A study on the conformation-anomeric effect-stereoselectivity relationship in anomeric radical reactions, using conformationally restricted glucose derivatives as substrates

Article abstract of DOI:10.1021/jo030128+

We previously theorized that, since the stereoselectivity of anomeric radical reactions is significantly influenced by the kinetic anomeric effect, which can be controlled by restricting the conformation of the radical intermediate, the proper conformational restriction of the pyranose ring of the substrates would therefore make highly α- and β-stereoselective anomeric radical reactions possible. This theory was based on our previous results of the anomeric radical reactions with D-xylose derivatives as the substrates. We herein report the anomeric radical deuteration reactions with the conformationally restricted 1-phenylseleno-D-glucose derivatives, 2g and 3g, restricted in a ⁴C₁-conformation by an O-cyclic diketal moiety, and 4g, 5g, 6g, 7g, and 8g, restricted in a ¹C ₄-conformation by bulky O-silyl protecting groups. The radical deuterations with Bu₃SnD, using the ⁴C ₁-restricted substrates 2g and 3g, afforded the corresponding α-products (α/β = 98:2) highly stereoselectively, whereas the ¹C₄-restricted substrate 6g, having a trigonal (sp ²) carbon substituent, i.e., -CHO, at the 5-position, selectively gave the β-products α/β = 0:100). Thus, the stereoselectivity was significantly increased by the conformational restriction and was completely inverted by changing the substrate conformation from the ⁴C₁-form to the ¹C₄-form. On the other hand, the deuterations with the ¹C₄-restricted substrates 4g and 5g showed that the 1,5-steric effect due to the tetrahedral carbon substituent (-CH₂OTIPS or -CH₂OH) at the 5-axial position dominantly prevented the hydride transfer from the β-face competing with the kinetic anomeric effect. This study suggests that, depending on the restricted conformation of the substrates to the ⁴C ₁- or the ¹C₄-form, the α- or β-products would be obtained highly stereoselectively via anomeric radical reactions of hexopyranoses.

Full text of DOI:10.1021/jo030128+

A Stu d y on th e Con for m a tion -An om er ic Effect-Ster eoselectivity
Rela tion sh ip in An om er ic Ra d ica l Rea ction s, Usin g
Con for m a tion a lly Restr icted Glu cose Der iva tives a s Su bstr a tes
Hiroshi Abe, Masaru Terauchi, Akira Matsuda, and Satoshi Shuto*
Graduate School of Pharmaceutical Sciences, Hokkaido University,
Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, J apan
shu@pharm.hokudai.ac.jp
Received April 14, 2003
We previously theorized that, since the stereoselectivity of anomeric radical reactions is significantly
influenced by the kinetic anomeric effect, which can be controlled by restricting the conformation
of the radical intermediate, the proper conformational restriction of the pyranose ring of the
substrates would therefore make highly R- and â-stereoselective anomeric radical reactions possible.
This theory was based on our previous results of the anomeric radical reactions with D-xylose
derivatives as the substrates. We herein report the anomeric radical deuteration reactions with
the conformationally restricted 1-phenylseleno-D-glucose derivatives, 2g and 3g, restricted in a
4C1-conformation by an O-cyclic diketal moiety, and 4g, 5g, 6g, 7g, and 8g, restricted in a
1C4-conformation by bulky O-silyl protecting groups. The radical deuterations with Bu3SnD, using
4
the C1-restricted substrates 2g and 3g, afforded the corresponding R-products (R/â ) 98:2) highly
stereoselectively, whereas the 1C4-restricted substrate 6g, having a trigonal (sp2) carbon substituent,
i.e., -CHO, at the 5-position, selectively gave the â-products (R/â ) 0:100). Thus, the stereoselectivity
was significantly increased by the conformational restriction and was completely inverted by
4
1
changing the substrate conformation from the C1-form to the C4-form. On the other hand, the
1
deuterations with the C4-restricted substrates 4g and 5g showed that the 1,5-steric effect due to
the tetrahedral carbon substituent (-CH2OTIPS or -CH2OH) at the 5-axial position dominantly
prevented the hydride transfer from the â-face competing with the kinetic anomeric effect. This
4
study suggests that, depending on the restricted conformation of the substrates to the C1- or the
1C4-form, the R- or â-products would be obtained highly stereoselectively via anomeric radical
reactions of hexopyranoses.
In tr od u ction
meric pyranosyl radicals I, such as glucosyl radicals,
stereoselectively afford the corresponding R-product II,5,6
as shown in Scheme 1, the â-selective anomeric radical
reaction is more difficult to realize.7
Giese and co-workers have significantly contributed to
the development of the anomeric radical reactions. They
pointed out that in the radical C-glycosylation reaction
There has been growing interest in radical reactions
because of their facility to proceed under mild neutral
conditions.1 In carbohydrate chemistry, the reactions of
anomeric radicals have been extensively studied.2 For
example, intramolecular radical cyclizations are effective
in constructing the C-glycosidic bonds highly stereose-
lectively, and we have also been working to develop
efficient C-glycosylation reactions by intramolecular radi-
cal cyclization3 using a silyl tether.4 On the other hand,
in intermolecular anomeric radical reactions, while ano-
(3) (a) Yahiro, Y.; Ichikawa, S.; Shuto, S.; Matsuda, A. Tetrahedron
Lett. 1999, 40, 5527-5531. (b) Shuto, S.; Yahiro, Y.; Ichikawa, S.;
Matsuda, A. J . Org. Chem. 2000, 65, 5547-5557. (c) Shuto, S.;
Terauchi, M.; Yahiro, Y.; Abe, H.; Ichikawa, S.; Matsuda, A. Tetrahe-
dron Lett. 2000, 41, 4151-4155. (d) Abe, H.; Shuto, S.; Matsuda, A.
Tetrahedron Lett. 2000, 41, 2391-2394. (e) Abe, H.; Shuto, S.; Matsuda,
A. J . Org. Chem. 2000, 65, 4315-4325.
* To whom all correspondence and reprint requests should be
addressed. Phone: +81-11-706-3228. Fax: +81-11-706-4980.
(1) (a) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J .; Thoma, G.;
Kulicke, K. J .; Trach, F. Org. React. 1996, 48, 301-856. (b) Motherwell,
W. B.; Crich, D. Free-Radical Chain Reactions in Organic Synthesis;
Academic Press: London, UK, 1992. (c) Curran, D. P. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, UK, 1991; Vol. 4, pp 715-831. (d) J asperse, C. P.; Curran, D.
P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286. (e) Thebtaranonth,
C.; Thebtaranonth, Y. Tetrahedron 1990, 46, 1385-1489. (f) Laird, E.
E.; J orgensen, W. L. J . Org. Chem. 1990, 55, 9-27.
(2) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599. (b)
J aramillo, C.; Kanapp S. Synthesis 1994, 1-20. (c) Leavy, D. E.; Tang,
C. The Chemistry of C-Glycosides; Pergamon Press: Oxford, UK, 1995.
(d) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
FL, 1995. (e) Du, Y.; Linhardt, R. J . Tetrahedron 1998, 54, 9913-9959.
(4) (a) Shuto, S.; Kanazaki, M.; Ichikawa, S.; Matsuda, A. J . Org.
Chem. 1997, 62, 5676-5677. (b) Shuto, S.; Kanazaki, M.; Ichikawa,
S.; Minakawa, N.; Matsuda, A. J . Org. Chem. 1998, 63, 746-754. (c)
Sugimoto, I.; Shuto, S.; Matsuda, A. J . Org. Chem. 1999, 64, 7153-
7157. (d) Sugimoto, I.; Shuto, S.; Matsuda, A. Synlett 1999, 1766-
1768. (e) Shuto, S.; Sugimoto, I.; Abe, H.; Matsuda, A. J . Am. Chem.
Soc. 2000, 122, 1343-1351.
(5) (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH Press: Weinheim, Germany, 1996. (b) Descotes,
G. J . Carbohydr. Chem. 1988, 7, 1-20.
(6) (a) Giese, B.; Dupes, J . Tetrahedron Lett. 1984, 25, 1349-1352.
(b) Giese, B.; Dupuis, J .; Leising, M.; Nix, M.; Lindner, H. J . Carbohydr.
Res. 1987, 171, 329-341.
(7) A â-selective radical C-glycosylation of xylose derivatives has
been reported: see ref 6b.
10.1021/jo030128+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/27/2003
J . Org. Chem. 2003, 68, 7439-7447
7439

Abe et al.
SCHEME 1
anomeric effect works effectively to give the R-product E
highly selectively. Similarly, when the conformation of
the radical intermediate is restricted to the unusual
1C4-chair-form B, the corresponding â-product F should
be selectively obtained due to the kinetic anomeric effect
via the â-axial attack transition state D. The transition
states 4C1-restricted C and 1C4-restricted D can be
effectively stabilized by the interaction between the
antibonding σ*q of the newly forming anomeric bond and
the p-orbital of a nonbonded electron pair (nO) on the ring
oxygen because of the periplanar arrangement,12,13 which
is the kinetic anomeric effect in anomeric radical reac-
tions.10 Accordingly, depending on the conformation of
the substrates which are restricted to the 4C1- or the
1C4-form, the R- or â-products can be obtained highly
stereoselectively by the anomeric radical reactions. On
the basis of this idea, we previously studied anomeric
radical reactions using xylose derivatives as model
substrates to show that the R- and â-selective anomeric
radical reactions actually occur.10
SCHEME 2
In hexopyranoses, such as glucose or mannose deriva-
tives, steric effect due to the hydroxymethyl moiety
attached at the 5-position would affect the stereoselec-
tivity of the anomeric radical reactions, which was likely
to disturb the exact estimation of the anomeric effect on
the stereoselectivity. Therefore, we used the xylose
derivatives as the model substrates in the previous study,
since they lack the carbon substituent at the 5-position.
However, hexopyranoses are major components in natu-
ral carbohydrates, and therefore, especially from the
viewpoint of synthetic organic chemistry, reactions with
hexopyranoses as the substrates are important. Thus, we
planned to investigate further the conformation-ano-
meric effect-stereoselectivity relationship in the ano-
meric radical reactions using conformationally restricted
hexose substrates. These studies would also clarify the
effect of the hydroxymethyl moiety attached to the
5-carbon of the pyranose on the stereoselectivity of
anomeric radical reactions. Here we report the results
of deuterium-labeling radical reactions using conforma-
tionally restricted glucose derivatives as the substrates.
the R-selectivity can be a result of the anomeric effect,
similar to SN1-like glycosylations.8 The anomeric effect
should be influenced by the conformation of the sugar
molecule, since it is a stereoelectronic effect on the
anomeric position due to the nonbonding electrons on the
ring oxygen.9 The transition state of anomeric radical
reactions of pyranoses would be significantly stabilized
when it adopts a 4C1 or a 1C4-chairlike conformation,
where the newly forming bond orbital effectively interacts
with the p-orbital of a lone pair on the ring oxygen in a
periplanar arrangement. Consequently, we theorized that
the anomeric effect might be employed to effectively
control the stereoselectivity in anomeric radical reactions
by using conformationally restricted substrates.10,11 As
shown in Scheme 2, in the reaction of an anomeric radical
intermediate A, the conformation of which is restricted
Resu lts a n d Discu ssion
Design a n d Syn t h esis of D-Glu cose Der iva t ives
4
1
Restr icted in a C1- or a C4-Ch a ir Con for m a tion a s
th e Su bstr a tes. The conformations of pyranoses can be
restricted by introducing proper protecting groups on the
hydroxy groups. We designed the phenyl 1-seleno-â-D-
4
1
glucosides 2g-8g restricted in a C1- or a C4-conforma-
tion as the substrates for this study. The conformation-
ally unrestricted tetra-O-acetylglucoside 1g was also
employed as the reference substrate.14 The structures of
these substrates are shown in Figure 1.
4
in the C1-chair form, the R-axial attack transition state
C also assumes the 4C1-like form, where the kinetic
(8) Giese, B. Angew. Chem., Int. Ed. Engl. 1989, 28, 969-980.
(9) (a) J uaristi, E.; Cuevas, G. Tetrahedron 1992, 48, 5019-5087
and references sited therein. (b) Thatcher, G. R. J ., Ed. The Anomeric
Effect and Associated Stereoelectronic Effects; ACS Symp. Ser. No. 539;
American Chemical Society: Washington, DC, 1993. (c) J uaristi, E.;
Cuevas, G. The Anomiric Effect; CRC Press: Boca Raton, FL, 1995. (d)
Thibaudeau, C.; Chattopadhyaya, J . Stereoelectronic Effects in Nucleo-
sides and Nucleotides and their Structural Implications; Uppsala
University Press: Uppsala, Sweden, 1999.
(12) Cieplack pointed out the importance of hyperconjugation in the
transition state of nucleophilic addition reactions to carbonyls, since
the energy of the transition state is lowered by delocalization of
electrons from an antiperiplanar vicinal σ-bond to the antibonding
component (σ*q) of the newly forming bond: (a) Cieplack, A. S. J . Am.
Chem. Soc. 1981, 103, 4540-4552. (b) J ohnson, C. R.; Tait, B. D.;
Cieplack, A. S. J . Am. Chem. Soc. 1987, 109, 5857-5876 and references
therein.
(10) Abe, H.; Shuto, S.; Matsuda, A. J . Am. Chem. Soc. 2001, 123,
11870-11882.
(11) The R- and â-stereoselectivity in SN1-type anomeric allylation
is also controlled by the kinetic anomeric effect by using conforma-
tionally restricted substrates: Tamura, S.; Abe, H.; Matsuda, A.; Shuto,
S. Angew. Chem., Int. Ed. 2003, 42, 1021-1023.
(13) For explanations of radical reaction transition states by this
kind of orbital interaction see: (a) Renaud, P. Helv. Chim. Acta 1991,
74, 1305-1313. (b) Bodpudi, V. R.; le Noble, W. J . J . Org. Chem. 1991,
56, 2001-2006.
7440 J . Org. Chem., Vol. 68, No. 19, 2003

Anomeric Effect-Dependent Stereoselective Radical Reaction
SCHEME 3
fore, the 2,3,4,6-tetrakis- and 2,3,4,-tris-O-triisopropysilyl
(TIPS)-protected D-glucose derivatives 4g and 5g, respec-
1
tively, would adopt a C4-conformation due to the steric
effect of the bulky silyl groups.
As described below, in the substrates 4g and 5g
1
conformationally restricted in the C4-form, both the R-
and â-sides of the anomeric position were likely to be
significantly sterically hindered due to the 1,3- and 1,5-
diaxial repulsion, especially due to the tetrahedral carbon
substituent attached to the 5-position and also due to a
bulky protecting group at the 2-hydroxyl. The 2,3,4-tris-
O-TIPS-6-aldehyde derivative 6g was therefore designed
as the 1C4-restricted substrate, in which the 1,5-steric
repulsion for the 5-substituent on the anomeric â-side
should be moderated because of the trigonal C6 struc-
ture of the formyl group, compared with 4g and 5g
bearing a tetrahedral carbon substituent (-CH2OTIPS
or -CH2OH). The substrates 7g and 8g, in which the
1
2-silyloxy moiety of the C4-restricted substrate 4g was
replaced with a free hydroxyl or an acetoxy group, were
also designed. In these substrates, the steric hindrance
on the R-side of the anomeric position should be signifi-
cantly reduced compared with that of 4g.
The preparation of the substrates 2g-6g is sum-
marized in Schemes 3. Phenyl 1-seleno-â-D-glucopyrano-
side (9)19 was heated with 2,2,3,3-tetramethoxybutane-
dione (TMB) and CH(OMe)3 in MeOH in the presence of
catalytic CSA15 to give the corresponding 2,3-O-cyclic-
diketal 2g (43%) and the 3,4-O-cyclic-diketal 3g (52%).
Although 3,4-bis-O-silyl pyranoses have been synthesized
via introduction of the silyl groups on the 3,4-trans-diol
of the glycal,3a-c,16,18 we most recently developed an
efficient method for directly introducing the bulky silyl
groups on the trans-vicinal-diol of pyranoses with a
TIPSOTf/NaH/THF system.17 Thus, treatment of 9 with
TIPSOTf/NaH in THF at room temperature successfully
gave the 2,3,4,6-tetrakis-O-TIPS substrate 4g in 85%
yield. The 6-O-silyl group of 4g was selectively removed
by acidic treatment in aqueous THF to give 5g, Dess-
Martin oxidation20 of which afforded the corresponding
6-formyl derivative 6g.
F IGURE 1. Conformationally restricted and unrestricted
glucose derivatives as the anomeric radical reaction substrates.
The conformation of the pyranose ring of the substrates
2g and 3g bearing a 2,3- or a 3,4-O-cyclic-diketal group
would be restricted in the 4C1-form due to its trans-
decalin-type ring system.13 The glucose derivatives 4g,
1
5g, 6g, 7g, and 8g were designed as the C4-restricted
substrates. It is known that introducing a quite bulky
protecting group at the 3,4-trans-hydroxy groups of
pyranoses causes a flip of their conformation leading to
the 1C4-form, in which the bulky substituents are in axial
positions due to mutual steric repulsion.3a-c,10,16-18 There-
The 2-free-hydroxy and 2-O-acetyl substrates, 7g and
8g, respectively, were synthesized from the glycal 10 as
shown in Scheme 4. TIPS groups were introduced at all
three hydroxyls by treatment of 10 with TIPSOTf in 2,6-
lutidine,21 and the resulting tris-O-silylated 11 was
(14) An R-selective deuteration with 1-bromo-2,3,4,6-tetra-O-acetyl
glucose as a substrate was reported: Giese, B.; Dupes, J . Tetrahedron
Lett. 1984, 25, 1349-1352.
(15) (a) Montchamp, J . L.; Tian, F.; Hart, M. E.; Frost, J . W. J . Org.
Chem. 1996, 61, 3897-3899. (b) Hense, A.; Ley, S. V.; Osborn, H. M.
I.; Owen, D. R.; Poisson, J .-F.; Warriner, S. L.; Wesson, K. E. J . Chem.
Soc., Perkin Trans. 1 1997, 2023-2031
(16) Ichikawa, S.; Shuto, S.; Matsuda, A. J . Am. Chem. Soc. 1999,
121, 10270-10280.
(17) Abe, H.; Shuto, S.; Tamura, S.; Matsuda, A. Tetrahedron Lett.
2001, 42, 6159-6161.
(18) (a) Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahe-
dron Lett. 1996, 37, 636-666. (b) Futagami, S.; Ohashi Y.; Imura, K.;
Hosoya, T.; Ohmori, K.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett.
2000, 41, 1063-1067.
(19) Borner, W. A.; Robinson, A. J . Am. Chem. Soc. 1954, 72, 354-
356.
(20) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113,
7277-7287. (b) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48,
4155-4156.
(21) Do¨tz, K. H.; Otto, F.; Nieger, M. J . Organomet. Chem. 2001,
621, 77-88.
J . Org. Chem, Vol. 68, No. 19, 2003 7441

Abe et al.
TABLE 1. Ra d ica l Deu ter a tion of th e Glu cosyl
An om er ic Ra d ica ls
SCHEME 4
entry
substrate
conformation
yield (D rate)b
R/âc
1
2
3
4
5
6
7
8
1g
2g
3g
4g
5g
6g
7g
8g
unrestricted
91% (100%)
67% (100%)
71% (100%)
91% (0%)d
88:12
98:2
98:2
4C1
4C1
1C4
1C4
1C4
1C4
1C4
90% (0%)d
60% (87%)
65% (100%)
71% (100%)
0:100
52:48
83:17
successively treated with dimethyldioxirane in CH2Cl2
and PhSeH in 2,6-lutidine to stereoselectively give the
1-â-phenylselenide 7g. The 2-hydroxyl of 7g was acety-
lated to give 8g.
a
In entry 6, the radical reaction products were treated with
NaBH4 in THF to reduce the formyl group before the deprotection.
b
The conformations of the synthesized substrates were
investigated by 1H NMR, and the results are summarized
in Figure 1. The large coupling constants (J > 9 Hz)
between the vicinal protons of 2g or 3g showed that these
protons were in an axial orientation, where the pyranose
ring assumed the expected 4C1-conformation. On the
other hand, the small coupling constants (J e 3 Hz)
between the vicinal equatorial protons of 4g, 5g, 6g, 7g,
and 8g showed that these had the 1C4- or 1C4-like
conformation22 as expected. The conformationally unre-
stricted 1g had medium coupling constants (J ) 4.4 and
6.7 Hz), compared with the other two types of conforma-
tionally restricted substrates.
Deuterium incorporation rate at the 1-position determined by
1H NMR analysis. c Determined by 2H NMR analysis. The cor-
d
responding 1-deoxy compound 15 was obtained as the major
product (entry 4, 91%; entry 5, 90%) via 13 or 14.
R-selectivity (entry 3, R/â ) 98:2). Thus, the conforma-
tional restriction of the substrate in the 4C1-form resulted
in significantly increased R-selectivity compared with the
result of the unrestricted substrate 1g as expected.
Deu ter a tion of th e Con for m a tion a lly Restr icted
Glu cosyl Ra d ica ls. We first investigated the deutera-
tion of the anomeric glucosyl radicals produced from the
1
However, when the C4-restricted substrates 4g and 5g
were used, no deuterium was incorporated at the ano-
meric position in the corresponding reduction products,
which were produced in high yield (entries 4 and 5).
These unexpected results showed that intramolecular
abstraction of a hydrogen atom of the 2-O-TIPS moiety
by the anomeric radical occurred to produce 13 or 14,23
probably because both of the R- and â-sides of the
anomeric position were significantly sterically hindered
to prevent the approach of Bu3SnD.
4
unrestricted substrates 1g, the C1-restricted substrates
1
2g and 3g, and the C4-restricted substrates 4g and 5g
with Bu3SnD/AIBN. Such deuterium-labeling experi-
ments would be useful in estimating the stereoselectivity,
leading to a clarification of the influence of the steric
hindrance and the anomeric effect in anomeric radical
reactions. The substrates (0.07 M) were heated with
Bu3SnD (2.0 equiv)/AIBN (0.5 equiv) in benzene under
reflux and then deprotected under appropriate conditions,
and the resulting four hydroxyl groups of the products
were acetylated with Ac2O/pyridine. The deuterium-
labeled product 12g was purified by silica gel column
chromatography, and the stereoselectivity was deter-
On the basis of the above results, we next investigated
the reaction with the other C4-restricted substrates 6g,
1
7g, and 8g. The radical deuterations with the 6-aldehyde
substrate 6g, which has a formyl group attached at the
5-position instead of the hydroxymethyl or the silyloxym-
ethyl group in 4g and 5g, gave the â-deuterated products
highly selectively as expected (entry 6, R/â ) 0:100).
These results showed that significant 1,5-steric repulsion
2
mined by the H NMR spectrum. The results are sum-
marized in Table 1.
The deuteration of the unrestricted 1g as the substrate
showed an R-selectivity (entry 1, R/â ) 88:12), which was
in accord with the radical deuterium-labeling result of a
similar tetra-O-acetylglucosyl substrate previously re-
ported by Giese.14 The reaction with the substrate 2g,
restricted in the 4C1-conformation by a 2,3-O-cyclic-
diketal, showed high R-selectivity (entry 2, R/â ) 98:2).
The reaction with the other 4C1-restricted substrate 3g
having a 3,4-O-cyclic-diketal also showed the same high
1
occurred in the C4-restricted substrates 4g and 5g due
to the tetrahedral carbon structure (-CH2-) at the
5-position to prevent the approach of Bu3SnD to the
anomeric â-side. The radical reaction product from 6g
was then treated with NaBH4, which readily converted
it into the corresponding glucose derivative. These results
demonstrated that the conformational restriction of the
pyranose ring of the glucose derivatives in the 4C1- or
1C4-form increases and inverts the stereoselectivity in
anomeric radical reactions.
(22) In the 1H NMR spectrum of 8g, although the coupling constants
between the H2, H3, H4, and H5 (J ) 0-2.8 Hz) showed that these
protons were in axial orientations, the anomeric proton would not be
in an axial orientation because of the rather large constant between
H1 and H2 (J 1,2 ) 7.7 Hz). Therefore, the preferred conformation of 8b
might be somewhat different from the typical 1C4-form, especially
around the anomeric position.
In the reactions with 7g and 8g, in which the bulky
2-silyloxy moiety of 4g was replaced with a hydroxy or
(23) The molecular ion peaks corresponding to 13 or 14 were
observed in their mass spectra.
7442 J . Org. Chem., Vol. 68, No. 19, 2003

Anomeric Effect-Dependent Stereoselective Radical Reaction
F IGURE 3. 4C1-restricted and 1C4-restrected glucosyl radicals.
F IGURE 2. Xylose derivatives as the substrates used in the
previous study.
an acetoxy group to reduce the steric hindrance around
the anomeric R-position, deuteration at the anomeric
position proceeded efficiently. Although the 2-hydroxy
substrate 7g was nonstereoselectively deuterated (entry
7, R/â ) 52:48), the deuteration with 2-O-acetyl substrate
8g selectively gave the R-product (entry 9, R/â ) 83:17).
Con for m a tion a l An a lysis of th e An om er ic Ra d i-
ca ls. As described above, the 1H NMR analysis suggested
that the conformations of the substrates were restricted
to the 4C1- or the 1C4-form as expected. However, the
conformations of the radical intermediates, as shown in
Figure 2, should more importantly affect the stereose-
lectivity of the anomeric radical reactions. The sub-
strates 2g and 3g should be rigidly restricted to the
4C1-conformation due to the inflexible trans-decalin-type
ring system. Accordingly, the radical intermediates 2g′
and 3g′ derived from 2g and 3g would also rigidly assume
F IGURE 4. Relative energies of 1C4-conformers based on the
4C1-conformers calculated by the MM3 force field.
some conformational flexibility compared with 4g′ and
6g′, because the calculated energy differences between
the two conformations of the model compounds 18 and
19 were not so high (0.98 kcal/mol for 18 and 1.07 kcal/
mol for 19).
4
the C1-like conformation.
On the other hand, the conformational restriction of
the radical intermediates 4g′-8g′ derived from 4g-8g,
respectively, due to the bulky silyl groups, might not be
as rigid as those in the radicals 2g′ and 3g′. Therefore,
we estimated the stability of the 1C4-conformations by
MM3 calculations24 with the corresponding 1-deoxy de-
rivatives, i.e., 1,5-anhydro-2,3,4,6-tetra-O-TIPS-D-glucitol
(16), its 6-formyl derivative 17, 1,5-anhydro-3,4,6-tris-
O-TIPS-D-glucitol (18), and its 2-acetate 19, as model
compounds of the radical intermediates derived from 4g,
6g, 7g, and 8g, respectively (Figure 3). These calculations
would clarify the steric effect of the silyl protecting groups
on the conformation of the radical intermediates. The
calculated energies showed that in the 2,3,4-O-silylated
Discu ssion
We previously reported that anomeric radical deutera-
4
1
tions with C1- or C4-restricted xylose derivatives as the
substrates gave highly stereoselectively the correspond-
ing R- or â-products, respectively, and that the stereose-
lectivity was increased by the conformational restriction
and completely inverted by flipping the substrate con-
formation from the 1C4- into the 4C1-form, due to the
kinetic anomeric effect.10 The typical reaction substrates
and results of the previous study are shown in Figure 4
and Table 2.
1
16 and 17 the flipped C4-conformer is significantly more
stable (8.85 kcal/mol for 16 and 10.61 kcal/mol for 17)
than the usual 4C1-conformer. Therefore, the radical
intermediates 4g′ and 6g′ were likely to be restricted
rigidly in the 1C4-conformation. Although the 3,4,6-O-
silylated radical intermediates 7g′ and 8g′ would also
In the present study, the deuterium-labeling radical
reactions with the glucose substrates 2g and 3g restricted
in the 4C1-conformation by a 2,3- or a 3,4-O-cyclic-diketal
showed high R-selectivity as expected (Table 1, entries 2
and 3). These results were similar to those observed with
the corresponding 4C1-restricted xylose substrates 2x and
3x (Figure 4) reported previously, as shown in Table 2
(entries 2 and 3). However, no deuterium was incorpo-
1
4
prefer the C4- to the C1-confromation, they might have
(24) Mohanmadi, F.; Richard, N. G. J .; Guida, W. C.; Liskamp, R.;
Caufield, C.; Chang, G.; Hendrikson, T.; Still, W. C. J . Comput. Chem.
1990, 11, 440-467.
J . Org. Chem, Vol. 68, No. 19, 2003 7443

Abe et al.
TABLE 2. Th e P r eviou s Ra d ica l Deu ter a tion of th e
Xylosyl An om er ic Ra d ica lsa
entry
substrate
conformation
yield (D rate)b
R/âc
1
2
3
4
1x
2x
3x
4x
unrestricted
66% (100%)
83% (100%)
83% (100%)
80% (100%)
65:35
97:3
97:3
1:99
4C1
4C1
1C4
a
b
Data were taken from ref 10. Deuterium incorporation rate
at the 1-position determined by 1H NMR analysis. c Determined
by 2H NMR analysis.
F IGUR E 6. Transition state model of the reaction of the
1C4-conformationally restricted glucosyl radicals 4g′, 5g′, and
6g′ for an understanding of the â-stereoselectivity.
and 3g′, the R-axial attack would be preferred to the
equatorial attack (Figure 5b). In the reaction of the
radical intermediate conformationally restricted in the
4C1-conformation,27 the transition state likely assumes
the 4C1-like conformation due to the conformational
restriction, where the axial attack from the R-side could
be significantly stabilized by the interaction between the
antibonding σ*q of the newly forming anomeric bond and
the axial-directed nonbonding electrons of the ring
oxygen which have high p-character to yield the R-prod-
uct highly selectively. We, therefore, concluded that the
dominant factor controlling the stereoselectivity of the
radical reactions with the cyclic-diketal substrates 2g and
F IGUR E 5. Transition state model of the reaction of the
4C1-conformationally restricted glucosyl radicals 2g′ and 3g′
for an understanding of the R-stereoselectivity: considerations
of the steric effect (a) and the stereoelectronic effect (b).
4
3g restricted in the C1-conformation is not steric hin-
rated at the anomeric position in the reaction with the
1C4-restricted O-silylated glucose derivatives 4g and 5g
having bulky silyl groups as the substrates, where the
corresponding xylose derivative 4x effectively deuterated
with high â-selectivity (Table 2, entry 4). In contrast,
when the 6-aldehyde substrate 6g was used, the radical
deuteration at the anomeric position occurred with a high
â-selectivity (Table 1, entry 6).
In the reactions of anomeric radicals, a radical acceptor
can attack from both the axial and equatorial direc-
tions.25,26 We first considered the highly R-selective
reaction with the cyclic-diketal substrates 2g and 3g,
via the radical intermediates 2g′ and 3g′ in the
4C1-conformation (Figure 2). The steric effect in the
attack on the radical intermediates 2g′ or 3g′ in the
4C1-conformation is summarized in Figure 5a. The R-axial
attack on 2g′ or 3g′ is accompanied by 1,3- and 1,5-diaxial
repulsion. Moreover, the 1,2-steric repulsion in the
R-axial attack would be more significant than that in the
â-equatorial attack, because the axial attack of Bu3SnD
would proceed through the pseudoaxial direction,26 where
the newly forming carbon-deuterium bond and the
C2-O2 bond are nearly eclipsed. Hence, the equatorial
attack should be preferred over the axial attack from
the viewpoint of steric hindrance. However, considering
the stereoelectronic effect in the radical reaction of 2g′
drance but the kinetic anomeric effect.
We next considered the reactions with the substrates
4g, 5g, and 6g (Figure 6). As described above, the MM3
calculations of the corresponding 1-deoxy model com-
pounds 16 and 17 suggested that the intermediates 4g′,
5g′, and 6g′ seemed to be rigidly restricted in the
1C4-conformation. In the reaction of the 6-O-TIPS and
6-OH radicals 4g′ and 5g′, the axial attack by Bu3SnD
from the â-side would be preferred due to the kinetic
anomeric effect contributing to stabilize the transition
state assuming the 1C4-like conformation (Figure 6b). On
the other hand, with respect to steric hindrance in the
attack on the radicals 4g′ and 5g′, the â-axial attack of
Bu3SnD encounters 1,3- and 1,5-diaxial repulsion, where
the R-equatorial attack can also be disturbed by the 1,2-
steric repulsion derived from the bulky 2-O-TIPS moiety
(Figure 6a). The reaction results with the substrates 4g
and 5g would be due to the fact that the significant steric
hindrance on both the R- and the â-sides completely
prevented the approach of the reagent in the intramo-
lecular hydrogen transfer, while the kinetic anomeric
effect should promote the â-side attack. Notably, the
reaction of the 6-aldehyde 6g gave the â-product with
high stereoselectivity (R/â ) 0:100, Table 1, entry 6);
moderation of the 1,5-steric repulsion by replacement of
the tetrahedral carbon (-CH2O-) with the trigonal
carbon (-CHO) at the 6-positon accompanied by the
kinetic anomeric effect resulted in complete stereocontrol.
Finally, the reactions of the substrates 7g and 8g, in
which the 2-silyloxy moiety of the 1C4-restricted substrate
(25) The steric effect of substitutions at the 2-position was analyzed
by using the cyclohexyl radical as a model substrate: see ref 8.
(26) Theoretical calculations by Giese, Houk, and Zipse showed that
attack of radical acceptors on the cyclohexyl radical occurred through
the two pathways of axial and equatorial directions. They concluded
that the axial attack occurred from the direction slightly diverted from
the vertical, i.e., a pseudoaxial direction: Damm, W.; Giese, B.;
Hartung, J .; Hasskerl, T.; Houk, K. N.; Hu¨ter, O.; Zipse, H. J . Am.
Chem. Soc. 1992, 114, 4067-4079.
(27) Ab initio calculations of the xylosyl anomeric radical with 2,3-
or 3,4-cyclic-diketal structure showed that they have a stable 4C1-
conformation: see ref 10.
7444 J . Org. Chem., Vol. 68, No. 19, 2003

Anomeric Effect-Dependent Stereoselective Radical Reaction
TABLE 3. Sta biliza tion En er gies Du e to th e
Hyp er con ju ga tion In ter a ction s betw een a Sin gle
Occu p ied Or bita l (sp n ) a n d a n An tibon d in g Or bita l Bon d
(σ*) of th e Ad ja cen t C-Ra
radical orbital
(spn)
energy
(kcal/mol)
radical
R
G
H
I
-OAc
-OH
-H
sp8.91
sp8.23
sp7.38
14.12
11.23
6.30
F IGUR E 7. Transition state model of the reaction of the
1C4-conformationally restricted glucosyl radicals 7g′ and 8g′
for an understanding of the R-stereoselectivity.
a
Structure optimization and NBO analysis was performed by
UHF/3-21G*.
4g was replaced with a free hydroxyl or an acetoxy group,
were considered. We designed 7g and 8g to be 1,2-steric
repulsion-reduced substrates as shown in Figure 7a,
compared with the corresponding 2-O-TIPS substrate 4g
(Figure 5a). However, the radical deuteration with the
2-hydroxy substrate 7g was nonstereoselective (Table 1,
entry 7), while the corresponding 2-O-acetyl substrate 8g
was R-stereoselectively deuterated, as expected (entry 8,
R/â ) 83:17). Although 1H NMR data (Figure 1) indi-
cated that the two substrates 7g and 8g preferred the
1C4-conformation, the reaction results suggested that the
conformational feature of the radical intermediates 7g′
and 8g′ derived from 7g and 8g might be different.
Therefore, we investigated conformations of the radical
intermediates 7g′ and 8g′ by MM3 calculations using the
corresponding 1-deoxy derivatives 18 and 19 as the model
compounds (Figure 3). The calculations suggested that
in the two intermediates the 1C4-conformer was similarly
stable; the 1C4-conformer was about 1 kcal/mol more
stable than the 4C1-conformer in both of the model
compounds 18 and 19.
would not be so dominant because of the strong 1,5-steric
repulsion.31
Con clu sion
The present study together with our previous ones10
on the anomeric radical reactions showed that (1) the
kinetic anomeric effect can be manipulated by the
substrate conformation and that (2) the kinetic anomeric
effect determines and increases the R-stereoselectivity of
4C1-restricted substrates, such as 2g, 3g, 2x, or 3x, and
also the â-stereoselectivity of the 1C4-restrected sub-
strates lacking a tetrahedral carbon substituent at the
5-axial-position, such as 6g or 4x. Thus, depending on
the conformation of the substrates restricted to the
4C1- or the 1C4-form, the R- or â-products would be
obtained highly stereoselectively via anomeric radical
reactions.11 However, the results of the 1C4-restricted
substrates 4g and 5g having the 5′-tetrahedral carbon
substituent (-CH2OTIPS or -CH2OH) and 2′-OTIPS
group showed that the significant steric hindrance on
both the R- and the â-sides completely prevented the
intermolecular deuteration in the intramolecular hydro-
gen transfer, while the kinetic anomeric effect should
promote the â-side attack.
We next focused on the stereoelectronic effect of the
2-substituent on the conformation of the intermediates
of 7g′ and 8g′ from the point of view of orbital interac-
tions, since the single occupied radical orbital (spn) could
interact with the σ* of the C2-O2 bond in the radical
intermediates.8,28 Thus, the stabilization energies of the
orbital interactions between the radical orbital (spn) and
the σ* of the C-O bond were calculated based on NBO
(natural bond orbital) theory,29,30 using model radicals
G, H, and I, and the results are summarized in Table 3.
The calculated energies showed that the interaction
between the σ* of the C2-O2 bond stabilized the radical,
where the stabilization effect was more significant in the
2-acetoxy radical G than in the corresponding 2-hydroxy
Exp er im en ta l Section
P h en yl 2,3-O-[(2S,3S)-2,3-Dim eth oxybu ta n e-2,3-d iyl]-
1-selen o-â-D-glu cop yr a n osid e (2g) a n d P h en yl 3,4-O-
[(2S,3S)-2,3-Dim eth oxybu ta n e-2,3-d iyl]-1-selen o-â-D-glu -
cop yr a n osid e (3g). A mixture of 918 (1.0 g, 3.1 mmol), TMB
(490 µL, 6.3 mmol), CH(OMe)3 (2.7 mL, 25 mmol), and CSA
(36 mg, 15 µmol) in MeOH (10 mL) was heated under reflux
(30) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B.; Chen, W.;
Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J . A. Gaussian 98, Revision A.6; Gaussian, Inc.: Pitts-
burgh, PA, 1998.
1
radical H. Accordingly, the C4-conformer, in which the
spn-σ* interaction is maximum because of the periplanar
arrangement, might be more stable in 8g′ than in 7g′.
This may explain why the 2-O-acetoxy substrate 8g was
more selectively deuterated compared with the 2-hydroxy
substrate 7g. In the reactions of 8g, the kinetic anomeric
effect (Figure 7b), which should promote the â-attack,
(28) (a) Dupuis, J .; Giese, B.; Ruegge, D.; Fischer, H.; Korth, H.-G.;
Sustman, R. Angew. Chem., Int. Ed. Engl. 1984, 23, 896-898. (b)
Korth, H.-G.; Sustmann, R.; Dupuis, J .; Giese, B. J . Chem. Soc., Perkin
Trans. 2 1986, 1453-1459.
(29) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88,
899-926.
(31) Geise described that R-axial attack to the anomeric radical of
pyranoses could occur via a B2,5-boat intermediate stabilized by the
anomeric effect (ref 8). In the radical deuteration of 8g, the B2,5-boat
intermediate might contribute to the R-product formation, at least to
some extent.
J . Org. Chem, Vol. 68, No. 19, 2003 7445

Abe et al.
for 2 h. The mixture was partitioned between AcOEt and
aqueous saturated NaHCO3, and the organic layer was washed
with H2O and brine, dried (Na2SO4), and evaporated. The
residue was purified by column chromatography (SiO2, hexane/
AcOEt, 2:1-2:3) to give compound 2g (575 mg, 43% as an oil)
and 3g (704 mg, 52% as an oil). 2g: [R]D -127.6 (c 1.00 MeOH);
1H NMR (CDCl3, 400 MHz) δ 7.61-7.27 (m, 5 H), 5.00 (d, 1 H,
J ) 9.7 Hz), 3.90 (m, 1 H), 3.78 (m, 1 H), 3.73 (m, 1 H), 3.70
(dd, 1 H, J ) 9.7, 9.7 Hz), 3.63 (dd, 1 H, J ) 9.7, 9.7 Hz), 3.41
(m, 1 H), 3.28 (s, 3 H), 3.22 (s, 3 H), 2.48 (br s, 1 H), 1.99 (m,
1 H), 1.34 (s, 3 H), 1.33 (s, 3 H); FAB-HRMS calcd for C18H26O7-
SeNa 457.0741 (MNa+), found 457.0751. Anal. Calcd for
C18H26O7Se‚0.2H2O: C, 49.48; H, 6.09. Found: C, 49.37; H,
6.13. 3g: [R]D 70.8 (c 1.05 MeOH); 1H NMR (CDCl3, 400 MHz)
δ 7.62-7.35 (m, 5 H), 4.78 (d, 1 H, J ) 9.4 Hz), 3.88 (m, 1 H),
3.73 (dd, 1 H, J ) 9.4, 9.4 Hz), 3.72 (m, 1 H), 3.61 (dd, 1 H, J
) 9.4, 9.4 Hz), 3.57 (m, 1 H), 3.50 (ddd, 1 H, J ) 1.8, 9.4, 9.4
Hz), 3.30 (s, 3 H), 3.22 (s, 3 H), 2.45 (d, 1 H, J ) 1.8 Hz), 1.84
(m, 1 H), 1.32 (s, 3 H), 1.28 (s, 3 H); FAB-HRMS calcd for
4.24 (br s, 1 H), 4.12 (br s, 1 H), 1.08 (m, 63 H); 13C NMR
(CDCl3, 125 MHz) δ 200.3, 132.9, 132.4, 129.4, 127.4, 84.8,
84.1. 73.0, 72.0, 68.7, 18.5, 18.4, 18.4, 18.3, 12.7, 12.6, 12.5;
FAB-HRMS calcd for C39H74O5SeSi3Na 809.3907 (MNa+),
found 809.3885. Anal. Calcd for C39H74O5SeSi3: C, 59.58; H,
9.49. Found: C, 59.68; H, 9.54.
P h en yl 1-Selen o-3,4,6-tr is-O-tr iisop r op ylsilyl-â-D-glu -
cop yr a n osid e (7g). To a solution of 1120 (2.2 g, 3.6 mmol) in
CH2Cl2 (15 mL) was added a solution of dimethyldioxirane
(0.09 M in acetone, 60 mL, 5.4 mmol) at 0 °C, and the mixture
was stirred at room temperature for 2 h. The mixture was
evaporated and dried in vacuo at room temperature for 3 h.
To a solution of the resulting residue in 2,6-lutidine (10 mL)
was added PhSeH (666 µL, 6.2 mmol) at 0 °C, and the resulting
mixture was stirred at the same temperature for 3 h. The
mixture was partitioned between AcOEt and aqueous HCl (1
M), and the organic layer was washed with H2O, aqueous
saturated NaHCO3, H2O, and brine, and then dried (Na2SO4)
and evaporated. The residue was purified by column chroma-
tography (SiO2, hexane/Et2O, 50:1) to give 7g (1.94 g, 69% as
an oil): [R]D -92.6 (c 1.09 CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 7.64-7.25 (m, 5 H, Ar), 5.63 (d, 1 H, J ) 2.3 Hz), 4.61 (dd,
1 H, J ) 9.5, 9.5 Hz), 4.25 (br s, 1 H), 4.19 (br s, 1 H), 4.16 (m,
2 H), 4.10 (dd, 1 H, J ) 4.7, 9,5 Hz), 4.06 (br s, 1 H), 1.09 (m,
63 H); FAB-HRMS calcd for C39H76O5SeSi3Na 811.4063 (MNa+),
found 811.4049. Anal. Calcd for C39H76O5SeSi3: C, 59.43; H,
9.72. Found: C, 59.63; H, 9.64.
C
18H26O7SeNa 457.0741 (MNa+), found 457.0759. Anal. Calcd
for C18H26O7Se‚0.4H2O: C, 49.07; H, 6.13. Found: C, 49.04;
H, 6.08.
P h en yl 1-Selen o-2,3,4,6-tetr a k is-O-tr iisop r op ylsilyl-â-
D-glu cop yr a n osid e (4g). To a suspension of 9 (300 mg, 1.04
mmol) and NaH (60% in oil, 1.25 g, 31 mmol) in THF (20 mL)
was added TIPSCl (4.21 mL, 15.7 mmol) slowly over 20 min,
and the resulting mixture was stirred at room temperature
for 2 h. The reaction mixture was neutralized with AcOH and
partitioned between AcOEt and H2O, and the organic layer
was washed with aqueous saturated NaHCO3 and brine, dried
(Na2SO4), and evaporated. The resulting residue was purified
by column chromatography (SiO2, hexane/benzene, 50:1) to
P h en yl 2-O-Acet yl-1-selen o-3,4,6-t r is-O-t r iisop r op yl-
silyl-â-D-glu cop yr a n osid e (8g). A mixture of 7g (200 mg,
254 µmol), Ac2O (100 µL, 1.06 mmol), and DMAP (93 mg, 76
µmol) in pyridine (3 mL) was stirred at room temperature for
1 h. The mixture was partitioned between AcOEt and aqueous
HCl (1 M), and the organic layer was washed successively with
H2O, aqueous saturated NaHCO3, H2O, and brine, and then
dried (Na2SO4) and evaporated. The residue was purified by
column chromatography (SiO2, hexane/Et2O, 50:1) to give 8g
1
give 4g (2.51 g, 85% as an oil): [R]D -39.4 (c 1.01 CHCl3); H
NMR (CDCl3, 500 MHz) δ 7.62-7.21 (m, 5 H), 5.47 (d, 1 H, J
) 2.9 Hz), 4.31 (br s, 1 H), 4.25 (dd, 1 H, J ) 6.0, 9.9 Hz), 4.14
(br s, 1 H,), 4.04 (br s, 1 H), 4.02 (m, 2 H), 1.06 (m, 84 H); 13
C
1
NMR (CDCl3, 125 MHz) δ 133.0, 132.7, 128.7, 126.7, 84.6, 82.5,
75.3, 75.2, 70.5, 65.9, 65.1, 18.8, 18.5, 18.4, 18.4, 18.3, 18.3,
18.0, 12.9, 12.7, 12.6, 12.1; ESI-HRMS calcd for C48H96O5-
SeSi4Na 967.5398 (MNa+), found 967.5389. Anal. Calcd for
(195 mg, 92% as an oil): [R]D -7.5 (c 0.86 CHCl3); H NMR
(CDCl3, 500 MHz) δ 7.54-7.14 (m, 5 H), 5.34 (d, 1 H, J ) 7.7
Hz), 5.06 (d, 1 H, J ) 7.7 Hz), 4.12 (d, 1 H, J ) 2.8 Hz), 4.02
(d, 1 H, J ) 2.8 Hz), 3.96 (m, 2 H), 3.85 (dd, 1 H, J ) 5.3, 9.6
Hz), 1.95 (s, 3 H), 0.99 (m, 63 H); 13C NMR (CDCl3, 125 MHz)
δ 168.5, 133.0, 132.9, 128.7, 127.74, 126.3, 77.4, 74.0, 73.6, 69.1,
19.9, 17.1, 17.1, 17.0, 17.0, 16.7, 11.3, 11.2, 11.0; FAB-HRMS
calcd for C41H78O6SeSi3Na 853.4168 (MNa+), found 853.4182.
Anal. Calcd for C41H78O6SeSi3: C, 59.31; H, 9.47. Found: C,
59.24; H, 9.38.
C
48H96O5SeSi4‚H2O: C, 59.89; H, 10.26. Found: C, 59.57; H,
10.20.
P h en yl 1-Selen o-2,3,4-tr is-O-tr iisop r op ylsilyl-â-D-glu -
cop yr a n osid e (5g). A solution of 4g (200 mg, 212 µmol) in
TFA/H2O/THF (1:1:2.5, 4.5 mL) was stirred at room temper-
ature for 6 h. The mixture was partitioned between AcOEt
(50 mL) and H2O (50 mL), and the organic layer was washed
with H2O, aqueous saturated NaHCO3, and brine, dried (Na2-
SO4), and evaporated. The residue was purified by column
chromatography (SiO2, hexane/AcOEt, 30:1) to give 5g (117
mg, 70% as an oil): [R]D -32.3 (c 0.98 CHCl3); 1H NMR (CDCl3,
400 MHz) δ 7.60-7.15 (m, 5 H), 5.51 (d, 1 H, J ) 2.1 Hz), 4.41
(br s, 1 H), 4.27 (m, 1 H), 4.13 (br s, 1 H), 4.04 (m, 1 H), 3.90
(br s, 1 H), 3.65 (m, 1 H), 2.25 (m, 1 H), 1.07 (m, 63 H); 13C
NMR (CDCl3, 100 MHz) δ 132.3, 132.2, 129.0, 126.9, 84.6, 81.0,
74.93, 74.3, 70.2, 62.3, 18.4, 18.3, 18.3, 18.2, 18.2, 17.7, 12.8,
12.6, 12.5, 12.3; FAB-HRMS calcd for C39H76O5SeSi3Na 967.5398
(MNa+), found 967.5389. Anal. Calcd for C39H76O5SeSi3: C,
59.43; H, 9.72. Found: C, 59.45; H, 9.71.
P h en yl 1-Selen o-2,3,4-tr is-O-tr iisop r op ylsilyl-â-D-glu -
cop yr a n osid -6-u r ose (6g). A suspension of 5g (370 mg, 469
µmol) and Dess-Martin reagent19 (220 mg, 516 µmol) in
CH2Cl2 (10 mL) was stirred at room temperature for 30 min.
After addition of AcOEt (50 mL), aqueous Na2S2O3 (saturated,
40 mL), and aqueous NaHCO3 (saturated, 10 mL) to the
mixture, the resulting mixture was partitioned. The organic
layer was washed with aqueous saturated NaHCO3 and brine,
dried (Na2SO4), and evaporated. The residue was purified by
column chromatography (SiO2, hexane/benzene, 4:1) to give
6g (342 mg, 93% as an oil): [R]D -10.2 (c 0.98 CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 10.25 (s, 1 H), 7.63-7.27 (m, 5 H), 5.75
(d, 1 H, J ) 2.0 Hz), 4.50 (d, 1 H, J ) 2.2 Hz), 4.25 (m, 1 H),
Gen er a l P r oced u r e for Ra d ica l Deu ter a tion . AIBN (5
mg, 30 µmol) was added to a solution of a substrate (140 µmol,
0.07 M) and Bu3SnD (113 µL, 418 µmol) in benzene (2 mL) at
80 °C. After the complete disappearance of the starting
material on TLC, the mixture was evaporated and the residue
was treated by the procedure as described below to give 12g.
2
The R/â ratio of the product was determined by H NMR.
1-[2H]-1,5-An h ydr o-2,3,4,6-tetr a-O-acetyl-D-glu citol (12g)
fr om 1g (Ta ble 1, en tr y 1). After the treatment of 1g (68
mg, 140 µmol) according to the above general procedure, the
resulting residue was purified by column chromatography
(SiO2, hexane/AcOEt, 2:1) to give 12g (42 mg, 91% as an oil,
deuteration rate ) 100%, R/â ratio ) 88:12): 1H NMR (CDCl3,
500 MHz) δ 5.21 (dd, 1 H, J ) 9.6, 9.6 Hz), 5.03 (dd, 1 H, J )
9.6, 9.6 Hz), 5.02 (m, 1 H), 4.21 (dd, 1 H, J ) 4.9, 12.4 Hz),
4.16 (m, 0.88 H), 4.13 (dd, 1 H, J ) 2.5, 12.4 Hz), 3.60 (ddd, 1
H, J ) 2.5, 4.9, 9.6 Hz), 3.31 (m, 0.12 H), 2.10-2.03 (m, 12 H);
2H NMR (CHCl3, 400 MHz) δ 3.60 (â-anomer), 2.75 (R-anomer);
FAB-HRMS calcd for
334.1261.
C
14H20O9D 334.1248 (MH+), found
Com p ou n d 12g fr om 2g (Ta ble 1, en tr y 2). After the
treatment of 2g (61 mg, 140 µmol) according to the above
general procedure, the residue was shortly filtrated through
a column (SiO2, hexane/AcOEt, 1:1) to give a crude product. A
solution of the product in aqueous TFA (80%, 3 mL) was stirred
at room temperature for 15 min, and the mixture was
7446 J . Org. Chem., Vol. 68, No. 19, 2003

Anomeric Effect-Dependent Stereoselective Radical Reaction
evaporated and azeotroped with toluene (3 times). A mixture
of the resulting residue, Ac2O (50 µL, 703 µmol), and DMAP
(17 mg, 140 µmol) in pyridine (2 mL) was stirred at room
temperature for 2 h. After addition of ice, the mixture was
partitioned between AcOEt and aqueous HCl (1 M), and the
organic layer was washed successively with H2O (10 mL),
aqueous saturated NaHCO3, and brine, dried (Na2SO4), and
then evaporated. The residue was purified by column chro-
matography (SiO2, hexane/AcOEt, 3.5:1) to give 12g (31 mg,
67% as an oil, deuteration rate ) 100%, R/â ratio ) 98:2): 2H
NMR (CHCl3, 400 MHz) δ 3.60 (â-anomer), 2.75 (R-anomer);
Com p ou n d 12g fr om 6g (Ta ble 1, en tr y 6). After the
treatment of 6g (110 mg, 140 µmol) according to the above
general procedure, the residue was shortly filtrated through
column chromatography (SiO2, hexane/Et2O, 40:1) to give a
crude product. The mixture of the product and NaBH4 (15 mg,
397 µmol) in THF (2 mL) was stirred at room temperature for
1 h and partitioned between AcOEt and H2O, and the organic
layer was washed with aqueous saturated NaHCO3 and brine,
and then dried (Na2SO4) and evaporated to give a crude
product. The crude product was deprotected and acetylated
according to the procedure described for 13 to give 12g (14
mg, 60% as an oil, deuteration rate ) 87%, R/â ratio ) 0:100):
2H NMR (CHCl3, 400 MHz) δ 3.60 (â-anomer), 2.75 (R-anomer);
FAB-HRMS calcd for C14H19DO9Na 356.1068 (MNa+), found
356.1080.
Com p ou n d 12g fr om 7g (Ta ble 1, en tr y 7). Compound
7g (105 mg, 140 µmol) was deuterated, deprotected, acetylated,
and purified according to the above procedure for 4g to
give 12g (29 mg, 65% as an oil, deuteration rate ) 100%, the
R/â ratio was 52:48): 2H NMR (CHCl3, 400 MHz) δ 3.60
(â-anomer), 2.75 (R-anomer); FAB-HRMS calcd for C14H19DO9-
Na 356.1068 (MNa+), found 356.1041.
FAB-HRMS calcd for
334.1248.
C
14H20DO9 334.1248 (MH+), found
Com p ou n d 12g fr om 3g (Ta ble 1, en tr y 3). Compound
11g (33 mg, 71% as an oil, deuteration rate ) 100%, R/â ratio
) 98:2) was obtained from 3g (61 mg, 140 µmol) according
to the procedure described for 2g: 2H NMR (CHCl3, 400 MHz)
δ 3.60 (â-anomer), 2.75 (R-anomer); FAB-HRMS calcd for
C
14H20DO9 334.1248 (MH+), found 334.1232.
1,5-An h yd r o-2,3,4,6-tetr a -O-a cetyl-D-glu citol (15) a s th e
Refer en ce Com p ou n d . Compound 15 (44 mg, 95% as an oil)
was obtained from 1g (68 mg, 140 µmol) according to the
procedure described for the deuteration of 1g with Bu3SnH
instead of Bu3SnD: 1H NMR (CDCl3, 500 MHz) δ 5.21 (dd, 1
H, J ) 9.6, 9.6 Hz), 5.03 (dd, 1 H, J ) 9.6, 9.6 Hz), 5.02 (m, 1
H), 4.21 (dd, 1 H, J ) 4.9, 12.4 Hz), 4.16 (dd, 1 H, J ) 5.7,
10.6 Hz), 4.13 (dd, 1 H, J ) 2.5, 12.4 Hz), 3.60 (ddd, 1 H, J )
2.5, 4.9, 9.6 Hz), 3.31 (dd, 1 H, J ) 10.8, 10.8 Hz), 2.10-2.03
(m, 12 H). FAB-HRMS calcd for C14H21O9 333.1186 (MH+),
found 333.1185.
Com p ou n d 12g fr om 8g (Ta ble 1, en tr y 8). Compound
8g (116 mg, 140 µmol) was deuterated, deprotected, acetylated,
and purified according to the above procedure for 4g to give
12g (33 mg, 71% as an oil, deuteration rate ) 100%, the
R/â ratio was 83:17): 2H NMR (CHCl3, 400 MHz) δ 3.60
(â-anomer), 2.75 (R-anomer); FAB-HRMS calcd for C14H20O9D
334.1248 (MH+), found 334.1272.
Com p u ta tion a l Meth od s. MM3 calculations were per-
formed with the Macro Model 5.0 program.24 Ab initio molec-
ular orbital calculations were performed with the Gaussian
98 program30 running on an SGI O2 computer. The geometries
of all stationary points were fully optimized at the UHF/
3-21G(d) level. The stationary points were characterized by
frequency analysis (minimum with 0). The natural bond orbital
(NBO) method was used to analyze and understand hybrid
orbitals and energy stabilizations, which determine molecular
conformations. Energy stabilizations were examined in terms
of second-order perturbation from almost filled orbitals to
almost empty neighboring orbitals.
Com p ou n d 15 fr om 4g via [2H]-1,5-An h yd r o-2,3,4,6-
tetr a k is-O-tr iisop r op ylsilyl-D-glu citol (13) (Ta ble 1, en tr y
4). After the treatment of 4g (131 mg, 140 µmol) according to
the above general procedure, the resulting residue was purified
by column chromatography (SiO2, hexane/benzene, 25:1-20:
1) to give 13 (100 mg, 91% as white amorphous): 1H NMR
(CDCl3, 500 MHz) δ 4.05-3.67 (m, 8 H), 1.06 (m, 83 H); 13C
NMR (CDCl3, 125 MHz) δ 81.1, 75.2, 72.1, 71.1, 64.1, 63.7,
18.5, 18.5, 18.5, 18.5, 18.4, 18.4, 18.3, 18.2, 12.9, 12.8, 12.7,
12.3; ESI-HRMS calcd for C42H91DO5Si4Na 812.5982 (MNa+),
found 812.5982. A solution of 13 (89 mg, 0.10 mmol) and TBAF
(1 M in THF, 600 µL, 600 µmol) in THF (1 mL) was stirred at
room temperature for 1 h and then evaporated. The residue
was acetylated by the procedure described for 2g to give 15
(34 mg, quant, deuteration rate ) 0%): FAB-HRMS calcd for
Ack n ow led gm en t . This investigation was sup-
ported by a Grant-in-Aid for Creative Scientific Re-
search (13NP0401) from the J apan Society for Promo-
tion of Science. We also thank the J apan Society for
Promotion of Sciences for support of H.A and also Ms.
H. Matsumoto, A. Maeda, S. Oka, and N. Hazama
(Center for Instrumental Analysis, Hokkaido Univer-
sity) for technical assistance with NMR, MS, and
elemental analysis.
C
14H21O9 333.1186 (MH+), found 333.1175.
Com p ou n d 15 fr om 5g via [2H]-1,5-An h yd r o-2,3,4-tr is-
O-tr iisop r op ylsilyl-D-glu citol (14) (Ta ble 1, en tr y 5).
According to the above procedure for 4g, compound 5g (110
mg, 140 µmol) was deuterated and purified by column chro-
matography (SiO2, hexane/AcOEt, 15:1) to give 14 (81 mg, 90%
as an oil): 1H NMR (CDCl3, 400 MHz) δ 3.99-3.72 (m, 6 H),
3.60 (dd, 1 H, J ) 4.4, 11.7 Hz), 3.51 (m, 1 H), 2.29 (m, 1 H),
1.00 (m, 63 H); 13C NMR (CDCl3, 100 MHz) δ 80.2, 74.2, 74.2,
71.3, 71.2, 71.2, 63.9, 61.9, 61.8, 18.3, 18.2, 18.2, 18.1, 17.8,
12.7, 12.5, 12.5, 12.4, 12.2. FAB-HRMS calcd for C33H72O5DSi3
Su p p or tin g In for m a tion Ava ila ble: 1H NMR charts of
12g (from 1g), 13, and 15, 2H NMR charts of 12g (from 1g,
2g, 3g, 6g, 7g, and 8g), and general methods of experiments.
This material is available free of charge via the Internet at
http://pubs.acs.org.
634.4829 (MH+), found 634.4789. Anal. Calcd for C33H71
-
DO5Si3: C, 62.50; H, 11.60. Found: C, 62.46; H, 11.07.
Compound 14 (63 mg, 1.0 mmol) was deprotected and acety-
lated according to the procedure described for 13 to give 15
(33 mg, quant, deuteration rate ) 0%).
J O030128+
J . Org. Chem, Vol. 68, No. 19, 2003 7447