Efficient synthesis of β-C-glucosides via radical cyclization with a silicon tether based on the conformational restriction strategy

Article abstract of DOI:10.1016/j.tetlet.2005.07.087

An efficient method for preparing β-C-glucosides using radical cyclization with a temporary connecting silicon tether was developed. In this reaction, conformational restriction of the substrates to the unusual ¹C₄-form is essential

Full text of DOI:10.1016/j.tetlet.2005.07.087

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6555–6558
Efficient synthesis of b-C-glucosides via radical cyclization with
a silicon tether based on the conformational restriction strategy
Masaru Terauchi, Akira Matsuda and Satoshi Shuto*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
Received 12 May 2005; revised 11 July 2005; accepted 15 July 2005
Abstract—An efficient method for preparing b-C-glucosides using radical cyclization with a temporary connecting silicon tether was
1
developed. In this reaction, conformational restriction of the substrates to the unusual C4-form is essential for the cyclization to
occur.
Ó 2005 Published by Elsevier Ltd.
C-Glycosides are stable mimics for natural O-glycosides
possessing biological activity.1 During our studies on C-
glycosidic ligands of myo-inositol 1,4,5-trisphosphate
(IP3) receptors,2 we newly designed the b-C-glucoside
trisphosphates 1 and 2 (Fig. 1) as stable IP3 mimics.
Owing to the six-membered chair-conformation of these
compounds, the 3,4-trans-bisphosphate on D-glucose
backbone of 1 and 2 can be superimposed with the
4,5-trans-bisphosphate of IP3.
tether at the 6-hydroxyl.4 As shown in Scheme 1, heating
the substrate with Bu3SnH and AIBN in benzene, fol-
lowed by treatment with TBAF, gave the 2-phenylvinyl
b-C-glucoside in 54% yield. They described the radical
cyclization as proceeding via a conformationally flipped
1
intermediate that assumes the C4-form (Scheme 1).4 In
this conformation, the tethered hydroxymethyl moiety
adopts an axial orientation, placing the radical-accepting
sp carbon of the ethynyl moiety close to the anomeric
radical, thereby allowing the cyclization to occur.
Although numerous methods exist for the preparation of
C-glycosides, the synthesis of b-C-glycosides has proved
to be considerably more difficult than the synthesis of
their a-counterparts.1,3d The use of radical reactions is
an efficient process for constructing C-glycosidic bonds,
and stereoselective intramolecular and intermolecular
radical C-glycosidation reactions have been devel-
oped.1,2b,c,3b,c,4 Stork et al. reported a facile synthesis
of a b-C-glucoside via the stereoselective radical cycliza-
tion using a phenyl l-seleno-b-D-glucose derivative
having a phenylethynylsilyl group as a radical acceptor
Based on these results, we speculated that effective intro-
duction of a carbon-unit at the anomeric b-position
could be realized via radical cyclizations with substrates
1
I conformationally restricted to the unusual C4-form.
Me
Si
Me
O
Ph
SePh
1.Bu3SnH
AIBN
2.TBAF
OH
O
Ph
BnO
BnO
O
BnO
BnO
OBn
54 %
OBn
only β
unrestricted
OH
OH
2
HO
2
O3PO
O3PO
O3PO
O
CH
2 n
OPO32
2
2
Me
Me
Si
O
O3PO
OPO23
OH
HO
1: n = 2
2: n = 3
IP3
OBn
O
Ph
Figure 1. IP3 and newly designed b-C-glucosidic IP3 mimics.
BnO
OBn
1C4-fliped intermediate
*
Corresponding author. Tel.: +81 11 706 3229; fax: +81 11 706
4980; e-mail: shu@pharm.hokudai.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.087

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M. Terauchi et al. / Tetrahedron Letters 46 (2005) 6555–6558
1C4-restricted
R
Si
unrestricted
R
O
R
Si
R
O
n
R
Si
n
R
R
R
Bu3SnH
AIBN
SePh
Si
OPg
O
n
OPg
O
O
n
O
SePh
TBS O
O
BnO
BnO
PgO
OPg
O
PgO
OPg
SePh
OBn
II
I (1C4-restricted) n = 0, 1
R = Me, Ph
TBSO
OAc
3: R = Ph, n = 0
4: R = Me, n = 1
5: R = Ph, n = 0
6: R = Me, n = 1
Pg=bulkysilyl-protectinggroup
R
R
OH
Si
Figure 2. Conformationally restricted and unrestricted substrates for
n
the radical cyclization.
O
O
PgO
PgO
ox.
n
OH
OPg
O
PgO
larly an allyldimethylsilyl group was introduced at the 6-
hydroxyl with allyldimethylchlorosilane to give the
other substrate 4.
IV
PgO
Scheme 2.
OPg III
The conformationally unrestricted substrates, that is, 6-
O-vinyldiphenylsilyl and 6-O-allyldimethylsilyl ethers 5
and 6 of tri-O-benzyl-protected l-phenylseleno-b-D-glu-
cose, were also prepared from phenyl 2,3,4-tri-O-benz-
yl-l-seleno-b-D-glucose (15),4 as shown in Scheme 4, in
order to clarify whether the conformational restriction
of the substrates to the 1C4-form actually facilitated
the b-selective radical cyclization.
As shown in Scheme 2, the radical reaction using the
1C4-restricted substrate I was expected to form stereo-
selectively the desired b-cyclization product III, via the
1C4-chair-like anomeric radical intermediate II, in which
the cis-cyclization would effectively occur without con-
formational change because of the axial orientation of
the 60-hydroxylmethyl moiety with the tether. Oxidative
cleavage of the C–Si bond would produce the desired b-
C-glucoside IV. Thus, we designed the radical reaction
substrates 3 and 4 with a 6-O-vinylsilyl5 or a 6-O-ally-
silyl6 group as the radical-accepting tether (Fig. 2), the
conformation of which can be restricted by significantly
bulky silyl-protecting groups at the secondary hydroxyl
groups.3,7
The unrestricted substrates 5 and 6 had large coupling
constants (ca. 9 Hz) between the ring protons in
1H NMR,8 showing their preference for the usual
4C1-chair-like conformation. On the other hand, the
considerably smaller coupling constants between the
ring protons in the 3,4-O-silyl-protected substrates 3
and 48 suggested that these preferred the flipped 1C4-like
conformation.
The synthesis of the substrates 3 and 4 is shown in
Scheme 3. The 2-hydroxyl of the phenyl 3,4-bis-TBS-6-
O-trityl-l-seleno-b-D-glucose (7)2c was acetylated, and
the 6-O-trityl group of the product 8 was selectively re-
moved with aqueous TFA to give 9. Treatment of 9 with
vinyldiphenylchlorosilane/DMAP/Et3N in toluene at
room temperature gave the 6-O-vinylsilyl ether 3. Simi-
These radical reactions of the 1C4-restricted substrates 3
and 4 as well as the unrestricted substrates 5 and 6 were
performed by slow addition of a mixture of Bu3SnH
(1.2 equiv) and AIBN (0.6 equiv) to a heated solution
of the substrate (5 mM) in benzene (80 °C) (Schemes 3
and 4). The reaction was carried out first with the
R
Si
R
n
2SiCl
Et3N, DMAP
n
TrO
TBSO
HO
TBSO
O
TBSO
R
SePh
SePh
SePh
aq. TFA
CH3Cl
O
O
O
toluene
TBSO
OR
TBSO
OAc
9 (96%)
TBSO
OAc
n = 0 or 1
Ac2O
DMAP
MeCN
7: R = H
8: R = Ac (86%)
3: n = 0, R = Ph (83%)
4: n = 1, R = Me (90%)
R
R
Si
O
OH
O
Me
Si
n
Me
O
Bu3SnH
AIBN
AcOOH
HBr, KBr
TBSO
TBSO
n
TBSO
benzene, reflux
OH
TBSO
DMF
AcO
O
O
13: n = 0 (quant.)
14: n = 1 (61%)
TBSO
OAc
TBSO
OAc
10: n = 0, R = Ph (40%)
11: n = 1, R = Me (72%)
12 (20%)
Scheme 3.

M. Terauchi et al. / Tetrahedron Letters 46 (2005) 6555–6558
6557
tive introduction of a 2-hydroxyethyl group can be
achieved via the 6-endo-type cyclization product E, after
oxidative ring-cleavage by treating the cyclization
product under Tamao oxidation conditions.5 During
these studies, we showed that the kinetically favored
5-exo-cyclized radical C, initially formed from radical
B, rearranged to the more stable ring-enlarged 4-oxa-
3-silacyclohexyl radical D via a pentavalent-like silicon
radical transition state X, which was then trapped with
Bu3SnH to give E.5c
n
R
Si
R
O
R2SiCl
Et3N, DMAP
OH
O
n
BnO
BnO
O
SePh
BnO
BnO
toluene
SePh
OBn
OBn
n = 0 or 1
15
5: n = 0, R = Ph (98%)
6: n = 1, R = Me (90%)
Bu3SnH
AIBN
cyclization
benzene, reflux
Scheme 4.
We were interested in the reaction pathway forming the
8-endo-cyclization product 10, which can be formed, as
shown in Scheme 6, either via the ring-enlarged rear-
rangement (path a), analogous to the previous case
(Scheme 5), or via the direct 8-endo-cyclization (path
b).9 Thus, a deuterium-labeling experiment of the sub-
strate 3 with Bu3SnD instead of Bu3SnH was carried
out. The radical cyclization product was identified by
1C4-restricted vinylsilyl ether 3, and afforded the desired
b-endo-cyclization product 10 in 40% yield. When the
1C4-restricted allylsilyl ether 4 was subjected to the reac-
tion under the same conditions, the endo-cyclization
effectively occurred to give the desired b-product 11 in
72% yield along with the anomeric reduction product
12 in 20% yield.9 On the other hand, in the treatment
of either of the conformationally unrestricted substrates
5 or 6 under similar Bu3SnH/AIBN conditions, many
spots were observed on TLC, and none of the cycliza-
tion products were obtained (Scheme 4).
2
1H and H NMR analyses not as 10Da but as 10Db,
Ph
Si
a
Ph
Ph
Si
Ph
O
Ph
Ph
Si
O
b
O
These results show that the conformational restriction
strategy works effectively in radical cyclization. It is
worth noting that the reaction of the allylsilyl ether 4
produced the unusual 9-endo-cyclization product 11 in
good yield. In the case of the vinylsilyl ether 3, although
the yield was not high, the C4-conformational restric-
tion of the substrate allowed the formation of the un-
usual 8-endo-cyclization product 10.
TBSO
D
TBSO
TBSO
Path-b
O
O
O
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
10Db
1
path-a
Ph
Si
Ph
Si
Ph
Ph
Ph
Ph
Si
O
O
O
We previously developed a regio- and stereoselective
method for introducing a C2-substituent at the b-posi-
tion of a hydroxyl in halohydrins or a-phenylselenoalk-
anol substrate A using an intramolecular radical
cyclization with a vinylsilyl group as a temporary con-
necting radical acceptor tether (Scheme 5).5 The selec-
TBSO
TBSO
D
TBSO
O
O
O
TBSO
OTBS
10Da
TBSO
OTBS
TBSO
Scheme 6.
OTBS
in which only the protons of the methylene adjacent to
the silicon were replaced exclusively by deuterium, dem-
onstrating that the direct 8-endo-cyclization (path b) had
occurred in this case.10
Bu Sn
3
X
O
O
Si
R
Si
R
R
R
X = Br, I, SePh
R = Me, Ph
B
A
The eight- or nine-membered ring-opening via the oxi-
dative Si–C bond fission was next examined. The desired
Si–C bond fission was achieved without removing the
silyl-protecting groups by treatment of 10 or 11 with
AcOOH/HBr/KBr in DMF,11 where the b-C-glucosides
13 and 14 were obtained quantitatively and in 61% yield,
respectively.
O
O
O
Si
Si
R R
X
Si
R
R
R
R
C
D
As described above, we have developed an efficient
method for preparing b-C-glucosides via a radical cycli-
zation based on the 1C4-conformational restriction strat-
egy.12 The reaction can be effectively employed as the
key step in the synthesis of the C-glucoside trisphos-
phates 1 and 2, designed as potential IP3 receptor
ligands, which is now under investigation.
ox.
O
OH
Si
R
HO
R
E
F
Scheme 5.

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M. Terauchi et al. / Tetrahedron Letters 46 (2005) 6555–6558
6. Radical reactions with an allylsilyl group as a tether: (a)
References and notes
Xi, Z.; Agback, P.; Plavec, J.; Sandstro¨m, A.; Chatto-
padhyaya, J. Tetrahedron 1992, 48, 349–370; (b) Kana-
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Soc. 2000, 122, 2422–2432.
1. (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545–8599;
(b) Jaramillo, C.; Knapp, S. Synthesis 1994, 1–20; (c)
Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Pergamon Press: Oxford, 1995; (d) Postema, M. H. D.
C-Glycoside Synthesis; CRC Press: Boca Raton, 1995.
2. (a) Shuto, S.; Tatani, K.; Ueno, Y.; Matsuda, A. J. Org.
Chem. 1998, 63, 8815–8824; (b) Abe, H.; Shuto, S.;
Matsuda, A. J. Org. Chem. 2000, 65, 4315–4325; (c)
Shuto, S.; Yahiro, Y.; Ichikawa, S.; Matsuda, A. J. Org.
Chem. 2000, 65, 5547–5557; (d) Terauchi, M.; Yahiro, Y.;
Abe, H.; Ichikawa, S.; Tovey, S. C.; Dedos, S. G.; Taylor,
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hedron 2005, 61, 3697–3707.
3. (a) Ichikawa, S.; Shuto, S.; Matsuda, A. Tetrahedron Lett.
1998, 39, 4525–4528; (b) Yahiro, Y.; Ichikawa, S.; Shuto,
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Shuto, S. Angew. Chem., Int. Ed. 2003, 42, 1021–1023, and
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7. Conformational restriction of pyranoses by bulky silyl-
protecting groups: (a) Tius, A. M.; Bushe-Petersen, J.
Tetrahedron Lett. 1994, 29, 5181–5184; (b) Hosoya, T.;
Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett.
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and references cited therein.
8. Compound 3, J2,3 = 4.2 Hz; 4, J2,3 = 2.0 Hz, J3,4 = ca.
0 Hz; 5, J2,3 = J3,4 = J4,5 = 9.4 Hz; 6, J2,3 = J3,4 = J4,5
=
8.7 Hz.
9. The anomeric b-stereochemistry of the cyclization prod-
ucts 10 and 11 was confirmed by NOE experiments.
10. The eight- and nine-membered ring formations in radical
reactions are known to occur usually via endo-mode
cyclization: Srikrishna, A. In Radicals in Organic Synthe-
sis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 2, pp 151–187.
4. Stork, G.; Suh, H. S.; Kim, G. J. Am. Chem. Soc. 1991,
113, 7054–7055.
5. Radical reactions with a vinylsilyl group as a tether: (a)
Shuto, S.; Kanazaki, M.; Ichikawa, S.; Matsuda, A.
J. Org. Chem. 1997, 62, 5676–5677; (b) Sugimoto, I.;
Shuto, S.; Matsuda, A. J. Org. Chem. 1999, 64, 7153–7157;
(c) Shuto, S.; Sugimoto, I.; Matsuda, A. J. Am. Chem. Soc.
2000, 122, 1343–1351, and references cited therein.
11. Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem.
Commun. 1984, 29–31.
12. The 1C4-conformational restriction strategy is also effec-
tive in the radical cyclization to synthesize a-C-glycosides:
Ref. 2c,d.