Stereoselective synthesis of α- and β-C-glucosides via radical cyclization with an allylsilyl tether. Control of the stereoselectivity by changing the conformation of the pyranose ring

Article abstract of DOI:10.1016/S0040-4039(00)00556-6

An efficient method for preparing both 1α- and 1β-C-glucosides having a 3-hydroxypropyl group at the anomeric position via a radical cyclization reaction with an allylsilyl tether was developed. The stereoselectivity of the radical cyclization can be cont

Full text of DOI:10.1016/S0040-4039(00)00556-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4151–4155
Stereoselective synthesis of α- and β-C-glucosides via radical
cyclization with an allylsilyl tether. Control of the
stereoselectivity by changing the conformation of
the pyranose ring
Satoshi Shuto,∗ Masaru Terauchi, Yumi Yahiro, Hiroshi Abe, Satoshi Ichikawa and
Akira Matsuda
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
Received 6 March 2000; revised 27 March 2000; accepted 31 March 2000
Abstract
An efficient method for preparing both 1α- and 1β-C-glucosides having a 3-hydroxypropyl group at the
anomeric position via a radical cyclization reaction with an allylsilyl tether was developed. The stereoselectivity of
the radical cyclization can be controlled by the conformation of the pyranose ring, which is effectively manipulated
by the hyroxyl protecting groups. © 2000 Elsevier Science Ltd. All rights reserved.
In recent years, we have been working to develop novel efficient D-myo-inositol 1,4,5-trisphosphate
(IP3, 1) receptor ligands, which are highly useful for proving the mechanism of IP3-mediated Ca2+
signaling pathways (Fig. 1).1 During the course of our synthetic study using the D-glucose structure
as a mimic of myo-inositol in IP3,2 we designed the C-glucoside trisphosphates 2 and 3 as potential
IP3 receptor ligands. In this communication, we describe an efficient stereoselective synthesis of β-C-
glucoside 4 and α-C-glucoside 5, which are useful intermediates for the synthesis of our target molecules
2 and 3, via a radical cyclization reaction with an allylsilyl tether as the key step.
Because of the unique biological activities of C-glycosides, considerable effort has been devoted to
developing practical methods for their preparation.3 The use of radical reactions is one of the most
efficient methods for constructing C-glycosidic bonds, and a number of studies have been reported using
these reactions.3,4 We planned to develop a novel procedure for introducing a C3 unit stereoselectively
at both the 1α- and 1β-positions of D-glucose via the radical cyclization reaction with an allylsilyl group
as a temporary connecting tether.5 Scheme 1 shows our synthetic plan. We chose the phenyl β-seleno-
D-glucopyranosides 6 and 7, which have an allylsilyl tether on the 2-hydroxyl group, as the substrates
for the radical reaction. We expected the stereoselectivity in the radical cyclization to change, depending
∗
Corresponding author. Fax: +81-11-706-4980; e-mail: shu@pharm.hokudai.ac.jp (S. Shuto)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00556-6
tetl 16835

4152
Fig. 1.
on the conformation of the substrates. Since the approach of the terminal of the tether to the anomeric
position from the α-face would not be favored because of significant 1,3-diaxial repulsion (A in Scheme
1a), the radical derived from the tri-O-benzyl-protected substrate 6 in a boat-like conformation6 should
cyclize selectively via an equatorial-attack (B in Scheme 1a) to give the 1β-product 8. On the other
hand, the radical reaction of the 3,4-di-O-TBS-protected substrate 7, which would predominantly exist
in an unusual 1C4 conformation due to the significant steric repulsion between the bulky TBS groups,4,7
would give the α-cyclization product 9 for the following reason. The 1,2-trans-cyclization would be
impossible sterically because of the axial orientation of the 20-tether, as shown in Scheme 1b. Oxidative
treatments8 of the radical reaction products 8 and 9 would give the corresponding C-glucosides having a
3-hydroxypropyl group at the anomeric β- and α-positions, respectively.
Scheme 1.
Phenyl 3,4,6-tri-O-benzyl-1-seleno-β-D-glucose (10), which was prepared by a known method,9 was
treated with commercially available allyldimethylsilyl chloride, DMAP, and Et3N in toluene at room
temperature to give the corresponding 2-O-allylsilyl ether 6 quantitatively (Scheme 2). The 3,4-O-
TBS-protected substrate 7 was prepared from the known glycal 1210 as shown in Scheme 3. The TBS
groups were introduced at the 3,4-trans-hydroxyl groups of 12, and the resulting compound 13 was
successively treated with dimethyldioxirane and PhSeH/Et3N in CH2Cl2 to give 1β-phenylselenide 14.
An allyldimethylsilyl tether was then introduced at the 2-hydroxyl group of the phenylselenide 14 to give
7, the other substrate for the radical reaction.
The conformation of the substrate 7 was investigated by 1H NMR and compared to that of the tri-O-
benzyl-protected substrate 6 (Fig. 2). While the relatively large coupling constants in the benzyl substrate

4153
Scheme 2.
Scheme 3.
6 suggest that it exits in the usual 4C1-conformation (Fig. 2a), the rather small coupling constants in the
TBS-protected compound 7 indicate that it prefers a flipped 1C4-conformation, as expected (Fig. 2b).
Fig. 2.
The radical reactions of 6 and 7 were performed by adding a mixture of Bu3SnH and AIBN slowly to a
solution of the substrate in benzene (80°C), toluene (110°C), or t-butylbenzene (130°C), and the products
were isolated after Tamao oxidation.8 The results are summarized in Table 1. The reaction of 6 (0.005
M) was first carried out in benzene under reflux. The reaction gave selectively the desired β-C-glucoside
4 as the major product along with the corresponding α-C-glucoside 11, after Tamao oxidation (entry 1:
yield 73%, α:β=1:2.9). When the reaction was performed at 110°C in toluene, both the yield and the
stereoselectivity were improved (entry 2: yield 80%, α:β=1:4.1). However, at higher temperatures, the
yield decreased (entry 3). Thus the radical reaction and the subsequent Tamao oxidation selectively gave
the 1β-C-glucoside 4, as expected.
The reactions with the TBS-protected substrate 7 were next examined. Treatment of 7 under conditions
identical to those in entry 1 did not initiate the radical reaction,11 and the substrate 7 was completely
recovered. However, when 7 was reacted with an excess of Bu3SnH under higher substrate concentration
conditions (0.05 M), the reaction gave the desired α-C-glucoside 5 as the sole product in 75% yield, after

4154
Table 1
Synthesis of C-glucosides by radical reactions with 2-O-allylsilyl-tethered substratesa
Tamao oxidation (entry 5). Similar treatment of 7 at 110°C in toluene further improved the yield of 5 to
85% (entry 6).
As described, we have developed an efficient method for preparing both 1α- and 1β-C-glucosides
having a 3-hydroxypropyl group at the anomeric position via the radical cyclization with an allylsilyl
tether. We demonstrated that the stereoselectivity of the radical cyclization can be controlled by the
conformation of the pyranose ring, which was effectively manipulated by the choice of the hydroxyl
protecting groups. The conversion of 4 and 5 into the potential IP3 ligands 2 and 3 is now under
investigation.
Acknowledgements
This investigation was supported in part by a Grant from the Ministry of Education, Science, Sports,
and Culture of Japan.
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4155
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