Bu]); HR-EIMS
calcd for C18H21O2Si [MϪt-Bu]: 297.1311, found:
297.1319. To a stirred solution of LiEt3BH (1.0 M in
THF, 12.1 ml, 12.1 mmol) in THF (12 ml) was added 24-1
(2.858 g, 8.060 mmol) in THF (15 ml) dropwise at 0ЊC.
After 1 h, the mixture was diluted with brine (20 ml) and
extracted with ether (3×10 ml). The combined organic
layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, hexane/
EtOAcˆ5) provided 25 as a colorless oil (2.813 g 98%).
6-(tert-Butyldiphenylsilyloxy)-2-methylhexane-1,2-diol
(16f). To a mixture of 26 (914.0 mg, 2.592 mmol) and NMO
(616.0 mg, 5.258 mmol) in 1,4-dioxane–H2O (3:1, 24 ml)
was added OsO4 (0.02 M in t-BuOH, 6.6 ml, 0.13 mmol) at
20ЊC, and the mixture was stirred for 1.5 h. Then, the
mixture was treated with saturated aqueous Na2S2O3
(5 ml), stirred for 30 min, diluted with brine (15 ml), and
extracted with EtOAc (3×15 ml). The combined organic
layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, hexane/
EtOAcˆ1) provided 16f (1.001 g, ϳ100%) as a colorless
oil. 16f: 1H NMR (300 MHz, CDCl3) d 7.64–7.70 (4H, m),
7.33–7.46 (6H, m), 3.68 (2H, t, Jˆ6.3 Hz), 3.44 (1H, dd,
Jˆ5.9, 10.8 Hz), 3.39 (1H, dd, Jˆ6.1, 10.8 Hz), 1.79 (1H,
brt, Jˆ6.0 Hz, OH), 1.71 (1H, s, OH), 1.53–1.63 (2H, m),
1.35–1.51 (4H, m), 1.15 (3H, s), 1.05 (9H, s); IR (film) nmax
3386, 3071, 3049, 2932, 2858, 1472, 1463, 1428, 1389,
1362, 1112, 1060, 1008, 998, 823, 741, 701, 688, 622,
614 cmϪ1; LR-EIMS m/z 199 (bp, C12H11OSi), 311
(33.9%, [MϪC3H7O2]), 371 (0.31%, [MϪCH3]), 387
(0.14%, [MϩH]); HR-EIMS calcd for C22H31O3Si
[MϪCH3]: 371.2042, found: 371.2027; calcd for
C23H35O3Si [MϩH]: 387.2355, found: 387.2324.
1
25: H NMR (300 MHz, CDCl3) d 7.63–7.70 (4H, m),
7.33–7.46 (6H, m), 3.70–3.84 (1H, m), 3.67 (2H, t,
Jˆ6.3 Hz), 1.64–1.32 (6H, m), 1.27 (1H, d, Jˆ4.6 Hz,
OH), 1.17 (3H, d, Jˆ6.1 Hz), 1.05 (9H, s); IR (film) nmax
3346, 3071, 3049, 2960, 2931, 2858, 1472, 1462, 1428,
1389, 1112, 823, 741, 701, 688, 622, 614 cmϪ1; LR-EIMS
m/z 199 (bp, C12H11OSi), 299 (33.1%, [MϪt-Bu]); HR-
EIMS calcd for C18H23O2Si [MϪt-Bu]: 299.1467, found:
299.1457.
tert-Butyldiphenylsilyl 5-methyl-5-hexen-1-yl ether (26).
To oxalyl chloride (1.03 ml, 11.8 mmol) in CH2Cl2 (60 ml)
was added DMSO (1.34 ml, 18.9 mmol) in CH2Cl2 (10 ml)
dropwise at Ϫ78ЊC and the reaction mixture was stirred for
10 min. Then, 25 (2.807 mg, 7.873 mmol) in CH2Cl2
(15 ml) was added dropwise at Ϫ78ЊC. The mixture was
stirred for 30 min. Et3N (5.5 ml, 39.5 mmol) was added
dropwise at Ϫ78ЊC and the mixture was warmed to 0ЊC
and stirred for 1 h. Then, the mixture was treated with
water (50 ml), diluted with hexane (100 ml), and washed
with 1 M aqueous HCl (2×50 ml), saturated aqueous
NaHCO3 (50 ml), and brine (50 ml). The organic layer
was dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by
flash chromatography (silica gel, hexane/EtOAcˆ10!3)
provided tert-butyldiphenylsilyl 5-oxohexyl ether (25-1)
(2.113 g, 76%) as a colorless oil. 25-1: 1H NMR
(300 MHz, CDCl3) d 7.62–7.69 (4H, m), 7.33–7.46 (6H,
m), 3.66 (2H, t, Jˆ6.1 Hz), 2.40 (2H, t, Jˆ7.2 Hz), 2.11
4-[4-(tert-Butyldiphenylsilyloxy)butyl]-2,2-dimethyl-4-
methoxymethyl-1,3-dioxolane (27a). A mixture of 16a
(428.4 mg, 1.028 mmol), 2,2-dimethoxypropane (0.63 ml,
5.1 mmol), and PPTS (12.9 mg, 0.0513 mmol) in CH2Cl2
(15 ml) was stirred at 20ЊC for 1 h. The reaction was
quenched with saturated aqueous NaHCO3 (30 ml). After
extractive work up (CH2Cl2×3), the combined organic
layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, hexane/
EtOAcˆ5) provided acetal 27a (458.0 mg, 98%) as a

1074
K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
colorless oil. 27a: 1H NMR (300 MHz, CDCl3) d 7.30–7.71
(10 H, m), 3.90 (1H, d, Jˆ8.6 Hz), 3.71 (1H, d, Jˆ8.6 Hz),
3.67 (2H, t, Jˆ6.2 Hz), 3.36 (3H, s), 3.30 (2H, s), 1.40 (3H,
s), 1.37 (3H, s), 1.16–1.68 (6H, m), 1.04 (9H, s); IR (film)
nmax 2988, 2936, 2896, 2864, 1430, 1214, 1114, 1056, 824,
702, 614 cmϪ1; LR-EIMS m/z 309 (bp), 399 (36.2%, [MϪt-
Bu]), 411 (25.8%, [MϪCH2OCH3]), 441 (21.7%,
[MϪCH3]); HR-EIMS calcd for C26H37O4Si [MϪCH3]:
441.2461, found: 441.2464.
2,2,5-Trimethyl-5-[4-(tert-butyldiphenylsilyloxy)butyl]-
1,3-dioxolane (27f) was prepared from 16f in 96% yield
similarly as described for 27a. 27f: a colorless oil; 1H
NMR (300 MHz, CDCl3) d 7.64–7.70 (4H, m), 7.33–7.46
(6H, m), 3.75 (1H, d, Jˆ8.3 Hz), 3.68 (1H, d, Jˆ8.3 Hz),
3.66 (1H, t, Jˆ6.2 Hz), 1.34–1.63 (6H, m), 1.40 (3H, s),
1.36 (3H, s), 1.25 (3H, s), 1.04 (9H, s); IR (film) nmax 3071,
3050, 2981, 2932, 2859, 1472, 1462, 1428, 1377, 1368,
1243, 1212, 1158, 1112, 1061, 1008, 998, 984, 862, 823,
808, 741, 702, 688, 614 cmϪ1; LR-EIMS m/z 199 (73.8%,
C12H11OSi), 311 (bp, [MϪC6H11O2]), 411 (6.9%,
(4Rء,5Rء)-2,2,5-Trimethyl-4-[4-(tert-butyldiphenylsilyl-
oxy)butyl]-4-methoxymethyl-1,3-dioxolane (27b) was
prepared from 16b in 89% yield similarly as described for
[MϪCH3]);
HR-EIMS
calcd
for
C25H35O3Si
[MϪCH3]:411.2355, found: 411.2365.
1
27a. 27b: a colorless oil; H NMR (270 MHz, CDCl3) d
7.31–7.73 (10H, m), 4.15 (1H, q, Jˆ6.6 Hz), 3.67 (2H, t,
Jˆ6.3 Hz), 3.40 (1H, d, Jˆ9.6 Hz), 3.28 (1H, d, Jˆ9.6 Hz),
3.33 (3H, s), 1.41 (3H, s), 1.35 (3H, s), 1.15–1.63 (6H, m),
2,2-Dimethyl-4-(4-hydroxybutyl)-4-methoxymethyl-1,3-
dioxolane (28a). To a solution of 27a (1.255 g, 2.75 mmol)
in THF (20 ml) was added TBAF (6.04 ml, 1.0 M in THF,
6.04 mmol) at 0ЊC, and the mixture was stirred at 20ЊC for
1.5 h. Then, saturated NaHCO3 (20 ml) and brine (20 ml)
were added and the resulting mixture was extracted with
ether (4×50 ml). The combined organic layers were dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash
chromatography (silica gel, hexane/EtOAcˆ5!0.25)
provided alcohol 28a (588.0 mg, 98%) as a colorless oil.
28a: 1H NMR (300 MHz, CDCl3) d 3.92 (1H, d,
Jˆ8.7 Hz), 3.73 (1H, d, Jˆ8.7 Hz), 3.66 (2H, t,
Jˆ6.3 Hz), 3.37 (3H, s), 3.32 (2H, s), 1.40 (3H, s), 1.38
(3H, s), 1.19–1.74 (6H, m); IR (film) nmax 3436, 2988,
2940, 2872, 1382, 1372, 1256, 1214, 1176, 1154, 1112,
1.04 (9H, s); IR (film) nmax 2936, 2864, 1114, 702 cmϪ1
;
LR-EIMS m/z 213 (bp), 323 (31.5%), 355 (15.9%), 367
(8.8%), 413 (14.0%), 455 (9.8%, [MϪCH3]); HR-EIMS
calcd for C27H39O4Si [MϪCH3]: 455.2617, found:
455.2604.
(4Rء,5Sء)-2,2,5-Trimethyl-4-[4-(tert-butyldiphenylsilyl-
oxy)butyl]-4-methoxymethyl-1,3-dioxolane (27c) was
prepared from 16c in 81% yield similarly as described for
1
27a. 27c: a colorless oil; H NMR (270 MHz, CDCl3) d
7.31–7.76 (10H, m), 3.98 (1H, q, Jˆ6.6 Hz), 3.67 (2H, d,
Jˆ6.1 Hz), 3.32 (1H, d, Jˆ9.2 Hz), 3.31 (3H, s), 3.20 (1H,
d, Jˆ9.2 Hz), 1.46–1.82 (6H, m), 1.42 (3H, s), 1.33 (3H, s),
1.23 (2H, d, Jˆ6.6 Hz), 1.04 (9H, s); IR (film) nmax 2988,
2940, 2896, 2864, 1432, 1380, 1248, 1218, 1188, 1112,
1006, 702, 614 cmϪ1; LR-EIMS m/z 213 (bp), 323
(79.5%), 355 (56.4%), 367 (43.9%), 413 (20.8%), 425
(15.0%), 455 (23.7%, [MϪCH3]); HR-EIMS calcd for
C27H39O4Si [MϪCH3]: 455.2617, found: 455.2624.
1058 cmϪ1
; LR-EIMS m/z 115 (bp), 173 (41.2%,
[MϪCH2OCH3]), 203 (45.5%, [MϪCH3]); HR-EIMS
calcd for C10H19O4 [MϪCH3]: 203.1283, found: 203.1281.
(4Rء,5Rء)-2,2,5-Trimethyl-4-(4-hydroxybutyl)-4-methoxy-
methyl-1,3-dioxolane (28b) was prepared from 27b in 92%
yield similarly as described for 28a. 28b: a colorless oil; 1H
NMR (270 MHz, CDCl3) d 4.16 (1H, q, Jˆ6.6 Hz), 3.60–
3.72 (2H, m), 3.44 (1H, d, Jˆ9.6 Hz), 3.28 (1H, d,
Jˆ9.6 Hz), 3.35 (3H, s), 1.16–1.66 (6H, m), 1.42 (3H, s),
1.36 (3H, s), 1.24 (3H, d, Jˆ6.6 Hz); IR (film) nmax 3440,
2988, 2940, 2872, 1380, 1372, 1248, 1216, 1190, 1112,
1032 cmϪ1; LR-EIMS m/z 129 (bp), 157 (38.4%), 187
(26.1%), 217 (75.9%, [MϪCH3]); HR-EIMS calcd for
C11H21O4 [MϪCH3]: 217.1440, found: 217.1427.
(4Rء,5Rء)-2,2,5-Trimethyl-4-[4-(tert-butyldiphenylsilyl-
oxy)butyl]-4-benzyloxymethyl-1,3-dioxolane (27d) was
prepared from 16d in 96% yield similarly as described for
1
27a. 27d: a colorless oil; H NMR (300 MHz, CDCl3) d
7.59–7.70 (4H, m), 7.19–7.47 (11H, m), 4.55 (1H, d,
Jˆ12.2 Hz), 4.46 (1H, d, Jˆ12.2 Hz), 4.19 (1H, q,
Jˆ6.6 Hz), 3.65 (2H, t, Jˆ6.2 Hz), 3.49 (1H, d,
Jˆ9.7 Hz), 3.36 (1H, d, Jˆ9.7 Hz), 1.18–1.64 (6H, m),
1.40 (3H, s), 1.35 (3H, s), 1.23 (3H, d, Jˆ6.6 Hz), 1.04
(9H, s); IR (film) nmax 3072, 2984, 2936, 2860, 1430,
1246, 1214, 1194, 1110, 702, 612 cmϪ1; LR-EIMS m/z 91
(bp), 263 (87.7%), 531 (MϪCH3, 7.3%); HR-EIMS calcd
for C33H43O4Si [MϪCH3]: 531.2931, found: 531.2961.
(4Rء,5Sء)-2,2,5-Trimethyl-4-(4-hydroxybutyl)-4-methoxy-
methyl-1,3-dioxolane (28c) was prepared from 27c in
ϳ100% yield similarly as described for 28a. 28c: a colorless
oil; 1H NMR (270 MHz, CDCl3) d 3.98 (1H, q, Jˆ6.6 Hz),
3.67 (2H, t, Jˆ6.3 Hz), 3.34 (1H, d, Jˆ9.6 Hz), 3.32 (3H, s),
3.22 (1H, d, Jˆ9.6 Hz), 1.44–1.84 (6H, m), 1.42 (3H, s),
1.35 (3H, s), 1.24 (3H, d, Jˆ6.6 Hz); IR (film) nmax 3432,
2988, 2940, 1460, 1380, 1250, 1218, 1186, 1154, 1112,
1072, 1034, 1006, 860 cmϪ1; LR-EIMS m/z 129 (bp), 157
(9.8%), 187 (24.8%), 217 (25.4%, [MϪCH3]); HR-EIMS
calcd for C11H21O4 [MϪCH3]: 217.1440, found: 217.1450.
(4Rء,5Sء)-2,2,5-Trimethyl-4-[4-(tert-butyldiphenylsilyl-
oxy)butyl]-4-benzyloxymethyl-1,3-dioxolane (27e) was
prepared from 16e in 96% yield similarly as described for
1
27a. 27e: a colorless oil; H NMR (300 MHz, CDCl3) d
7.60–7.70 (6H, m), 7.21–7.46 (9H, s), 4.49 (2H, s), 3.97
(1H, q, Jˆ6.4 Hz), 3.66 (2H, t, Jˆ6.2 Hz), 3.40 (1H, d,
Jˆ9.3 Hz), 3.26 (1H, d, Jˆ9.3 Hz), 1.42–1.80 (6H, m),
1.39 (3H, s), 1.33 (3H, s), 1.24 (3H, d, Jˆ6.4 Hz), 1.04
(9H, s); IR (film) nmax 2988, 2936, 2904, 2860, 1112, 700,
612 cmϪ1; LR-EIMS m/z 91 (bp), 263 (68.5%), 531
(MϪCH3, 4.7%); HR-EIMS calcd for C33H43O4Si
[MϪCH3]: 531.2931, found: 531.2923.
(4Rء,5Rء)-2,2,5-Trimethyl-4-(4-hydroxybutyl)-4-benzyl-
oxymethyl-1,3-dioxolane (28d) was prepared from 27d in
ϳ100% yield similarly as described for 28a. 28d: a color-
less oil; 1H NMR (300 MHz, CDCl3) d 7.27–7.40 (5H, m),
4.57 (1H, d, Jˆ12.1 Hz), 4.47 (1H, d, Jˆ12.1 Hz), 4.19 (1H,

K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
1075
q, Jˆ6.4 Hz), 3.64 (2H, brm), 3.53 (1H, d, Jˆ9.5 Hz), 3.36
(1H, d, Jˆ9.5 Hz), 1.44–1.65 (6H, m), 1.42 (3H, s), 1.35
(3H, s), 1.25 (3H, d, Jˆ6.4 Hz); IR (film) nmax 3432, 2988,
2940, 2868, 1380, 1370, 1246, 1218, 1192, 1104,
1030 cmϪ1; LR-EIMS m/z 91 (bp), 129 (54.9%), 293
(MϪCH3, 8.8%); HR-EIMS calcd for C17H25O4
[MϪCH3]: 293.1753, found: 293.1764.
(3×150 ml). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification of the resultant residue by flash
chromatography (silica gel, hexane/EtOAcˆ3) provided
1
29b (570.3 mg, 90%) as a brownish yellow oil. 29b: H
NMR (270 MHz, CDCl3) d 9.78 (1H, brs), 4.15 (1H, q,
Jˆ6.3 Hz), 3.45 (1H, d, Jˆ9.6 Hz), 3.29 (1H, d,
Jˆ9.6 Hz), 3.35 (3H, s), 2.47 (2H, brt, Jˆ6.8 Hz), 1.12–
1.95 (4H, m), 1.43 (3H, s), 1.36 (3H, s), 1.23 (3H, d,
Jˆ6.3 Hz); IR (film) nmax 2988, 2940, 2888, 1730,
1114 cmϪ1; LR-EIMS m/z 127 (94.9%), 185 (94.9%,
[MϪC2H5O]), 215 (bp, [MϪCH3]); HR-EIMS calcd for
C11H19O4 [MϪCH3]: 215.1283, found: 215.1277.
(4Rء,5Sء)-2,2,5-Trimethyl-4-(4-hydroxybutyl)-4-benzyl-
oxymethyl-1,3-dioxolane (28e) was prepared from 27e in
92% yield similarly as described for 28a. 28e: a colorless
1
oil; H NMR (270 MHz, CDCl3) d 7.24–7.38 (5H, m),
4.45–4.46 (2H, m), 3.98 (1H, q, Jˆ6.4 Hz), 3.64 (2H, m),
3.42 (1H, d, Jˆ9.2 Hz), 3.28 (1H, d, Jˆ9.2 Hz), 1.39 (3H,
s), 1.34 (3H, s), 1.26 (3H, d, Jˆ6.4 Hz), 1.18–1.88 (6H, m);
IR (film) nmax 3440, 2988, 2940, 2868, 1456, 1380, 1248,
1216, 1190, 1102, 1030, 1008, 736, 698 cmϪ1; LR-EIMS
m/z 91 (bp), 129 (81.6%), 293 (MϪCH3, 15.1%); HR-EIMS
calcd for C17H25O4 [MϪCH3]: 293.1753, found: 293.1722.
(40Rء,50Sء)-4-(20,20,50-Trimethyl-40-methoxymethyl-
10,30-dioxolan-40-yl)butanal (29c) was prepared from 28c
in 85% yield similarly as described for 29b. 29c: a colorless
oil; 1H NMR (270 MHz, CDCl3) d 9.78 (1H, brs), 3.98 (1H,
q, Jˆ6.6 Hz), 3.34 (1H, d, Jˆ9.3 Hz), 3.32 (3H, s), 3.22
(1H, d, Jˆ9.3 Hz), 2.48 (2H, t, Jˆ6.6 Hz), 1.45–1.86 (4H,
m), 1.41 (3H, s), 1.34 (3H, s), 1.24 (3H, d, Jˆ6.6 Hz); IR
(film) nmax 2988, 2940, 2888, 1730, 1380, 1248, 1218, 1186,
1170, 1110, 1006 cmϪ1; LR-EIMS m/z 127 (99.7%), 185
(bp, [MϪC2H5O]), 215 (47.1%, [MϪCH3]); HR-EIMS
calcd for C11H19O4 [MϪCH3]: 215.1283, found: 215.1287.
2,2,5-Trimethyl-5-(4-hydroxybutyl)-1,3-dioxolane (28f).
A mixture of 27f (1.040 g, 2.438 mmol) and TBAF (1.0 M
in THF, 2.9 ml, 2.9 mmol) was stirred at 20ЊC for 50 min
and then concentrated under reduced pressure. Purification
of the residue by flash chromatography (silica gel, hexane/
etherˆ2!ether, then silica gel, hexane/EtOAcˆ1) provided
28f (457.0 mg, ϳ100%) as a colorless oil. 28f: H NMR
(40Rء,50Rء)-4-(20,20,50-Trimethyl-40-benzyloxymethyl-
10,30-dioxolan-40-yl)butanal (29d) was prepared from 28d
in 80% yield similarly as described for 29a. 29d: a brownish
1
(300 MHz, CDCl3) d 3.78 (1H, d, Jˆ8.3 Hz), 3.70 (1H, d,
Jˆ8.3 Hz), 3.66 (1H, dt, Jˆ5.5, 6.2 Hz), 1.34–1.68 (6H, m),
1.40 (3H, brs), 1.38 (3H, brs), 1.28 (3H, s), 1.27 (1H, t,
Jˆ5.5 Hz, OH); IR (film) nmax 3426, 2983, 2938, 2867,
1459, 1377, 1250, 1212, 1161, 1117, 1060, 984, 941, 912,
860, 807 cmϪ1; LR-EIMS m/z 95 (bp), 115 (87.9%,
C6H11O2), 173 (68.7%, [MϪCH3]); HR-EIMS calcd for
C9H17O3 [MϪCH3]: 173.1178, found: 173.1192.
1
yellow oil; H NMR (300 MHz, CDCl3) d 9.74 (1H, t,
Jˆ1.8 Hz), 7.27–7.39 (5H, m), 4.57 (1H, d, Jˆ12.0 Hz),
4.48 (1H, d, Jˆ12.0 Hz), 4.18 (1H, q, Jˆ6.4 Hz), 3.55
(1H, d, Jˆ9.5 Hz), 3.36 (1H, d, Jˆ9.5 Hz), 2.44 (2H, dt,
Jˆ1.8, 7.0 Hz), 1.46–1.88 (4H, m), 1.43 (3H, s), 1.35 (3H,
s), 1.24 (3H, d, Jˆ6.4 Hz); IR (film) nmax 2988, 2940,
2868, 1728, 1248, 1216, 1102 cmϪ1; LR-EIMS m/z 91
(bp), 127 (62.7%), 185 (60.6%), 291 (M0ϪCH3, 18.0%);
HR-EIMS calcd for C17H23O4 [MϪCH3]: 291.1596,
found: 291.1594.
4-(2,2-Dimethyl-4-methoxymethyl-1,3-dioxolan-4-yl)-
butanal (29a). To a mixture of the alcohol 28a (588.0 mg,
2.69 mmol), NMO (0.49 g, 4.04 mmol), molecular sieves
˚
4 A (0.6 g), and acetonitrile (1.5 ml) in CH2Cl2 (15 ml)
was added TPAP (0.05 g, 0.13 mmol) at 20ЊC. The reaction
mixture was stirred for 1.5 h and then purified directly by
flash chromatography (silica gel, ether) to give ketone 29a
(496.9 mg, 85%) as a colorless oil. 29a: 1H NMR
(300 MHz, CDCl3) d 9.77 (1H, t, Jˆ1.6 Hz), 3.93 (1H, d,
Jˆ8.7 Hz), 3.73 (1H, d, Jˆ8.7 Hz), 3.36 (3H, s), 3.32 (2H,
s), 2.48 (2H, dt, Jˆ1.6, 7.0 Hz), 1.52–1.83 (4H, m), 1.40
(3H, s), 1.38 (3H, s); IR (film) nmax 2988, 2936, 2884, 2828,
1730, 1382, 1372, 1254, 1214, 1114, 1058 cmϪ1; LR-EIMS
m/z 171 (bp), 201 (48.9%, [MϪCH3]); HR-EIMS calcd for
C10H17O4 [MϪCH3]: 201.1127, found: 201.1120.
(40Rء,50Sء)-4-(20,20,50-Trimethyl-40-benzyloxymethyl-
10,30-dioxolan-40-yl)butanal (29e) was prepared from 28e
in 81% yield similarly as described for 29a. 29e: a colorless
1
oil; H NMR (300 MHz, CDCl3) d 9.74 (1H, t, Jˆ1.8 Hz),
7.27–7.38 (5H, m), 4.49 (2H, s), 3.97 (1H, q, Jˆ6.6 Hz),
3.43 (1H, d, Jˆ9.4 Hz), 3.28 (1H, d, Jˆ9.4 Hz), 2.45 (2H,
dt, Jˆ1.8, 7.2 Hz), 1.67–1.88 (4H, m), 1.38 (3H, s), 1.34
(3H, s), 1.26 (3H, d, Jˆ6.6 Hz); IR (film) nmax 2988, 1728,
1218, 1102 cmϪ1; LR-EIMS m/z 91 (bp), 127 (63.2%), 185
(56.8%), 291 (MϪCH3, 10.6%), 306 (M, 0.07%); HR-EIMS
calcd for C17H23O4 [MϪCH3]: 291.1596, found: 291.1571.
(40Rء,50Rء)-4-(20,20,50-Trimethyl-40-methoxymethyl-
10,30-dioxolan-40-yl)butanal (29b). To oxalyl chloride
(0.48 ml, 5.5 mmol) in CH2Cl2 (30 ml) was added DMSO
(0.49 ml, 6.9 mmol) in CH2Cl2 (2 ml) dropwise at Ϫ78ЊC
and the reaction mixture was stirred for 10 min. Then, 28b
(642.0 mg, 2.763 mmol) in CH2Cl2 (12 ml) was added drop-
wise at Ϫ78ЊC. The mixture was warmed to Ϫ45ЊC and
stirred for 30 min. Et3N (254 ml, 1.82 mmol) was added
dropwise at Ϫ45ЊC and the mixture was warmed to 0ЊC
and stirred for 20 min. Saturated aqueous NH4Cl (70 ml)
was added and the mixture was extracted with EtOAc
4-(2,2,5-Trimethyl-1,3-dioxolan-5-yl)butanal (29f) was
prepared from 28f in 81% yield similarly as described for
29a. 29f: a colorless oil; 1H NMR (300 MHz, CDCl3) d 9.78
(1H, t, Jˆ1.6 Hz), 3.79 (1H, d, Jˆ8.3 Hz), 3.72 (1H, d,
Jˆ8.3 Hz), 2.48 (1H, dt, Jˆ1.6, 7.2 Hz), 1.48–1.81 (3H,
s), 1.40 (3H, s), 1.38 (3H, s), 1.29 (3H, s); IR (film) nmax
2983, 2936, 2871, 2822, 2722, 1726, 1459, 1378, 1370,
1249, 1212, 1163, 1118, 1060, 984, 905, 858, 808 cmϪ1
;
LR-EIMS m/z 115 (59.5%, C6H11O2), 171 (bp,
[MϪCH3]); HR-EIMS calcd for C9H15O3 [MϪCH3]:
171.1021, found: 171.1050.

1076
K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
1-Methoxymethyl-6,8-dioxabicyclo[3.2.1]octane (4a). A
mixture of 29a (496.9 mg, 2.30 mmol) and TsOH·H2O
(8.7 mg, 0.046 mmol) in CH2Cl2 (15 ml) was stirred at
20ЊC for 1.5 h. The reaction was quenched with saturated
aqueous NaHCO3 (40 ml). After extractive work up
(CH2Cl2×3), the combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, ether) provided 4a (291.7 mg, 80%) as
a colorless oil. 4a: 1H NMR (300 MHz, CDCl3) d 5.56 (1H,
s), 3.94 (1H, d, Jˆ6.8 Hz), 3.57 (1H, dd, Jˆ1.5, 6.8 Hz),
3.49 (1H, d, Jˆ10.1 Hz), 3.44 (1H, d, Jˆ10.1 Hz), 3.40 (3H,
s), 1.50–1.98 (6H, m); IR (film) nmax 2948, 2886, 2816,
1477, 1458, 1440, 1365, 1344, 1329, 1310, 1190, 1141,
1111, 1093, 1050, 1013, 997, 981, 955, 939, 903, 888,
861, 834, 800 cmϪ1; LR-EIMS m/z 84 (bp), 140 (26.7%,
[MϪH2O]), 158 (5.4%, [M]); HR-EIMS calcd for
C8H14O3 [M]: 158.0943, found: 158.0946.
(12.3%), 107 (11.3%), 248 (M, 6.2%); HR-EIMS calcd
for C17H23O4 [MϪCH3]: 248.1376, found: 248.1420.
1-Methyl-6,8-dioxabicyclo[3.2.1]octane (4f) was prepared
from 29f in 66% yield similarly as described for 4a. 4f: a
colorless oil; 1H NMR (300 MHz, CDCl3) d 5.53 (1H, brs),
3.95 (1H, d, Jˆ6.8 Hz), 3.38 (1H, dd, Jˆ1.8, 6.8 Hz), 1.78–
1.98 (1H, m), 1.50–1.77 (5H, m), 1.34 (3H, s); IR (film)
nmax 2945, 2879, 2846, 1459, 1380, 1342, 1306, 1268, 1204,
1124, 1098, 1051, 1005, 984, 955, 938, 928, 891, 863, 856,
834, 796 cmϪ1; LR-EIMS m/z 72 (bp), 128 (74.3%, [M]);
HR-EIMS calcd for C7H12O2 [M]: 128.0837, found:
128.0848.
General method of reductive cleavage of 6,8-dioxabi-
cyclo[3.2.1]octanes with DIBAH
To a solution of 4 (20–50 mg) in CH2Cl2 (2 ml, the concen-
tration of 4 was in the range of 0.05–0.1 M) was added
DIBAH (1.0 M in hexane, 8 equiv.) dropwise at 0ЊC.
Then, the reaction mixture was stirred at 20ЊC for
2–3 days, quenched with MeOH (2 ml), treated with
saturated aqueous potassium sodium tartrate (10 ml), stirred
for 1 h, and extracted with CH2Cl2 (5×20 ml). The
combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, hexane/EtOAc system) provided the corresponding
oxane 31.
(1Rء,5Rء,7Rء)-1-Methoxymethyl-7-methyl-6,8-dioxabicyclo-
[3.2.1]octane (4b) was prepared from 29b in 79% yield
1
similarly as described for 4a. 4b: a colorless oil; H NMR
(270 MHz, CDCl3) d 5.53 (1H, brs), 3.90 (1H, q, Jˆ6.6 Hz),
3.39 (3H, s), 3.38 (1H, d, Jˆ10.2 Hz), 3.32 (1H, d,
Jˆ10.2 Hz), 1.08–2.12 (6H, m), 1.34 (3H, d, Jˆ6.6 Hz);
IR (film) nmax 2940, 2880, 1468, 1196, 1186, 1110, 1088,
936 cmϪ1
;
LR-EIMS m/z 71 (bp), 128 (75.4%,
[MϪC2H4O]), 172 (3.2%, [M]); HR-EIMS calcd for
C9H16O3 [M]: 172.1099, found: 172.1089.
(1Rء,5Rء,7Sء)-1-Methoxymethyl-7-methyl-6,8-dioxabicyclo-
[3.2.1]octane (4c) was prepared from 29c in 78% yield
similarly as described for 4a. 4c: a colorless oil; H NMR
General method of Lewis acid-catalyzed reductive
cleavage of 6,8-dioxabicyclo[3.2.1]octanes with Et3SiH
1
(270 MHz, CDCl3) d 5.53 (1H, brs), 4.21 (1H, q, Jˆ6.3 Hz),
3.43 (1H, d, Jˆ9.2 Hz), 3.38 (3H, s), 3.38 (1H, d,
Jˆ9.2 Hz), 1.51–1.97 (6H, m), 1.11 (3H, d, Jˆ6.3 Hz);
IR (film) nmax 2952, 2816, 1192, 1114, 1096, 1062,
To a solution of 4 (20–50 mg) and Et3SiH (8 equiv.) in
CH2Cl2 (2 ml, the concentration of 4 was in the range of
0.05–0.1 M) was added Lewis acid (2.4–4 equiv.) dropwise
at Ϫ78ЊC. Then, the reaction mixture was stirred under the
conditions indicated in Table 1. When TiCl4, SnCl4,
Sn(OTf)2, or BF3·OEt2 was used as a Lewis acid, the reac-
tion was quenched with brine (10 ml). When an aluminum
Lewis acid was used, the reaction mixture was quenched
with MeOH (2 ml), treated with saturated aqueous potas-
sium sodium tartrate (10 ml), and stirred for 1 h. After
extractive work up (CH2Cl2×5), the combined organic
layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, hexane/
EtOAc system) provided the corresponding 30 and 31.
Sometimes the crude residue contained a small amount of
silylated products. In such a case, purification was
performed after desilylation of the residue with TBAF.
944 cmϪ1
;
LR-EIMS m/z 71 (bp), 144 (83.8%,
[MϪC2H4]), 172 (2.5%, [M]); HR-EIMS calcd for
C9H16O3 [M]: 172.1099, found: 172.1100.
(1Rء,5Rء,7Rء)-1-Benzyloxymethyl-7-methyl-6,8-dioxabicyclo-
[3.2.1]octane (4d) was prepared from 29d in 78% yield
1
similarly as described for 4a. 4d: a colorless oil; H NMR
(300 MHz, CDCl3) d 7.23–7.39 (5H, m), 5.53 (1H, brs),
4.57 (2H, s), 3.92 (1H, dq, Jˆ1.3, 6.4 Hz), 3.44 (1H, d,
Jˆ10.3 Hz), 3.40 (1H, d, Jˆ10.3 Hz), 1.50–2.11 (6H, m),
1.32 (3H, d, Jˆ6.4 Hz); IR (film) nmax 3032, 2940, 2872,
1456, 1364, 1118, 1102, 1074, 1028, 936, 736, 698 cmϪ1
;
LR-EIMS m/z 91 (bp), 92 (13.4%), 107 (12.1%), 248 (M,
0.97%); HR-EIMS calcd for C15H20O3 [M]: 248.1376,
found: 248.1416.
3-Hydroxy-3-methoxymethyloxepane (30a):18 a colorless
(1Rء,5Rء,7Sء)-1-Benzyloxymethyl-7-methyl-6,8-dioxabicyclo-
[3.2.1]octane (4e) was prepared from 29e in 78% yield
1
oil; H NMR (400 MHz, CDCl3) d 3.80 (1H, brtd, Jˆ5.5,
12.2 Hz, H1b), 3.70 (1H, brddd, Jˆ5.3, 8.3, 12.2 Hz, H1a),
3.66 (1H, d, Jˆ12.6 Hz, H6b), 3.52 (1H, brd, Jˆ12.6 Hz,
H6a), 3.39 (3H, s, OMe), 3.35 (1H, d, Jˆ9.2 Hz, H7b), 3.25
(1H, d, Jˆ9.2 Hz, H7a), 1.47–1.84 (6H, m, H2, H3, H4);
13C NMR (100 MHz, CDCl3, 13CDCl3 as 77.0 ppm) d 77.7
(CH2, C7), 74.4 (C, C5), 74.3 (CH2, C6), 71.9 (CH2, C1),
59.4 (CH3, OMe), 37.8 (CH2, C4), 30.7 (CH2, C3 or C2),
20.6 (CH2, C2 or C3); IR (film) nmax 3440, 2929, 2863,
1470, 1461, 1450, 1264, 1198, 1150, 1111, 1091, 1007,
1
similarly as described for 4a. 4e: a colorless oil; H NMR
(300 MHz, CDCl3) d 7.23–7.40 (5H, m), 5.53 (1H, brs),
4.60 (1H, d, Jˆ12.1 Hz), 4.50 (1H, d, Jˆ12.1 Hz), 4.21
(1H, q, Jˆ6.4 Hz), 3.51 (1H, d, Jˆ9.4 Hz), 3.45 (1H, d,
Jˆ9.4 Hz), 1.52–2.06 (6H, m), 1.09 (3H, d, Jˆ6.4 Hz);
IR (film) nmax 3064, 3032, 2948, 2872, 1456, 1366, 1338,
1322, 1200, 1120, 1094, 1062, 1050, 1030, 984, 952, 944,
902, 860, 736, 698 cmϪ1; LR-EIMS m/z 91 (bp), 92

K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
1077
979 cmϪ1; LR-EIMS m/z 115 (bp, [MϪCH2OCH3]), 128
(67.9%, [MϪCH3OH]), 142 (6.0%, [MϪH2O]), 160
(19.3%, [M]); HR-EIMS calcd for C8H16O3 [M]:
160.1099, found: 160.1109.
Jˆ8.9 Hz, H8), 2.79 (1H, s, 5-OH), 1.75–1.90 (3H, m, H2b,
H4), 1.55–1.74 (3H, m, H2a, H3), 1.12 (3H, d, Jˆ6.4 Hz,
H7); 13C NMR (100 MHz, CDCl3, 13CDCl3 as 77.0 ppm) d
138.1 (c, Bn), 128.3 (CH2×(2, Bn), 127.6 (CH2×3, Bn), 76.4
(CH, C6), 75.2 (CH2, C8), 74.9 (C, C5), 73.5 (CH2, Bn),
68.9 (CH2, C1), 39.8 (CH2, C4), 29.5 (CH2, C2), 19.9 (CH2,
C3), 15.9 (CH3, C7); IR (film) nmax 3471, 3088, 3063, 3030,
2978, 2932, 2862, 1497, 1484, 1453, 1372, 1302, 1276,
1256, 1204, 1156, 1101, 1084, 1054, 1039, 1029, 993,
971, 945, 930, 904, 832, 737, 698 cmϪ1; LR-EIMS m/z 91
(bp), 250 (5.1%, [M]); HR-EIMS calcd for C15H22O3 [M]:
250.1569, found: 250.1564.
(2Rء,3Rء)-3-Hydroxy-3-methoxymethyl-2-methyloxepane
(30b):18 a colorless oil; 1H NMR (400 MHz, CDCl3) d 3.93
(1H, td, Jˆ5.1, 12.1 Hz, H1b), 3.61 (1H, ddd, Jˆ5.5, 6.6,
12.1 Hz, H1a), 3.56 (1H, q, Jˆ6.7 Hz, H6), 3.45 (1H, d,
Jˆ9.2 Hz, H8b), 3.38 (3H, s, H9), 3.33 (1H, d, Jˆ9.2 Hz,
H8a), 2.52 (1H, s, OH), 1.52–1.87 (6H, m, H2, H3, H4),
1.17 (3H, d, Jˆ6.7 Hz, H7); 13C NMR (100 MHz, CDCl3,
13CDCl3 as 77.0 ppm) d 80.8 (CH, C6), 75.9 (C, C5), 75.4
(CH2, C8), 70.9 (CH2, C1), 59.3 (CH3, C9), 38.6 (CH2, C4),
31.0 (CH2, C3 or C2), 20.4 (CH2, C2 or C3), 16.2 (CH3, C7);
IR (film) nmax 3465, 2930, 2867, 2818, 1461, 1453, 1376,
2-Hydroxymethyl-2-methoxymethyloxane (31a):18 a color-
1
less oil; H NMR (300 MHz, C6D6, C6HD5 as 7.15 ppm) d
3.61–3.73 (2H, m, H6), 3.42 (2H, t, Jˆ5.4 Hz, H1), 3.34
(1H, d, Jˆ9.2 Hz, H7b), 3.26 (1H, d, Jˆ9.2 Hz, H7a), 3.03
(3H, s, OCH3), 2.03 (1H, brt, Jˆ6.3 Hz, 6-OH), 1.43–1.50
(1H, m, H4b), 1.12–1.43 (5H, m, H2, H3, H4a); 13C NMR
(75 MHz, C6D6, C513CD6 as 128.0 ppm) d 74.8 (CH2, C7),
74.4 (C, C5), 65.0 (CH2, C6), 62.0 (CH2, C1), 59.2 (CH3,
OCH3), 27.6 (CH2, C4), 25.9 (CH2, C2), 19.1 (CH2, C3); IR
(film) nmax 3453, 2933, 2870, 2812, 1476, 1457, 1374, 1355,
1289, 1264, 1247, 1198, 1180, 1162, 1146, 1115, 1086,
1321, 1277, 1198, 1107, 1064, 1036, 1003, 970, 947 cmϪ1
;
LR-EIMS m/z 85 (bp), 98 (62%), 128 (62.7%,
[MϪC2H6O]), 129 (63.7%, [MϪC2H5O]), 142 (26.3%,
[MϪCH4O]), 174 (21.4%, [M]); HR-EIMS calcd for
C9H18O3 [M]: 174.1256, found: 174.1253.
(2Sء,3Rء)-3-Hydroxy-3-methoxymethyl-2-methyloxepane
1
(30c):18 a colorless oil; H NMR (400 MHz, CDCl3) d
3.77–3.81 (2H, m, H1), 3.55 (1H, q, Jˆ6.4 Hz, H6), 3.34
(3H, s, OMe), 3.27 (1H, d, Jˆ8.9 Hz, H8b), 3.22 (1H, d,
Jˆ8.9 Hz, H8a), 2.77 (1H, brs, OH), 1.75–1.86 (3H, m,
H2b, H4), 1.57–1.72 (3H, m, H2a, H3), 1.14 (3H, d,
Jˆ6.4 Hz, H7); 13C NMR (100 MHz, CDCl3, 13CDCl3 as
77.0 ppm) d 77.9 (CH2, C8), 76.4 (CH, C6), 74.8 (C, C5),
69.0 (CH2, C1), 59.4 (CH3, C9), 39.7 (CH2, C4), 29.5 (CH2,
C2), 19.9 (CH2, C3), 15.9 (CH3, C7); IR (film) nmax 3473,
2980, 2931, 2867, 1451, 1368, 1304, 1195, 1155, 1117,
1083, 1056, 1036, 995, 965, 930 cmϪ1; LR-EIMS m/z 85
(bp), 98 (73.3%), 128 (55.4%, [MϪC2H6O]), 129 (45.9%,
[MϪC2H5O]), 142 (26.3%, [MϪCH4O]), 174 (15.9%, [M]);
HR-EIMS calcd for C9H18O3 [M]: 174.1256, found:
174.1256.
1047, 973, 858 cmϪ1
;
LR-EIMS m/z 97 (69.8%,
[MϪC2H7O2]), 115 (bp, [MϪC2H5O]), 129 (71.8%,
[MϪCH3O]); HR-EIMS calcd for C6H11O2 [MϪC2H5O]:
115.0795, found: 115.0759; calcd for C7H13O2
[MϪCH3O]: 129.0948, found: 129.0915; LR-CIMS m/z
161 [MϩH]; HR-CIMS calcd for C8H17O3 [MϩH]:
161.1147, found: 161.1178.
(10Rء,2Rء)-2-(10-Hydroxyethyl)-2-methoxymethyloxane
(31b):18 a colorless oil; 1H NMR (400 MHz, CDCl3) d 3.93
(1H, brq, Jˆ6.6 Hz, H6), 3.75–3.82 (1H, m, H1b), 3.75 (1H,
d, Jˆ10.3 Hz, H8b), 3.64–3.72 (1H, m, H1a), 3.38 (3H, s,
OMe), 3.33 (1H, d, Jˆ10.3 Hz, H8a), 2.75 (1H, brs, OH),
1.65–1.83 (2H, m, H2b, H4b), 1.48–1.62 (3H, m, H2a, H3),
1.37–1.45 (1H, m, H4a), 1.12 (3H, d, Jˆ6.6 Hz, H7); 13C
NMR (100 MHz, CDCl3, 13CDCl3 as 77.0 ppm) d 76.1 (C,
C5), 71.2 (CH2, C8), 69.9 (CH, C6), 62.2 (CH2, C1), 59.5
(CH3, OCH3), 25.7 (CH2, C3), 24.4 (CH2, C4), 18.9 (CH2,
C2), 16.0 (CH3, C7); IR (film) nmax 3483, 2938, 2871, 2812,
1481, 1458, 1402, 1365, 1276, 1201, 1185, 1165, 1111,
1052, 1028, 1001, 974, 911, 894 cmϪ1; LR-EIMS m/z 55
(bp), 129 (78.6%, [MϪC2H5O]), 157 (1.5%, [MϪOH]), 175
(0.6%, [MϩH]); HR-EIMS calcd for C9H19O3 [MϩH]:
175.1334, found: 175.1330.
(2Rء,3Rء)-3-Benzyloxymethyl-3-hydroxy-2-methyloxepane
(30d):18 a colorless oil; 1H NMR (400 MHz, CDCl3, 45ЊC) d
7.24–7.37 (5H, m, Bn), 4.58 (1H, d, Jˆ12.0 Hz, Bn), 4.52
(1H, d, Jˆ12.0 Hz, Bn), 3.90 (1H, brtd, Jˆ5.5, 12.1 Hz,
H1b), 3.60 (1H, brtd, Jˆ6.7, 12.1 Hz, H1a), 3.57 (1H, d,
Jˆ9.3 Hz, H8b), 3.56 (1H, q, Jˆ6.8 Hz, H6), 3.43 (1H, d,
Jˆ9.3 Hz, H8a), 2.55 (1H, s, 5-OH), 1.93–2.11 (1H, m,
H4b), 1.62–1.79 (4H, m, H2, H3b, H4b), 1.48–1.62 (1H,
m, H3a), 1.17 (3H, d, Jˆ6.8 Hz, H7); 13C NMR (100 MHz,
CDCl3, 13CDCl3 as 77.0 ppm, 45ЊC) d 138.2 (C, Bn), 128.4
(CH×2, Bn), 127.7 (CH, Bn), 127.6 (CH×2, Bn), 80.9 (CH,
C6), 76.1 (C, C5), 73.7 (CH2, Bn), 73.1 (CH2, C8), 70.8
(CH2, C1), 38.8 (CH2, C4), 30.9 (CH2, C2), 20.4 (CH2,
C3), 16.3 (CH3, C7); IR (film) nmax 3484, 3064, 3032,
2936, 2864, 1500, 1456, 1376, 1320, 1278, 1098, 972,
944, 912, 842, 736, 698 cmϪ1; LR-EIMS m/z 91 (bp), 250
(10.4%, [M]); HR-EIMS calcd for C15H22O3 [M]: 250.1569,
found: 250.1568.
(10Sء,2Rء)-2-(10-Hydroxyethyl)-2-methoxymethyloxane
(31c):18 a colorless oil; 1H NMR (400 MHz, CDCl3) d 3.97
(1H, brdq, Jˆ5.3, 6.6 Hz, H6), 3.78 (1H, brtd, Jˆ5.0,
11.9 Hz, H1b), 3.71 (1H, brddd, Jˆ4.9, 6.8, 11.9 Hz,
H1a), 3.59 (1H, d, Jˆ9.9 Hz, H8b), 3.48 (1H, d,
Jˆ9.9 Hz, H8a), 3.37 (3H, s, OMe), 2.91 (1H, brd,
Jˆ5.3 Hz, OH), 1.50–1.70 (5H, m, H2, H3, H4b), 1.42–
1.50 (1H, m, H4a), 1.18 (3H, d, Jˆ6.6 Hz, H7); 13C NMR
(100 MHz, CDCl3, 13CDCl3 as 77.0 ppm) d 75.7 (C, C5),
73.2 (CH2, C8), 70.2 (CH, C6), 61.9 (CH2, C1), 59.4 (CH3,
OCH3), 26.7 (CH2, C4), 25.4 (CH2, C2), 18.8 (CH2, C3),
17.3 (CH3, C7); IR (film) nmax 3474, 2937, 2872, 2812,
1460, 1397, 1367, 1351, 1286, 1265, 1200, 1175, 1165,
(2Sء,3Rء)-3-Benzyloxymethyl-3-hydroxy-2-methyloxepane
1
(30e):18 a colorless oil; H NMR (400 MHz, CDCl3) d
7.25–7.38 (5H, m, Bn), 4.54 (1H, d, Jˆ11.9 Hz, Bn), 4.47
(1H, d, Jˆ11.9 Hz, Bn), 3.66–3.81 (2H, m, H1), 3.59 (1H,
q, Jˆ6.4 Hz, H6), 3.35 (1H, d, Jˆ8.9 Hz, H8), 3.31 (1H, d,
1113, 1084, 1046, 1024, 1007, 974, 908, 890 cmϪ1
;

1078
K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
LR-EIMS m/z 129 (bp, [MϪC2H5O]), 175 (1.2%, [MϩH]);
HR-EIMS calcd for C9H19O3 [MϩH]: 175.1334, found:
175.1340.
(15 ml), stirred at 20ЊC for an additional 2 h, diluted with
brine (15 ml), and extracted with CH2Cl2 (5×20 ml). The
combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, hexane/etherˆ10!5!ether) provided a mixture of 4d,
32, and 33 (32.0 mg, 4d: ϳ8%, 32: ϳ48%, 33: ϳ12%. The
(10Rء,2Rء)-2-Benzyloxymethyl-2-(10-hydroxyethyl)oxane
1
(31d):18 a colorless oil; H NMR (400 MHz, CDCl3) d
7.27–7.39 (5H, m, Bn), 4.61 (1H, d, Jˆ12.3 Hz, Bn), 4.49
(1H, d, Jˆ12.3 Hz, Bn), 3.97 (1H, dq, Jˆ3.7, 6.4 Hz, H6),
3.73–3.80 (1H, m, H1b), 3.76 (1H, d, Jˆ10.3 Hz, H8b),
3.59–3.67 (1H, m, H1a), 3.37 (1H, d, Jˆ10.3 Hz, H8a),
2.76 (1H, d, Jˆ3.7 Hz, 6-OH), 1.73–1.82 (1H, m, H4b),
1.63–1.73 (1H, m, H3b), 1.38–1.57 (4H, m, H2, H3a,
H4a), 1.07 (3H, d, Jˆ6.4 Hz, H7); 13C NMR (100 MHz,
CDCl3, 13CDCl3 as 77.0 ppm) d 137.8 (C, Bn), 128.4
(CH×2, Bn), 127.8 (CH×3, Bn), 76.2 (C, C5), 73.5 (CH2,
Bn), 70.0 (CH, C6), 68.0 (CH2, C8), 62.2 (CH2, C1), 25.6
(CH2, C2), 24.4 (CH2, C4), 18.9 (CH2, C3), 15.9 (CH3, C7);
IR (film) nmax 3512, 3088, 3064, 3032, 2940, 2864, 1456,
1404, 1366, 1274, 1208, 1094, 1052, 1028, 912, 894,
736, 698 cmϪ1; LR-EIMS m/z 91 (bp), 250 (2.1%, [M]);
HR-EIMS calcd for C15H22O3 [M]: 250.1569, found:
250.1565.
1
ratio was determined by H NMR as a colorless oil and an
inseparable mixture of 34 and 35 (10.2 mg, 34: ϳ15%, 35:
ϳ15%. The ratio was determined by 1H NMR as a colorless
oil. Ethers 32 and 33 were separated by HPLC (YMC-Pack
SIL-06, 250×10 mm, hexane/EtOAcˆ20). Diols 34 and 35
were converted to the corresponding monobenzoate 36 and
dibenzoate 37, respectively, for separation and characteri-
zation.
(2Rء,3Rء,7Sء)-3-Benzyloxymethyl-3-hydroxy-2-methyl-7-
(20-propenyl)oxepane (32):18 a colorless oil; 1H NMR
(400 MHz, CDCl3, 45ЊC) d 7.24–7.26 (5H, m, Bn), 5.82
(1H, tdd, Jˆ7.0, 10.3, 17.0 Hz, H2), 5.00–5.09 (2H, m,
H1), 4.60 (1H, d, Jˆ11.9 Hz, Bn), 4.52 (1H, d,
Jˆ11.9 Hz, Bn), 3.79 (1H, q, Jˆ6.8 Hz, H9), 3.70 (1H,
brtdd, Jˆ5.9, 7.7, 10.4 Hz, H4), 3.64 (1H, brd, Jˆ9.3 Hz,
H11b), 3.55 (1H, d, Jˆ9.3 Hz, H11a), 2.68 (1H, s, 8-OH),
2.25–2.35 (1H, m, H3b), 2.02–2.17 (2H, m, H3a, H7b),
1.78–1.87 (1H, m, H5b), 1.56–1.72 (1H, m, H6b), 1.42–
1.54 (1H, m, H5a), 1.24–1.40 (2H, m, H6a, H7a), 1.19 (3H,
d, Jˆ6.8 Hz, H10); 13C NMR (100 MHz, CDCl3, 13CDCl3 as
77.0 ppm, 45ЊC) d 138.3 (C, Bn), 135.6 (CH, C2), 128.4
(CH×2, Bn), 127.6 (CH×3, Bn), 116.6 (CH2, C1), 76.2 (CH,
C4), 75.2 (C, C8), 73.6 (CH2, Bn), 71.8 (CH, C9), 71.0
(CH2, C11), 40.0 (CH2, C7), 39.7 (CH2, C3), 34.3 (CH2,
C5), 20.5 (CH2, C6), 16.3 (CH3, C10); IR (film) nmax
3473, 3072, 3031, 2975, 2929, 2857, 1641, 1497, 1454,
1414, 1377, 1367, 1332, 1262, 1235, 1217, 1100, 1076,
1067, 1029, 1014, 997, 963, 948, 933, 913, 826, 736,
697 cmϪ1; LR-EIMS m/z 91 (bp), 249 (4%, [MϪC3H5]),
290 (2.4%, [M]); HR-EIMS calcd for C18H26O3 [M]:
290.1882, found: 290.1886.
(10Sء,2Rء)-2-Benzyloxymethyl-2-(10-hydroxyethyl)oxane
(31e):18 a colorless oil; 1H NMR (400 MHz, CDCl3) d
7.26–7.38 (5H, m, Bn), 4.59 (1H, d, Jˆ12.1 Hz, Bn), 4.51
(1H, d, Jˆ12.1 Hz, Bn), 3.94 (1H, dq, Jˆ5.7, 6.4 Hz, H6),
3.73–3.80 (1H, m, H1b), 3.63–3.70 (1H. m, H1a), 3.66 (1H,
d, Jˆ9.7 Hz, H8b), 3.56 (1H, d, Jˆ9.7 Hz, H8a), 2.89 (1H,
d, Jˆ5.7 Hz, 6-OH), 1.42–1.68 (6H, m, H2, H3, H4), 1.16
(3H, d, Jˆ6.4 Hz, H7); 13C NMR (100 MHz, CDCl3,
13CDCl3 as 77.0 ppm) d 137.9 (C, Bn), 128.4 (CH×2, Bn),
127.71 (CH, Bn), 127.68 (CH×2, Bn), 75.8 (C, C5), 73.7
(CH2, Bn), 70.7 (CH, C6), 70.0 (CH2, C8), 62.0 (CH2, C1),
26.7 (CH2, C4), 25.4 (CH2, C3 or C2), 18.8 (CH2, C2 or C3),
17.2 (CH3, C7); IR (film) nmax 3475, 3088, 3063, 3030,
2937, 2867, 1497, 1472, 1454, 1399, 1367, 1286, 1265,
1206, 1099, 1083, 1047, 1028, 1015, 909, 891, 737,
698 cmϪ1
;
LR-EIMS m/z 91 (bp), 205 (30.9%,
[MϪC2H5O]), 250 (0.2%, [M]); HR-EIMS calcd for
C15H22O3 [M]: 250.1569, found: 250.1564.
(10Rء,2Rء,6Sء)-2-Benzyloxymethyl-2-(10-hydroxyethyl)-6-
(200-propenyl)oxane (33):18 a colorless oil; 1H NMR
(400 MHz, CDCl3) d 7.27–7.38 (5H, m, Bn), 5.78 (1H,
ddd, Jˆ6.6, 7.3, 10.3 Hz, H2), 4.96–5.06 (2H, m, H1),
4.53 (1H, d, Jˆ12.0 Hz, Bn), 4.50 (1H, d, Jˆ12.0 Hz,
Bn), 4.25 (1H, brqd, Jˆ6.6, 10.3 Hz, H9), 3.70 (1H, d,
Jˆ8.8 Hz, H11b), 3.42–3.50 (1H, m, H4), 3.25 (1H, dd,
Jˆ1.2, 8.8 Hz, H11a), 3.22 (1H, d, Jˆ10.3 Hz, 9-OH),
2.40–2.48 (1H, m, H7b), 2.01–2.19 (2H, m, H3), 1.64–
1.72 (2H, m, H6), 1.54–1.64 (1H, m, H5b), 1.22–1.33
(1H, m, H7a), 1.20 (3H, d, Jˆ6.6 Hz, H10), 1.12–1.22
(1H, m, H5a); 13C NMR (100 MHz, CDCl3, 13CDCl3 as
77.0 ppm) d 137.3 (C, Bn), 135.0 (CH, C2), 128.5
(CH×2, Bn), 127.9 (CH, Bn), 127.8 (CH×2, Bn), 116.5
(CH2, C1), 76.7 (CH2, C11), 74.4 (C, C7), 73.9 (CH2, Bn),
70.2 (CH, C4), 66.2 (CH, C9), 41.3 (CH2, C3), 30.9 (CH2,
C5), 29.2 (CH2, C7), 18.3 (CH2, C6), 17.3 (CH3, C10); IR
(film) nmax 3516, 3071, 3031, 2961, 2931, 2858, 1738, 1732,
1642, 1497, 1454, 1442, 1429, 1415, 1370, 1290, 1260,
1205, 1103, 1078, 1043, 1029, 906, 867, 802, 737, 699,
2-Methoxymethyl-2-methyloxane (31f):18 a colorless oil;
1H NMR (300 MHz, CDCl3) d 3.69 (1H, brt, Jˆ5.1 Hz),
3.50 (1H, brd, Jˆ11.2 Hz), 3.37 (1H, brd, Jˆ11.2 Hz),
2.32 (1H, brs, OH), 1.57–1.73 (3H, m), 1.45–1.56 (2H,
m), 1.25–1.42 (1H, m), 1.18 (3H, s); 13C NMR (75 MHz,
CDCl3, 13CDCl3 as 77.0 ppm) d 73.4 (C), 69.4 (CH2), 61.7
(CH2), 30.9 (CH2), 25.8 (CH2), 19.3 (CH3), 19.0 (CH2); IR
(film) nmax 3433, 2936, 2866, 1475, 1456, 1441, 1402, 1372,
1350, 1288, 1225, 1207, 1191, 1168, 1130, 1088, 1046, 987,
963, 899, 856, 839, 812, 724, 711, 691 cmϪ1; LR-EIMS m/z
99 (bp, [MϪCH2OH]), 115 (5.9%, [MϪCH3]), 131 (2.1%,
[MϩH]); HR-EIMS calcd for C6H11O2 [MϪCH3]:
115.0759, found: 115.0764; calcd for C6H11O
[MϪCH2OH]: 99.0810, found: 99.0803.
TiCl4-catalyzed allylation of 4d
To a mixture of 4d (39.2 mg, 0.158 mmol) and allyl-
trimethylsilane (0.20 ml, 1.26 mmol) in CH2Cl2 (3.2 ml) was
added TiCl4 (0.069 ml, 0.63 mmol) at Ϫ78ЊC. The reaction
mixture was stirred at Ϫ78ЊC for 2 h, quenched with H2O
661 cmϪ1
;
LR-EIMS m/z 91 (bp), 245 (43.8%,
[MϪC2H5O]); HR-EIMS calcd for C16H21O2 [M]:
245.1541, found: 245.1548.

K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
1079
(2Rء,3Rء,7Sء)-3-Benzoyloxymethyl-3-hydroxy-2-methyl-
7-(20-propenyl)oxepane (36) and (10Rء,2Rء,6Sء)-2-(10-
Benzoyloxyethyl)-2-benzoyloxymethyl-6-(200-propenyl)-
oxane (37). To a solution of 34 and 35 (10.2 mg,
0.0509 mmol) in CH2Cl2 (1.5 ml) was added BzCl (0.0355
ml, 0.306 mmol), pyridine (0.0330 ml, 0.408 mmol), and
DMAP (a catalytic amount) at 0ЊC. The reaction mixture
was stirred at 20ЊC for 12 h, quenched with saturated
aqueous NaHCO3 (10 ml) and brine (10 ml), and extracted
with CH2Cl2 (4×20 ml). The combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by
flash chromatography (silica gel, hexane/EtOAcˆ9!5!
EtOAc) provided 36 (3.8 mg, 25%) as a colorless oil and
37 (6.6 mg, 32%) as a colorless oil. 36:18 1H NMR
(400 MHz, C6D6, C6HD5 as 7.15 ppm) d 8.09–8.14 (2H,
m, Bz), 7.00–7.14 (3H, m, Bz), 5.86 (1H, dddd, Jˆ6.4,
7.5, 9.5, 17.8 Hz, H2), 4.99–5.06 (2H, m, H1), 4.42 (2H,
s, H11), 3.46 (1H, q, Jˆ6.8 Hz, H9), 3.22–3.31 (1H, m, H4),
2.17–2.26 (1H, m, H3b), 2.13 (1H, s, 11-OH), 1.96–2.05
(1H, m, H3a), 1.77–1.85 (1H, m, H7b), 1.15–1.62 (5H, m,
H5, H6, H7a), 1.21 (3H, d, Jˆ6.8 Hz, H10); 13C NMR
(100 MHz, C6D6, 13CC5D6 as 128.0 ppm) d 162.7 (C, Bz),
136.1 (CH, C2), 133.0 (CH, Bz), 130.7 (C, Bz), 130.0
(CH×2, Bz), 128.6 (CH×2, Bz), 116.3 (CH2, C1), 82.1
(CH, C4), 81.0 (CH, C9), 76.3 (C, C8), 69.4 (CH2, C11),
41.7 (CH2, C3), 38.8 (CH2, C7), 36.8 (CH2, C5), 19.8 (CH2,
C6), 16.0 (CH3, C10); IR (film) nmax 3491, 3072, 2976,
2931, 2863, 1722, 1641, 1603, 1584, 1451, 1370, 1315,
1276, 1177, 1099, 1071, 1027, 914, 711 cmϪ1; LR-EIMS
m/z 105 (bp), 263 (4.5%, [MϪC3H5]), 304 (0.3%, [M]); HR-
EIMS calcd for C18H24O4 [M]: 304.1674, found: 304.1652.
37:18 1H NMR (400 MHz, CDCl3) d 8.06–8.11 (2H, m, Bz),
7.97–8.02 (2H, m, Bz), 7.51–7.60 (2H, m, Bz), 7.41–7.47
(2H, m, Bz), 7.35–7.40 (2H, m, Bz), 5.89 (1H, q, Jˆ6.6 Hz,
H9), 5.86 (1H, tdd, Jˆ7.1, 10.1, 17.6 Hz, H2), 5.00–5.10
(2H, m, H1), 4.55 (1H, d, Jˆ11.5 Hz, Bn), 4.49 (1H, d,
Jˆ11.5 Hz, Bn), 3.62–3.71 (1H, m, H4), 2.12–2.30 (2H,
m, H3), 1.56–1.86 (5H, m, H5b, H6, H7), 1.45 (3H, d,
Jˆ6.6 Hz, H10), 1.18–1.34 (1H, m, H5a); 13C NMR
(100 MHz, CDCl3, 13CDCl3 as 77.0 ppm) d 166.6 (C, Bz),
165.8 (C, Bz), 134.8 (CH, C2), 133.1 (CH, Bz), 132.9 (CH,
Bz), 130.4 (C, Bz), 129.9 (C, Bz), 129.69 (CH×2, Bz),
129.66 (CH×2, Bz), 128.40 (CH×2, Bz), 128.36 (CH×2,
Bz), 116.8 (CH2, C1), 75.0 (C, C8), 70.9 (CH, C4), 67.8
(CH, C9), 67.3 (CH2, C11), 41.2 (CH2, C3), 30.2 (CH2, C5),
26.3 (CH2, C7), 18.5 (CH2, C6), 13.7 (CH3, C10); IR (film)
nmax 3072, 2937, 2872, 2856, 1720, 1603, 1585, 1451, 1373,
1314, 1281, 1266, 1219, 1205, 1176, 1158, 1108, 1098,
with H2O (10 ml), stirred at 20ЊC for an additional 2 h,
diluted with brine (10 ml), and extracted with CH2Cl2
(5×20 ml). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chroma-
tography (silica gel, hexane/etherˆ10!5!ether) provided
38 (16.7 mg, 98%).
(2Sء,3Rء,7Rء)-3-Hydroxy-3-hydroxymethyl-2-methyl-7-
(20-propenyl)oxepane (38):18 a colorless oil; 1H NMR
(300 MHz, CDCl3) d 5.84 (1H, tdd, Jˆ7.0, 10.1, 17.1 Hz,
H2), 5.02–5.14 (2H, m, H1), 3.77 (1H, tdd, Jˆ5.3, 8.3,
11.4 Hz, H4), 3.72 (1H, q, Jˆ6.4 Hz, H9), 3.51 (1H, brdd,
Jˆ4.4, 10.6 Hz, H11b), 3.43 (1H, brdd, Jˆ5.0, 10.6 Hz,
H11a), 3.10 (1H, s, 8-OH), 2.25–2.38 (1H, m, H3b),
2.10–2.22 (1H, m, H3a), 1.23–1.96 (6H, m, H5, H6, H7),
1.14 (3H, d, Jˆ6.4 Hz, H10). Diol 38 was converted to the
corresponding monobenzoate 39 for characterization.
(2Sء,3Rء,7Rء)-3-Benzoyloxymethyl-3-hydroxy-2-methyl-
7-(20-propenyl)oxepane (39). A mixture of 38 (7.0 mg,
0.035 mmol), BzCl (0.0243 ml, 0.209 mmol), pyridine
(0.0226 ml, 0.279 mmol), and DMAP (a catalytic amount)
in CH2Cl2 (1.5 ml) was stirred at 20ЊC for 1 day, quenched
with saturated aqueous NaHCO3 and brine. After extractive
workup (CH2Cl2×4), the combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by
flash chromatography (silica gel, hexane/EtOAcˆ5)
provided 39 (5.3 mg, 50%) as a colorless oil.
39:18 1H NMR (400 MHz, acetone-d6, CHD2C(O)CD3 as
2.04 ppm) d 8.02–8.06 (2H, m, Bz), 7.61–7.66 (1H, m,
Bz), 7.49–7.55 (2H, m, Bz), 5.87 (1H, tdd, Jˆ7.0, 10.3,
17.2 Hz, H2), 5.06 (1H, tdd, Jˆ1.5, 2.3, 17.2 Hz, H1b),
4.98 (1H, tdd, Jˆ1.1, 2.3, 10.3 Hz, H1a), 4.12 (1H, d,
Jˆ11.0 Hz, H11b), 4.11 (1H, d, Jˆ11.0 Hz, H11a), 3.95
(1H, q, Jˆ6.6 Hz, H9), 3.76 (1H, tdd, Jˆ5.1, 8.1, 11.2 Hz,
H4), 3.72 (1H, s, 8-OH), 2.32 (1H, brtddd, Jˆ1.5, 6.8, 8.1,
14.1 Hz, H3b), 2.15 (1H, brtddd, Jˆ1.3, 5.1, 7.2, 14.1 Hz,
H3a), 1.81–1.90 (2H, m, H5b, H7b), 1.68–1.81 (2H, m,
H6b, H7a), 1.57–1.66 (1H, m, H6a), 1.40–1.52 (1H, m,
H5a), 1.14 (3H, d, Jˆ6.6 Hz, H10); 13C NMR (100 MHz,
acetone-d6, 13CD3C(O)CD3 as 29.8 ppm) d 166.5 (C, Bz),
137.1 (CH, C2), 134.0 (CH, Bz), 131.1 (C, Bz), 130.2
(CH×2, Bz), 129.4 (CH×2, Bz), 116.4 (CH2, C1), 76.7
(CH, C4), 74.7 (C, C8), 70.2 (CH2, C11), 70.1 (CH, C9),
40.5 (CH2, C3), 39.9 (CH2, C7), 35.1 (CH2, C5), 20.5 (CH2,
C6), 16.3 (CH3, C10); IR (film) nmax 3519, 3073, 2978,
2930, 2859, 1722, 1642, 1602, 1452, 1367, 1315, 1273,
1198, 1177, 1159, 1111, 1083, 1070, 1026, 980, 944, 915,
712, 688, 629 cmϪ1; LR-EIMS m/z 105 (bp), 263 (17.9%,
[MϪC3H5]), 304 (0.2%, [M]); HR-EIMS calcd for C18H24O4
[M]: 304.1674, found: 304.1680.
1070, 1054, 1027, 1002, 915, 711, 687, 667 cmϪ1
;
LR-EIMS m/z 105 (86.8%, C6H5CO), 259 (bp,
[MϪCH3CHOBz]), 273 (2.0%, [MϪCH2OBz]), 367
(2.8%, [MϪC3H5]); HR-EIMS calcd for C16H19O3
[MϪCH3CHOBz]: 259.1334, found: 259.1328; calcd for
C17H21O3 [MϪCH2OBz]: 273.1491, found: 273.1482;
calcd for C22H23O5 [MϪC3H5]: 367.1545, found: 367.1516.
Acknowledgements
TiCl4-catalyzed allylation of 4e
To a mixture of 4e (21.1 mg, 0.0850 mmol) and allyl-
trimethylsilane (0.108 ml, 0.680 mmol) in CH2Cl2 (1.7 ml)
was added TiCl4 (0.0373 ml, 0.340 mmol) at Ϫ78ЊC. The
reaction mixture was stirred at Ϫ78ЊC for 1.5 h, quenched
This study was supported in part by a Grant-in-Aid (K.F.:
No. 08780533) from the Ministry of Education, Science,
Sports and Culture, Japan, and by the Sumitomo Foundation
(K.F.).

1080
K. Fujiwara et al. / Tetrahedron 56 (2000) 1065–1080
11. Alexandre, C.; Rouessac, F. Bull. Soc. Chim. Fr. 1971, 1840–
References
1873.
12. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651; Mancuso,
A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482;
Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
13. (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem.
Soc. 1978, 100, 3611–3613. (b) Pine, S. H.; Kim. G.; Lee, V. Org.
Synth. 1990, 69, 72–79.
14. In order to accelerate the cleavage reaction, an excess amount
of TiCl4 was required. In fact, when 1.2 equiv. of TiCl4 were used
in the case of 4b or 4d, the amount of recovered starting 4b or 4d
increased (4b: 3%, 4d: 70%), while the selectivity of oxepane in
each case remained unchanged.
15. At present, we can only speculate on the origins of these
selectivities. Obstruction of the coordination of TiCl4 to O8 by
bulkiness of C7-methyl group may increase the selectivity in 4b
and 4c rather than in 4a. The steric repulsion of C7-methyl group to
methylene at C3 may improve the cleaving ability of C5–O8 bond
in 4b and 4d rather than in 4c and 4e, respectively. Detailed
mechanistic study is currently under way.
16. The chelation ability of aluminum reagents is well docu-
mented. For recent examples, see: (a) Ooi, T.; Kagoshima, N.;
Ichikawa, H.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 3328–
3333. (b) Evans, D. A.; Allison, B. D.; Yang, M. G. Tetrahedron
Lett. 1999, 40, 4457–4460. (c) Evans, D. A.; Halstead, D. P.;
Allison, B. D. Tetrahedron Lett. 1999, 40, 4461–4462. (d) Heller,
D. P.; Goldberg, D. R.; Wulff, W. D. J. Am. Chem. Soc. 1997, 119,
10 551–10 552.
1. For reviews for natural fused polycyclic ethers, see: (a)
Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897–1909. (b)
Shimizu, Y. Chem. Rev. 1993, 93, 1685–1698.
2. (a) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. Chem. Lett.
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97–106.
3. (a) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron Lett.
1987, 28, 6613–6616. (b) Ishihara, K.; Mori, A.; Yamamoto, H.
Tetrahedron 1990, 46, 4595–4612.
4. For reductive cleavage with aluminum hydride, see: (a) Kim,
Y.; Mundy, B. P. J. Org. Chem. 1982, 47, 3556–3557. (b) Masaki,
Y.; Serizawa, Y.; Nagata, K.; Kaji, K. Chem. Lett. 1983, 1601–
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Chem. 1991, 56, 4141–4147.
6. Rychnovsky, S. D.; Dahanukar, V. H. Tetrahedron Lett. 1996,
37, 339–342.
7. For oxepane formation in reductive cleavage of 6,8-dioxa-
bicyclo[3.2.1]octan-7-one, see: (a) Utaka, M.; Makino, H.;
Oota, Y.; Tsuboi, S.; Takeda, A. Tetrahedron Lett. 1983, 24,
2567–2570. (b) Jun, J.-G.; Lee, D. W. Tetrahedron Lett. 1997,
38, 8207–8201.
8. For a preliminary communication, see: Fujiwara, K.; Amano, A.;
Tokiwano, T.; Murai, A. Heterocycles 1998, 47 111–112.
9. For acetal cleavage with TiCl4–Et3SiH, SnCl4–Et3SiH, or
AlCl3–Et3SiH, see: (a) Mori, A.; Ishihara, K.; Yamamoto, H.
Tetrahedron Lett. 1986, 27, 987. For the cleavage with
BF3·OEt2–Et3SiH, see: (e) Rolf, D.; Gray, G. R. J. Am. Chem.
Soc. 1982, 104, 3539. See also: Ref. 5a.
17. Bulkiness around the reaction center of the silyl reagent may
play a role in the oxepane selection. Detailed mechanistic study is
currently under way.
18. Position numberings of cyclic ethers (30, 31, 32, 33, 36, 37,
38, and 39) in NMR data are specified in Figs. 1–3.
10. Abiko, A.; Lin, J. F.; Masamune, S. J. Org. Chem. 1996, 61,
2590–2591.