Achievement of ring inversion of myo-inositol derivatives due to silyloxy/silyloxy repulsion enhanced by the trans-substituents on both sides

Article abstract of DOI:10.1016/j.tet.2005.01.124

The introduction of quite bulky trialkyl or diarylalkylsilyl groups into vicinal trans-hydroxy groups induced a conformational flip of certain multifunctionalized cyclohexane rings from the usual chair form possessing more equatorial substituents (equatorial-rich chair form) into another chair-form that has more axial substituents (axial-rich chair form). This realization was experimentally revealed by the conformational study of the synthetic myo-inositol derivatives possessing two tert-butyldimethylsilyl (TBS), two triisopropylsilyl (TIPS), or two tert-butyldiphenylsilyl (TBDPS) groups on an adjacent trans-diol. Among them, the cyclohexane rings of the 4,5-bis-O-TIPS-myo-inositol, 4,5-bis-O-TBDPS-myo-inositol, and 1,2,3,6-tetra-O-benzyl-4,5-bis-O-TBDPS-myo-inositol were in the axial-rich chair form. Comparison of the ring conformations also revealed that the order of the repulsion was OTBDPS/OTBDPS>OTIPS/OTIPS>OTBS/OTBS, and the silyloxy/silyloxy repulsion was enhanced when the two silyloxy groups were placed in the center of the contiguous four equatorial substituents.

Full text of DOI:10.1016/j.tet.2005.01.124

Tetrahedron 61 (2005) 3497–3506
Achievement of ring inversion of myo-inositol derivatives
due to silyloxy/silyloxy repulsion enhanced by the
trans-substituents on both sides
Kotaro Okajima,a Tatsuya Mukae,a Hiroshi Imagawa,b Yoshiaki Kawamura,a Mugio Nishizawab
and Hidetoshi Yamadaa,
*
aSchool of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan
bFaculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamaboji, Tokushima 770-8514, Japan
Received 1 December 2004; revised 27 January 2005; accepted 31 January 2005
Abstract—The introduction of quite bulky trialkyl or diarylalkylsilyl groups into vicinal trans-hydroxy groups induced a conformational flip
of certain multifunctionalized cyclohexane rings from the usual chair form possessing more equatorial substituents (equatorial-rich chair
form) into another chair-form that has more axial substituents (axial-rich chair form). This realization was experimentally revealed by the
conformational study of the synthetic myo-inositol derivatives possessing two tert-butyldimethylsilyl (TBS), two triisopropylsilyl (TIPS), or
two tert-butyldiphenylsilyl (TBDPS) groups on an adjacent trans-diol. Among them, the cyclohexane rings of the 4,5-bis-O-TIPS-myo-
inositol, 4,5-bis-O-TBDPS-myo-inositol, and 1,2,3,6-tetra-O-benzyl-4,5-bis-O-TBDPS-myo-inositol were in the axial-rich chair form.
Comparison of the ring conformations also revealed that the order of the repulsion was OTBDPS/OTBDPSOOTIPS/OTIPSOOTBS/OTBS,
and the silyloxy/silyloxy repulsion was enhanced when the two silyloxy groups were placed in the center of the contiguous four equatorial
substituents.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
methylsilyl (TBS) groups into the hydroxy groups on the
tetrahydropyrane flipped the ring conformation from the
usual chair form possessing more equatorial substituents
(equatorial-rich chair form) into another chair-form holding
more axial substituents (axial-rich chair form). Since then
many conformational flips of tetrahydropyrane rings have
occurred due to the introduction of bulky silyl groups thus
making effective substrate-controlled stereoselective reac-
tions possible.3,4
The introduction of bulky trialkyl or diarylalkylsilyl groups
into a vicinal hydroxy groups induces a conformational bias
due to the repulsion between the two bulky silyloxy groups.
The first observation of such a conformational distribution
control is the trans-1,2-anti orientation of tert-butyldi-
methylsilyloxy groups on acyclic compounds reported by
Saito and co-workers (Fig. 1).1 In 1994, Tius’ group found
that the silyloxy repulsion also changed the conformation of
a tetrahydropyrane ring.2 The introduction of tert-butyldi-
Recently, a conformational change in a cyclohexane ring
was reported by Marzabadi and co-workers based on the
NMR experiments of the trans-1,2-bis-silyloxycyclohex-
anes.5 They demonstrated that the introduction of triisopro-
pylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS) groups
into trans-1,2-cyclohexanediol favored the 1,2-diaxial
Figure 1. Conformational restrictions of acyclic, tetrahydropyrane, and
pyranose derivatives due to the repulsion between adjacent silyloxy
groups.1,2,3f
Keywords: Ring conformation; Myo-inositol; Axial-rich chair; Silyl
protecting groups.
* Corresponding author. Tel.: C81 79 565 8342; fax: C81 79 565 9077;
e-mail: hidetosh@kwansei.ac.jp
Figure 2. Ring conformation of trans-1,2-bis-silyloxycyclohexanes in
CD2Cl2 at 200 K.5
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.124

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K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
conformation in the solution (Fig. 2). In contrast, the
1,2-diequatorial conformation was favored when TBS,
triphenylsilyl, and other smaller silyl protecting groups
were introduced. If the silyl groups could flip a cyclohexane
ring possessing other functional groups on the same ring, the
conformational control would become an essential and
effective synthetic means as well as the flipped sugar
chemistry.4,6 Our objective is accomplishing such a
conformational control on a multifunctionalized cyclo-
hexane ring, myo-inositol, by introduction of two bulky silyl
protecting groups.7
been crucial to flip the ring. Since myo-inositol has one
axial hydroxy group, there are two different sets of adjacent
trans-diols, that is, the 3- and 4-positions and the 4- and
5-positions. For the investigation of a conformational
change in the multifunctionalized cyclohexane ring due to
the repulsion of two bulky silyloxy groups, we designed
myo-inositol derivatives possessing two TBS, two TIPS, or
two TBDPS groups into the adjacent trans-diols (3,4- and
4,5-positions). Thus, we synthesized (G)-3,4-bis-O-TBS,
TIPS, and TBDPS-myo-inositols (1–3) and the correspond-
ing 4,5-analogues 4–6 (Fig. 4), and investigated their ring
conformations. The conformations of the synthetic inter-
mediate 1p–6p were also studied. The ring conformations
Myo-inositol has six hydroxy groups on a cyclohexane ring,
and five of them occupy the equatorial positions because the
compound is generally in the equatorial-rich chair form
(Fig. 3). As the previous ring-inversions shows,2–6 intro-
duction of the bulky silyl groups into a pair of adjacent
trans-hydroxy groups—generally these are equatorial—has
1
were determined based on the coupling constants in the H
NMR spectra. When the derivatives afforded single crystals,
we also carried out X-ray diffraction studies.
2. Results and discussion
2.1. Preparation of the adjacent trans-silyloxy
derivatives of myo-inositol
Figure 3. Myo-inositol in the equatorial-rich chair form.
Scheme 1 shows the syntheses of 1–6. The dibenzylation of
(G)-4,5-di-O-benzyl-1,6-bis-O-(4-methoxybenzyl)-myo-
inositol (7)8 gave the 1,2,5,6-tetrabenzylated derivative 11,
then removal of the two p-methoxybenzyl (PMB) groups
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
produced the 3,4-diol 8. The protection of the two generated
hydroxy groups with TBSOTf, TIPSOTf, and TBDPSOTf9
gave 1p, 2p, and 3p, respectively, whose benzyl groups
were hydrogenated with Pd(OH)2 in THF to give the
3,4-bis-O-silylated 1, 2, and 3.12 The complete removal of
the benzyl groups was complicated. These reactions
required a long time and sometimes a high hydrogen gas
pressure, but the resulting yields of the full debenzylated
compounds were not very high. The steric hindrance due to
Figure 4. Compounds whose ring conformations were investigated.
Scheme 1. Reagents and conditions: (a) NaH, DMF, rt, 2 h, then BnBr, rt, 10 h, 68%, (b) DDQ, 17:1 CH2Cl2-H2O, rt, 45 min, 77%, (c) TBSOTf, 2,6-lutidine,
DMF, 100 8C, 1 h, 94% to 1p; TIPSOTf, 2,6-lutidine, DMF, 100 8C, 12 h, 83% to 2p; TBDPSOTf, 2,6-lutidine, DMF, 100 8C, 7 h, 85% to 3p, (d) H2 (1 atm),
Pd(OH)2, THF, rt, 15 days, 12% to 1; H2 (1 atm), Pd(OH)2, THF, rt, 17 days, 48% to 2; H2 (100 atm), Pd(OH)2, THF, rt, 8 days, 23% to 3, (e) NaH, DMF, rt,
2 h, then BnBr, rt, 5 h, 98%, (f) DDQ, 17:1 CH2Cl2-H2O, rt, 6 h, 82%, (g) TBSOTf, 2,6-lutidine, DMF, 120 8C, 10 h, 100% to 4p; TIPSOTf, 2,6-lutidine, DMF,
100 8C, 12 h, 90% to 5p; TBDPSOTf, 2,6-lutidine, DMF, 100 8C, 1.5 h, 100% to 6p, (h) H2 (100 atm), Pd(OH)2, THF, rt, 5 days, 31% to 4; H2 (1 atm),
Pd(OH)2, THF, rt, 11 days, 35% to 5; H2 (1 atm), Pd(OH)2, THF, rt, 10 days, 50% to 6.

K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
Table 1. H NMR coupling constants and dihedral angles of 1–6, 1p–6p, 8 and 10
3499
1
Compound
3JHH (Hz) [caluculated dihedral angle (8)]
4JHH (Hz)
(positions)
H-1–H-2 [H-1–
C-1-C-2–H-2]
H-2–H-3 [H-2–
C-2–C-3–H-3]
H-3–H-4 [H-3–
C-3–C-4–H-4]
H-4–H-5 [H-4–
C-4–C-5–H-5]
H-5–H-6 [H-5–
C-5–C-6–H-6]
H-6–H-1 [H-6–
C-6–C-1–H-1]
1a
2.7 [61]
2.9 [59]
2.8 [60]
2.1 [68]
1.8 [72]
3.0 [58]
2.1 [68]
3.4 [54]
3.4 [54]
2.9 [59]
2.9 [59]
2.7 [61]
2.1 [68]
2.4 [64]
1.8 [72]
2.4 [64]
3.4 [54]
3.4 [54]
9.5 [162]
8.1 [149]
7.4 [144]
9.3 [160]
9.3 [160]
8.4 [152]
9.3 [160]
7.2 [143]
3.7 [52]
9.2 [159]
8.1 [149]
7.2 [143]
9.0 [157]
8.7 [154]
8.1 [149]
9.3 [160]
7.1 [142]
3.9 [50]
8.8 [155]
8.5 [153]
7.6 [146]
9.3 [160]
9.0 [157]
8.4 [152]
9.3 [160]
7.1 [142]
3.8 [51]
9.0 [157]
8.5 [153]
7.9 [148]
9.6 [164]
9.3 [160]
8.7 [154]
9.6 [164]
7.4 [144]
3.6 [53]
—
—
—
—
—
—
—
—
2a
3a
1pb
2pb
3pc
8c
4a
5a
0.8 (H-3–H-5)
1.7 (H-4–H-6)
1.0 (H-5–H-1)
0.9 (H-3–H-5)
1.8 (H-4–H-6)
0.9 (H-5–H-1)
—
—
1.2 (H-4–H-6)
—
6a
3.3 [55]
3.3 [55]
3.6 [53]
3.3 [55]
3.3 [55]
3.6 [53]
4pb
5pb
6pc
10c
2.4 [64]
2.4 [64]
2.7 [61]
2.4 [64]
2.1 [68]
2.4 [64]
3.6 [53]
2.4 [64]
9.6 [164]
8.4 [152]
3.6 [53]
8.7 [154]
7.8 [147]
3.3 [55]
9.3 [160]
7.8 [147]
3.6 [53]
9.6 [164]
9.0 [157]
4.8 [43]
9.6 [164]
9.3 [160]
9.3 [160]
9.6 [164]
a In CD3CN.
b In CDCl3.
c In C6D6.
the bulky silyl groups supposedly prevents the approach of
the benzyl groups to the surface of the catalyst.3b,10 Starting
from (G)-1,4-di-O-benzyl-5,6-bis-O-(4-methoxybenzyl)-
myo-inositol (9),11 a similar sequence produced 4,5-bis-O-
silylated 4p–6p and 4–6 through the 1,2,3,6-tetrabenzylated
derivative 12 and the diol 10.12
what smaller than the others, the reduced amount did not
indicate a drastic change in the ring conformation. There-
fore, the introduction of the bulky silyl protecting groups
into the 3,4-hydroxy groups of myo-inositol did not change
the original equatorial-rich chair form.
2.2. Determination of the ring conformations
Since the original Cs symmetry of the myo-inositol was
already deformed, the accurate observation of the 1H NMR
coupling constants based on both vicinal protons (3JHH) and
w-shaped long-range couplings (4JHH) were possible for
investigating the ring conformations of 1–6 and 1p–6p.
Table 1 summarizes the coupling constants of 1–6 and
1p–6p at room temperature and the calculated dihedral
Figure 5. Ring conformation of the 3,4-bis-O-silylated myo-inositol
derivatives.
In contrast, the rings of certain 4,5-bis-O-silylated com-
pounds, 5,6, and 6p existed in the axial-rich chair form
(Fig. 6). The coupling constants of these compounds were in
the range of 2.7–4.8 Hz (Table 1), and these values
indicated that the cyclohexane cores of 5, 6, and 6p were
in the axial-rich chair form. The long-range w-couplings
due to H-3–H-5, H-4–H-6, and H-5–H-1 supported this
conclusion. Furthermore, the X-ray diffraction study
elucidated that 6p existed as the axial-rich chair form in a
3
13,14
angles based on JHH
.
Although the solution of the
Karplus equation has two values for a given coupling
constant, the six-membered cyclic structure limits the
possible dihedral angles of the vicinal C–H bonds on the
ring. The calculated values were confirmed for their validity
by assembling molecular models. The coupling constants of
8 and 10, which are the precursor diols for the correspond-
ing silyl-protected compounds, are also listed for compari-
son. The coupling constants of the tetraols 1–6 were
measured in CD3CN and those of the tetrabenzyl derivatives
1p–6p were the data in CDCl3. When the signals heavily
overlapped, C6D6 was employed.
The assembled molecular models based on the dihedral
angles indicated that all the 3,4-bis-O-silylated myo-inositol
derivatives 1–3 and 1p–3p existed in the equatorial-rich
chair form (Fig. 5). The coupling constants of the 3,4-bis-O-
silylated 1–3 and 1p–3p were substantially similar to those
of the non-silylated diol 8 indicating the large values due
to the protons in the 1,2-diaxial relationship at H-3–H-4,
H-4–H-5, H-5–H-6, and H-6–H-1. Although the coupling
constants of the 3,4-bis-O-TBDPS-protected 3 were some-
Figure 6. Ring conformation of 4,5-bis-O-silylated myo-inositol
derivatives.

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K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
Figure 7. ORTEP drawing and Chem-3D model based on the X-ray diffraction study of 6p. In the model, the benzyl groups and substituents on the silicon
atoms are omitted for clarity.
crystal (Fig. 7). These are the first observations to show that
the multifunctionalized cyclohexane rings are able to flip
into the axial-rich chair form by the introduction of bulky
silyl protections. On the other hand, the tetrabenzylated 4p
and 5p as well as the tetraol 4 retained the equatorial-rich
chair form, although the silyl protections were introduced at
the 4,5-positions. The coupling constants of these com-
pounds were generally similar to those of the nonsilylated
diol 10 indicating the large values due to the 1,2-diaxial
H-3–H-4, H-4–H-5, H-5–H-6, and H-6–H-1.
chair form, but the ring of the corresponding tetra-benzyl-
protected 5p was in the equatorial-rich chair form. Thus the
benzyloxy groups prevented the ring flip more than the
hydroxy groups. On the basis of this result, we envisaged
that the axial-rich conformation of 5 was stabilized by
hydrogen bondings.16 Because the ring flip of 5 occurred in
CD3CN (Table 1), we changed the solvent to CD3OD. The
result listed in Table 2 indicated that the ring conformation
of 5 was still the axial-rich chair form even in methanol. The
coupling constants were in the range of 3.1–5.6 Hz. The
clear long-range w-coupling due to H-4–H-6 (1.2 Hz) was
observed along with small (!1 Hz) w-couplings due to
H-1–H-3, H-3–H-5, and H-5–H-1. These small couplings
were confirmed by the decoupling experiments because the
correlated signals became sharper and taller. On the other
hand, each NMR spectrum of the benzyl-protected 5p in
CDCl3, acetone-d6, and CD3OD indicated that the equa-
torial-rich chair form was retained in all cases. These
observations demonstrated that the influence of both solvent
effects and hydrogen bondings were less marked on these
ring conformations.
2.3. Considerations of the ring conformations
Marzabadi’s report shows that trans-1,2-bis(tert-butyl-
dimethylsilyloxy)cyclohexane preferred the equatorial-rich
chair form (Fig. 2).5 At first, we postulated that increasing
the functional groups surrounding the trans-adjacent OTBS
groups would reinforce the steric repulsion of the silyloxy
groups and flip the multifunctionalized cyclohexane ring
into the axial-rich chair form. Contrary to our expectation,
however, all the synthesized bis-O-TBS-protected com-
pounds, 1, 1p, 4, and 4p maintained the original equatorial-
rich chair form regardless of the introduced places (3,4- or
4,5-positions) and the presence of the benzyl groups.
Therefore, the two OTBS groups are not big enough to
induce the ring flip of cyclohexane in solution even when
they are placed trans-adjacent and even in a multifunction-
alized cyclohexane.15
The introduction of TBDPS groups into the 4,5-hydroxy
groups of myo-inositol, 6 as well as 6p, induced complete
ring flip into the axial-rich chair form. A comparison of the
ring conformations of 4, 5, 5p, and 6p (Fig. 6) demonstrated
that the steric repulsion is OTBDPS/OTBDPS OOTIPS/
OTIPSOOTBS/OTBS. Eliel and Satici reported the con-
formational energy of monosilyloxycyclohexanes.17 The
population of the axial-rich chair form is 9 and 20% in the
TIPS derivative and in the TBDPS derivative, respectively
When the TIPS groups were introduced to the 4,5-positions,
the cyclohexane ring of the tetraol 5 was in the axial-rich
Table 2. 1H NMR coupling constants and calculated dihedral angles of 5 and 5p in several solvents
3JHH (Hz) [calculated dihedral angle (8)]
Compound
Solvent
H-1–H-2 [H-1–
C-1–C-2–H-2]
H-2–H-3 [H-2–
C-2–C-3–H-3]
H-3–H-4 [H-3–
C-3–C-4–H-4]
H-4–H-5 [H-4–
C-4–C-5–H-5]
H-5–H-6 [H-5–
C-5–C-6–H-6]
H-6–H-1 [H-6–
C-6–C-1–H-1]
5
5
5p
5p
5p
CD3CN
CD3OD
CDCl3
CD3COCD3
CD3OD
3.4 [54]
3.1 [57]
2.4 [64]
1.7 [74]
2.4 [64]
3.4 [54]
3.1 [57]
2.4 [64]
2.1 [68]
2.2 [66]
3.7 [52]
5.1 [40]
8.4 [152]
9.2 [159]
9.0 [157]
3.9 [50]
4.4 [46]
7.8 [147]
8.2 [150]
8.1 [149]
3.8 [51]
4.4 [46]
7.8 [147]
8.4 [152]
8.3 [151]
3.6 [53]
5.6 [40]
9.0 [157]
9.1 [158]
9.0 [157]

K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
3501
(Fig. 8). Therefore, the OTBDPS group is easier to axially
orient than the OTIPS group when it is the only substituent
on the cyclohexane ring. On the contrary, when these
silyloxy groups are placed side by side in a trans-adjacent
manner, the OTIPS/OTIPS repulsion increased more than
that of OTBDPS/OTBDPS (Fig. 2).5 In the multifunctiona-
lized case, the functionalities except for the silyloxy groups
are likely to affect the ring conformation.
6, and 6p are the first axial-rich chair myo-inositol
derivatives isolated in the pure form, although the ring flip
of inositols itself has been previously observed in solution.18
As well as the famous ring conformation of the all-trans-
1,2,3,4,5,6-hexaisopropylcyclohexane reported by Biali and
co-workers,19 the flipped compounds are also the counter
examples to the general stability of equatorial-rich chair six-
membered rings. It is noteworthy that the introduction and
removal of the silyl protecting groups switch the ring
conformation, that is, the conformation of the multi-
functionalized cyclohexane ring has become controllable.
The cyclohexane-ring of myo-inositol was flipped into the
axial-rich chair form when the TIPS or TBDPS groups were
introduced into the 4- and 5-hydroxy groups. In contrast,
when the bulky silyl groups were introduced into the 3- and
4-positions, the equatorial-rich chair forms were retained
regardless of the variety of the silyloxy groups. This
observation displayed an enhanced silyloxy/silyloxy repul-
sion as expected due to the oxygen functionalities on both
sides of the adjacent silyloxy groups. It may be possible to
state that the introduction of TBDPS groups will flip the
cyclohexane ring when the silylating vicinal hydroxy
groups are in the center of the contiguous four equatorial
hydroxy groups.
Figure 8. Conformational equilibrium of trialkylsilyloxycyclohexanes in
CD2Cl2 at 179–188 K.17
One of the most important observations is that all the
3,4-bis-O-silylated myo-inositol derivatives, 1–3 and 1p–3p
maintained the equatorial-rich chair form in contrast to the
ring conformation of the 4,5-bis-O-silylated compounds.
In myo-inositol, both the side-functionalities of the 4- and
5-positions are in the trans-relationship. In contrast, one
side of the 3,4-bis-O-silyloxy derivatives, that is, the
2-position, is in the cis-relationship. In these cases, rotation
of the C-3–O bond let the bulky silyl group escape into a
space in the 2-equatorial direction (Fig. 9) reducing the
silyloxy/silyloxy repulsion. In the bis-4,5-O-silylated com-
pounds, there is no such space to reduce the repulsion. In the
equatorial-rich chair form, the silyloxy/silyloxy repulsion
is enhanced when they are located in the center of the
contiguous trans-hydroxy groups.15 Because each ring
conformation would be the result of a balance between the
1,3-diaxial interactions with the 1,2-diequatorial silyloxy/
silyloxy interactions, the bis-4,5-O-silylated derivatives, 5,
6, and, 6p are in the axial-rich chair form.
4. Experimental
4.1. General method and materials
All commercially available reagents were used without
further purification. All moisture and air sensitive reactions
were performed under a positive pressure of argon in a
glassware equipped with rubber septa. The glassware was
dried under reduced pressure by heating with a heat-gun
before use. When necessary, the solvents and reagents were
distilled prior to use and were transferred using a syringe or
cannula. The reaction mixture was magnetically stirred.
Thin layer chromatography was performed on Merck
precoated silica gel 60 F-254 plates or Merck RP-19
F-254 plates. Column chromatography was performed on
Merck silica gel 60 (0.063–0.200 mm) or Merck silica gel
60 230–400 mesh for ordinary phase or Nacalai tesque
cosmosil 140C18-PREP for reverse phase. Spots were
detected by dipping in a solution of 2% anisaldehyde, 5%
H2SO4 in EtOH or a solution of 10% phosphomolybdic acid
in EtOH followed by heating at ca. 200 8C.
The melting points were determined using a Yanagimoto
micro-melting point apparatus. The infrared (IR) spectra
were recorded on JASCO FT/IR-5300 or 8000 instruments
and the major absorbance bands are all reported in
wavenumber (cmK1). The nuclear magnetic resonance
(NMR) spectra were recorded on a-JEOL 400, Varian
UNITY 300 and JEOL JNM-ECA 300 instruments. The
spectral settings for the proton (1H) NMR were as follows:
8.0 kHz spectral width, 32768 data points, 4.10 sec
acquisition time, 0.24 Hz digital resolution for the a-JEOL
400; 4.5 kHz spectral width, 64000 data points, 7.11 sec
acquisition time, 0.14 Hz digital resolution for the Varian
UNITY 300; and 5.6 kHz spectral width, 32768 data points,
Figure 9.
3. Conclusion
Two adjacent bulky silyloxy groups can flip a cyclohexane-
ring into the axial-rich chair form even it is multi-
functionalized, as in these reported results. Compounds 5,

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K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
5.81 sec acquisition time, 0.17 Hz digital resolution for the
JEOL JNM-ECA 300. Chemical shifts of the NMR spectra
are reported in d units downfield from tetramethylsilane.
The 1H NMR data are indicated by a chemical shift with the
multiplicity, the coupling constants, the integration, and the
assignment in parentheses in this order. The multiplicities
are abbreviated as s: singlet, d: doublet, t: triplet, q: quartet,
m: multiplet, and br: broad. The 13C NMR data are reported
as the chemical shift with the hydrogen multiplicity
obtained from the DEPT spectra and the number of carbons
in parentheses. When the number of carbons could not be
analyzed due to heavy overlapping, the number is not
indicated. High-resolution mass spectra (HRMS) were
obtained on either JEOL JMS-T100LC or a JEOL JMS-
700 spectrometer for electrospray ionization (ESI) or fast
atom bombardment ionization (FAB) and are reported in
units of mass to charge.
AcOEtZ2/1 to 1/1) to give 8 (885 mg, 77%) as a white
powder. mp. 162–164 8C; IR (KBr, disk) nmax (cmK1) 3387,
3100, 3080, 3040, 2909, 2890, 1453, 1445, 1354, 1132,
1
1049, 1026, 727, 694; H NMR (C6D6, 300 MHz) d 7.40–
7.08 (m, 20H), 4.97 (d, JZ11.7 Hz, 2H), 4.94 (d, JZ
11.1 Hz, 1H), 4.85 (d, JZ11.7 Hz, 1H), 4.81 (d, JZ
11.1 Hz, 1H), 4.74 (d, JZ11.7 Hz, 1H), 4.42 (d, JZ
12.3 Hz, 1H), 4.37 (d, JZ12.0 Hz, 1H), 4.15 (dd, JZ9.6,
9.3 Hz, 1H, H-6), 3.92 (dd, JZ9.3, 9.3 Hz, 1H, H-4), 3.84
(dd, JZ2.4, 2.1 Hz, 1H, H-2), 3.27 (dd, JZ9.3, 9.3 Hz, 1H,
H-5), 3.18 (dd, JZ9.6, 2.1 Hz, 1H, H-1), 3.15 (dd, JZ9.3,
2.4 Hz, 1H, H-3), 2.17 (br, 1H), 2.10 (br, 1H); 13C NMR
(CDCl3, 100 MHz) d 138.6 (s, 3C), 138.1 (s, 1C), 128.5 (d),
128.4 (d), 128.3 (d), 128.1 (d), 128.0 (d), 127.9 (d), 127.7
(d), 127.6 (d), 83.0 (d, 1C), 81.4 (d, 1C), 81.3 (d, 1C), 77.2
(d, 1C), 75.7 (t, 1C), 75.4 (t, 1C), 74.8 (t, 1C), 73.9 (d, 1C),
73.1 (t, 1C), 72.1 (d, 1C); HRMS-FAB (m/z) [MCH]C
calcd for C34H37O6, 541.2590; found, 541.2583.
4.2. Preparation of the 3,4-bis-O-silylated myo-inositol
derivatives
4.2.3. 1,2,5,6-tetra-O-Benzyl-3,4-bis-O-tert-butyldi-
methylsilyl-myo-inositol (1p). TBSOTf (176 mg,
0.665 mmol) was added to a stirring solution of 8 (90 mg,
0.17 mmol) and 2,6-lutidine (356 mg, 3.33 mmol) in DMF
(2 mL). After stirring for 1 h at 100 8C, the reaction mixture
was cooled to room temperature and diluted with hexane.
The mixture was successively washed with water and brine.
The organic layer was dried over MgSO4, filtered through a
cotton-pad, and evaporated. The resulting residue was
purified by silica gel chromatography (5 g of SiO2 eluted
with hexane/AcOEtZ100/0 to 50/1) to give 1p (120 mg,
4.2.1. 1,2,5,6-tetra-O-Benzyl-3,4-bis-O-(4-methoxyben-
zyl)-myo-inositol (11). NaH (60% in oil, 180 mg,
4.50 mmol) was added to a stirring solution of 5,6-di-O-
benzyl-3,4-bis-O-(4-methoxybenzyl)-myo-inositol (7)8
(900 mg, 1.50 mmol) in DMF (5 mL) at room temperature.
After stirring for 2 h at room temperature, BnBr (769 mg,
4.50 mmol) was added. After stirring for 10 h at room
temperature, the reaction was quenched with saturated
NH4Cl (30 mL). The aqueous mixture was extracted with
CH2Cl2 (3!10 mL). The combined organic layer was
successively washed with water and brine. The combined
organic layer was dried over MgSO4, filtered through a
cotton-pad, and evaporated. The resulting residue was
purified by silica gel chromatography (30 g of SiO2 eluted
with hexane/AcOEtZ100/0 to 6/1) to give 11 (791 mg,
68%) as a white powder. mp. 96–98 8C; IR (KBr, disk) nmax
(cmK1) 3100, 3080, 3030, 2913, 2838, 1615, 1514, 1454,
94%) as colorless syrup. IR (NaCl, thin film) nmax (cmK1
)
3034, 2930, 2859, 1726, 1456, 1360, 1256, 1130, 1069, 839,
777, 735, 696; 1H NMR (CDCl3, 300 MHz) d 7.45–7.17 (m,
20H), 5.00–4.64 (m, 8H), 4.11 (dd, JZ9.3, 9.0 Hz, 1H,
H-4), 4.05 (dd, JZ9.6, 9.3 Hz, 1H, H-6), 3.85 (dd, JZ2.1,
2.1 Hz, 1H, H-2), 3.44 (dd, JZ9.6, 2.1 Hz, 1H, H-1), 3.43
(dd, JZ9.3, 2.1 Hz, 1H, H-3), 3.25 (dd, JZ9.3, 9.0 Hz, 1H,
H-5), 0.91 (s, 9H), 0.89 (s, 9H), 0.10–0.00 (m, 12H); 13C
NMR (CDCl3, 75 MHz) d 140.0 (s, 1C), 139.4 (s, 1C), 138.9
(s, 1C), 138.5 (s, 1C), 128.4 (d), 128.2 (d), 128.1 (d), 128.0
(d), 127.9 (d), 127.7 (d), 127.3 (d), 127.1 (d), 127.0 (d),
126.7 (d), 84.3 (d, 1C), 82.6 (d, 1C), 80.9 (d, 1C), 80.2 (d,
1C), 75.7 (t, 1C), 75.2 (t, 1C), 74.6 (t, 1C), 74.5 (d, 1C), 73.2
(d, 1C), 72.8 (t, 1C), 26.5 (q, 6C), 18.4 (s, 2C), 18.1 (s, 1C),
K2.9 (q, 1C), K3.6 (q, 1C), K3.7 (q, 1C), K4.2 (q, 1C);
HRMS-FAB (m/z) [MCH]C calcd for C46H65O6Si2,
769.4320; found, 769.4341.
1
1358, 1250, 1096, 1036, 824, 733, 696; H NMR (CDCl3,
300 MHz) d 7.40–7.19 (m, 24H), 6.87–6.78 (m, 4H), 4.90
(d, JZ10.8 Hz, 1H), 4.87 (s, 4H), 4.83 (d, JZ10.5 Hz, 1H),
4.81 (d, JZ10.5 Hz, 1H), 4.74 (d, JZ10.2 Hz, 1H), 4.65 (d,
JZ11.7 Hz, 1H), 4.62 (d, JZ6.3 Hz, 1H), 4.56 (d, JZ
4.8 Hz, 1H), 4.53 (d, JZ11.1 Hz, 1H), 4.07 (dd, JZ9.6,
9.6 Hz, 1H), 4.05 (dd, JZ9.6, 9.6 Hz, 1H), 4.00 (dd, JZ2.1,
2.1 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.45 (dd, JZ9.3,
9.3 Hz, 1H), 3.34 (dd, JZ9.9, 2.1 Hz, 1H), 3.32 (dd, JZ9.9,
2.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 139.0 (s, 1C),
138.9 (s, 1C), 138.4 (s, 1C), 131.1 (s, 1C), 130.5 (s, 1C),
129.7 (d), 129.1 (d), 128.3 (d), 128.1 (d), 128.0 (d), 127.7
(d), 127.5 (d), 127.4 (d), 127.3 (d), 113.7 (d, 4C), 83.7 (d,
1C), 81.7 (d, 1C), 81.4 (d, 1C), 80.9 (d, 1C), 80.7 (d, 1C),
75.8 (t, 1C), 75.5 (t, 1C), 74.4 (d, 1C), 74.1 (t, 1C), 72.7 (t,
1C), 72.4 (t, 1C), 55.2 (q, 2C); HRMS-ESI (m/z) [MCNa]C
calcd for C50H52NaO8, 803.3560; found, 830.3563.
4.2.4. 1,2,5,6-tetra-O-Benzyl-3,4-bis-O-triisopropylsilyl-
myo-inositol (2p). TIPSOTf (138 mg, 0.450 mmol) was
added to a stirring solution of 8 (50 mg, 0.090 mmol) in
2,6-lutidine (248 mg, 2.32 mmol) at 100 8C. After stirring
for 12 h at 100 8C, the reaction mixture was cooled to room
temperature, and then diluted with CH2Cl2 (10 mL). The
mixture was successively washed with water (3 mL) and
brine (3 mL). The organic layer was dried over MgSO4,
filtered through a cotton-pad, and evaporated. The resulting
residue was purified by silica gel chromatography (15 g of
SiO2 eluted with hexane/AcOEtZ100/0 to 30/1) to give 2p
4.2.2. 1,2,5,6-tetra-O-Benzyl-myo-inositol (8). DDQ
(1.05 g, 4.66 mmol) was added to a stirring solution of 11
(1.66 g, 2.12 mmol) in CH2Cl2/H2O (17/1, 20 mL) at room
temperature. After stirring for 45 min at room temperature,
the reaction mixture was filtered through a cotton-Celite pad
and evaporated. The resulting residue was purified by silica
gel chromatography (75 g of SiO2 eluted with hexane/
(65 mg, 83%) as colorless syrup. IR (KBr, disk) nmax (cmK1
)
3090, 3060, 3020, 2946, 2866, 1458, 1130, 1090, 1065,
1026, 883, 735, 685; 1H NMR (CDCl3, 300 MHz) d
7.40–7.13 (m, 20H), 5.13 (d, JZ11.7 Hz, 1H), 5.08 (d,

K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
3503
JZ12.0 Hz, 1H), 4.88 (d, JZ10.5 Hz, 1H), 4.74 (d, JZ
12.0 Hz, 1H), 4.73 (d, JZ12.0 Hz, 1H), 4.68 (d, JZ
12.3 Hz, 1H), 4.66 (d, JZ12.0 Hz, 1H), 4.61 (d, JZ
10.5 Hz, 1H), 4.34 (dd, JZ9.3, 8.7 Hz, 1H, H-4), 4.06 (dd,
JZ9.3, 9.0 Hz, 1H, H-6), 3.95 (dd, JZ2.4, 1.8 Hz, 1H, H-
2), 3.66 (dd, JZ9.3, 1.8 Hz, 1H, H-1), 3.48 (dd, JZ9.3,
2.4 Hz, 1H, H-3), 3.27 (dd, JZ9.0, 8.7 Hz, 1H, H-5), 1.08–
0.99 (m, 42H); 13C NMR (CDCl3, 100 MHz) d 139.6 (s,
1C), 139.5 (s, 1C), 138.7 (s, 1C), 138.4 (s, 1C), 128.4 (d),
128.2 (d), 128.0 (d), 127.9 (d), 127.8 (d), 127.7 (d), 127.4
(d), 127.0 (d), 126.8 (d), 126.7 (d), 126.3 (d), 84.2 (d, 1C),
83.3 (d, 1C), 81.6 (d, 1C), 79.4 (d, 1C), 75.4 (t, 1C), 74.5 (d,
1C), 74.1 (t, 1C), 73.9 (d, 1C), 73.7 (t, 1C), 72.8 (t, 1C), 18.5
(q, 3C), 18.4 (q, 9C), 13.8 (d, 6C); HRMS-FAB (m/z) [MC
H]C calcd for C52H77O6Si2, 853.5259; found, 853.5245.
1373, 1256, 1132, 1065, 1018, 860, 835, 777, 721, 669; 1H
NMR (400 MHz, CD3CN) d 3.87 (dd, JZ2.9, 2.7 Hz, 1H,
H-2), 3.70 (dd, JZ9.0, 8.8 Hz, 1H, H-6), 3.51 (dd, JZ9.0,
2.7 Hz, 1H, H-1), 3.47 (dd, JZ9.5, 9.2 Hz, 1H, H-4), 3.30
(dd, JZ9.5, 2.9 Hz, 1H, H-3), 3.05 (dd, JZ9.2, 8.8 Hz, 1H,
H-5), 0.91 (s, 9H), 0.90 (s, 9H), 0.11 (s, 6H), 0.10 (s, 3H),
0.08 (s, 3H); 13C NMR (100 MHz, CDCl3) d 76.2 (d, 1C),
75.3 (d, 1C), 75.1 (d, 1C), 74.2 (d, 1C), 74.1 (d, 1C), 72.6
(d, 1C), 26.7 (q, 2C), 26.6 (q, 4C), 19.0 (s, 1C), 18.9 (s, 1C),
K2.8 (q, 1C), K3.3 (q, 1C), K3.5 (q, 1C), K4.2 (q, 1C);
HRMS-FAB (m/z) [MCH]C calcd for C18H41O6Si2,
409.2442; found, 409.2439.
4.2.7. 3,4-bis-O-Triisopropylsilyl-myo-inositol (2).12
Same procedure as the debenzylation of 1p was performed
starting from 2p (147 mg, 0.172 mmol) with Pd(OH)2 on C
(20 wt%, 363 mg, 0.517 mmol) in THF (1 mL). The
reaction needed 17 days. Purification was performed by
silica gel chromatography (3 g of SiO2 eluted with hexane/
AcOEtZ3/1 to 1/1) to give 2 (40 mg, 48%) as colorless
syrup. IR (ZnSe, thin film) nmax (cmK1) 3385, 2946, 2868,
2361, 2342, 1466, 1385, 1256, 1121, 1059, 1015, 943, 920,
883, 829, 806, 712, 681, 652; 1H NMR (400 MHz, CD3CN)
d 3.94 (dd, JZ8.1, 8.1 Hz, 1H, H-4), 3.93 (dd, JZ2.9,
2.9 Hz, 1H, H-2), 3.77 (dd, JZ8.1, 2.9 Hz, 1H, H-3), 3.54
(dd, JZ8.5, 8.5 Hz, 1H, H-6), 3.36 (dd, JZ8.5, 2.9 Hz, 1H,
H-1), 3.20 (dd, JZ8.5, 8.1 Hz, 1H, H-5), 1.26–1.08 (m,
42H); 13C NMR (100 MHz, CDCl3) d 75.2 (d, 1C), 75.0 (d,
1C), 73.7 (d, 1C), 73.6 (d, 1C), 73.1(d, 1C), 69.5 (d, 1C),
18.4 (q, 4C), 18.3 (q, 8C), 13.2 (d, 3C), 13.1 (d, 3C); HRMS-
FAB (m/z) [MCH]C calcd for C24H53O6Si2, 493.3381;
found, 493.3383.
4.2.5. 1,2,5,6-tetra-O-Benzyl-3,4-bis-O-tert-butyldi-
phenylsilyl-myo-inositol (3p). TBDPSOTf (144 mg,
0.371 mmol) was added to a stirring solution of 8 (45 mg,
0.083 mmol) in 2,6-lutidine (178 mg, 1.66 mmol) at 100 8C.
After stirring for 7 h at 100 8C, the reaction mixture was
cooled to room temperature, and then water (5 mL) was
added. The aqueous mixture was extracted with hexane (3!
5 mL). The organic layer was successively washed with
water (3 mL) and brine (3 mL). The organic layer was dried
over MgSO4, filtered through a cotton-pad, and evaporated.
The resulting residue was purified by silica gel chromato-
graphy (3 g of SiO2 eluted with hexane/AcOEtZ80/1 to
40/1) to give 3p (72 mg, 85%) as colorless syrup. IR (KBr,
disk) nmax (cmK1) 3069, 3050, 3030, 2932, 2859, 1427,
1
1360, 1113, 824, 737, 696; H NMR (C6D6, 300 MHz) d
8.10–6.65 (m, 40H), 5.03 (dd, JZ8.4, 8.1 Hz, 1H, H-4),
4.80 (d, JZ12.0 Hz, 1H), 4.73 (d, JZ12.0 Hz, 1H), 4.71 (d,
JZ12.0 Hz, 1H), 4.65 (d, JZ12.0 Hz, 1H), 4.17 (d, JZ
11.4 Hz, 1H), 4.14 (dd, JZ8.4, 1.8 Hz, 1H, H-3), 4.10 (d,
JZ12.0 Hz, 1H), 4.06 (d, JZ12.0 Hz, 1H), 4.00 (dd, JZ
8.7, 8.4 Hz, 1H, H-6), 3.96 (d, JZ11.7 Hz, 1H), 3.58 (dd,
JZ3.0, 1.8 Hz, 1H, H-2), 3.46 (dd, JZ8.4, 8.1 Hz, 1H,
H-5), 3.13 (dd, JZ8.7, 3.0 Hz, 1H, H-1), 1.27 (s, 9H), 1.22
(s, 9H); 13C NMR (CDCl3, 75 MHz) d 139.4 (s, 1C), 139.3
(s, 1C), 138.7 (s, 1C), 138.4 (s, 1C), 136.3 (d, 1C), 136.2 (d,
1C), 135.9 (d, 1C), 135.8 (d, 1C), 135.2 (s, 1C), 135.1 (s,
1C), 133.6 (s, 1C), 133.5 (s, 1C), 129.8 (d), 129.6 (d), 129.0
(d), 128.9 (d), 128.1 (d), 128.0 (d), 127.8 (d), 127.6 (d),
127.5 (d), 127.4 (d), 127.3 (d), 127.2 (d), 127.1 (d), 127.0
(d), 126.7 (d), 126.6 (d), 126.2 (d), 83.7 (d, 1C), 82.6 (d,
1C), 81.3 (d, 1C), 75.9 (d, 1C), 74.7 (d, 1C), 74.6 (d, 1C),
74.5 (t, 1C), 72.7 (t, 1C), 72.3 (t, 1C), 71.9 (t, 1C), 27.5 (q,
3C), 27.2 (q, 3C), 19.9 (s, 1C), 19.2 (s, 1C); HRMS-ESI
(m/z) [MCNa]C calcd for C66H73O6Si2, 1017.4946; found,
1017.4961.
4.2.8. 3,4-bis-O-tert-Butyldiphenylsilyl-myo-inositol
(3).12 Same procedure as the debenzylation of 1p was
performed starting from 3p (347 mg, 0.340 mmol) with
Pd(OH)2 on C (20 wt%, 719 mg, 1.00 mmol) in THF
(2 mL). The reaction needed 8 days. Purification was
performed by silica gel chromatography (20 g of SiO2
eluted with hexane/AcOEtZ4/1 to 2/1) to give 3 (52 mg,
23%) as colorless syrup along with 2-O-benzyl-3,4-bis-O-
TBDPS-myo-inositol (54 mg, 24%) as pale yellow syrup.
Data for 3: IR (ZnSe, thin film) nmax (cmK1) 3418, 3073,
3050, 2932, 2892, 2859, 1472, 1427, 1113, 1061, 1006, 939,
826, 741, 704; 1H NMR (400 MHz in CD3CN) d 7.75–7.66
(m, 8H), 7.45–7.35 (m, 12H), 4.17 (dd, JZ7.4, 7.2 Hz, 1H,
H-4), 4.14 (dd, JZ7.4, 2.7 Hz, 1H, H-3), 3.66 (dd, JZ2.8,
2.7 Hz, 1H, H-2), 3.46 (dd, JZ7.9, 7.6 Hz, 1H, H-6), 3.33
(dd, JZ7.6, 7.2 Hz, 1H, H-5), 3.28 (dd, JZ7.9, 2.8 Hz, 1H,
H-1), 1.03 (s, 9H), 0.90 (s, 9H); 13C NMR (100 MHz in
CDCl3) d 136.0 (d, 2C), 135.9 (d, 2C), 135.7 (d, 2C), 135.4
(d, 2C), 133.3 (s, 1C), 132.9 (s, 1C), 138.2 (s, 1C), 132.5 (s,
1C), 130.1 (d, 1C), 130.0 (d, 2C), 129.9 (d, 1C), 127.9 (d,
4C), 127.8 (d, 2C), 127.7 (d, 2C), 75.5 (d, 1C), 75.1 (d, 1C),
73.1 (d, 1C), 73.0 (d, 1C), 72.9 (d, 1C), 67.7 (d, 1C), 27.1 (q,
6C), 19.2 (s, 2C); HRMS-FAB (m/z) [MCNa]C calcd for
C38H48NaO6Si2, 679.2887; found, 679.2886. Data for 2-O-
benzyl-3,4-bis-O-TBDPS-myo-inositol: IR (ZnSe, thin film)
nmax (cmK1) 3445, 3073, 3050, 2932, 2894, 2859, 1723,
1472, 1428, 1393, 1271, 1111, 1061, 1007, 824, 758, 704,
4.2.6. 3,4-bis-O-tert-Butyldimethylsilyl-myo-inositol
(1).12 Pd(OH)2 on C (20 wt %, 329 mg, 0.470 mmol) was
added to a stirring solution of 1p (120 mg, 0.160 mmol) in
THF (1 mL). The atmosphere of the flask was replaced with
H2, and the mixture was stirred for 15 days under H2. The
reaction mixture was filtered through a cotton-Celite pad,
and the filtrate was evaporated. The resulting residue was
purified by silica gel chromatography (3 g of SiO2 eluted
with hexane/AcOEtZ1/1) to give 1 (7.9 mg, 12%) as a
white powder. mp. 94–97 8C; IR (ZnSe, thin film) nmax
(cmK1) 3574, 3214, 2924, 2884, 2855, 2361, 1643, 1472,
1
611; H NMR (400 MHz, CD3CN) d 7.72–7.63 (m, 8H),
7.45–7.25 (m, 17H), 4.51 (d, JZ12.2 Hz, 1H), 4.38 (d, JZ
12.2 Hz, 1H), 4.33 (dd, JZ6.3, 6.3 Hz, 1H, H-4), 4.21 (dd,

3504
K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
JZ6.3, 1.5 Hz, 1H, H-3), 3.62–3.56 (br m, 2H, H-1, H-6),
3.52 (br s, 1H, H-2), 3.45 (br m, 1H, H-5), 1.02 (s, 9H), 0.93
(s, 9H); 13C NMR (100 MHz in CDCl3) d 137.6 (s, 1C),
136.5 (d), 136.2 (d), 136.0 (d), 135.5 (d), 133.0 (s, 1C),
132.0 (s, 1C), 131.9 (s, 1C), 131.8 (s, 1C), 130.1 (d), 129.8
(d), 129.6 (d), 128.3 (d), 127.9 (d), 127.8 (d), 127.7 (d),
127.5 (d), 127.4 (d), 74.7 (d, 1C), 73.5 (d, 1C), 73.1 (d, 2C),
71.6 (d, 2C), 70.4 (t, 1C), 27.0 (q, 3C), 26.8 (q, 3C), 19.0 (s,
1C), 18.9 (s, 1C); HRMS-ESI (m/z) [MCNa]C calcd for
C45H54NaO6Si2, 769.3357; found 769.3327.
2.4 Hz, 1H, H-2), 3.46 (dd, JZ9.3, 9.3 Hz, 1H, H-5), 3.17
(dd, JZ9.6, 2.4 Hz, 1H, H-1), 3.00 (dd, JZ9.6, 2.4 Hz, 1H,
H-3); 13C NMR (C6D6, 100 MHz) d 140.8 (s, 1C), 139.7 (s,
1C), 139.2 (s, 2C), 128.7 (d), 128.6 (d), 128.5 (d), 128.3 (d),
128.2 (d), 128.1 (d), 128.0 (d), 127.8 (d), 127.6 (d), 127.5
(d), 81.7 (d, 1C), 81.2 (d, 1C), 80.5 (d, 1C), 75.9 (d, 1C),
75.6 (t, 1C), 75.3 (d, 1C), 74.7 (t, 1C), 73.6 (d, 1C), 72.9 (t,
1C), 72.7 (t, 1C); HRMS-FAB (m/z) [MCH]C calcd for
C34H37O6, 541.2590; found, 541.2617.
4.3.3. 1,2,3,6-tetra-O-Benzyl-4,5-bis-O-tert-butyldi-
methylsilyl-myo-inositol (4p). TBSOTf (119 mg,
0.448 mmol) was added to a stirring solution of 10
(50 mg, 0.092 mmol) in 2,6-lutidine (248 mg, 2.32 mmol)
at 120 8C. After stirring for 10 h at 120 8C, the reaction
mixture was cooled to room temperature. Then the mixture
was diluted with water (10 mL). The aqueous mixture was
extracted with hexane (3!5 mL) and successively washed
with water (3 mL) and brine (3 mL). Then it was dried over
MgSO4, filtered through a cotton-pad, and evaporated. The
resulting residue was purified by silica gel chromatography
(6 g of SiO2 eluted with hexane/AcOEtZ100/0 to 30/1) to
give 4p (74 mg, 100%) as colorless syrup. IR (NaCl, thin
film) nmax (cmK1) 3090, 3060, 3020, 2930, 2857, 1721,
1456, 1362, 1258, 1128, 1071, 1028, 839, 775, 735, 696; 1H
NMR (CDCl3, 300 MHz) d 7.41–7.19 (m, 20H), 5.01 (d, JZ
11.7 Hz, 1H), 4.81 (d, JZ11.7 Hz, 1H), 4.76 (d, JZ
11.7 Hz, 1H), 4.66 (d, JZ11.7 Hz, 1H), 4.60 (d, JZ
12.0 Hz, 1H), 4.52 (d, JZ12.0 Hz, 2H), 4.48 (d, JZ
11.7 Hz, 1H), 4.11 (dd, JZ9.6, 8.7 Hz, 1H, H-4), 3.93 (dd,
JZ2.4, 2.1 Hz, 1H, H-2), 3.78 (dd, JZ9.6, 9.3 Hz, 1H,
H-6), 3.43 (dd, JZ9.3, 8.7 Hz, 1H, H-5), 3.35 (dd, JZ9.6,
2.4 Hz, 1H, H-1), 3.11 (dd, JZ9.6, 2.1 Hz, 1H, H-3), 0.89
(s, 9H), 0.88 (s, 9H), 0.14 (s, 3H), 0.10 (s, 6H), 0.02 (s, 3H);
13C NMR (CDCl3, 75 MHz) d 139.6 (s, 1C), 139.4 (s, 1C),
138.3 (s, 1C), 138.2 (s, 1C), 128.2 (d), 128.1 (d), 127.9 (d),
127.7 (d), 127.5 (d), 127.4 (d), 127.3 (d), 127.0 (d), 126.7
(d), 81.7 (t, 1C), 81.5 (t, 1C), 81.3 (t, 1C), 74.8 (t, 1C), 74.3
(t, 1C), 74.1 (d, 1C), 73.1 (d, 1C), 72.7 (t, 1C), 72.4 (t, 1C),
26.7 (q, 6C), 18.3 (s, 1C), 18.2 (s, 1C), K1.9 (q, 1C), K2.1
(q, 1C), K3.0 (q, 1C), K3.1 (q, 1C); HRMS-FAB (m/z)
[MCH]C calcd for C46H65O6Si2, 769.4320; found,
769.4324.
4.3. Preparation of the 4,5-bis-O-silylated myo-inositol
derivatives
4.3.1. 1,2,3,6-tetra-O-Benzyl-4,5-bis-O-(4-methoxyben-
zyl)-myo-inositol (12).12 NaH (60% in oil, 190 mg,
4.74 mmol) was added to a stirring solution of 3,6-di-O-
benzyl-4,5-bis-O-(4-methoxybenzyl)-myo-inositol (9)11
(950 mg, 1.58 mmol) in DMF (5 mL) at room temperature.
After stirring for 2 h at room temperature, BnBr (811 mg,
4.74 mmol) was added. After stirring for 5 h at room
temperature, the reaction was quenched with saturated
NH4Cl (30 mL). The aqueous mixture was extracted with
CH2Cl2 (3!10 mL). The combined organic layer was
successively washed with water (5 mL), and brine (5 mL).
The combined organic layer was dried over MgSO4, filtered
through a cotton-pad, and evaporated. The resulting residue
was purified by silica gel chromatography (30 g of SiO2
eluted with hexane/AcOEtZ100/1 to 4/1) to give 12
(1.21 g, 98%) as a white powder. mp. 76–78 8C; IR (KBr,
disk) nmax (cmK1) 3100, 3070, 3030, 3005, 2920, 1615,
1514, 1454, 1360, 1252, 1173, 1130, 1092, 1038, 822, 739,
1
696; H NMR (CDCl3, 300 MHz) d 7.42–7.25 (m, 26H),
6.84–6.81 (m, 4H), 4.92–4.57 (m, 12H), 4.09–4.01 (m, 3H),
3.79 (s, 3H), 3.78 (s, 3H), 3.44 (dd, JZ9.3, 9.3 Hz, 1H),
3.34 (dd, JZ9.3, 9.3 Hz, 1H), 3.33 (dd, JZ9.9, 2.4 Hz, 1H);
13C NMR (CDCl3, 100 MHz) d 159.1 (s, 1C), 139.0 (s, 1C),
138.4 (s, 1C), 131.1 (s, 1C), 129.7 (d), 129.4 (d), 128.4 (d),
128.1 (d), 128.0 (d), 127.8 (d), 127.6 (d), 127.3 (d), 113.8 (d,
8C), 83.5 (d, 1C), 81.8 (d, 1C), 81.5 (d, 1C), 81.0 (d, 2C),
75.8 (t, 1C), 75.6 (t, 1C), 75.5 (t, 1C), 74.4 (d, 1C), 74.1 (t,
1C), 72.8 (t, 2C), 55.3 (q, 2C); HRMS-ESI (m/z): [MC
Na]C calcd for C50H52NaO8, 803.3560; found, 803.3544.
4.3.2. 1,2,3,6-tetra-O-Benzyl-myo-inositol (10).12 DDQ
(2.67 g, 11.8 mmol) was added to a stirring solution of 22
(4.18 g, 5.35 mmol) in CH2Cl2/H2O (17/1, 50 mL) at room
temperature. After stirring for 6 h at room temperature, the
reaction mixture was filtered through a cotton-Celite pad.
The mixture was diluted with CH2Cl2 (100 mL) and
successively washed with saturated NaHCO3 (20 mL) and
brine (20 mL). The organic layer was dried over MgSO4,
filtered through a cotton-pad, and evaporated. The resulting
residue was purified by silica gel chromatography (120 g of
SiO2 eluted with hexane/AcOEtZ6/1 to 1/1) to give 10
(2.37 g, 82%) as a white powder. mp. 83–85 8C; IR (KBr,
disk) nmax (cmK1) 3549, 3422, 3063, 3030, 2899, 1454,
4.3.4. 1,2,3,6-tetra-O-Benzyl-4,5-bis-O-triisopropylsilyl-
myo-inositol (5p). TIPSOTf (138 mg, 0.450 mmol) was
added to a stirring solution of 10 (50 mg, 0.090 mmol) in
2,6-lutidine (248 mg, 2.32 mmol) at 100 8C. After stirring
for 12 h at 100 8C, the reaction mixture was cooled to room
temperature, and then diluted with CH2Cl2 (10 mL). It was
successively washed with water (3 mL), and brine (3 mL).
The organic layer was dried over MgSO4, filtered through a
cotton-pad, and evaporated. The resulting residue was
purified by silica gel chromatography (15 g of SiO2 eluted
with hexane/AcOEtZ100/0 to 30/1) to give 5p (71 mg,
90%) as a white powder. mp. 80–81 8C; IR (KBr, disk) nmax
(cmK1) 3030, 3000, 2942, 2865, 1638, 1458, 1355, 1127,
1
1
1364, 1200, 1115, 1063, 1030, 731, 696; H NMR (C6D6,
1086, 885, 720, 696, 670; H NMR (CDCl3, 300 MHz) d
300 MHz) d 7.48–7.08 (m, 20H), 4.93 (d, JZ11.4 Hz, 1H),
4.90 (d, JZ12.3 Hz, 1H), 4.85 (d, JZ11.4 Hz, 1H), 4.83 (d,
JZ12.3 Hz, 1H), 4.50 (d, JZ12.0 Hz, 1H), 4.44 (s, 2H),
4.42 (d, JZ12.0 Hz, 1H), 4.21 (dd, JZ9.6, 9.3 Hz, 1H, H-
4), 4.09 (dd, JZ9.6, 9.3 Hz, 1H, H-6), 3.92 (dd, JZ2.4,
7.35–7.22 (m, 20H), 5.15 (d, JZ12.3 Hz, 1H), 4.82 (d, JZ
12.3 Hz, 1H), 4.60 (d, JZ12.0 Hz, 3H), 4.56 (d, JZ
11.4 Hz, 1H), 4.48 (d, JZ11.4 Hz, 1H), 4.40 (d, JZ
11.7 Hz, 1H), 4.23 (dd, JZ8.4, 7.8 Hz, 1H, H-4), 4.09 (dd,
JZ2.4, 2.4 Hz, 1H, H-2), 3.88 (dd, JZ9.0, 7.8 Hz, 1H,

K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
3505
H-6), 3.68 (dd, JZ7.8, 7.8 Hz, 1H, H-5), 3.51 (dd, JZ9.0,
2.4 Hz, 1H, H-1), 3.26 (dd, JZ8.4, 2.4 Hz, 1H, H-3), 1.13–
1.00 (m, 42H); 13C NMR (CDCl3, 100 MHz) d 139.8 (s,
1C), 139.3 (s, 1C), 138.3 (s, 1C), 138.2 (s, 1C), 128.3 (d),
128.1 (d), 127.9 (d), 127.7 (d), 127.5 (d), 127.4 (d), 127.3
(d), 127.2 (d), 127.1 (d), 126.7 (d), 126.5 (d), 82.0 (d, 1C),
81.4 (d, 1C), 81.3 (d, 1C), 76.8 (d, 1C), 74.8 (d, 1C), 73.7 (t,
1C), 73.4 (t, 1C), 72.9 (d, 1C), 72.3 (t, 1C), 71.2 (t, 1C), 18.6
(q, 3C), 18.5 (q, 3C), 18.4 (q, 3C), 18.3 (q, 3C), 13.9 (d, 3C),
13.8 (d, 3C); HRMS-FAB (m/z) [MCH]C calcd for
C52H77O6Si2, 852.5229; found, 853.5247.
7.4, 7.1 Hz, 1H, H-6), 3.49 (dd, JZ7.1, 7.1 Hz, 1H, H-5),
0.91 (s, 18H), 0.12–0.11 (m, 12H); 13C NMR (100 MHz in
CDCl3) d 74.3 (d, 1C), 73.8 (d, 1C), 73.7 (d, 1C), 73.6 (d,
1C), 72.3 (d, 1C), 65.6 (d, 1C), 25.7 (q, 6C), 17.9 (s, 1C),
17.8 (s, 1C), K4.8 (q, 1C), K4.9 (q, 2C), K5.0 (q, 1C);
HRMS-FAB (m/z) [MCH]C calcd for C18H41O6Si2,
409.2442; found, 409.2449.
4.3.7. 4,5-bis-O-Triisopropylsilyl-myo-inositol (5). Same
procedure as the debenzylation of 1p was performed starting
from 5p (43 mg, 0.050 mmol) with Pd(OH)2 on C (20 wt%,
106 mg, 0.150 mmol) in THF (1 mL). The reaction needed
11 days. Purification was performed by silica gel chroma-
tography (6 g of SiO2 eluted with hexane/AcOEtZ6/1 to 4/
1) to give 5 (8.5 mg, 35%) as a white powder. mp. 86–88 8C;
IR (ZnSe, thin film) nmax (cmK1) 3420, 2943, 2868, 2361,
2339, 1464, 1385, 1256, 1061, 883, 825, 764, 683; 1H NMR
(400 MHz, CD3CN) d 4.27 (ddd, JZ3.9, 3.7, 1.7 Hz, 1H,
H-4), 4.02 (dddd, JZ3.9, 3.8, 1.0, 0.9 Hz, 1H, H-5), 3.96
(ddd, JZ3.8, 3.6, 1.7 Hz, 1H, H-6), 3.94 (dd, JZ3.4,
3.4 Hz, 1H, H-2), 3.83 (ddd, JZ3.7, 3.4, 0.7 Hz, 1H, H-3),
3.80 (ddd, JZ3.6, 3.4, 1.0 Hz, 1H, H-1), 1.25–1.10 (m,
42H); 13C NMR (100 MHz, CDCl3) d 74.8 (d, 1C), 74.2 (d,
1C), 74.0 (d, 2C), 72.2 (d, 1C), 64.8 (d, 1C), 18.1 (q, 6C),
18.0 (q, 6C), 12.2 (d, 6C); HRMS-FAB (m/z) [MCH]C
calcd for C24H53O6Si2, 493.3381; found, 493.3384.
4.3.5. 1,2,3,6-tetra-O-Benzyl-4,5-bis-O-tert-butyldi-
phenylsilyl-myo-inositol (6p). TBDPSOTf (86 mg,
0.22 mmol) was added to a stirring solution of 10 (30 mg,
0.055 mmol) and 2,6-lutidine (118 mg, 1.10 mmol) in DMF
(0.5 mL) at 100 8C. After stirring for 1.5 h at 100 8C, the
reaction mixture was cooled to room temperature. Water
(5 mL) was added and the aqueous mixture was extracted
with hexane (3!5 mL). The organic layer was successively
washed with water (3 mL) and brine (3 mL). Then it was
dried over MgSO4, filtered through a cotton-pad, and
evaporated. The resulting residue was successively purified
by silica gel chromatography (3 g of SiO2 eluted with
hexane/AcOEtZ100/0 to 10/1) and by a reverse phase
chromatography (6 g of cosmosil 140C18-PREP eluted with
MeOH) to give 6p (70 mg, 100%) as a white powder. The
single crystal used for the X-ray diffraction study was
obtained by cooling the hot solution of 6p in EtOH. mp
115.0–117.0 8C; IR (KBr, disk) nmax (cmK1) 3060, 2920,
2857, 1142, 1117, 1057, 815, 790, 737, 698; 1H NMR
(C6D6, 300 MHz) d 7.84–7.05 (m, 40H), 4.78 (ddd, JZ3.6,
3.3, 1.2 Hz, 1H, H-4), 4.73 (d, JZ11.7 Hz, 1H), 4.59 (d, JZ
12.3 Hz, 1H), 4.58 (d, JZ11.7 Hz, 1H), 4.54 (dd, JZ3.6,
3.3 Hz, 1H, H-5), 4.53 (d, JZ12.3 Hz, 1H), 4.25 (d, JZ
12.0 Hz, 1H), 4.23 (d, JZ12.3 Hz, 1H), 4.23 (dd, JZ3.6,
2.7 Hz, 1H, H-2), 4.15 (ddd, JZ4.8, 3.6, 1.2 Hz, 1H, H-6),
4.03 (d, JZ12.0 Hz, 1H), 4.02 (d, JZ12.3 Hz, 1H), 3.98
(dd, JZ4.8, 2.7 Hz, 1H, H-1), 3.76 (dd, JZ3.6, 3.6 Hz, 1H,
H-3), 1.06 (s, 9H), 1.05 (s, 9H); 13C NMR (CDCl3,
100 MHz) d 139.2 (s, 1C), 139.1 (s, 1C), 134.1 (s, 1C),
134.0 (s, 1C), 129.5 (d), 129.4 (d), 129.3 (d), 129.2 (d),
128.1 (d), 128.0 (d), 127.9 (d), 127.7 (d), 127.5 (d), 127.4
(d), 127.3 (d), 127.1 (d), 127.0 (d), 126.9 (d), 126.6 (d), 81.1
(d, 1C), 79.1 (d, 1C), 78.2 (d, 1C), 74.6 (d, 1C), 74.4 (d, 1C),
73.9 (d, 1C), 72.6 (t, 1C), 71.8 (t, 1C), 71.7 (t, 1C), 71.1
(t, 1C), 26.8 (q, 6C), 19.3 (s, 1C), 19.1 (s, 1C); HRMS-FAB
(m/z) [MCH]C calcd for C66H73O6Si2, 1017.4946; found,
1017.4959.
4.3.8. 4,5-bis-O-tert-Butyldiphenylsilyl-myo-inositol (6).
Same procedure as the debenzylation of 1p was performed
starting from 6p (490 mg, 0.480 mmol) with Pd(OH)2 on C
(20 wt%, 203 mg, 0.290 mmol) in THF (5 mL). The
reaction needed 9.5 days. Purification was performed by
silica gel chromatography (15 g of SiO2 eluted with hexane/
AcOEtZ4/1 to 3/1) to give 6 (149 mg, 50%) as a white
powder. mp. 58–61 8C; IR (NaCl, thin film) nmax (cmK1
)
3517, 3073, 2930, 2859, 1472, 1427, 1113, 820, 748, 694;
1H NMR (CD3CN, 300 MHz) d 7.62–7.58 (m, 2H), 7.53–
7.32 (m, 14H), 7.28–7.22 (m, 4H), 4.18 (ddd, JZ3.6, 3.3,
1.8 Hz, 1H, H-4), 4.05 (dddd, JZ3.3, 3.3, 0.9, 0.9 Hz, 1H,
H-5), 4.00 (dd, JZ3.3, 3.3 Hz, 1H, H-2), 3.95 (ddd, JZ3.6,
3.3, 1.8 Hz, 1H, H-6), 3.84 (dd, JZ3.6, 3.3 Hz, 1H, H-1),
3.59 (dd, JZ3.6, 3.3 Hz, 1H, H-3), 0.90 (s, 9H), 0.88 (s,
9H); 13C NMR (CD3CN, 100 MHz) d 136.7 (d, 4C), 136.6
(d, 2C), 136.5 (d, 2C), 134.2 (s, 1C), 134.0 (s, 1C), 133.8 (s,
1C), 133.7 (s, 1C), 131.0 (d, 1C), 130.9 (d, 2C), 130.7 (d,
1C), 128.8 (d, 2C), 128.7 (d, 2C), 128.6 (d, 4C), 76.5 (d,
1C), 74.9 (d, 1C), 74.8 (d, 1C), 74.6 (d, 1C), 74.4 (d, 1C),
65.9 (d, 1C), 27.2 (q, 6C), 19.6 (s, 1C), 19.5 (s, 1C); HRMS-
FAB (m/z) [MCH]C calcd for C38H49O6Si2, 657.3068;
found, 657.3039.
4.3.6. 4,5-bis-O-tert-Butyldimetylsilyl-myo-inositol (4).
Same procedure as the debenzylation of 1p was performed
starting from 4p (720 mg, 0.940 mmol) with Pd(OH)2 on C
(20 wt%, 1.97 g, 2.80 mmol) in THF (5 mL). The reaction
needed 4 days under 100 atm of H2 at room temperature.
Purification was performed by silica gel chromatography
(25 g of SiO2 eluted with hexane/AcOEtZ4/1 to 1/1) to
give 4 (118 mg, 31%) as a white powder. mp. 121–123 8C;
IR (ZnSe, thin film) nmax (cmK1) 3445, 2932, 2859, 1472,
1389, 1254, 1117, 1053, 937, 837, 777, 692; 1H NMR
(400 MHz in CD3CN) d 3.86 (dd, JZ3.4, 3.4 Hz, 1H, H-2),
3.79 (dd, JZ7.2, 7.1 Hz, 1H, H-4), 3.63 (dd, JZ7.4, 3.4 Hz,
1H, H-1), 3.62 (dd, JZ7.2, 3.4 Hz, 1H, H-3), 3.57 (dd, JZ
4.4. X-ray diffraction study of 6p
X-ray data for 6p was measured on a MacScience dip image
plate diffractometer using graphite-monochromated Mo Ka
˚
radiation (lZ0.71073 A). All diagrams and calculations
were performed using maXus (Bruker Nonius, Delft &
MacScience, Japan). The structure was solved by direct
method with SIR-9720 and refined by a full-matrix least-
squares method on F2 with SHELXS-97.21 Crystallographic
data (excluding structure factors) for the structure of 6p has
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC

3506
K. Okajima et al. / Tetrahedron 61 (2005) 3497–3506
Gaffney, P. R. J.; White, C. G. H.; Tocher, D. A.; Todaro, L. J.
J. Am. Chem. Soc. 2003, 125, 15163–15173.
227525. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ UK (Fax: C44 1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk). Data of the analysis are follows: C66H72O6Si2,
MZ1017.46, crystal size 0.5!0.3!0.2 mm, triclinic,
6. (a) Yamada, H.; Ikeda, T. Chem. Lett. 2000, 432–433.
(b) Ikeda, T.; Yamada, H. Carbohydr. Res. 2000, 329,
889–893.
˚
ꢀ
space group P1, aZ11.75, bZ13.45, cZ20.10 A, aZ
7. (a) Yamada, H.; Okajima, K.; Imagawa, H.; Mukae, T.;
Kawamura, K.; Nishizawa, M. Tetrahedron Lett. 2004, 45,
3157–3160. (b) Yamada, H.; Okajima, K.; Imagawa, H.;
Nagata, Y.; Nishizazwa, M. Tetrahedron Lett. 2004, 45,
4349–4351.
3
˚
˚
87.80, bZ78.71, gZ66.80 A, VZ2862.55 A , ZZ2,
DcalcdZ1.180 Mg/m3, m(Mo Ka)Z0.113 mmK1, measured
temp. 298 K, reflections collected 9656, independent
reflections 9085, RZ0.082, wRZ0.224, GOFZ1.164.
8. Watanabe, Y.; Ogasawara, T.; Shiotani, N.; Ozaki, S.
Tetrahedron Lett. 1987, 28, 2607–2610.
Acknowledgements
9. Bassindale, A. R.; Stout, T. J. Organomet. Chem. 1984, 271,
C1–C3.
Financial supports by the Naito Foundation (Japan), the
Sunbor Grant (Suntory Institute for Bioorganic Research,
Japan), and the Cosmetology Research Foundation (Japan)
are gratefully acknowledged. Thanks are also due to
Professor Yutaka Watanabe (Ehime University, Japan) for
his helpful discussions.
10. Hydrogenation of 3p afforded 2-O-benzyl-3,4-bis-O-TBDPS-
myo-inositol in 24% yield along with the full debenzylated 3.
11. Ozaki, S.; Kohno, M.; Nakahira, H.; Bunya, M.; Watanabe, Y.
Chem. Lett. 1988, 77–80.
12. For the consistency with the numbering of the compounds, the
numbering of 1–3, 4p–6p, 10, and 12 do not follow the IUPAC
guidelines.
13. The dihedral angles of the adjacent C–H bonds were calculated
3
based on the observed JHH using the modified Karplus
References and notes
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