Stable axial-rich chair conformer of myo-inositol derivatives due to introduction of two adjacent bulky silyl protections

Article abstract of DOI:10.1016/j.tetlet.2004.02.080

The ring-conformational change of myo-inositol derivatives by introducing two tert-butyldimethylsilyl, triisopropylsilyl, or tert-butyldiphenylsilyl groups into the 1,2-trans hydroxy groups - 3,4- and 4,5-positions - were investigated. The cyclohexane cores of the 4,5-bis-O-silylated derivatives with tert-butyldiphenylsilyl or triisopropylsilyl groups were present in the axial-rich chair form.

Full text of DOI:10.1016/j.tetlet.2004.02.080

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3157–3160
Stable axial-rich chair conformer of myo-inositol derivatives
due to introduction of two adjacent bulky silyl protections
Hidetoshi Yamada,a,* Kotaro Okajima,a Hiroshi Imagawa,b Tatsuya Mukae,a
Yoshiaki Kawamuraa and Mugio Nishizawab
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 15 January 2004; revised 16 February 2004; accepted 16 February 2004
Abstract—The ring-conformational change of myo-inositol derivatives by introducing two tert-butyldimethylsilyl, triisopropylsilyl,
or tert-butyldiphenylsilyl groups into the 1,2-trans hydroxy groups––3,4- and 4,5-positions––were investigated. The cyclohexane
cores of the 4,5-bis-O-silylated derivatives with tert-butyldiphenylsilyl or triisopropylsilyl groups were present in the axial-rich chair
form.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Introduction of trialkylsilyl or alkyldiarylsilyl groups
into vicinal diols sometimes induces significant changes
in conformation. Such conformational changes have
been observed in the acyclic 1,2-disilyloxy compounds
and the tetrahydropyrane rings bearing two or more
silyloxy groups (Fig. 1).1–3 Recently, conformational
flips of cyclohexane rings have been carried out by
introducing bulky silyl groups into trans-1,2-cyclohex-
anediol.4 Control of the ring conformation is important
to develop substrate-controlled stereoselective reactions,
because such conformational changes have been effec-
tively used in stereoselective reactions.1;3;5 We have
aimed at accomplishing such conformational flip on a
multifunctionalized cyclohexane ring, and here we
report that certain myo-inositol derivatives possessing
two adjacent silyl protections were stably present in the
chair conformation with more axial substituents (the
axial-rich chair form).
We introduced two tert-butyldimethylsilyl (TBS), two
isopropylsilyl (TIPS), or two tert-butyldiphenylsilyl
(TBDPS) groups into adjacent trans-diols (3,4- and 4,5-
positions) of myo-inositol, because the flips of cyclo-
hexane rings were achieved by the introduction of the
bulky silyl groups into trans-1,2-cyclohexanediol.4 Thus,
( )-3,4-bis-O-TBS-myo-inositol (1), ( )-3,4-bis-O-TIPS-
myo-inositol (2), and ( )-3,4-bis-O-TBDPS-myo-inositol
(3), and the corresponding 4,5-analogues 4–6 (Fig. 2)
were prepared and investigated the conformations. We
also studied the ring conformations of tetrabenzylated
1p–6p, which were the synthetic intermediates of 1–6.
TBSO
TBSO
TIPSO
OTBS
O
H
OR
OR
5
COOEt
COOEt
Me
RO
RO
OSiR
RO
RO
OR
3
3
H
TBSO
TIPSO
TBSO
4
4 OSiR
OR
OSiR
3
3
OSiR
3
Figure 1. Conformational changes of acyclic, tetrahydropyrane, and
cyclohexane derivatives due to the adjacent trialkylsilyloxy groups.1;2a;4
1: R = H, SiR = TBS
4: R = H, SiR = TBS
3
3
2: R = H, SiR = TIPS
5: R = H, SiR = TIPS
3
3
3: R = H, SiR = TBDPS
6: R = H, SiR = TBDPS
3
3
1p: R = Bn, SiR = TBS
4p: R = Bn, SiR = TBS
3
3
Keywords: Ring conformation; myo-Inositol; Axial-rich chair; Silyl
protecting groups.
2p: R = Bn, SiR = TIPS
5p: R = Bn, SiR = TIPS
3
3
3p: R = Bn, SiR = TBDPS
6p: R = Bn, SiR = TBDPS
3
3
* Corresponding author. Tel.: +81-79-565-8342; fax: +81-79-565-9077;
e-mail: hidetosh@kwansei.ac.jp
Figure 2. Compounds whose ring conformations were investigated.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.080

3158
H. Yamada et al. / Tetrahedron Letters 45 (2004) 3157–3160
Compounds 1–6 were synthesized as follows (Scheme 1).
Dibenzylation of the known myo-inositol derivative 76
followed by removal of the two p-methoxybenzyl (PMB)
groups provided the 3,4-diol 8. Protection with
TBSOTf, TIPSOTf, and TBDPSOTf7 gave 1p, 2p, and
3p, respectively, which were hydrogenated to give 3,4-
bis-O-silylated 1, 2, and 3. Starting from the known 9,8 a
similar sequence obtained 4,5-bis-O-silylated 4p–6p and
4–6.
The respective ring conformations of 1–6 and 1p–6p
were determined based on the coupling constants due to
the vicinal protons on the cyclohexane rings (3JHH) in
1H NMR spectra. The accurate coupling constants
based on both vicinal protons and w-shaped long range
couplings were observed,9 since the original Cs symme-
try of the myo-inositol was already deformed. Table 1
summarizes the coupling constants of 1–6 and 1p–6p at
room temperature. Coupling constants of 8 and 10,
which are the precursor diols for the corresponding silyl-
protected compounds, are also listed for a comparison.
The coupling constants of the tetraols 1–6 were mea-
sured in CD3CN and those of the tetrabenzyl derivatives
1p–6p were the data in CDCl3. When the signals heavily
overlapped, C6D6 was employed.
OBn
OH
HO
OPMB
OPMB
BnO
BnO
3
OH
OH
a, b
4
BnO
Molecular models assembled based on dihedral angles
calculated by the Karplus equation indicated that all the
3,4-bis-O-silylated myo-inositol derivatives 1–3 and 1p–
3p existed in the chair conformation with more equa-
torial substituents (equatorial-rich chair form) (Fig. 3).10
The coupling constants of the 3,4-bis-O-silylated 1–3
and 1p–3p were substantially similar to those of 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. Therefore, introduction of
the bulky silyl protecting groups at the 3,4-hydroxy
groups of myo-inositol did not change the original
equatorial-rich chair form.
OBn
OBn
7
8
d
c
1p - 3p
1 - 3
OH
OBn
HO
OBn
BnO
BnO
OBn
OH
e, f
5
4
BnO
OPMB
OPMB
OH
9
10
g
h
4p - 6p
4 - 6
Scheme 1. Reagents and conditions: (a) NaH, DMF, rt, 2 h, then
BnBr, rt, 10 h, 68%; (b) DDQ, 17:1 CH2Cl2–H2O, rt, 1 h, 79%; (c)
TBSOTf, 2,6-lutidine, DMF, 100 ꢁC, 1 h, 93% to 1p. TIPSOTf, 2,6-
lutidine, DMF, 100 ꢁC, 12 h, 83% to 2p. TBDPSOTf, 2,6-lutidine,
DMF, 100 ꢁC, 20 h, 81% 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, 47% 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 ꢁC, 10 h, 100% to 4p. TIPSOTf, 2,6-
lutidine, DMF, 100 ꢁC, 12 h, 90% to 5p. TBDPSOTf, 2,6-lutidine,
DMF, 100 ꢁC, 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, 34% to 5. H2
(1 atm), Pd(OH)2, THF, rt, 10 days, 50% to 6.
OBn
OH
O
BnO
HO
BnO
BnO
R SiO
HO
HO
R SiO
3
OSiR
SiR
3
3
4
3
3
1: SiR = TBS
2: SiR = TIPS
3: SiR = TBDPS
1p: SiR = TBS
3
2p: SiR = TIPS
3
3p: SiR = TBDPS
3
3
3
3
Figure 3. Ring conformation of 3,4-bis-O-silylated myo-inositol
derivatives.
Table 1. 1H NMR coupling constants of 1–6, 1p–6p, 8, and 10
Compound
Protecting group
3JHH (Hz)
O-1
O-2
O-3
O-4
O-5
O-6
H-1–H-2 H-2–H-3 H-3–H-4 H-4–H-5 H-5–H-6 H-6–H-1
1c
––
––
––
––
TBS
TIPS
TBDPS TBDPS
TBS
TIPS
––
––
––
––
––
Bn
Bn
Bn
Bn
––
––
2.8
3.0
2.8
2.1
1.8
1.8
2.1
3.4
3.4
3.3
2.1
2.4
2.7
2.4
2.9
2.9
2.7
2.1
2.4
2.1
2.4
3.4
3.4
3.3
2.4
2.4
3.6
2.4
9.2
7.6
7.4
9.3
9.3
8.7
9.3
7.2
3.7
3.6
9.6
8.4
3.6
9.6
9.0
7.6
7.2
9.0
8.7
8.4
9.3
7.1
3.9
3.3
8.7
7.8
3.3
9.3
8.7
7.9
7.6
9.0
9.0
8.1
9.3
7.1
3.8
3.3
9.6
7.8
3.6
9.3
8.6
8.3
7.9
9.6
9.3
8.4
9.6
7.4
3.6
3.6
9.6
9.0
4.8
9.3
2c
3c
––
––
––
1pb
2pb
3pa
8a
Bn
Bn
Bn
Bn
––
Bn
Bn
Bn
Bn
––
TBS TBS
TIPS TIPS
TBDPS TBDPS
Bn
Bn
Bn
Bn
TBS
TIPS
––
––
––
TBS
4c
5c
––
––
––
––
––
––
TIPS
TBDPS
TBS
6c
TBDPS ––
4pb
5pb
6pa
10a
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
TBS
TIPS
Bn
Bn
TIPS
TBDPS
––
TBDPS Bn
–– Bn
a In C6D6.
b In CDCl3.
c In CD3CN.

H. Yamada et al. / Tetrahedron Letters 45 (2004) 3157–3160
3159
On the other hand, a part of the compounds silylated at
the 4,5-positions, 5, 6, and 6p, existed in the axial-rich
chair form (Fig. 4). The coupling constants of these
compounds were in the range of 2.7–4.8 Hz (Table 1),
and these values suggested that 5, 6, and 6p took the
axial-rich chair conformation. Long range w-couplings
due to H-3–H-5, H-4–H-6, and H-5–H-1 supported this
conclusion.11 Furthermore, the X-ray diffraction study
showed that 6p existed as the axial-rich chair form in the
solid state (Fig. 5).12 These are the first observations to
show that the multifunctionalized cyclohexane rings are
able to flip into the axial-rich chair conformation by
introduction of vicinal bulky silyloxy groups.
4,5-bis-O-silylated 5, 6, and 6p existed in the axial-rich
chair form. Therefore, the two TBS groups are not big
enough to induce the ring flip.4 Introduction of TBDPS
groups into the 4,5-hydroxy groups of myo-inositol, 6 as
well as 6p, induced complete flipping into the axial-rich
chair conformation probably due to the serious
equatorial/equatorial interaction with the hydroxy or
benzyloxy groups at the C-3 and C-6 positions. The
TIPS- and benzyl-protected 5p took the equatorial-rich
chair conformation, in contrast, tetraol 5 existed in the
axial-rich chair form due to the balance of the increased
1,3-diaxial interactions with the 1,2-diequatorial silyl-
oxy/silyloxy interactions. Because we anticipated that
the delicate balance could be upset by a decrease in
strength of intramolecular hydrogen bondings, we
changed the solvent used for NMR experiments.13 The
ring of 5, however, existed in the axial-rich chair form
even in methanol-d4. Thus, the influence of the hydrogen
bondings would be small. NMR spectra of benzyl-pro-
tected 5p in the different solvents indicated that varia-
tion of the solvents did not affect the ring conformation,
because the equatorial-rich chair form was retained in
all cases.12 Therefore, the steric repulsion of the silyl
protecting groups would be the main cause of these
conformational changes, and comparison of the ring
conformations of 4, 5, 5p, and 6p indicates that the steric
repulsion is in the order of TBDPS, TIPS, and then
TBS.
In contrast, the tetrabenzylated 4p and 5p as well as the
tetraol 4 retained the equatorial-rich chair form (Fig. 4),
although the silyl protections were introduced at the 4,5-
positions. The coupling constants of these compounds
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.
Although the trans-1,2-bis[(trialkylsilyl)oxy]cyclohex-
anes tend to take the 1,2-diaxial chair conformation, the
cyclohexane rings of the 3,4-bis-O-silylated 1–3 and 1p–
3p as well as the 4,5-bis-O-silylated 4, 4p, and 5p
retained the equatorial-rich chair form. In contrast, the
OH
R SiO
3
OH
HO
HO
In conclusion, the cyclohexane ring of myo-inositol was
flipped into the axial-rich chair form when TIPS or
TBDPS groups were introduced into the 4- and
5-hydroxy groups. Although the ring flip of inositols
itself has been previously observed,14 we have first iso-
lated the pure myo-inositol derivatives as in the axial-
rich chair form. These results indicate that two adjacent
bulky silyloxy groups can flip the multifunctionalized
cyclohexane ring, and showed that the axial-rich and
equatorial-rich chair conformations are in delicate bal-
ance. Finally we would like to state that the ring of the
all-trans-1,2,3,4,5,6-hexaisopropylcyclohexane, reported
by Biali and co-workers, is the most famous stable axial-
rich chair conformer.15
5
HO
R SiO
OH
OH
3
4
4
5
OH
R SiO
R SiO
3
3
4: SiR = TBS
5: SiR = TIPS
3
6: SiR = TBDPS
3
3
OBn
BnO
OBn
R SiO
3
BnO
BnO
R SiO
OBn
OBn
3
OBn
R SiO
R SiO
3
3
4p: SiR = TBS
5p: SiR = TIPS
6p: SiR = TBDPS
3
3
3
Figure 4. Ring conformation of 4,5-bis-O-silylated myo-inositol
derivatives.
Acknowledgements
Financial supports by the Naito Foundation (Japan),
the Sunbor Grant (Suntory Institute for Bioorganic
Research, Japan), the Cosmetology Research Founda-
tion (Japan) are gratefully acknowledged. Thanks are
also due to Professor Yutaka Watanabe (Ehime Uni-
versity, Japan) for his helpful discussions.
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ꢀ
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ꢁ
ꢀ
triclinic, space group P1, a ¼ 11.75, b ¼ 13.45, c ¼ 20.10 A,
3
ꢀ
ꢀ
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