Highly β-selective O-glucosidation due to the restricted twist-boat conformation

Article abstract of DOI:10.1021/ol070427b

Equation presented Ethyl 1 -thlo-2,3,4,6-tetrakis-O-triisopropylsilyl- β-D-glucopyranoside, ethyl 6-O-benzyl-1 -thio-2,3,4-tris-O- triisopropylsilyl-β-D-glucopyranoside, and ethyl 6-Opivaloyl-1-thio-2,3,4- tris-O-triisopropylsilyl-β-D-glucopyranoside induced highly β-selective O-glucosidations. Among them, the 6-O-pivaloylated substrate provided the best selectivity up to α/β = 3:97 with cyclohexylmethanol, and the substrate was used for glucosidations with secondary and tertiary alcohols in a highly β-selective manner. The selectivity would be caused by the twist-boat conformation of the pyranose; this is the first β-selective O-glucosidation based on conformational control of the pyranose ring.

Full text of DOI:10.1021/ol070427b

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1573-1576
Highly
â-Selective O-Glucosidation Due
to the Restricted Twist-Boat
Conformation
Yasunori Okada, Tatsuya Mukae, Kotaro Okajima, Miyoko Taira, Mari Fujita, and
Hidetoshi Yamada*
School of Science and Technology, Kwansei Gakuin UniVersity, 2-1 Gakuen,
Sanda 669-1337, Japan
hidetosh@kwansei.ac.jp
Received February 20, 2007
ABSTRACT
Ethyl 1-thio-2,3,4,6-tetrakis-O-triisopropylsilyl-
ethyl 6-O-pivaloyl-1-thio-2,3,4-tris-O-triisopropylsilyl-
pivaloylated substrate provided the best selectivity up to
with secondary and tertiary alcohols in a highly -selective manner. The selectivity would be caused by the twist-boat conformation of the
pyranose; this is the first -selective O-glucosidation based on conformational control of the pyranose ring.
â-D
-glucopyranoside, ethyl 6-O-benzyl-1-thio-2,3,4-tris-O-triisopropylsilyl-
-glucopyranoside induced highly -selective O-glucosidations. Among them, the 6-O-
â ) 3:97 with cyclohexylmethanol, and the substrate was used for glucosidations
â-D-glucopyranoside, and
â
-D
â
r
/
â
â
The â-O-glucosidic linkage is an essential structure in
numerous natural products containing sugar chains and
glycosides of terpenes, steroids, polyphenols, and antibiotics.
For the construction of the â-O-glucosides, neighboring
group participation by a 2-O-acyl group has been the most
reliable method.1 When the acyl group cannot be employed
due to the synthetic convenience, the benzyl-protected
glycosyl donors have often been employed using SN2-type
reactions or the nitrile effect.2
However, the latter conditions have occasionally been
affected by the steric character of both the glycosyl donors
and acceptors; the high â-selectivity has not always ap-
peared.3 Therefore, the development of stereoselective gly-
cosylations based on a new concept other than the traditional
control, such as the participation of neighboring groups,
solvent effects, or the properties of leaving groups, would
make it flexible to design for the syntheses of the sugar-
containing molecules.
A potential for such a new concept is the application of
the conformational control of the pyranose rings of glycosyl
donors. A six-membered ring has occasionally been in the
chair conformation with more axial substituents when bulky
trialkylsilyl groups were introduced into a suitable adjacent
trans-diol.4 When the six-membered ring is the pyranose of
a sugar, such inversion drastically changes its steric and
electronic circumstances around the anomeric center, hence
it has been used to control the anomeric stereoselectivity
during glycosidations.5 We now report that ethylthiogluco-
sides protected by triisopropylsilyl (TIPS) groups at the 2,3,4-
oxygens, that is, ethyl 1-thio-2,3,4,6-tetrakis-O-TIPS-â-D-
glucopyranoside (1), corresponding 6-O-benzylated 2, and
(1) (a) Stachulski, A. V.; Jenkins, G. N. Nat. Prod. Rep. 1998, 15, 173-
186. (b) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(2) (a) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980,
19, 731-732. (b) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett.
1984, 25, 1379-1382. (c) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28,
4701-4704. (d) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990,
694-696. (e) Vankar, Y. D.; Vankar, P. S.; Behrendt, M.; Schmidt, R. R.
Tetrahedron 1991, 47, 9985-9992. (f) Hashihayata, T.; Mandai, H.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 2004, 77, 169-178.
(3) (a) Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1987, 28, 4315-
4318. (b) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405-2407.
10.1021/ol070427b CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/15/2007

6-O-pivaloylated 3, showed a highly â-selective O-glucosi-
dation. Among them, 3 provided the best selectivity, which
could be used for glucosidations with secondary and tertiary
alcohols.
Table 1. Glucosidation of Ethylthioglucosides Protected by
TIPS Groups with Cyclohexylmethanola
Scheme 1. Preparations of Compounds 1-3
glucosyl
entry donor
time
yield R/â
solvent
(h) prod. (%) ratiob
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
2
3
3
CH2Cl2
1.5
8
8
8
8
8
9
9
70 14/86
45 11/89
77d 9/91
73e 12/88
73 9/91
85 9/91
82 6/94
92 5/95
84 3/97
CH2Cl2-CH3CN (3:2)c 1.5
Et2O
22.0
35.5
7.3
1.5
4.5
n-C6H14
PhCH3
CH2Cl2
PhCH3
CH2Cl2
PhCH3
1.5 10
11.0 10
a
A small amount of 11 was detected as the byproduct.
The substrates 1-3 were prepared as follows (Scheme 1).
Treatment of ethyl 1-thio-â-D-glucopyranoside (4)6 with
TIPSOTf afforded 1 in 53% yield. The regioselective
reductive cleavage of ethyl 2,3-di-O-acetyl-4,6-benzylidene-
1-thio-â-D-glucopyranoside (5)7 followed by the deacetyla-
tion of 6 and the introduction of the TIPS groups produced
2. The regioselective pivaloylation of 4, followed by the TIPS
protections of the resulting triol 7, afforded 3.
As our preliminary investigations, the glycosidations with
cyclohexylmethanol were examined (Table 1). Methyl triflate
smoothly activated 1-3 to provide the corresponding cy-
clohexylmethyl glucosides 8-10 in a â-selective manner.
Small amounts of respective glycals 11 were detected as the
byproducts. The stereochemistries of the products were
b Determined on the basis of the 1H NMR. c CH3CN itself did not dissolve
1. Compound 1 remained (4%). Compound 1 remained (5%).
d
e
unclear in this stage, but the anomeric ratios could be
determined on the basis of the integral of the anomeric peaks
in the 1H NMR spectra. The structures of the products were
clarified by further transformations, that is, the removal of
the TIPS groups to return the ring back to the 4C1 conformers,
followed by the acetylation of the resulting hydroxy groups
(Scheme 2).
Scheme 2. Clarification of the Structures of 8a
(4) For the ring inversions of pyranose derivatives: (a) Tius, M. A.;
Busch-Peterson, J. Tetrahedron Lett. 1994, 35, 5181-5184. (b) Walford,
C.; Jackson, R. F. W.; Rees, N. H.; Clegg, W.; Heath, S. L. Chem. Commun.
1997, 1855-1856. (c) Yamada, H.; Nakatani, M.; Ikeda, T.; Marumoto,
Y. Tetrahedron Lett. 1999, 40, 5573-5576. (d) Yamada, H.; Tanigakiuchi,
K.; Nagao, K.; Okajima, K.; Mukae, T. Tetrahedron Lett. 2004, 45, 5615-
5618. (e) Yamada, H.; Tanigakiuchi, K.; Nagao, K.; Okajima, K.; Mukae,
T. Tetrahedron Lett. 2004, 45, 9207-9209. For the cyclohexane deriva-
tives: (f) Marzabadi, C. H.; Anderson, J. E.; Gonzalez-Outeirino, J.;
Gaffney, P. R. J.; White, C. G. H.; Tocher, D. A.; Todaro, L. J. J. Am.
Chem. Soc. 2003, 125, 15163-15173. (g) Okajima, K.; Mukae, T.; Imagawa,
H.; Kawamura, Y.; Nishizawa, M.; Yamada, H. Tetrahedron 2005, 61,
3497-3506.
a Similar clarifications of 9 and 10 are in the Supporting
Information.
(5) (a) Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahedron
Lett. 1996, 37, 663-666. (b) Ichikawa, S.; Shuto, S.; Matsuda, A. J. Am.
Chem. Soc. 1999, 121, 10270-10280. (c) Ikeda, T.; Yamada, H. Carbohydr.
Res. 2000, 329, 889-893. (d) Yamada, H.; Ikeda, T. Chem. Lett. 2000,
432-433. (e) Futagami, S.; Ohashi, Y.; Imura, K.; Hosoya, T.; Ohmori,
K.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2000, 41, 1063-1067.
(f) Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123, 11870-
11882. (g) Tamura, S.; Abe, H.; Matsuda, A.; Shuto, S. Angew. Chem.,
Int. Ed. 2003, 42, 1021-1023. (h) Abe, H.; Terauchi, M.; Matsuda, A.;
Shuto, S. J. Org. Chem. 2003, 68, 7439-7447.
First, solvent effects were investigated, but the â-selectivity
was unaffected (Table 1, entries 1-5). In CH2Cl2 (entry 1),
the reaction was complete within 1.5 h and produced a 70%
yield of the cyclohexylmethyl glucoside 8. Although CH3-
CN and Et2O have displayed remarkable stereocontrol effects
in previous glycosidations,2b,c,8 the anomeric selectivity did
not drastically change (entries 2 and 3). The use of Et2O
slightly increased the â-selectivity, but the reaction rate
decreased. In n-hexane, the anomeric selectivity was similar
(6) Vic, G.; Hastings, J. J.; Howarth, O. W.; Crout, D. H. G. Tetrahe-
dron: Asymmetry 1996, 7, 709-720.
(7) Lu, S.; O’yang, Q.; Guo, Z.; Yu, B.; Hui, Y. J. Org. Chem. 1997,
62, 8400-8405.
1574
Org. Lett., Vol. 9, No. 8, 2007

to those of the others and the reaction rate decreased (entry
4). In toluene and ether, the â-selectivity increased, and the
decrease in the reaction rate was lower. The anomeric
selectivity was R/â ) 14:86 to 9:91 in all cases with 1;
therefore, the anomeric selectivity of this reaction was not
solvent-dependent.
The anomeric stereochemistry of the substrate did not
affect the â-selectivity. Thus, the R-isomer of 1 similarly
demonstrated the â-selectivity in a reaction with cyclohexyl-
methanol in CH2Cl2 at room temperature (72% yield, R/â )
14:86). Therefore, the reaction would proceed via the
oxocarbenium ion intermediate.
By replacement of the protecting group at O-6, the
â-selectivity increased to R/â ) 3:97 (Table 1, entries 6-9).
The reaction was faster in CH2Cl2, but the â-selectivity was
greater in toluene in both cases using 2 and 3. Considering
the substantial yield of the â-glucoside 9 or 10, the use of 3
in CH2Cl2 (entry 8) was fixed as the standard for further
applications, although the reaction in toluene (entry 9)
provided the best â-selectivity.
12 with an alcohol, and the R/â ratio of the resulting
glucoside was 1:1.11 Generation of intermediate 13 would
be followed by nonselective attack due to the steric hindrance
of the â-face by O-3 and C-6 and of the R-face by O-2.
Shuto reported that even the radical deuteration cannot
proceed using a 1C4 glucose derivative 14.5h In contrast, the
1
â-selective C-allylation using a C4 xylose derivative 15 is
possible5g because xylose lacks the C-6 methylene group.
Therefore, to hinder the approach of the glycosyl acceptors,
the steric hindrance due to the C-6 methylene group is
1
certainly present in the C4-glucosyl donors.
Contrary to this context, thioglucosides 1-3 provided the
â-selective reaction. The occurrence of the selectivity can
be rationalized by assuming an intermediate restricted in the
twist-boat conformation as the substrate (Figure 2). In the
The rings of the donors and the products were all in the
twist-boat conformation. The observed ring proton vicinal
1
coupling constants in the H NMR spectra were linked to
ring torsion angles9 and show that each of 1-3 and 8-10 is
in the 3S1 conformation. Significant long-range 4J couplings
between H-2 and H-4 were detected in all these compounds
and support that ring conformation.4e,10
Reaction control due to the flipped ring conformation of
the glycosyl donors has been previously reported. However,
this concept has not been applied to the formation of the
â-O-glucosidic bond. In the case of glucose, achievement
Figure 2. Credible mechanism for our â-selective glucosidation
3
1
from the S1-glucosyl donor. PG ) protecting group.
of the â-selective reaction seems difficult using the C4-
glucosyl donor (Figure 1). The sole reported attempt of
O-glucosidation with a 1C4-glucosyl donor is the reaction of
twist conformation adopted, the C-6 hinders the â-face less
than in the conventional chair conformation, and the C-2
substituent still hinders the R-face. Therefore, the â-selectiv-
ity would be attributed to the restricted twist-boat conforma-
tion.
This restricted twist-boat system permitted the highly
â-selective glucosidation with more hindered alcohols using
3 (Table 2). The reactions with both (+)- and (-)-menthols
afforded similar â-selectivities (entries 2 and 3); conse-
quently, the matching-mismatching effect due to the asym-
metry of the glucosyl donor and the acceptors is negligible.12
The reactions with cholestanol, 1-adamantanol, and methyl
(8) (a) Igarashi, K.; Irisawa, J.; Honma, T. Carbohydr. Res. 1975, 39,
213-225. (b) Fukase, K.; Hasuoka, A.; Kinoshita, I.; Aoki, Y.; Kusumoto,
S. Tetrahedron 1995, 51, 4923-4932. (c) Schmidt, R. R.; Jung, K. In
PreparatiVe Carbohydrate Chemistry; Hanessian, S., Eds.; Marcel Dek-
ker: New York, 1997; pp 283-312.
(9) The dihedral angles were calculated from the Karplus equation
modified by Haasnoot and Altona: J ) 7.76 cos2 w - 1.1 cos w + 1.4,
where J is the vicinal coupling constant and w is the dihedral angle:
Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron 1980,
36, 2783-2792.
(10) Yamada, H.; Okajima, K.; Imagawa, H.; Nagata, Y.; Nishizawa,
M. Tetrahedron Lett. 2004, 45, 4349-4351.
(11) Jensen, H. H.; Bols, M. Acc. Chem. Res. 2006, 39, 259-265.
(12) (a) Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1-30. (b) Spijker, N. M.; van Boeckel, C.
A. A. Angew. Chem., Int. Ed. Engl. 1991, 30, 180-183.
Figure 1. O-Glucosidation using a 1C4-glucosyl donor and
examples that show the large steric hindrance of the 6-CH2 group.
Org. Lett., Vol. 9, No. 8, 2007
1575

a trace of the desired glucoside 22; 11 was the main product
in this case. Jensen and Bols reported that axial OR groups
increased the reactivity at the anomeric position of sugars
using the term “conformationally armed glycosyl donors”.11
Substrate 3 is a typical example of this case, and in reality,
the substrate easily generated the oxocarbenium ion inter-
mediate. However, when the next step, which is the formation
of the glucosidic C-O bond, is slow as in the reaction with
a hindered hydroxy group, a significant amount of 11 would
be produced via elimination. The anomeric stereochemistry
of each of the products (16-21) was confirmed as clarifica-
tion of the structures 8-10.
Table 2. Glucosidations of 3 with Various Alcohols
In conclusion, we have developed a highly â-selective
O-glucosidation using thioglucosides whose ring was in the
twist-boat conformation. This conformation would be the
most significant factor for the selectivity, and the concept
was applicable even to a tertiary alcohol. This new method
would be an alternative to the traditional â-O-glucosidations.
Acknowledgment. We thank Ms. Yasuko Okamoto
(Tokushima Bunri University) for analyzing a part of the
mass spectra. This work was partly supported by the Grants-
in-Aid for Scientific Research (16510170) from JSPS and
for Scientific Research on Priority Areas (17035086) from
MEXT.
1
b
a Determined on the basis of the H NMR. Determined by HPLC.
Supporting Information Available: Experimental pro-
cedures, product characterization, and additional conforma-
tional information. This material is available free of charge
via the Internet at http://pubs.acs.org.
2,3,4-tri-O-benzyl-R-D-glucopyranoside were effective (en-
tries 4-6). In all cases, the byproduct 11 (PG ) Piv) was
produced. On the other hand, the reaction with methyl 2,3,6-
tri-O-benzyl-R-D-glucopyranoside (entry 7) produced only
OL070427B
1576
Org. Lett., Vol. 9, No. 8, 2007