Ring conformations of D-glucose derivatives possessing two bulky silyl protecting groups at the 3,4-positions; the first observation of a stable full-axial chair conformer without bridge structures

Article abstract of DOI:10.1016/j.tetlet.2004.05.126

The ring conformations of 3,4-bis-O-tert-butyldimethylsilyl- and 3,4-bis-O-tert-butyldiphenylsilyl-D-glucopyranoses as well as the corresponding phenyl 1-thio-D-glucopyranosides were investigated. Observations showed that the introduction of the two tert-butyldiphenylsilyl groups can flip the pyranose-ring into the ¹C₄ conformation possessing more axial substituents. All the substituents of the 3,4-bis-O-tert- butyldiphenylsilyl-β-D-glucopyranose were axially oriented.

Full text of DOI:10.1016/j.tetlet.2004.05.126

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5615–5618
Ring conformations of D-glucose derivatives possessing two bulky
silyl protecting groups at the 3,4-positions; the first observation of
a stable full-axial chair conformer without bridge structures
Hidetoshi Yamada,* Koki Tanigakiuchi, Kohei Nagao, Kotaro Okajima
and Tatsuya Mukae
School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan
Received 20 April 2004; revised 21 May 2004; accepted 26 May 2004
Available online 15 June 2004
Abstract—The ring conformations of 3,4-bis-O-tert-butyldimethylsilyl- and 3,4-bis-O-tert-butyldiphenylsilyl-
well as the corresponding phenyl 1-thio- -glucopyranosides were investigated. Observations showed that the introduction of the two
tert-butyldiphenylsilyl groups can flip the pyranose-ring into the 1C4 conformation possessing more axial substituents. All the
D-glucopyranoses as
D
substituents of the 3,4-bis-O-tert-butyldiphenylsilyl-b-D-glucopyranose were axially oriented.
Ó 2004 Elsevier Ltd. All rights reserved.
The introduction of bulky trialkylsilyl or alkyldiarylsilyl
protecting groups into adjacent diols on a tetrahydro-
pyran ring sometimes flips the ring from a chair form
with more equatorial substituents (equatorial-rich chair
form) into another chair form that has more axial sub-
stituents (axial-rich chair form) (Fig. 1).1;2 Although
such conformational inversions have been used for
substrate-controlled stereoselective synthetic reac-
tions,2;3 the relative thermodynamical stability in such
ring-flips has not been rationalized. This communication
reports the ring conformation of D-glucose derivatives
bearing two tert-butyldimethylsilyl (TBS) or two tert-
butyldiphenylsilyl (TBDPS) groups at the 3,4-positions.
The first D-glucose derivative whose substituents are all
oriented axially is also disclosed.
TBSO
TBSO
TBSO
TBSO
OTBS
O
We prepared the 3,4-bis-O-tert-butyldimethylsilyl- and
3,4-bis-O-tert-butyldiphenylsilyl-D-glucopyranoses 2–5
Me
O
SPh
OH
(Scheme 1) to investigate the ring conformations. We
studied the ring conformation of the corresponding
phenylthioglucosides 6–9 as well, which were the syn-
thetic intermediates of 2–5, because these compounds
were comparable to the phenylthioglucoside 1 (Fig. 1)
reported by Walford and co-workers, whose stable
axial-rich chair conformation has already been estab-
lished by X-ray crystallography.1b
TBSO
HO
OH
1
OH
OTBDPS
O
OTBS
O
OH
TBDPSO
TBDPSO
Figure 1. Examples of the stable conformers of tetrahydropyrane rings
existing in the axial-rich chair form induced by two or more bulky
trialkylsilyloxy groups.1a;b;d;2
Compounds 2–5 were synthesized as follows (Scheme 1).
Discrimination of the 3,4-positions was achieved by
applying van Boeckel’s method using the 1,1,2,2-tetra-
isopropyldisiloxanyl (TIPDS) group.4 Thus, the respec-
tive treatment of the phenyl 1-thio-D-glucopyranosides
Keywords: Ring conformation; 1C4; Pyranose ring;
silyl protecting groups.
D-Glucose; Bulky
105 and 116 with TIPDSCl2 followed by migration of the
generated 4,6-TIPDS protection into the 3,4-positions
under acidic conditions provided 12 and 13. Each
* Corresponding author. Tel.: +81-79-565-8342; fax: +81-79-565-9077;
e-mail: hidetosh@kwansei.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.126

5616
H. Yamada et al. / Tetrahedron Letters 45 (2004) 5615–5618
1
The ring conformations of 2–9 were determined by H
NMR analyses. Table 1 summarizes the coupling con-
stants due to the vicinal protons on each pyranose- or
pyranoside ring.8 The coupling constants of 1 (Fig. 1)
and the nonsilylated 10 and 11 (Scheme 1) are also listed
for comparison.9 The coupling constants of 10 and 11
were observed in CD3OD. Other compounds were
recorded in acetone-d6 because of the good separation of
each signal.
Y
X
Y
X
Y X
OH
OH
OH
OTroc
OH
O
O
O
a
b
O
Si
O
i
Pr
HO
OH
HO
O
TrocO
OH
i
Pr
Si
i
Pr
i
Pr
10: X = SPh , Y = H 12: X = SPh, Y = H
11: X = H, Y = SPh
14: X = SPh, Y = H
15: X = H, Y = SPh
13: X = H, Y = SPh
The pyranoses protected by the two TBS groups, 2 and
4
3, were in the C1 form (Fig. 2). Although the coupling
OH
OH
Y
X
OH
1
4
O
O
c
d
constants of 2 were smaller than those of the nonsilyl-
ated 10 (Table 1), the molecular model assembled based
on the dihedral angles calculated by the Karplus equa-
tions indicated that the ring conformation of 2 was still
in the range of the equatorial-rich chair (4C1) form, even
though the ring was slightly flattened like a reclining
chair.10;11 The coupling constants of the b-isomer 3 were
similar to those of 11. Therefore, both pyranoses pos-
sessing TBS groups at the 3,4-positions, 2 and 3,
maintained the equatorial-rich chair form.
3
OSiR
OSiR
3
3
HO
OSiR
HO
OSiR
3
3
6:
7:
8:
9:
2:
3:
4:
5:
X = SPh , Y = H, SiR = TBS
X = SPh, Y = H, SiR = TBDPS
X = H, Y = SPh, SiR = TBS
X = H, Y = SPh, SiR = TBDPS
SiR = TBS, 1- α-OH
3
SiR = TBS, 1-β-OH
SiR = TBDPS, 1-α-OH
SiR = TBDPS, 1-β-OH
3
3
3
3
3
3
3
Scheme 1. Reagents and conditions: (a) TIPDSCl2, pyridine, rt, then
cat. p-TsOH, DMF, rt, 49% for 12 (from 10) or 66% for 13 (from 11);
(b) TrocCl, TMEDA, CH2Cl2, rt then TBAF, AcOH, THF, rt, 58% for
14 (from 12) or 96% for 15 (from 13); (c) TBSOTf or TBDPSOTf, 2,6-
lutidine, DMF, 60–100 °C, then Zn dust, AcOH, Et2O, rt, 51% for 6
(from 14), 27% for 7 (from 14), 31% for 8 (from 15), or 52% for 9 (from
15); (d) NBS, THF/H2O (1:1), rt, 68% for 2 and 3 (from 8) or 56% for 4
and 5 (from 9).
On the other hand, the pyranoses protected by the two
TBDPS groups, 4 and 5, existed in the 1C4 conformation
(Fig. 2), because the 1H NMR spectra of 4 and 5 did not
show large coupling constants due to the 1,2-diaxial
protons (Table 1). The range of the coupling constants
1
was substantially similar to those of 1 in which the C4
conformation is confirmed by an X-ray study.1b The
long range w-couplings between H-2 and H-4 and be-
tween H-3 and H-5 also supported the conformation in
solution. It is noteworthy that all substituents on the
pyranose ring of the b-isomer 5 were axially oriented,
and this is the first observation of a stable ‘full-axial’
compound was independently introduced the 1,1,1-tri-
chloroethoxycarbonyl (Troc) groups7 at the 2- and 6-
positions followed by removal of the TIPDS group to
give 3,4-diols 14 and 15, respectively. The introduction
of the TBS and TBDPS groups into the 3,4-diol of 14
followed by cleavage of the Troc groups provided 6 and
7. Similar treatment of 15 afforded 8 and 9. Hydrolysis
of the phenylthio group of 8 and 9 produced anomeric
mixtures of the desired 3,4-bis-O-TBS-glucopyranoses 2
chair conformer of the
bridge structure.12
D-glucose derivative without a
and
3
(a:b ¼ 60:40), and the corresponding
Whereas the ring conformation of the pyranoses 2–5
differed in the use of the TBS or TBDPS groups, the ring
conformations of the corresponding thioglucosides were
bis(TBDPS)-protected 4 and 5 (a:b ¼ 89:11), respec-
tively.
Table 1. Coupling constants in the 1H NMR spectra of 1–11
Compound
Substituent at the
anomeric position
Protecting groups
at the 3,4-positions
3JHH (Hz)
H-2–H-3 H-3–H-4
W-coupling (Hz)
(position)
H-1–H-2
H-4–H-5
1a
2a
3a
4a
a-SPh
a-OH
b-OH
a-OH
TBSc
TBS
2.9
3.1
7.0
2.2
5.5
7.0
8.4
5.2
4.5
6.3
7.6
2.7
3.1
6.3
8.6
1.5
1.0 (H-2–H-4)
––
––
TBS
TBDPS
1.5 (H-2–H-4), 0.8
(H-3–H-5)
1.1 (H-2–H-4), 1.0
(H-3–H-5)
1.3 (H-2–H-4)
1.5 (H-2–H-4), 1.9
(H-3–H-5)
––
5a
b-OH
TBDPS
4.8
2.4
2.9
1.9
6a
7a
a-SPh
a-SPh
TBS
TBDPS
2.9
2.0
5.7
3.0
4.7
3.0
4.0
1.5
8a
9a
b-SPh
b-SPh
TBS
TBDPS
9.3
7.8
7.2
1.2
7.2
3.3
8.0
1.2
1.2 (H-2–H-4), 1.2
(H-3–H-5)
––
10b
11b
a-SPh
b-SPh
––
––
5.2
9.6
10.0
8.8
8.8
7.6
10.0
9.2
––
a In acetone-d6.
b In CD3OD.
c The compound possesses one more TBS group at O-6.

H. Yamada et al. / Tetrahedron Letters 45 (2004) 5615–5618
5617
4
1
In conclusion, the introduction of the two TBDPS
groups at the 3,4-positions of the -glucopyranose
C
C
1
4
D
HO
fundamentally flipped the ring into the axial-rich chair
form, but use of the two TBS groups itself was too short
to flip. Among the compounds prepared for this study, 5
showed that a glucose derivative can stably exist in the
full-axial chair conformation without a bridge structure.
The axial-rich chair form of 6 is seemingly the ring-flip
induced by just two TBS groups, however, the cause of
this stability is the support of the phenylthio group at
the anomeric position.
HO
TBSO
TBDPSO
OH
O
O
TBSO
HO OH
TBDPSO
OH
2: α-OH
3: β-OH
4: α-OH
5: β-OH
HO
R SiO
HO
TBSO
3
α
O
HO
8
O
SPh
SPh
TBSO
β
R SiO
3
OH
6: SiR = TBS
3
Acknowledgements
7: SiR = TB DPS
3
3
S
1
Financial support by the Naito Foundation (Japan), the
Sunbor Grant (Suntory Institute for Bioorganic Re-
search, Japan), and the Cosmetology Research Foun-
dation (Japan) is gratefully acknowledged.
OTBDPS
HO
O
SPh
β
OH
TBDPSO
9
References and notes
Figure 2. Ring conformation of 3,4-O-silylated
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5618
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